Simona Anca Frati a

ermatovenero o
not:es

Editura Ljniversitatii din Oradea,

nns ~

SIMONA ANCA FRATILA

DERMRTOWENEROEOQYNOTES

Editura Universitagii din Oradea

20I3

Referenti ytiintifici:
Conf.dr. FIoarea Sarac University of Oradea
Conf.dr. Francisc Benedek University of Oradea

Descrierea CIP a Bibiiotecii Nationale a Romaniei

FRATILA, SIMONA ANCA
Dermatovenerology notes / Sirnona Anca Fratila.
Ed. a 2-a, rev.. - Oradea: Editura Universitatii din Oradea,
2013
Bibliogr.
ISBN 978-606-10-1138-4
-

616.5

Editura Universitatii din Oradea este recunoscuta de CNCSIS,

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CONTENT

STRUCTURE AND FUNCTION OF THE SKIN, HAIR AND NAILS...........11

T HK DIAG N O S IS OF THE DER M A T O L O G I C A L DISEA SES .....
...............15

F UNGAL INFECTIONS ........ ............................. . . .... . .

.......23

Superficial fungal infections

23
23

Pityriasis (tinea) versicolor .

Dermatophyte infections
Mucocutaneous candidosis .

.24
....27
.

Deep fungal infections .

BAC T E R IAL INFECT IONS OF THE SKIN .
Pyodermas
Non-folicular pyodermas

29
. ....... ................33

Follicular pyodermas.
Other bacterial infections of the skin.

Mycobacterial infection
Cutaneous tuberculosis - Typical forms.

Cutaneous tuberculosis - atypical forms (tuberculids).

Leprosy (Hansen's disease)
Atypical mycobacteria INFECTIONS.

ECTOPA R A SITE INFECTIONS.

Scabies
Pediculosis
Ticks .

... 33

...34
...36
...38
...38
... 3 8

. 40
...40

42
...........47
....47
....49
50

Cutaneous Larva Migrans.

VIRAL INFECTIONS .... ......

. ........51

Warts (Verrucae)
Molluscum contagiosum

Milker's nodules.
Or f.
Herpes simplex
Herpes zoster (Shingles).
.

SEXUALLY TRANSMITTED DISEASES (STD) ..... .............

Syphilis.
Acquired Syphilis
Congenitalsyphilis.

Differential diagnosis of Genital Ulcer Diseases

Gonorrhea (Blenorrhea) .
Direct mucosal infection.
Local extension of gonococcal infection
Extragenital direct gonorrhoea

Disseminated gonococcal infection (gonococcemia),

Diseases caused by Chlamydiae
Aquired immunodeficiency syndrome (AIDS) .

51
....53
. 53
...54

o63

.... 63
.... 64

....68
.... 7 1
72
....72

73
74

... 74
... 75
.... 76

A < < K R G I C S K I N D I S O R D K R S e eoooooooooooooeooo

ooeoooee sooeee o e o o s o o

ee

oe oo e o o o osooS 1

82
86
86
87
88
92
93

Urticaria.
dermatitis or eczema.
Contact dermatitis/eczema (Exogenous eczema)
Atopy andatopic eczema (Endogenous eczema)
Mixt Eczema (Exo-/Endogenous).
Prurigo .
drug eruptions.

.99

DISEASES OF CONNECTIVE TISSUE -----

99
99
101
102
104
104
105

Lupus erythematosus (LE) .

Cutaneous lupus erythematosus.
Systemic lupus erythematosus.
Dermatomyositis
Sclerodermas.
Localized or circumscribed scleroderma (morphea)
Progressive systemic scleroderma (systemic sclerosis)

BUL O U

o o oe o
S D I S E A S E S oooeoeooo

oo oo eo o o

oo oo so o

ooo o o o o o o oo o

Pemphigus vulgaris .
Other forms of pemphigus

Pemphigusvegetan
s.

Pemphigus foliaceus.
Pemphigus erythematosus
Paraneoplastic pemphigus.
Drug-induced pemphigus
Bullous pemphigoid
Herpes gestationis (pemphigoid gestationis)
Dermatitis herpetiformis Duhring-Brocq .
Epidermolysis bullosa aquisita .

porphyrias.

Porphyria Cutanea Tarda

Erythema multiforme .
Stevens-Johnson Syndrome And Toxic epidermal necrolysis.

oo o o oe

eo eo oe oo e

109

109
111
111
111
111
111
111
.. 111
113
113
114
115
116
117
117

ERYTH K M A T O - SQ U A M O U S SKIN DISEASES......

....................................121
Psoriasis vulgaris.

121
126
127
128

Parap
soriasis.

Lichen planus
Pityriasis rosea..

GKNODKRMATOSES.

.........................................................................133

Disorders of keratinization.
Ichthyosis.
Darier's disease (Keratosis Follicularis).
Benign familial chronic pemphigus (Hailey-Hailey Disease) .
Inherited epidermolysis bulosa
N

EVI (moles, Ibu-ihmarks) .......

Organoid nevi.
Melanocytic nevi (nevocytic nevi)

133
133
134
.... 135
.... 135

oooooessooooosoeseeoooooeoo eoooooeoeoseoooseosoeeooeoooe s 1 3 9

.. 139
.... 139

B ENIGN TUMORS .......................... . . ..........................................................143

Benign epithelial tumors .

.... 143

Seborrheic keratosis (seborrheic wart)

Keratoacanthoma.

Syringoma (hidradenoma).
Epidermal and pilar cysts.
Benign mesenchymal tumors

Dermatofibroma
Fibroma pendulum (acrochordon, skin tag) .
Keloid.
Hemangiomas
Pyogenic granuloma (lobular capilary hemangioma).
PRECANCEROSES .
Actinic keratosis (solar keratosis, keratosis senilis)
Actinic keilitis
Radiation keratoses ..............................

Xeroderma pigmentosum.
Bowen disease (sqamous cell carcinoma in situ) .
Paget disease of the nipple.................
Lentigo mal igna (melanosis Dubreuilh) .
Other precanceroses .

M ALIGNANT EPITHELIAL TUM O R S .

143
143
143
144
144
144
144
144

145
145

149
149
149

150
150
150

150
153
153

155

Basal cell carcinoma.

155

Squamous cell carcinoma.

156
158

Malignant melanoma

PREFACE
This book was written in order to provide basic in formation for the students of the
Faculty of Medicine. I have been teaching dermatology for 16 years and throughout this

time I have done my best to offer visual information (examining patients or digital images)

to the students, aiming for a better understanding of the theoretical notions. Dermatology
is a visual specialty and there is no substitute for the clinical photography to illustrate
cutaneous disease. Thus, within this book clinical photographs were selected from my
p ersonal c o l l ection t o i ll u s trate t h e m o s t Pequently e n countered d e r matological
conditions.
The recognition o f t h e e l e inentary l e sions i n t h e c l i n i ca l p i c t ur e of t h e
dermatological disorders of fers the f i rst p at h t o t h e c o r r ect d i agnosis. Paraclinical
investigations add supplementary in formation that will aid in di fferential diagnosis. This
book contains th e m ai n c u t aneous diseases with t h ei r p a t hogeny, description and
illustration of the clinical aspect, paraclinical characteristics and updated treatment.
I hope that this book will both educate and stimulate interest in this truly fascinating
medical specialty.

Oradea, September 2013

Simona Fratila, MD, PhD

Chapter 1
STRUCTURE AND FUNCTION OF THE SKIN, HAIR
AND NAILS
k'

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l y

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derived from the ectoderm and h) the dermis the major support layer, with mesodermai
ri in.
o~
The
nda es - h air, nails, sebaceous glands and sweat glands are
composed of cells derived from b o
derm a n dm esoderm.
In addition, there is the subcutaneous fat that may be involved in some cutaneous
diseases, such as erythema nodosum.

THE EPIDERMIS
The epidermis is multilayered and renews itself by the division of the basal layer.
'
The princi al
1 cell
e i s t h e keratinocyte.It is formed in the basal cell layer and
ascends to the surface of the skin in ap r o x imat 1 3 0 da s (epidermal transit time). The
kerati
nthesize keratin.
The basal layer is composed of one row of keratinocytes of columnar shape. They
undergo cell division, after which one daughter keratinocyte remains in the basal layer
and the other moves upwards through the epidermis, to differentiate and finally die. The
basal cells are anchored throu h hemidesmosomes to the basement membrane.
Interspersed amongst the basal cells there are the melanocytes,dendritic cells
d erived f r o m t h e n e u ra l c r est. T hese cells c o ntai n to las m i c organelles called
osomes that produce the melanin pigment from t y r osine. The melan
transferred from the dendrites
the keratinocytes in the prickle cell

layer, being responsible for the skin color (fototype). In white eo le the me os o mes are
grouped to e ther i n "melanosome complexes" t h at
r adu a l l de ene r a te a s t h e
keratinocytes move towards the surface the epidermis. In black e o l e t h e s kin contains
mb
te s in bu t t e m e lanosomes are lar er, remain

karate and do not degenerate.

Melanin synthesis is increased by UV radiation, resulting in the sun tan. This is a
natural protective mechanism for the keratinocytes. When the sun exposure exaggerates, the

keratinocyte nuclei are damaged, thus cellular atypia can appear and progress in time (years)
to skin cancer. In dark-skin people, skin cancer can also be observed, but much more rare.
The prickle cell layer contains keratinocytes connected together by intercellular

bridges called desmosomes, with a spiky appearance in optic microscopy. The cytoplasm
of basal and prickle keratinocytes contains tonofilaments formed from the keratin. These
tonofilaments are grouped in bundles and are continuous with the desmosomes to connect
the keratinocytes and give strength to the epidermis.
Scattered between keratinocytes in the prickle cell layer there are dendritic cells
called Langerhans cells or antigen presenting cells (APC), which are modified macrophages
11

originating in the bone marrow. They are responsible for the first line of immunological
defense in the skin. APC take up and process environmental antigen and then migrate to the
lymphoid tissue where the antigen is presented to the immunocompetent T lymphocytes.
The granular layer, above the prickle cell layer, is com o sed of f l a ttened c

containin keratohyalin granules (darkly staining particles) and lamellar a n ules (Odland
bodies). The lamellar granules are vesicles (liposomes) that dascharge their lipidic and
enz matte content into the intercellular ~saces,~rovidin

"mortar" between the cellular

"bricks
"

The stratum corneum is composed of flattened, corn letel k e r a tinized dead cells
l acking nuclei and cytoplasmic organelles and filled with keratin filaments embedde m
an amorfous protein matrix. The superficial cells are gradually abraded, every d ay .
Stratum corneum forms a barrier w hich is i m permeable to substances from inside or
outside the body. The thickness of the stratum corneum varies on different regions of the
body, for example it is the thickest on palms and soles.

THE BASEMENT MEMBRANE

The basement membrane divides the epidermis from the dermis. It is a complex
m ultilayered structure, f ormed b y l a m i n a l u c id a ( r ara), l amina d e nsa an d l a m i n a
fibroreticulara.

Hemidesmo some s attach th e

b a sal k e ratinocytes t o t h e l a m in a l u cida.

Hemidesmosome defects are seen in some forms of epidermolysis bulosa, a genetically

determined blistering disease. Lamina fibroreticulara, rich in collagen, is deficient in other
forms of e p i dermolysis bulosa. Autoantibodies to t h e c o m ponents of t h e b a sement
membrane are found i n d i f f erent bullous disorders (e.g. to l a m ina l u cida i n b u l ous

pemphigoid).
The basement membrane is not a rigid structure, as cells like lymphocytes and
Langerhans cells pass it with relative ease. Also, it is a convoluted layer, forming dermal
papillae and rete ridges, maximizing the contact area between dermis and epidermis and
minimizing the chance of discohesion between the two layers.

THE DERMIS
The dermis lies beneath the epidermis and forms the bulk of the skin. It is formed of
c onnective tissue with u p w ard p r ojections (dermal papillae) that interdigitate with t h e
downward epidermal projections (rete ridges). The dermal connective tissue is composed of:
cells:
o f i b r oblasts produce collagen and the connective tissue matrix,
o m a s t c e lls contain g r anules w i t h m e d i ators i m p o rtant i n t y p e I
immunological reactions (such as histamine, prostaglandins, leucotrienes)
and in the interaction with eosinophils and neutrophils (eosinophil and
neutrophil chemotactic factors)
o m a c rophages general scavengers that originate in the bone marrow
a network of protein fibers of collagen, elastin and reticulin that give strength and
elasticity to the dermis
ground substance of mucopolysaccharides.
12

The outer layer of the dermis, called papillary dermis, contains finer collagen fibers
than deeper reticular dermis.

The dermis is richly supplied with blood vessels, lyrnphatics, nerves and sensory
receptors. There are two vascular networks in the dermis: a superficial one at the interface
between papillary and r eticular dermis and a l o we r an d m o r e v i g orous one located
between dermis and subcutis. The tw o v a scular networks are connected by v e rtical
vessels. In normal conditions, the blood supply operates at 10-20% of capacity, but in some

skin diseases it is greatly increased, causing body redness (erythema) or even high-output
cardiac failure. The epidermis has no blood vessels; all the nutritive substances diffuse to
the intercellular spaces of the keratinocytes through the basement membrane.

THE SKIN APPENDAGES

The pilosebaceous unit, the apocrine and eccrine sweat glands and th e n ails

represent skin appendages. The pilosebaceous unit includes: hair follicle, sebaceous gland
and arrector pili muscle.
The hair follicle results from the interaction between the hair shaft, derived from
the fetal ectoderm, and the vascular papilla of the hair bulb, derived from the mesoderm.
There are three types of hair: a) lanugo hair present in utero and shed by the 8th
month of fetal life; b) vellus hair, fine, thin, covering most of the body, except the areas of
the terminal h air and c) terminal hair, that is thick and pigmented, found on the scalp,
beard, eyebrows, eyelashes, axillae and pubic area. The development of the terminal hair is

under hormonal control on some areas (beard, axillae, pubic region), where hairs are of
vellus type until the onset of puberty. On the scalp, the reverse occurs in male pattern

balding, where terminal hairs are replaced by vellus hair.

The hair bulb is at the lower end of the follicle and contains the hair matrix, a zone

of rapidly dividing cells. The cells become gradually keratinized as they ascend and from
the hair shaft. Terminal hairs have a central core (medulla) with air spaces, a cortex formed
of keratinized spindle-shaped cells and a cuticle at the surface, formed of cells which
overlap like the tiles on a roof.
The arrector pili muscles extend from beneath the epidermis to the side of the follicle

just under the opening of the sebaceous gland. They are supplied by adrenergic nerves and
are responsible for the erection of hairs during cold or emotional stress ("goose flesh").

The growth of the hair is cyclical, periods of active growth (anagen, 85 % of the
hair, 2-5 years on the scalp) alternating with resting phases (telogen, 15 % of the hair, 3-4
months on the scalp). The duration of these cyclical phases are genetically determined and

depend upon the age of the individual and the location of the follicle on the body. The
activity of each follicle is independent of that of its neighbors.
T he color o f t h e h a i r i s p r o d uced b y t h e m e l anin p i g m ent f o r med i n t h e

melanocytes of the hair bulb (eumelanin in black and brown hair, phaeomelanin in auburn
and blond hair). Graying of h air i s the result of g r adually decrease of the tyrosinase
activity in the melanocytes of the hair bulb, which is genetically determined.
Sebaceous glands are particularly numerous and prominent on the head, neck,
chest and the back. These glands are under hormonal influence: they are prominent at
birth due to maternal hormones, but atrophy soon after, and enlarge after puberty due to

androgenic stimulation. Sebum i s p r o d uced by t h e d i s integration of g l andular cells

(holocrine secretion), then drained into the hair follicle and discharged on the surface of
the skin through the hair follicle opening. Some modified sebaceous glands open directly
on the skin surface (eyelids, lips, nipples, glans penis, prepuce, oral mucosa).
Apocrine sweat glands are found principally in the axillae and anogenital region;
specialized apocrine glands are in the ear (wax glands) and breast (milk glands). Apocrine
glands are composed of a secretory coil found in the deep dermis and a duct that opens
into a hair follicle. The secretion forms by a "nipping off" of the tops of the cells in the coil
(decapitation secretion). The glandular secretion is oily, without smell, controlled by the
adrenergic nerve fibers and starts only after puberty. Pungent axillary body odour is the
result of the action of bacteria on apocrine secretion.
Eccrine sweat glands are important for the body temperature regulation and are
seen all over the body, being particularly numerous on the palms and soles. They are
anatomically independent from the other appendages and are formed from a secretory coil
deep in the dermis and a d uct t o th e surface of the skin. The sweat made of w ater,
electrolytes, lactate, urea and ammonia is i sotonic in th e secretory coil, but becomes
hypotonic on the surface of the skin as sodium chloride is reabsorbed in the duct. Eccrine
g lands ar e i n n ervated b y t h e s ympathetic n ervous s y stem, bu t
acetycholine.

t h e m ediator i s

The nails are transparent plates of keratin on the dorsum of the terminal phalanx
of the digits. The nail matrix, which produces the nail plate, lies deep to the proximal nail
fold and is partly visible as a pale "half moon" (lunula) at the base of the nail. The nail
plate adheres firmly to the underlying nail bed. The cuticle is an extension of the proximal
nail fold onto the nail plate, to seal these two structures, in order to prevent penetration of
extraneous material.
Nails growth is more rapid in youth than in old age, taking an average of 6 months
to grow from matrix to free edge for finger nails and 18 months for toenails.

SKIN FUNCTIONS

Prevents loss of body fluids

Protects against entry of environmental toxic chemicals and microorganisms
Protects against damage from UV radiation
R egulates t h e bo d y temperature b y vas o c onstriction/vasodilatation and
perspiration
Synthesis of vitamin D (cholecalciferol)
Important in social interaction

Chapter 2
THE DIAGNOSIS OF THE DERMATOLOGICAL
DISEASES
There are three important elements for the dermatological diagnosis:
history:
o e v olution of lesions: site of onset, spread, duration, resolution and reactivation
o s y m p t oms associated with the eruption: itching, burning, pain; systemic
symptoms: fever, chills, malaise, arthralgias
o c u r r ent or recent medication
o p a st history (previous illness, allergies, photosensitivity), family history,
occupation and hobbies
examination of the patient (type of elementary lesions, distribution of the lesions,
arrangement of individual lesions)
diagnostic techniques:
o sk in biopsy:a skin sample is removed, fixed in formaldehyde, embedded in
paraffin, colored, cut in very thin slices and examined under a microscope
o po t assium hydroxide( KOH) p r e p aration: w h en t h e f u n g al e t i o logy i s
suspected, the skin or nail is scraped with a scalpel, causing dead cells to
fall off on a glass slide; potassium hydroxide is then added and the slide
slightly heated; KOH dissolves the keratinocytes releasing the fungus that
will be observed under a microscope
o Tz a nck smear
is a cytological technique performed on liquid lesions that are
unroofed and the base is scraped gently with a scalpel blade; the material

placed on a glass slide is stained with Giemsa stain to identify the types of
cells, for example in herpes simplex, bullous diseases
di a scopyis performed by pressing a microscopic slide against a skin lesion to
determine whether a red lesion is hemorrhagic (purpura) or only blood-filled
(erythema); granulomas often have an "apple jelly" appearance on diascopy
de r matoscopyis the examination of a skin lesion with a dermatoscope (a
magnifier with light) that illuminates the lesion without reflecting light;
melanin distribution and disposition is visualised, as well as fine vessels;
the technique aids i n d i s t inguishing benign f ro m m a l i gnant l esions,
especially melanoma
Wo o d's tightis a 360 nm ultraviolet light that aids the evaluation of certains
skin disorders. For example, under Wood's light, erythrasma will appear
coral red, pigmented lesions of the epidermis (freckles) are augmented,
while dermal pigment (postinflammatory hyperpigmentation) fades
pa t ch testsare designed to document contact allergic sensitivity to a specific
antigen. A battery of suspected allergens, diluted, are applied on the back
of the patient under occlusive dressings, left in contact with the skin for 48
hours and then examined for type IV hypersensitivity.
15

TYPES OF ELEMENTARY LESIONS

Dermatological diseases are characterized by the presence of elementary lesions.
The original lesions are known as the primary lesions (e.g. macules, papules, nodules,
tumors, wheals, vesicles, bullae etc ), which are v ery i m p o rtant i n t h e d e r matologic
physical examination. They may b e m o d i fied by r e gression, trauma or o t her factors,
producing secondary lesions (e.g. scales, crusts, excoriations, erosions, ulcers, scars ).
1. D i s coloration of the skin, called macule: a flat, nonpalpable, circumscribed area
of color change; macules that are larger than 1 cm are called patches.
Disorders of pigmentation

melanic macules
o h y p e rpigmented
congenital: cafe-au-lait spots
acquired:
pr i m a r y:epheli des, melasma(Fig.2.1)
secondary
(postlesional):
l ic h en p la n u s (Fig.11.19),
pemphigus vulgaris (Fig.10.4)
o

a cr omic
congenital:
albinism
acquired: vitiligo (Fig.2.2)

hemosideric macules: posttrombotic syndrome (Fig.2.3)

Vasculo-sanguin macules

erythema: red s k in , w i t h r a i sed l o cal t e mperature, d isappears on pressure

(diascopy); it is caused by vasodilatation; types:

o l ocalized

erythema
(halo, plaque)

o e x anthema: disseminated erythematous macules

o s c arlatiniform: diffuse red patches with numerous red points
o r o seoliform: alternation of red and normally colored macules
o r u b eoliform: raised erythematous macules
o e r y t hroderma: the whole skin is red ("red man"-Fig.11.14)
cyanosis: the skin is cold, violaceous, due to the decrease of amount of oxygen
delivered to the tissues, secondary to the spasm or constriction of small blood
vessels (in acrocyanosis)
pu r p u r a: red macules that do not disappear on pressure (diascopy); the cause is
the extravasation of red cells
o n o n -palpable purpura caused by extravasation of red blood cells, with

minimal inflammation; through evolution the lesions change colors from

red-blue or purple to green, yellow or brown before complete fading
pe t e chiae round to oval, <3 mm diameter purpura(Fig.8.29) ex.
thrombocytopenia < 50 000/mm', traunza(linear aspect)

macular purpura (5-9 mm d i ameter) ex.hypergamaglobulinemic

purpura Waldenstronz
macular echymosis (>1 cm) (Fig.2.4): ex. hepatic insuffi'cienny, vit.K
defi'cienny, actinic purpura, corticosteroid purpura

p a l p able purpura due to inflammatory hemorrhage

16

pu r p u r ic papules, vesicles and necrosis:leukocytoclastic vasculitis of

small vessel(Fig.8.29), erythema multiforma, rheumatic vasculitis (LES,

rheumatoid arthritis)

retiform p u r p ura serpentine, branching o r

s t elate aspect of

purpura due to hemorrhage around small dermal vessels prior to

complete obstruction of th e vessel : a ) n o n-inflammatory type:
heparin necrosis, monoclonal cryoglobulinemia, cholesterol emboli,

spider bite reaction; b) inflammatory type: mixed cryoglobulinemia,

rheumatic vasculitis (LES, rheumatoid arthritis), polyarteritis nodosa,
septic vasculitis
2. Solid lesions
Wheals (hives = urtica) are transient, plateau-like, sharply demarcated elevations of various
size and shape associated with severe itching. The dermal edema is responsible for the aspect of

the wheal and also for the sudden appearance and rapid resolution (pathognomonic, in a few
hours). Their color may be red, due to vasodilatation or whitish, due to the compression of the
capillaries by the dermal edema (Fig.8.1). Wheals are characteristic for urticaria.
Papule: a circumscribed solid elevation of the skin, less than 0.5 cm in diameter

o e p idermal papules result from thickening of the epidermis (e.g. plane wart - Fig.6.5)
o

d e r mal p a pules are due t o cellular proliferation in t h e d e rmis (inflammatory

infiltrations in syphilitic papules- Fig.7.5-7. 12)

o d e rmoepidermal papules result from the thickening of both epidermis and dermis
(lichen planus-Fig.11.18)
Plaque elevated, circumscribed lesions that are larger than elevated (Fig.11.1). The
elevation is due to thickening of the epidermis (psoriasis, neurodermitis, nummular eczema)or

dermis (keloid, morfeea).Secondary changes may add, like scales, crusts.

A tuber - an elevation resembling a papule, but deeper and very liable to ulceration

and scarring (tuberculosisand tertiary syphilis)

Nodule or node - a circumscribed visible or only palpable lump, larger than 0.5 cm and
with greater mass beneath the skin surface, within dermis or subcutaneous

acute nodes (erythema nodosum-Fig.8.32)

subacute nodes (gumma of syphilis or tuberculosis-Fig.4.20) they evolve in four

stages: 1) firm node, 2) abcedation, 3) ulceration with fistulisation 4) scarring

chronic (cysts, lipoma, skin metastases)
Lichenifi'cation - flat thickening of the skin characterized by accentuated skin-fold
markings; secondary to scratching (in chronic eczema, Fig.8.9)
Vegetations - soft pathlogical excrescences of the skin with i r r egular, papilomatous
surface; may be primary (condiloma acuminate,also called venereal vegetations-Fig.6.10,

6.11) or may appear secondary, in other skin diseases(pemphigus vegetans).

Verucosity hard papilomatous, pathological excrescens covered by keratosis (common
wart Fig.6.1,6.2)
Tumors are solid masses of tissue in the skin. A tumor may be benign (well delimited
with no distal spreading- Fig.14.2) or malignant (rapid growth, recurrence after excision,
metastatic spreading at long distance from the original tumor and alteration of the general

health-Fig.16.10).
17

3. Lesions containing fluid

Vesicle (small blister): elevated, circumscribed collection of clear fluid, with diameter
less than 0.5 cm; on histopathologic examination we can distinguish between:
o i n t erstitial v esicles - fl u i d a c cumulates between th e k e r atinocytes; they a r e
preceded by spongiosis (epidermal edema with the stretching of desmosomes) in

eczema (Fig.8.8)
o p a r enchimatous vesicles - fluid accumulates instead of destructed keratinocytes,

for example in herpes simplex (Fig.6.17), herpes zoster,as herpetic viruses are
cytopathogenic
Bulla: elevated, circumscribed collection of clear fluid with d iameter over 0.5 cm; on
histopathologic examination we can distinguish between:

o s uperficial (subcorneal) bulla (impetigo, bullous erysipela-Fig.4.5, pemphigus foliaceus)

o d eep bulla or subepidermal (bullous pemphigoid-Fig.10.7),Duhring disease
o

i n t r aepidermal bulla - in the prickle cell layer, due to the autoimmune destruction

of desmosomes, called acantholysis (Fig.10.5), in pemphigus vulgaris- Fig.10.3

Pustule: elevated, circumscribed accumulation of pus (usually necrotic inflammatory
cells, with/without bacteria)

o p r i mary pustules - not preceded by any lesion

sterile pustules (pustular psoriasis-Fig.11.10)

microbial pustules (folliculitis-Fig.4.11,furuncle)

o

s e condary p u stules develop f ro m v e sicles or b u l lae (superinfection of s o m e

dermatoses like herpes simplex, pemphigus)

4. B reaks of continuity of the skin
Erosion (exulceration): a loss of epidermis; it heals without a scar; impetigo, pemphigus

Ulcer.a loss of epidermis and dermis; it heals with scar (ecthyma, leg ulcer-Fig.2.5)
Excoriation: exogeneous injury of the epidermis: posttraumatic, due to scratching in
itching dermatoses like scabies, pediculosis, eczema
Fissure: a linear cleft through the epidermis or into the dermis (in skin folds like the
submammary area, between the fingers, on the tips and flexural creases of the thumbs,

fingers and toes)

Rhagades: are periorificial tears caused by stretching of s kin ( at the angles of the
mouth, at the lips, about the anus)
5. C u taneous debris

Scale: visible and palpable masses of keratin (flakes) due to rapid epidermal cell
formation or abnormal keratinization.
The scales can be fine, delicate as in tinea versicolor (Fig.3.16); coarse in eczema, ichtiosis;
stratified, micaceous, with silvery aspect given by the air trapped between the layers in

occal
psoriasis (Fig.11.4); large sheets desquamation in toxic epidermal necroiysis, staphyloc
scalded skin syndrome and scarletfever. T he l o cation of t h e s c a le o ver t h e l e s ion i s
characteristic: at the periphery of the lesion (leading scale in tinea, collarette in candida

intertrigo), over the whole lesion (eczema, actinic keratosis),leaving a peripheric rim of
nonscaly lesion (psoriasis),peripheral collarette and thin central scaling (pytiriasis rosea).
The maturation of normal epidermis is called orthokeratosis and results in flat, nonnucleated keratinocytes in the horny layer. When the differentiation of the epidermis is
18

abnormal and/or accelerated, the outer layer will be parakeratotic, with nucleated cells.
parakeratosis is most commonly exemplified in psoriasis and in eczema.Byskeratosis is the
precocious keratinization o f individual cells w i t hi n t h e p r i c kle cell l a yer w i t h t h e
formation of round eosinophilic cells (corps ronds), with a pale halo in the prickle cell
layer and as flat, intense basophilic grains in the granular and corneal layers. Dyskeratosis
can be benign in Da r ier's disease (dyskeratosisfollicularis) or malignant in squamous cell
carcinoma.
Crust: dried exudates like serum, pus or b lood, usually mixed wi th e pithelial and
sometimes bacterial debris. Yellow crusts result from dried serum or dried pus (impetigo
contag'osa-Fig. 4.1, infected herpes) and hematic crusts result when the dermal vessels are
injured (ecthyma-Fig. 4.2, traumatic ulcers).
1Vecrotic scab (necrosis or sphacelus) results from a circumscribed death of tissue. It
may be black and dry due to arterial obstruction (ischemic necrosis-Fig.2.6) or yellow and
moist, due to necrotising bacteria (bourbillon of the furuncle-Fig.4.14).
6. Scars, atrophy
Scars are secondary type, permanent fibrous skin lesions that result from the process
of skin repair by replacement with connective tissue. Their size and shape are determined
by the form of the previous destruction. The collagen fibers are abundant and rigid, the
skin appendages and elastic fibers are absent.
Scars may be smooth (tertiary syphilis) or i r r egular (secondanj skin tuberculosis),
pliable or firm, atrophic or hypertrophic.
Scars may be preceded by ulceration (traumatic or venous ulcer) or by inflammatory
infiltrate, the latter being called interstitial scar (lupus vulgaris, chronic venous insufficiennj).
The interstitial scar that appears in chronic venous insufficiency is called Milian's white
atrophy and is due to the slow necrosis and replacement of the dermis with fibrous scar
tissue (Fig.2.8). It is localized in the lower part of the leg of varicous patients.
When the scar grows beyond the limits of the original injury, often sending out
clawlike prolongations, it is called keloid (Fig.14.12).
Sclerosis i s t h e t h i c k ening o f t h e s kin o n b e h al f o f c o l l agen f i b ers, l ik e i n
lipodermatosclerosis, morpheea, systemic sclerosis (Fig.2.3).
Atrophy of the skin is a thinning of the dermis and epidermis with loss of appendages.
In atrophic skin the dermal vessels are visible, like in old people (Fig.2.7).
The elementary lesions usually combine like in papulo-erosive or papulo-pustulous,
ulcero-crustous or ulcero-vegetant lesions.

19

CONFIGURATION AND DISTRIBUTION OF LESIONS

Configuration or a r r angement of s ki n
important clues to the diagnosis.

l esions and t h eir d i stribution pr ovides

The shape of the lesions is usually round or oval. Ring-shaped or annular lesions
result when lesions heal at th e centre w h ile p r ogressing at th e p eriphery (e.g. tinea
corporis). The confluence of several roundish elements results in p o l ycyclic lesions or
circinated lesions (e.g. tinea inguinalis). Lesions made up of several concentric circles are
called target lesions (e.g. erythema multiforma) or cocardiform. Serpiginous lesions are
snake-like, set on curved lines, e.g. in larva migrans. Clustered or grouped lesions appear in
herpetic infections (herpes simplex, herpes zoster) and herpeti
fonn eruptions. Corymbose
pattern looks like exploding bomb, with a large lesion in the center and smaller ones in the
periphery (e.g. late secondary syphilis).
Linear arrangement m a y f o l l o w B l a schko's l i n es
which reflect p a ttern of
embryonic development (e.g. epidermal nevi) or a d ermatome which is an a rea of skin
innervated by a single spinal nerve (e.g. herpes zoster). In both these situations there is
characteristic midline demarcation of the lesions. Short linear arrangement also results
from trauma-induced Koebner phenomenon (isomorphic response), as in lichen planus,
psoriasis and viti1igo or from trauma-induced autoinoculation, as in plane warts.
The anatomic distribution of the lesions may be localised, sometimes unilateral
(tinea), or symmetric (e.g. dyshidrotic eczema), disseminated (on more than 2 anatomical
areas, e.g. di s seminated stasis dermatitis), g e n eralized ( o n
all a n atomical a r eas,
e.g.exanthematous drug eruptions) or universal (the whole skin is involved, with no healthy
areas, e.g. er y throdermia). Ex tensor areas of t h e l i m b s ( e l b ows
a nd k n ees) a r e
characteristically involved in psoriasis,while flexural involvement suggests atopic dermatitis
in older children and adults.
Seborrheic areas (head, neck and the upper trunk) are favoured by acne, seborrheic
dermatitis and pihjriasis versicolor. When lesions are localized in areas exposed to ultraviolet
irradiation (phtodistribution), photodermatosis are suggested (e.g. phototoxic drug reactions,
as to doxiclicline) or diseases favoured by UV (systemic lupus erytheniatosus).

20

Fig.2.2. Aquired acromic macules (Vitiligo)

Fig.2.1. Hyperpigmented aquired
macules (Melasma)

Fig.2.3. Hemosiderinic pigmentation (right

leg) and sclerosis (left leg)

Fig.2.4. Purpura

Fig.2.5. Ulceration

Fig.2.6. Ischemic necrosis

Fig.2.7. Atrophic skin

Fig,2.8. Milian's white atrophy (Interstitial scar)

91

Chapter 3
FUNGAL INFECTIONS

Fungi (Tabel 1) may cause superficial (frequent) and deep infections (very rare) of
the skin. The superficial dermatomycoses are important in medical practice.
Dermato h y t es
S ecies

Yeasts

Trico h

Microscopic
characteristics
Tissue inhabited

t o n , E i d e rm o h y t on, Microsporum Candid a

- w ith
b r a n c he d fi l a m e n t s Pseudomycelium - c hains o f
( hyphae); som e w i t h c r o s s-walls, f o r m i n g r ound/oval cells t h a t d i v i d e b y
Mycelium

septate hyphae.

budding

Skin, hair, nails

Skin, mucosa, nails

Tabel 1. Differential characters of fungi causing superficial infections.

SUPERFICIAL FUNGAL INFECTION S

Pityriasis (tinea) versicolor

This is a common superficial mycosis, caused by yeasts of the genus Malasezia (the
actual name for Pityrosporum). These yeasts are part of the normal skin flora. Because it
requires oil to grow, it occurs predominantly in seborrheic areas. Factors that lead to the
conversion of the saprophytic yeast to the parasitic mycelia form include high temperature
a nd h i g h hu m i d i t y in tr op i ca l c l i m ates w h i l e o i l y sk i n , excessive s w eating,
immunodeficiency, corticosteroid use, Cushing disease and malnutrition are involved in
temperate climates. The condition is not considered contagious because the causative
fungal pathogen is a normal inhabitant of the skin.
The lesions are usually asymptomatic. They present as i scoloured macules, with
colours ranging from white to brown, sometimes red (as the name implies, versi meaning
several) and a fine scale. The lesions occur predominantly on the trunk, shoulders, back,
abdomen and upper arms (Fig.3.1) and more rare, in children, on the face. There are two
possible explanations for depigmentation: a) light f i ltering effect by scales and fungal
layer; b) d i sturbance of m elanogenesis and/or destruction of m e l anocytes by f u n gal
metabolites.
Differential d i agnosis i n cludes p ostinflammatory h y p o pigmentation, vitiligo,
pityriasis rosea, tinea corporis and secondary syphilis.
Pityriasis versicolor is primarily treated with topical antimicotic preparations, like
shampoos and c r eams. Shampoos containing k e toconazole ( N i zoral), f e nticonazole
(Lomexine), ciclopiroxolamine, selenium sulphide 2.5%, zinc pyrithione are used for 10
minutes at the end of bath daily for 2 weeks and weekly after, to prevent recurrences.
Topical azoles and allylamine antifungal creams have to be applied also for 2 weeks on the

23

whole area of the neck, thorax, abdomen and arms. In cases of extensive disease or
frequent recurrences, oral antimicotic therapy is indicated.
Depigmentation resolves within 1-2 months after treatment has been initiated. As
endogenous factors of the patients are thought to be of g reat importance, recurrence is
common, and prophylactic therapy may help reduce the high rate of recurrence. One-monthly

dosing of ketoconazole (400 mg), fluconazole (300 mg), itraconazole (400 mg) may be used.

Dermatophyte infections
The dermatophytes are responsible for so-called "ringworm" infections or tinea (Latin: a

gnawing worm). Dermatophytes can be acquired from different sources: people (anthropophilic
infections), animals (zoophilic infections) or soil (geophilic infections). Contact with contaminated
fomites (e.g. hairbrushes, combs, towels etc) can spread infection. Fungi spores can survive
several months in the environment (especially recreational and sport f acilities), resulting in
recurrent outbreaks. Infection is usually acquired by contact with keratin debris carrying fungal

hyphae. Dermatophytes grow only in the keratin of the skin, hair and nails(Tabel1). Animal and
geopMic fungi usually cause severe inflammatory reaction in humans.
Dermatophytes can be seen on direct examination by taking skin scrapings, nail
c lippings or plucked hair from th e affected area and mounting them on a s l ide w i t h
coverslip i n 2 0 % p o t assium h y d r o xide, which i s g e n tl y w a r m e d a n d e x a m ined

microscopically. Dermatophytes appear as branched septate filaments (mycelium). To

identify the particular species it is necessary to culture the sample for up to 3 weeks on a

suitable medium such as Sabouraud's.

1.Dennatophyte infections of the skin

Tinea pedis (Athlete's foot) is the commonest of the dermatophyte infections. It
involves the soles and interdigital web spaces of the feet. It is favoured by the m oist
environment created by occlusive shoes and is usually acquired from contact with infected
keratin debris on the floors of locker rooms, gyms, swimming-pools, showers and other
public facilities. There are three forms, with different location and clinical presentation:
interdigital f or m - i t c h y , s c aling o r m a c erated, f issured w e b s p aces, most
frequently the tstro lateral ones (Fiff 3 2);
moccasin type diffuse hyperkeratosis, erythema, scaling and fissures on the
.

sole(s), extending on the lateral and dorsa of the feet (Fig.3.3).

inflammatory (vesicular) form - on the central part of the sole, as areas of discrete
erythema with recurrent pruritic vesicles or bullae; it i s o f ten associated with
dermatophytid r eaction consisting of d y s hidrotic-like eruption o n t h e l a teral
aspects of the fingers of the hands
Tinea pedis can be complicated by allergic reactions (dermatophytids), bacterial

superinfection, cellulitis, erysipelas especially in p a tients with v enous insuficciency or

even osteomielitis in patients with chronic arterial obstruction or diabetes.
The feet are initially asymmetrically involved i n t i nea pedis, in contrast with
eczema and psoriasis, in which the involvement is symmetrical from the beginning.
Tinea cruris is m o r e c o m mon i n m e n . T h e l e s ion i s i t c h y, h a s p o l y cyclic

(circinated) erythematous margins that gradually spread down on the medial aspect of the
thighs, perineum and b u t tocks, whith central clearing (Fig.3.4). The margin t y p i cally

or

presents thin scales and tiny vesicles or pustules. Tinea pedis or tinea unguium frequently
associates. The fungus is transferred to the groins on the fingers, towels or on trousers.
Tinea cruris, which starts unilaterally but might become later bilateral, should be
easily distinguished from candida intertrigo, erythrasma, flexural psoriasis or benign

pemphigus Haley-Haley.
Tinea corporis i s typ ically a nnular, sometimes arcuated or c i r c inated, wi t h

|:a

ilic
:ed
ive

gal
nd
ail
ith

ed
To
1a

scaly, pustular, inflammatory margin that spreads centrifugally and central clearing. It
may be located on the chest, abdomen, dorsum (Fig.3.4), upper or lo wer extremities,
dorsal hand or dorsal foot. In children the fungus is usually of animal origin (kitten),

while in adults it is spread from the feet or groins.

The differential d i agnosis includes nu m m u lar eczema, pity riasis versicolor,
pjtyriasis rosea, annular psoriasis, subacute lupus erythernatosus and impetigo.
Tinea manuum refers to the palmar involvement. It is often unilateral, may begin
on the 4th finger, under the ring and presents as mild scaling erythema or hyperkeratosis

(Fig.3.6). Tinea manum is frequently associated with tinea pedis ("two feet and one hand
syndrome" ). An important clue to diagnosis is tinea unguium of the involved hand.
The differential di agnosis may i n cl ude p soriasis, irritant o r a l l ergic contact
dermatitis.
Tinea faciei involves asymmetrically the glabrous skin of t he face, usually the
c heek. The typical aspect is annular p atch w i t h

c i r cinate or a r cuate margin t hat i s

erythematous, scaling, pustular and extends peripherally (Fig.3,7).It is frequently acquired

It
ist

from pets in home, but also from individuals with other forms of tinea.
Tinea faciei may r esemble systemic or c h ronic l u pus erythematosus, rosacea,
allergic or irritant contact dermatitis or seborrheic dermatitis.

ier

Tinea incognito is a fungal infection with altered appearance due to inappropriate

treatment with topical steroid preparations that suppress the inflammatory response to the
fungus while favouring its multiplication and spreadin . The typical scaly erythematous

)st

margin may disappear, leaving an ill-defined area with ustules (Fig.3.8).

ed

he
'te
ith
ral
ial

2. Dennatophyte infections of the hair (pilomycosis or tinea capitis)

Tinea capitisis the involvement of the scalp hair by dermatophyte fungi (Microsporum
and Tricophyton sp). There are non-inflammatory forms of tinea capitis (microsporosis,
trichophytosis and favus) and inflammatory forms (kerion celsi and tinea barbae), depending
of the type of the dermatophyte and consequently the type of the hair involvement (endothrix,
ectothrix or favus), but also depending on the immune response of the body. Microsporosis
and tricophytosis are both very contagious in small children collectivities but are rare after
puberty because of the fatty acid constituents of sebum that become fungistatic.

Microsporosis capitis (caused by Microsporum sp) appears as 1-2 round, scaly patches
ith

of alopecia with hair that is broken at the same level, 2-3 rnm above the surface of the

scalp. The alopecic areas have dull gray appearance due to the disposition of spores on
the exterior of the hair shaft, with destruction of the cuticle (ectotrix invasion).
11c

he

Tnchophytosis capitis ("black dot tinea capitis", caused by Trichophyton sp) appears as

Lly

several small round alopecic areas, with scales and hairs broken at different lengths,
25

some at their base, causing black dots. The hair shaft is involved, with normal cuticle

(endotrix invasion).

Favus is caused by Tr i cophyton Schoenleini and lasts even after puberty. Scarring
alopecia with some persistent greyish hairs and y ellow c u p-shaped crusts called
scutulas are characterstic features. The hair i n t h e occipital and t emporal regions
remains healthy. Hyphae and air spaces are observed within the hair shaft.

Kerion Celsi (Kerion meaning in Greek honeycomb) is a deep, highly inflammatory

scalp infection. One or several painful, round raised, purulent and inflamed lesions

appear on the scalp. Hair fall out rather than break off or can be painlessly pulled
out. B a c t erial su p e r i n fection w ith
sta p h y l o cocci is f r e q u ent . Re g i o n al
lymphadenpathy is associated. Kerion may heal with scarring and permanent hair
loss within several weeks. Immunity is developed against re-infection.

Tinea barbae (micotic sycosis) is a dermatophytic infection of the hair-covered portion

of the face in adult men, provoked by zoophilic dermatophytes, sometimes as

professional disease, from i n f ected cattles. Tinea barbae shows agminated deep
folliculitis with sw ollen pseudotumoral purulent lesions on th e f ace (Fig.3.9) and
lymphadenopathy. This is i n c o n trast to staphylococcal sycosis, characterized by
disseminated folliculitis (Fig.3.10). In tinea barbae the infected hair is easily pulled off.
The removing of the infected hairs and a rim of healthy hairs surrounding the
inflammatory skin lesion is essential for a faster resolution in both inflammatory forms of
pilomycosis and is useful to prevent the extension of the infection.
The hair and skin scrapings should be sent for culture to confirm the diagnosis and
to identify the animal or human reservoir of infection.

3. Dermatophyte onychomycosis (Tinea unguium) ~

Tinea unguium is very common in adults and elderly, frequently associated with
tinea pedis. It has three forms depending upon the point of fungal entry into the nail unit:
o d i s t al/lateral sunungual with i n v asion via th e h y p onychium, i t i s t h e m o st

common. The distal/lateral nail bed becomes hyperkeratotic, with yellowing and

thickening of the distal/lateral nail plate, as well as onycholysis (detachment of the

nail plate from the nail bed). The infection progresses proximally and eventually
involves the entire nail bed and plate (total dystrophic pattern).
s u p erficial onicomycosis with direct penetration into (and confinement to) the

nail plate; white irregular spots appear on the surface of the nail plate (Fig.3,11).
o

p r o x i mal subungual with invasion under the proximal nail fold, usually appears
in immunocompromised persons.
Trauma and other nail disorders (e.g. psoriasis) represent predisposing factors.
T oenail d e r m atophytic i n f ections a r e mo r e co m m o n th a n fingernail i n f ections.
Onicodystrophy from venous insufficiency of the legs can be very similar to onicomycosis. We
should always perform mycological exam to con6rm onicomycosis, as only the oral treatment
is efficient and this is costly, takes a long time (3-6 months) and might be hepatotoxic.

Treatment of dermatophyte infections

Topical therapy should be applied at least 2 weeks and continued for another 2
weeks after lesions resolve. Topical therapeutically agents include:
26

cle

ng
ed
ins

iod (Betadine = polyvidon iodide)

topical azoles: econazole, ketoconazole (Nizoral), dotrimazole, miconazole, oxiconazole,
bifonazol (Biazol), fenticonazol (Lomexin). The mechanism of action is fungistatic, by
inhibition of the synthesis of ergosterol, which is an important component of the fungal
cell wall. Membrane damage results in p ermeability problems, in i n hibition of
replication and maturation of the mold into the invasive and pathogenic form

allylamines: naftifine (Exoderil), terbinafine (~

il, Terbisil) are fungicidal agents; they

iry

inhibit squalene epoxidase, which converts squalene to ergosterole, causing intracellular

ns

accumulation of toxic leveL~ of squalene that lead to rapid fungal cell death
c iclopiroxolamine (Batrafen, Ciprox) a s l o t i ons, creams, p o w ders o r s p r ays
interfere with amino acid transport across the fungal cell membrane.
Mistreatment of tinea cruris with topical steroids usually results in exacerbation of

ed
>al

on
as

ep
A.d

by
f.
he
of
md

the disease, although patients note initial relief of symptoms.

Systemic therapy may be indicated for extensive or resistant fungal infections of
the skin, infections of the hair and nails. Use of oral agents requires attention to liver
enzyme levels that have to be m onitored before and throughout treatment if t h erapy
extends more than 2 months. Systemic antifungal agents include:
griseofuivine is an antifungal antibiotic that arrests the fungal cell mitosis
systemic azoles:

o k etoconazole (Nizoral) one 200 mg tablet daily for 2-3 weeks in tinea pedis,
corporis, m anuum; i t i s n o t us e d f o r t i n e a u n g u iu m b e cause of
h epatotoxicity t h a t u s u ally r e sults d u r in g t h e n e cessary p e rio d o f
treatment (6 months for finger nail and18 months fo toenail mycosis);

o i t raconazole (Orungal, Sporanox) and fluconazol (Dif lucan) have less

hepatotoxic action under pulse therapy regimens:

.th
)st

zd
he

300 mg fluconazole once weekly for 2-4 weeks in skin mycosis, for
6 months in fingernail mycosis and up t o 18 months in toenail

mycosis;
itraconazole 2x200 mg daily for 1 week/month, 2 and 4 pulses for
fingernail and toenail mycosis, respectively;

l.ly

terbinafine (250 mg/tb) may be used for 2 weeks for skin infections, 1-3 months for
tinea capitis, 2 and 4 months for fingernail and toenail mycosis, respectively.

he

Mucocutaneous candidosis

mrs
rs.

Yeasts are unicellular round or oval fungi that typically reproduce by budding
(pinching off of the mother cell). Candida albicansis the commonest member of the Candhda

genus (>150 species) and the principal infectious agent of human candidosis (Tabel1).
It is a no r mal commensal of the h uman gastrointestinal tract (mouth through

anus), and vagina (13% of women) in balance with the bacterial fiora. Candida species are
Ve
.nt

not part of the normal flora of the skin; however, they may colonize fingers or body folds
transiently. The commensal form of candida is unicellular yeast. When pathogenic, it

multiplies resulting in budding and mycelial (pseudohyphae) forms. Pseudohyphae are

chains of pinched cells that do not separate.
Candida albicans becomes pathogenic in c e r tain f a v ourable situations: broadspectrum a n t i biotics, t o p i cal a n d sy s t emic steroid t h e r apy, i m m u n o defficiency,
27

hyperhidrosis, diabetes mellitus, iron deficiency anaemia, deflciencies including vitamins

B1, B2, B6, C, and folic acid, or local factors like warm and moist environment, increased
contact with invasive monitoring devices in an intensive care unit, decreased salivary flow,
use of denture.

1. Mucosal candidosis
Oral candidosis ( thrush) is c o m m on i n ne w - b o rn i n f a nts, b ecause of t h e
insufficient secretion of the salivary glands, immaturity of host defence and incomplete
establishment of the normal orointestinal flora. It may be acquired in neonates from the
infected maternal mucosa during passage of the infant through the birth canal. In adults,
candida stomatitis appears in i m m une deficiency, xerostomia, use of b r oad-spectrum
antibiotics and inhaled corticosteroids. It may also affect up to 65% of patients who wear
dentures, especially full sets. Oral infections presents as:
- white plaques that adhere to the erythematous, inflamed buccal mucosa (chronic

hyperplastic form)
- white exudates resembling cottage cheese (psudomembranous form)
- patch of erythema (chronic atrophic form)
glossitis painful atrophy of the dorsal tongue
Angular cheilitis (perleche) appears at the angles of the mouth where saliva
macerates the skin, especially in edentulous, denture waerers and elderly patients. It
presents with sore fissures with creamy white discharge (Fig.3.72).
Candida vulvitis and vaginitis presents with a c reamy vaginal discharge and
itchy erythema of the vulva. Predisposing factors are: pregnancy, oral contraceptives and
diabetes mellitus. Candidal colonization of vaginal mucosa is estrogen dependent and
'despread use of hormone
subsequently d ecreases sharply a f ter m e n opause, but
replacement for reduction of osteoporosis and heart disease
y c a u se an increasing trend
in candidal vulvovaginitis among older women.
Candida balanitis appears as small white patches or eroded areas with creamy
satellite pustules or erosions with a collaret of ruptured skin on the foreskin and glans
(Fig.3.13). It may appear after oral antibiotics. If recurrent, diabetes mellitus is associated or
a sexual partner has Candida vaginitis.
Perianal candidosis, extended from digestive or genital candidosis, appears as itchy
erythematous swollen skin covered by small white patches or erosions with creamy discharge.

2. Cutaneus candidosis
Candid a involves i n tertriginous a reas, l ik e

a x i l lae, sub-mammary, b eneath

pannus, inguinal creases or intergluteal fold. Candida intertrigois clinically suggested by

intense erythematous, erosive patches accompanied by satellite pustules. The pustules are

easily ruptured, leaving collarets of scale, with characteristic scalloped edge.

The 3'd interdigital web space is involved when hands are frequently exposed to

water. Interdigital candidosisappear as white, soft macerated skin (Fig.3.74).

Napkin candidosis is exaplined by the particular susceptibility of moist macerated
skin to invasion by C.albicans from infected stools. It presents as erythematous perianal or

perigenital plaque with polycyclic edge, collarets of scale and satellite pustules (Fig.3.75).
28

ns

3. Candida onixis and perionixis ('chronic paronichia)

Chronic paronichia is a chroni" inflammatory process affecbng initially the proximal
~ f o l d and then the nail matrix(Fig.3.16).Bacteria may associate. The proximal nail fold
appears erythematous, swollen and tender, with occasional discharge and loss of the cuticle

(perionixis). The nail plate becomes dystrophic, discoloured (grey, yellow) and thick (onixis).
~o nic paronichia occurs predominantly in people who frequently submerge their hands in
he
.te
he
ts,
ar

~ater (housewife, bar staff, florists, and fishmongers). Diabetes is also a predisposing factor.

4. Chronic muco-cutanous candidosis

Chroruc muco-cutaneous candidosis refers to a heterogeneous group of disorders
c haracterized b y r e c u rrent o r p e r sistent superficial i n f ections o f t h e s k i n , mucous

mem
branes, and nails with Candida organisms, usually

Candida albicans,associated with a

d efect in cell-mediated im m unity. This begins in e a rly c h i l dhood an d r e sists to t h e

conventionally topic treatments. The clinical picture consists of oral chronic candidosis

(thrush), candida intertrigo, candida granuloma (inflammatory nodules of the scalp),

candida diaper dermatitis or perionixis.

Treatment of the candida infections
Topical treatment is recommended to change the pH to a lkaline (washing with
va
It

xd

sodium bicarbonicum 1%) because Candida prefers the acid environment. It is useful to
avoid contact between skin surfaces, isolating the skin folds with dry dressings and use of
antiperspir ants.
Topical treatment uses creams, ointments, lotions, powders in different regimens
and duration, depending on the clinical form of candidosis:

1d

polien antibiotics: amphotericine B, nystatin (Stamicin), natamycin (Pimafucin)

ld

azols: clotrimazole, econazole, miconazole, ketoconazole (Nizoral), bi

ze
xd

fenticonazol (Lomexin)

n a zol (Biazol),

Systemic treatment:

poliene antibiotics - nystatin (Stamicin) administered orally acts only locally in the
ly
ns
or

Xy

th
)y
re

g astro-intestinal t r act, i t i s n o t a b s orbed sy stemically; am photericin B i s u s e d

intravenously in severe cases
azols are recommended in cases resistant to topical therapy: ketoconazole (Nizoral)

200 mg/tb; fluconazole (Diflucan) 100 mg, or 150 mg/ cps; itraconazole (Orungal,
Sporanox), 100 mg/cps; voriconazole
fluorocitozin is metabolized in organism to fluorouracil, a cytostatic agent that acts
inhibiting the synthesis of the fungus DNA, without acting on the macroorganism.

DEEP FUNGAI. INFECTIONS

The majority of deep fungal infections are tropical diseases (histoplasmosis,

to

criptococcosis, coccidiosis), while others like sporotrichosis, micetoma and actinomycosis

are rarely seen in Romania.

.'d

Sporotrichosisis caused by Sporotrix Schenkii which is saprophytic on plants and

can be inoculated by a puncture wound (thorns, hay, conifer needles) or seed in any
common wound. The characteristic lesion is a dermal or subcutaneous nodule that may
29

ulcerate. After a few weeks the infection spreads along the regional lymphatic vessels and
satellite firm nodules appear, then ulcerate and open to the skin surface forming tortuous
fistulas. Sporotrix organisms can sometimes cause systemic involvement (lungs and

joints). Treatment: potassium iodide 2-4 g daily; itraconazol (Orungal) 100 mg daily, 3-4
months; amphotericin B 1-3 g daily in i.v. infusions.
Micetoma (pied de Madura, maduromycosis) is a chronic, granulomatous disease
of the skin, which sometimes involves the muscles, bones, and neighbouring organs. It is

caused by fungi (Madurella, Cephalosporium, Nocardia)or bacteria (Actinornyces)that are

inoculated in skin by a local traumatism (thorns, wood splinters or implantation with solid
objects), mostly in people who work in rural areas. The most common involved areas are
the feet and the lower legs, but also buttocks, groin area, head and neck.
Clinically, the disease begins as firm, painless, erythematous nodules that can

persist or evolve to form extensive suppurative plaques measuring up to 20 cm in

diameter and extending to the bones and joints of the feet with monstrous deformation of
the region. The exudates contain the microorganisms surrounded by inflammatory cells,
observed with the naked eye as black, white, yellow or red grains.
The treatment in my cotic mycetoma is less successful that for actinomycetoma.
High doses of ketoconazole, fluconazole, itraconazole or terbinafine can be used for 1-2
years, unless side effects warrant cessation of medication. Sometimes surgical treatment,

including amputation, remains a viable therapy.

The treatment for a ctinomycetoma is t r i m etoprim-sulfametoxazole for several
months or years, eventually associated with amikacin.
Actinomycosis is a chronic cervico-facial induration which enlarges to an abscesslike swelling, with penetration oi th e overlying skin and the develo~pm t of draining

fistulas that discharge sulphur granules.

The term actInomycosis is misleading. Because of the term mycosis (from the Greek

mykes), some believe that actinomycosis is a fungal infection, although Actinornyces Israeli is a
filamentous Gram positive aerob microorganism. Aktino referres to the radiating organism in the
sulphur granule. The microorganism enters the tissue through a break in the oral mucosa,
favoured by poor oral hygiene and dental caries. The presence of anaerobic bacteria that
enhances the growth and propagation of actinomyces species is necessary to initiate the infection.
."-S
Uncut'- ..
gjpjuqu~lq, .-'<
'

r.

Sulphur granule

The treatment of choice includes large doses of antibiotics and prolonged therapy
coupled wit h d r a inage of th e abscesses or radical excision of th e s i nus t r acts. High
penicillin concentrations are necessary to penetrate areas of fibrosis and suppuration and

possibly the granules themselves. Intravenous penicillin G (10-20 million U/d for 2-6 wk)
followed by oral penicillin (2-4 g/d for an additional 3-12 mo) is the typical therapy for the
most deep-seated infections.

30

js

.d
4

>e

ls

.e
d

Pig.3.1. Pityriazis versicolor

Fig.3.2. Tinea pedis, interdigital form

(brown and acromic macules)

S,

Pig.3.3. Tinea pedis-mokasin like. Onycomycosis

Pig.3.4. Tine curis extended on the buttok

.k
ie

Fig.3.5. Tinea corporis

Fig.3.6. Tinea manum

Fig.3.7. Tinea faciei

Fig.3.8. Tinea incognito

h
d

')
e

Fig.3.9. Inflammatory tinea of

Fig.3.10. Mixt sycosis

(tricophytic and staphylococic)

the upper lip (sycosis)

Fig.3.11 White superficial (left) and distal

lateral onicomycosis

Fig.3.12.

e (candidal angular cheilitis)

Fig.3.13. Candida balanitis n

Fig.3.14. Candida interdigital intertrigo

Fig.3.15. Napkin candidosis

Fig.3.16. Candida onixis and perionixis

Chapter 4
BACTERIAL INFECTIONS OF THE SKIN

The skin is sterile immediately before birth and is colonized by bacteria from the

first day of life.

Resident flora is represented by harmless bacteria which permanently colonize the
to prevent infections by providing ecological competition for pathogenic organisms; there
Ne different species varying among locations of the body and individuals:

gram positive - staphylococci; corynebacteria;

anaerob bacteria Propionibacter in the deeper part of the hair follicles, on the face

and upper trunk;

yeasts Malassezia on seborrheic areas
Imbalances between the resident flora of the skin, vagina or intestine and other
bacteria or fungi can appear after antibiotics use or weakening of the immune system
(AIDS, cancer, corticosteroids or chemotherapy). An example is vaginal yeast infection
after antibiotic treatment.
Temporary resident flora: b acteria and fu ngi w h i r ~ s
i st on t h e s k in f or a

limited period of time, multiply and cause infections (staphylococci, streptococci).

Transient flora: bacteria, fu ngi a n d v i r u s es f r om e x o genous s ources, that
contaminate the normal skin only at t i mes. In special conditions (immune deficiency,
irritated or injured skin) non-pathogenic organisms may change their behaviour, multiply
on the skin and cause infections.
Cutaneous infections are favoured by:
factors depending on the microorganism increased virulence
factors depending on t h e h u man b od y increased tisular glucose (diabetus
mellitus), p r eexisting d e r m atoses (eczema, s ki n p a r asitosis), m i cr otrauma,
denutrition, immunologic deficiencies (AIDS, immunosuppressive therapy)

PYODERMAS
Pyodermas are infections of the skin w it h p y ogenic bacteria (staphylococci and
streptococci, most frequently and o ther bacteria, as E.coli, pyocianic etc., more rare).
Streptococci and staphylococci can be unique etiologic agents, but they can also occur
simultaneously (impetigo, intertrigo, cheilitis, perionixis) and only the bacteriologic exam
can identify them.
Pyodermas are classified in: primary infections of the healthy skin (not preceded

by other skin disease) and secondary pyodermas that complicate previous eczema, ulcers,
herpes, pemphigus etc. Another classification refers to infections of the glabrous skin

(between the hair follicles) - caused mainly by streptococci and of the skin appendages
(pilosebaceous follicles, sweat glands) - caused mainly by staphylococci.
33

Non-f olicular pyodermas

patI

Impetigo is a highly contagious gram-positive bacterial infection of the superficial

epidermis.Staphylococcus aureus and Streptococcus beta-haemolyticgroup A (GABHS or

end

Strept.pyogenes) e both implicated in the etiology of impetigo.

There are 2 forms of th e d i sease: bullous impetigo and n onbullous impetigo.

]yrr

L esions may occur anywhere on the body, but mainly on the face of children. The typical
lesion is a rapidly enlarging bulla (superficial, subcorneal but transient and not observed

per

in non-bullous form) that is fragile and ruptures leaving peripheral scaly collaret and

sub
are

yellow (meliceric) crust over th e erosion. Infection spreads to contiguous areas and
satellite lesions appear due to autoinfection (Fig.4.1, 4.2). The lesions heal without atrophy

and scar. Rarely, poststreptococcal glomerulonephritis (pedal edema, hypertension) can

complicate impetigo.

While impetigo can manifest as a primary pyoderma of intact skin, it may occur as
a secondary infection of tr aumatized skin or p r e-existing dermatosis (varicella, atopic
dermatitis, m y cosis, scabies a nd l ouse i n fection), w h ic h h a s b ee n r e f erred t o as
impetiginous dermatitis.

usll

Ecthima is a streptococcal infection that extends into the dermis, being referred to
as a deeper form of i m p etigo. Streptococcimay initiate the lesion, usually on t he l egs

(primary ecthima) or may infect pre-existing wounds (secondary ecthima), in the presence
of factors like crowded living conditions, poor hygiene, immnneseppression. The initial
vesicle-pustule soon ruptures and the secretion dries to form a brown, adherent crust over

the ulcer (Fig.4.3). The dermis being damaged, ecthima heals with a round scar that is
frequently hypopigmented and peripherally hyperpigmented (Fig.4.4).
Streptococcal intertrigo appears most frequently in children and more frequent in
infants, due to irritation and friction in the deep folds of the neck, axillae, antecubital and
popliteal fosae. Well demarcated fiery red erythema in an intertriginous area with foul
smell and no satellite lesions differentiates clinically streptococcal from candida intertrigo.
Bacterial culture may confirm diagnosis.
Erysipelas is an acute infection of the superficial dermal lymphatics of the skin.
The majority of cases are caused by Streptococcus pyogenes or Staphylococcus aureus on

b]i,
alt~

ap
W]'
gar

the skin and its appendages that gain entry to the dermis and multiply.
The condition is most common localized on the lower legs, but any other part of
the body, like the face or ear may be involved. The portal of entry has always to be looked
for in the nelghbourlng area of the infected skin or mucosa. e g a f ssure. cut. laceration.

1Uf

insect bite, puncture wound, intravenous drug abuse, rhinovestibulitis, otitis externa - for
the erysipelas of the face or ear; tinea pedis, venous ulcers, pressure ulcers, lymphatic

ap]

obstruction (after lymphadenectomy or irradiation) - for lower leg erysipelas; lymphatic

obstruction (after surgery for breast cancer) - for arm erysipelas.
After an incubation of 2-5 days, there is an abrupt onset of fever, chills and
malaise. A few h ours to a day l ater, erythematous, edematous plaque appears, with
raised and sharply d elimited m argins, associated with p ain an d t enderness (Fig.4.5,

Fig.4.6). Regional lymphadenopathy and sometimes lymphangitis are present. The

erythematous plaque with important, non-pitting edema progressively enlarges over a
few days and bullae (Fig.4.6), purpura (Fig.4.7) or necrosis (Fig.4.8) may also develop. In
34

atjents with underlying disorders (diabetes mellitus, lymphedema, peripheral vascular

ial
or

d>ease) complications may occur, like abcedation (Fig.4.9), acute gloroerulonephritis,

go.

lyInphedema and later on, to elephantiasis, characterized by hypertrophic and fibrotic

ical
red

permanent lymphedema (Fig.4. 10).

lIld
lxld

Ihy
an
. as

er1docarditis and recurrences.

Repeated obstructions of the major lymphatic channels of the skin lead to chronic

Cellulitis d iffers from e r ysipelas in t he f a ct t h at i t i s d e e per, involving t h e

subcutaneous tissue and not the lymphatics. The margins of the red inflammatory plaque
are not sharply demarcated.

Differential diagnosis of erysipelas and cellulitis includes deep vein thrombosis,

stasis dermatitis, superflcial thromboflebitis and lipodermatosclerosis.

Necrotizing fasciibs (NF) is a v e ry severe, rapidly progressing necrotizing

as

infection of the subcutaneous fat and fascia. It may follow surgery or perforating trauma
pr may occur de novo.
In children necrotizing fasciitis is caused by group A streptococci,while in adults

l to

IIsually it results from a polymicrobial infection with aeobic and anaerobic bacteria, like
S,aureus,E.coli, Bacteroides and Clostridium sp, and rarely Pseudomona aeruginosa, or

P1C

egs
nce
tial
ver
t is

t1n

<nd
oui

.go.

H.influenzae.
Infection starts like erysipelas or cellulitis with red-purple hue but the pain is
s evere, out o f p r o p o r tion t o s k i n f i n d i ng s an d t h e p r o g ression i s r a p id , w i t h o u t
response to antibiotics. Within 36 hours from onset, gray-blue ill-defined patches with
blistering necrosis develop, the skin may become anesthetic due to necrosis of the nerve
fibers and systemic toxicity may associate with high fever, tachycardia, hypotension, and
altered level o f c o n sciousness. Fascial necrosis can b e d e m onstrated, u n der l o c al
anesthesia, through a 2-cm incision down to the fascia, by lack of resistance when passing

a probe (gloved finger) through the tissue.

The most common location is the lower legs in adults and the trunk in children.
When necrotizing fasciitis involves the perineum and genital area, it is called Fournier's

gangrene.
on
t of
(ed

.on,
for
atic
atic
End

ith
4.5,

%e
.r a
. In

Sepsis, renal failure and rapid death (in 20% of cases) can complicate the evolution.
Treatment of the streptococcal infections is both topical and systemic.
Topical treatment includes wet antiseptic dressings for 15-20 minutes, especially

when bullous and eroded lesions are present (chloramin B 500mg/200ml water, boric acid
10g/1000ml water, kalium permanganicum solution 1:6000, or isotonic sodium chloride
solution). When crusts are p resent, antimicrobial or a n t iseptic creams/ointments are

applied, e.g.

neom
ycin+bacitracin {Baneocin); mupirocin (Bactroban); fucidic acid

(Fucidine). Resistance to these antibiotics started to emerge and retapamulin (Altargo) is a

new option.
Systemic antibiotic treatment must provide coverage against both S. aureus and S.

pyogenes because the two o r g anisms frequently associate. Oxacylin, erithromycin,

cephalosporins like cephalexin (Ospexin), ceftriaxon (Rocephin) are indicated.
In cellulitis and erysipelas strict elevation and rest of the affected limb and the use
c ompression stockings as soon as pain fades away are recommended. Treatment of

35

predisposing lower extremity skin lesions (e.g., tinea pedis, stasis ulcers) and long-term
prophylactic antibiotic therapy (e.g. benzathine penicillin 2.4 MU i.m. every 3 weeks for up
to 2 years) reduce the recurrences of erysipela. Renal or cardiac complications might not be
prevented by oral antibiotic treatment in streptococcal impetigo and erysipelas.
T he treatment of N F i s a n e m ergency and th e p atient is better moved in a n
intensive care unit. Immediate surgical debridment and antibiotic treatment are necessary.

Follicular pyodermas
Follicular infections are mainly determined by S.aureus,a normal inhabitant of the
a nterior nostrils i n 2 0-40% of th e a d u lts an d o n t h e h a nd s an d p e rineum i n s o m e
individuals. Nasal carriers are particularly prone to recurrent staphylococcal infections.
FolIiculitis is defined clinically by a follicular-based pustule and histologically by
the presence of in fl ammatory cells w i t hi n t h e w a l l a n d l u m e n o f t h e h ai r f o l l icle.
Perifotticulitis is defined by the p resence of inflammatory cells within the perifollicular
tissues and adjacent reticular dermis.
Predisposing factors for staphylococcal folliculitis include: occlusion of the hair
follicles by tight clothing, shaving, plucking or waxing hair, hot and humid weather, use of
topical corticosteroids, obesity, atopic dermatitis and diabetes mellitus.
Folliculitis has been classically divided into superficial
deep forms; most of the
superficial forms can evolve into the deep form.

Superficial folliculitis appear as small (1-4 mm) erythematous papules or

pustules pierced by central hair, followed by a yellow crust and no scar, mostly on the face

(Fig.4.11), scalp, chest, back, buttocks or lower legs.

Deep folliculitis or staphylococcal sycosisconsists of multiple, isolated abcesses

of the hair follicles that have both a superficial and a deep, dermal component ("shirtbutton"-like abscess), explaining the inefficiency of superficial treatment. The involved

follicles are spread in staphylococcal sycosis (Fig.4.12) compared to the agminated lesions
in tinea barbae.
Furuncle (boil) develops when the entire follicle together with surrounding tissue
are infected by S.aureus haemolytic. It starts as a painful inflammatory nodule (Fig.4.13)
that becomes fluctuant and develops a central pustule centred by a velluls hair over a few
days. Staphilococcus has a necrotising toxin that induces the formation of the necrotic core

(necrotic pilo-sebaceus follicle, called bourbillon, Fig.4.14), which will be eventually

elimined, leaving a scar.
Several simultaneous boils in a patient or recurrent boils represent furunculosis.
These patients may have underlying favouring disorders (diabetes mellitus, cancer, AIDS,
etc.) or they are otherwise healthy, bnt they may he carriers of staphylococci ht the nostrils
or on the perineum, from where the organisms are transferred to various parts of the body I
on the digits.
The furuncle localized on the superior lip is. called "the malignant furuncle of the
face". Due to the laxity of the subcutaneous tissue at this level, the massive edema camouflages
the furuncle. The furuncle appears as lip edema with a small pustule. The name comes from
the possible complication that can appear after squeezing the lesion: septic thrombosis of the
hollow sinus, as the blood of the upper lip drain in the venous sinuses from the base of the
encephalon. This complication is i n dicated by e x treme headache, high fever (40'-42'),
36

up
be
an

the
me

hptophobia, conjunctival chemosis, diplopia and coma. Death may result in 90% of cases.
t is why th e f u runcle located on the upper lip i s t reated strictly conservatory with
and wet antiseptic dressings, while autotrauma is forbidden.
A confluence of several furuncles (agminated furunculosis) results in carbuncle,

anti
biotics

frequently localized on areas with t hicker skin, like nape of the neck, back, thigh in
patients suffering from diabetes or severe debility. It begins with a dome-shaped area of
tender erythematous swollen skin, and, i n a f e w d a ys, pu s d i scharge from m u l t iple
fpiljcular orifices. A deep ulcer results that resolves with a visible permanent scar.
Paronychia due to s taphylococcus is an acute soft tissue infection around the

=le.

fingernail that results from the breakdown of the cuticle, which prevents the inflltration of
the infectious agent barrier u n d er t he p r o ximal n ail f o l d. T he p a tients accuse pain,
tenderness, redness and swelling in the proximal and/or lateral nail folds. Pus may be

ilar

expressed by slight pressure (Fig.4.15).

by

Acute paronychia can also be caused by other microorganisms like streptococcus,

iair

pseudomonas species, gram negative and anaerobic bacteria. Favouring factors are

.of

hangnails, nail biting and finger sucking, manicuring, or artificial nail placerf1ent.
Acute paronychia has to be distinguished from chronic paronychia, caused by
candida albicans, in p e ople repeatedly exposed to m o ist environment (dishwashers,
housekeepers, bartenders, swimmers).

or
ace

Staphylococcal scaled skin syndrome (SSSS) is a toxin-mediated staphylococcal

syndrome, given by certain staphilococcal toxigenic phag types that cause intraepidermal

ses

splitting of the granular layer. It is more common in infants and young children, but adults
with renal insufficiency or immunodeficiency are also vulnerable, due to deficiency in the
elimination of toxins. SSSS originates from a focus of infection that may be impetigo, a

red
ons

sue

13)
'ew
ore

<lly

purulent conjunctivitis, otitis media or nasopharyngeal infection. It starts with general

malaise and a rash that rapidly progresses to bullae, shedding of epidermis and
erythematous erosions. The aspect is comparable with t hat of t h e scalded skin, w i t h
c omplete recovery i n 5 - 7 d a y s . T h e t r e atment p o i nt s t o t h e e r a d ication o f t h e

staphylococcus focus of infection with antistaphylococcal antibiotics (cloxacillin) and

appropriate attention to fluid and electrolyte management.
Treabnent of staphylococcal infections requires local and systemic measures.
Local treatment is sufficient in superficial folliculitis. One may use antiseptics

containing iod (tincture of 2% povydon iodide alcoholic solution - Betadine), chloride

S1s.

(chloramine B) or a n tibiotics (mupirocin ointment - B actroban, neomycin+bacitracin -

DS,
rils
)dy

Negamicin B, Neobasept), retapamulin 1% - Altargo.

ges
om
the
the

2'),

Deep folliculitis is very resistant to various topical treatments because the infection
of the deeper part o f t h e f o l licle is r arely r eached by t h e a ntimicrobial agents and
represents a source for reinfection.
Washes containing clorhexidine or triclosan and dilute household bleach (0.5 cup
of 6% sodium hypochlorid in a full bathtub) and topical antibiotic to the narines for 5-10
days are necessary to reduce the nasal carriage of S.aureusand decolonize the skin.
Systemic treatment is r e quired i n s e rious, painful an d f e brile i n fections like
carbuncle or m alignant f u r uncle of th e f ace. As staphylococci secrete beta-lactamase

37

enzyme (penicillinase) that inactivates the penicillins, beta-lactamase resistent drugs have
to used, like Augmentin (amoxycilin + clavulanic acid) or other antibiotics like oxacillin,
flucloxacillin, cephalexine, or macrolides (erythromycin, azitromycin).
A ntibiotic resistance is becoming a n i m p o rtant consideration, as m ethicillin- i ~
resistant S.aureus (MRSA), former a nosocomial infection, is now a community-acquired s
s kin infection. In these situations, trimetoprim-sulfamethoxazole, doxycyline, clindamycin, ( :
minocycline (I line treatment) or oral linezolid (II-line) are recommended, and in severe

infections, intravenous vancomycin (I-line), linezolid (II-line) or t igecycline (III-line

treatment) may be necessary.
In order to strengthen the immunological resistance of the patient one may use
v accines containing e x t racts o f k il l e d s t a p h ylococci o r th e i r in a c t ivated t o x i n s 0

(staphylococcal anatoxin).

Other bacterial infections of the skin

Erysipeloid is caused by Erysipelothrix rhusiopathiae that may afflict the hands of

those handling uncooked meat, fish or poultry (farmers, butchers, fishermen, housewives).
The organism enters the skin of the hands ( Qe interdigital webs) via an abrasion and
produces a well-defined, purplish-red plaque+hich spreads gradually, usually without
systemic involvement (Fig.4.16). Very rare fever, bacteremia and endocarditis can occur. The
infection can be controlled by penicillin. Disinfectants are important for the working areas.

li

Erythrasma is a superficial infection of the intertriginous areas (axillae, groins,

t oe w e b - spaces an d
s u b m a m m ar y r e g i o ns ) c a u sed b y Gr a m - p o sitiv e b a c i l l i

Corynebacterium minutissimum, members of the normal skin flora. It typically appears

as asymptomatic, symmetric, well demarcated brown-red macular patches covered by

I,'

fine scales that evolve for a long time (months-years) (Fig.4.17). The bacillus produces
a porphyrin w it h p ink f l u orescence under Wood's light. It di f fers from tinea corporis
because tinea is accompanied by p r u r i t us, i s u sually u n i l ateral and ha s an a ctive,

vesicular, red border.

Treatment: topical i m i d azoles (miconazole, econazole), topical f u c i di c a cid
(Fucidin), or systemic with a 2-week course of oral erythromycin.

MYCOBACTERIAL INFECTION
Cutaneous tuberculosis - Typical forms
Primary infection results from direct inoculation of Mycobacteria tuberculosis into the
injured skin or mucosa of a child who was neither previously infected with tuberculosis,
nor immunized with BCG (bacilli Calmette-Guerin). Ritual circumcision, tattooing, ear
piercing, ingestion of m il k c o ntaminated with M b o v is and a k i s s of i n f ected parent
(infected sputum) on a child's face might also result in the inoculation of the bacillus.
Two to four weeks after inoculation, an ulcer (chancre) appears at that site. It is

round, with necrotic, granular base and undermined edges. Lymphangitis and regional
lymphadenopaty with cold, suppurative and draining lesions follow about 6 weeks later.
Spontaneous healing occurs within one year or more, leaving irregular scars.
This primary tuberculous complex is the skin analog to the lung Ghon complex.

ave

colin,
.red
cin,
~ere
line
use
<ins

Typical secondary tuberculosis of the skin represents the inoculation of BK in the skin
pf /du] ts previous ly infected with M. tuberculosis.these patients have strong del aye d-type
l ypersensitivity r e action t o t u b erculin or p u r i fied p r o tein d e r ivative/PPD i n jected
>~adermal (positive Mantoux test, Fig.4.18). Cutaneous manifestations of th e t y p ical
t uberculosis a r e : w ar t y tub e r c ulosis, t u b e rculosis c u t i s gum m o s a

secon
dary

(scrophuloderma), ulcus tuberculous and lupus vulgaris.

Warty tuberculosis occurs from exogeneous inoculation of tuberculous bacilli into

fhe skin of a previously sensitized adult person with strong delayed-type hypersensitivity
tp M.tuberculosis (strongly positive tuberculin test). It m ay d e velop on t he f i n gers of

<edical personal (pathologists the prosector's wart; laboratory workers), on the buttocks
pr soles as a result of direct contact with ground contaminated by infected sputum.
Infection starts as an asymptomatic warty papule with an inflammatory rim. It
enlarges reaching several centimeters in di ameter, with f l uctuant center and p u r ulent

s of

discharge (Fig.4.19). Lesions usually are solitary, may evolve and persist for years.

es).

Regional nodes are not affected unless secondary bacterial ' e c tion occurs.

and
iout

The
ins,
cilli
.ars

. by
aces
311S

Tuberculosis cutis guxnmosa (scrofuloderma) resul s from direct extension from

an underlying tuberculous focus, a lymph node, infected bones or joints. The characteristic
lesions are gummae. These are firm subcutaneous nodules (cold abscess) that become soft
in their central part, discharge pus leaving an irregular ulcer and heal with an inesthetic,

retractile scar (Fig.4.20).

Tuberculosis cutis orificialis results from autoinoculation of mycobacteria into
the periorificial skin and m u cous membranes in p atients with a dvanced pulmonary,
intestinal, or genitourinary tuberculosis. It indicates impaired cell-mediated immunity.

Consequently, tuberculin positivity is variable, but usually present.

ive,

In orificial TB, th e ti p a n d l a t eral m argins of t h e t o n gue are affected most

frequently; however, lesions also are common on the hard and soft palate, the perianal

icid

skin, the vulva, the urinary meatus, and the glans penis. They start as red papules that
evolve into painful, soft, punched-out, shallow, persistent ulcers.
Lupus vulgaris is the most common form of t y p i cal cutaneous tuberculosis. It
results from direct extension, lymphatic or hematogeneous spread of endogeneous or
exogeneous foci of tuberculosis.
Lupus vulgaris is localized mostly on head and neck, in particular the nose, cheeks
and ear lobes. Bacilli from the infected sputum penetrate the nasal mucosa, enter the local
lymphatics and spread in the nearby in an around the nose. The typical manifestation of

lupus vulgaris is a red-brown plaque formed of tubercles with an apple-jelly color on

diascopy. The plaque extends slowly, for years and central scaring develops with
progressive destruction of subjacent cartilage (nose, ears). The scar is irregular, results in

disfiguring and might, in time complicate with squamous cell carcinoma.

The diagnosis is based on h i stology that shows tuber cles composed of
lymphocytes, epitheloid cells and Langhans' giant cells surrounding a central caseation.
Koch bacilli are present in very small number. The Mantoux test is strongly positive.
iter.

The diagnosis in cutaneous tuberculosis is based on biopsy with acid-fast staining

(Ziehl-Nielsen) and culture of My c obacteriaorganisms from a s p ecimen on a s p e ciflc

medium (Lowenstein-Jensen). PCR testing is increasingly used to identify mycobacterial

DNA in tissue specimens. It may be positive when both stains and cultures are negative in

a[

paucibacillary disease. Culture is the gold-standard and provides the means to determine
antibiotic sensitivity and response to treatment.
HIV testing is recommended in all patients diagnosed with tuberculosis, because
in this case longer courses of therapy are needed.

lel
sk
so

Treatment o f
ty p i ca l c u t aneous t u b erculosis i s s i m i l a r w i t h pul m o n ary
tuberculosis. Multidrug therapy is recommended as drug resistance of M.tuberculosis is
very common. The typical anti-tuberculous chemotherapy includes 4-drug combination of

cP
nI.

su
liL
be

rifampin, isoniazide, pyrazinamide and ethambutol (RIPE) for 3 months, then double
c mbination isoniazide+ethambutol for 6 months.

Cutaneous tuberculosis - atypical forms (tuberculids)

(pl

The tuber culids r e present a h y p e r sensitivity r e action w i t h i n t h e s k i n to

M.tuberculosis or its antigens released from a distant focus of infection in individuals with
strong antituberculous cell-mediated immunity (positive test to PPD) and current or past
tuberculosis infection. Mycobacterial organisms are absent in the tuberculid lesions (nor
stain positive neither culture out), but mycobacterial DNA has been detected by PCR in

tul

re1

(rr

the biopsy specimens.

m1

The tuberculids are chronic, recurrent and symmetric eruptions arising in crops:
p a p u l onecrotic tuberculids:
red-lilaceous papules centered by a necrotic core that

st

heals with pitted scars, on the superior half of the body (acnitis type,imitating

gl]

acne) or on the inferior half of the body (folliclis type, imitating folliculitis of the

Th

of

extremities).
lichen scrofglosorum: lichen planus-like papular eruption, on the lateral trunk

be!

erythema indurahIm (Basin's disease): chronic nodular vasculitis that appears on

the posterior calves of middle-aged women; the nodules are subcutaneous, 1-2 cm

in diameter, erythematous or violaceous and resolve spontaneously over several

months with or without ulceration, with scarring.
Papulonecrotic tuberculids and lichen scrofulosorum are widely accepted as true
tuberculids, while erythema induratum Bazin may not be uniquely caused by tuberculosis.
l

The t r eatment o f
t he at y p i ca l f o r m s o f the sk i n tu b e r culosis r e quires
antituberculous chemotherapy and sometimes corticotherapy with prednison.

in(
clo

LEPROSY (HANSEN'S DISEASE)

Leprosy is a disease of the peripheral nerves, but it also affects the skin, eyes,

r$
tlI1I

upper respiratory tract, the bones and testes. It is caused by acid-fast, -rod-shaped bacillus
Mycobacterium leprae, an obligate intracellular organism with a predilection for Schwann

hi

cells and macrophages.

trel

Bacilli can be identified on tissue smears using the Ziehl-Nielson acid-fast method
or the Fite method. The organism grows best at 27-30'C.
The degree of infectivity of the leprosy is rather low. The incubation period is long
(4-10 years) and it is likely that most patients acquire the infection in childhood as a result
of aerosol spread of nasal secretions from infected parents. Leprosy is not spread by touch,
40

1111

]
st
thy

rial

>ce the mycobacteria can not cross intact skin. Like in tuberculosis, the primary infection
sg1c
s in many persons, but the leprosy de~~lops in only 5-10'/o, who has decreased cell

iine

>~djated immunity. Depending on the level of the immune deficiency, different forms of

leprosy may develop.

use

Tuberculous leprosy (TL) (when the immune deficiency is minor) involves the

iary

sldn and peripheral nerves, with sharply demarcated hypopigmented macules that are
spInewhat elevated, with a d r y c e nter and erythematous borders, accompanied by a
loss of sensation, absent sweating and reduced hairs. The lesions are few in

s is
i of

able

cha
racteristic

>UInber (< 5) and are located on areas with lower temperature: buttocks, face, extensor
faces of limbs. There can be palpable thickened branches of cutaneous sensory nerves,
like lnar and common peroneal nerves. Severe neuropathic pain and muscle atrophy can
be present. Skin test with antigen from killed bacilli (lepromine test) is strongly positive

to
with
vast
'nor

< in

that
ting
the

(>5 mm) showing a well developed immune response, and histology in Fite stain shows
tUberculoid granuloma without the presence of bacilli.

Lepromatous leprosy (LL) is c haracterized by extensive skin, eyes, bones,

respiratory tract and testes involvement because expressed deficiency of immune system

(Ininimal cellular response) and uncontrolled multiplication of bacilli. The skin lesions are
multiple (> 6) symmetric macules, infiltrated nodules and plaques causing lion-like aspect
pf the face (facies leonine: hoarsness, loss of eyebrows and eyelashes, nasal collapse
secondary to septa perforation). Lepromin test is negative; the histology shows diffuse
granuloma in which acid-fast bacilli are present in greater number (multibacillary leprosy).

This form is highly contagious.

Borderline leprosy (BLL) represents intermediate cell-mediated response to bacilli

~ on
cm

eral
true
)S1S.

.ires

with variable extension and severity of manifestations, between the two forms described
before.
The diagnosis of leprosy is established when one or more of the following are

present (WHO):
hypopigmented or reddish patches with definite loss of sensation

thickened peripheral nerves

acid-fast bacilli on skin smears or biopsy material
Treatment o f l e p r osy w a s f o r m erly d o n e w i t h D a p sone, bu t a s r e sistance
increased, multidrug t h erapy w a s i n t r o duced (1981), w it h r i f a m pin, d a psone an d
clofazimine. The length of treatment ranges from 6 months to 2 years.
Sometimes antileprousy therapy i s c o m p licated b y i m m u n ological mediated
"reactional states" called leprous reactions. These are considered medical emergencies as

yes,
.llus

they can result in permanent neurological sequelae, disability and deformities. Patients at

highest risk are those with multibacillary leprosy (LL and BLL).
Type I reaction (type IV allergic hypersensitivity) can appear after 2-12 months of
treatment, with worsening of skin and nerve lesions, acute febrile illness. It indicates an

hod

impr
ovement of the cell-mediated immunity. It i s t reated with corticosteroids and the
specific antileprosy treatment should be continued.

ong

Type II reaction (type III humoral hypersensitivity) appears after a few years of

suit

therapy with a systemic inflammatory response to immune complexes deposition. It shows

sch,
41

erythematous nodules on the lower legs, being also called erythema nodosum leprosum
(ENL). The elective treatment is T h alidomide, but a lso corticosteroids can be u sed.
Thalidomide can cause severe birth defects when used in pregnancy.

A TYPICAL MYCOBACTERIA INFECTION S

"Swimming pool" granuloma or fish-tank granuloma is a chronic skin infection
caused by Mycobacterium marinum. This bacterium is found in aquatic environment (fresh
or salted water) of swimming pool, aquarium, or lakes. Cutaneous infection requires a
portal of entry, e.g. when cleaning fish-tank at home or in restaurants, or swimming in
contaminated lakes, trauma of the skin may result in exposure to M .marinum. After 3
weeks a solitary indolent papule appears at the site of inoculation (fingers, hands, feet,
elbows and knees, Fig.4.21). The lesion grows to form a verrucous plaque (granuloma) and
drains over several weeks, leaving an ulcer. A succession of nodules may ascend the arm,
along the draining lymphatics.
The diagnostic is made by the culture of tissue obtained from biopsy. Sometimes
polymerase chain reaction (PCR) can aid.
Conventional anti-tuberculous chemotherapy i s o f ten n o t v e r y e f fective, but
cotrimoxazole, doxycycline, clarithromycine for 3-4 months is usual curative.

42

sum
sed..

.tion

resh
es a

s)
er 3

Fig.4.1. Impetigo

Fig.4.2. Impetigo, disseminated

Fig.4.3. Ectima

Fig.4.4. Secondary ecthima in a patient wraith

pediculosis corporis

Fig.4.5. Erysipela of the face

Fig.4.6. Bullous erysipela

feet,
and

mes
but

Fig.4.7. Purpuric erysipela

Fig.4.8. Necrotic and bullous erysipela

Fig.4.9 Abcedated erysipela

and onicomycosis
Fig.4.10. Recurrent erysipela
and elefantiasis
'

yC

cQ

s. P'
C,

Fig.4.11. Superficial foliculitis

Fig.4.12. Staphylococcal sicozis

Fig.4.13. Furuncle at the onset, as an

in6amatory nodule

Fig.4.14. Furuncle with burbillon

Fig.4.15. Staphilococcal paronychia

Fig.4.16. Erysipeloid

Fig.4.17. Erythrasma

Fig.4.18. Positive reaction to PPD

Fig.4.19. Warty tuberculosis

Fig.4.20.Tuberculous gumma with

irregular scar

Fig.4.21. Pool granuloma

Fig.5.1. Dermatoscopic image of the

burrow in scabies

F.

Fig.5.2. Nodular scabies on genitalia

Fig.5.3. Scabies

L
Fig.5.4. Norwegian scabies

Fig.5.5. Pediculosis capitis

Sarc
and
Infe
rnjt(

mitt
Tile

befc
e$8'
per<

prul
Fig.5.7. Pubic lice and tinea.

Fig.5.6. Pediculus corporis

rr "'

epi(
inte

cha,'

pab
spR

ped

Fig.5.7. a. Detail of pubic lice

Fig.5.8. Tick

inf(
oftI

kE!

Fig.5.10. Larva migrans

Fig.5.9. Erythema chronic migrans.

46

ECT(3PARASITE INFECTIQNS

SCABIES
Scabies (Latin scabere = to scrach ) is a skin infection caused by the mite called
Sarcoptes scabiei var horninis, an obligate human parasite. Scabies is transmitted via direct
~d prolonged contact with an infected individual, also as a sexual transmitted disease.
Infested bedding and clothing is an alternate source of infection, as the
mite survives up to 3 days away from the human skin. The female scabies

mite burrows in the epidermis, and lays eggs in the burrow behind her.
The incubation period is 4-6 weeks if th e i n d i vidual was not i n fected
before {the time needed for the type IV hypersensitivity reaction to mites,

eggs and scybala) or 24-48 hours from reexposure in previously sensitized

persons. The hypersensitivity r e action i s r e sponsible fo r t h e i n t ense
Sarcoptes scabies
pruritus that is the clinical hallmark of the disease.
Lesion distribution, intractable pruritus that is characteristically worse at night and

epjdemiologic history (similar symptoms in close contacts) are very suggestive for scabies.
The lesions are sy mmetric, located on t h e f l e xor a spects of t h e w r i s ts, th e
interdigital we b s p aces, a xillae, e l b ows, b e l t li n e a nd but t o c ks. A r e o lae a r e
characteristically involved in w o m en, scrotum and penis in men (F ig.5.2),while soles,
palms, face and all the body diffusely in children. In adults, the interscapular region is
spared of lesions. Lesions found i n t h e i n t erscapular area and n ap e s u ggest scalp

pediculosis.
The primary lesions in scabies are:
the burrow - th e d i agnostic sign of scabies, 2-10 millimetres long, tortuous, lightbrown in color, surrounded by mild erythema. Dermatoscopy can aid visualizing the

burrow (Fig.5.7).
erythematous papulo-vesicles/pustules (1-3 mm) (Fig.5.3)
Secondary changes such as excoriations, eczematization, secondary b acterial

infection (impetigo, ecthyma and cellulitis) or postinflammatory hyperpigmentation are

often seen in patients with scabies.
There are two particular clinical forms:

nodular scabies - especially in c hildren, brownish-red papules and nodules

develop as an exagerated hyperergic reaction
crusted scabies - fu lminant i n festation, with c r u sted l esions (Fig.5.4), in
e lderly ( i n ability t o m ou n t a n i mmu n e response),

immun
ocompromised,

institutionalized persons and in neurological disorders (can't perceive pruritus,

can't scratch a m e chanism t o r i d t h e b o d y o f mi t e s), w h e n e n o r mous
multiplication mites occurs (to thousands, compared to less than 100, usually 10-15
in common forms ).

Treatment in a d u l ts: permethrine 5% cream (Scabex), washed off a f ter 8-l.,

h ours, can be used from 2 m o n th s of age; in i n f ants and p r egnant patients: benz~ h
b enzoate is th e c h oice. Topical su l p hu r i n c r e am s 2-10% may b e e f f ective bu t > e
f requently i r r i t a n t a nd le s s ac c e p te d b e c a us e i t s odour. G a m m a be n z e ne

hexachloride 1% ointment (Lindan) repeatedly for 3 days, washed off after 8 hours, i
u sed as a second-line therapy because of its toxicity (seizures, aplastic anemia), no f g
u nder 2 y e ars o f a ge. A l l t o p i cal t r e atments m ust b e a p p l ie d f r o m c h i n t o t o e <
including a reas under f i n g ernails an d t o enails. A n o r a l a g ent, I v e r mectin, i s a l s~
effective in one single dose of 200-250 micrograms/kg repeated in one-two w eeks i>
typical scabies, Crusted scabies may require 3 or more doses at 1-2 week interval.
m
Pruritus may p ersist up t o 2 w e ek s after succesfull t r eatment, but t y p i call>
decreases after the initiation of treatment. When persistent, antihistamines or a shor
course of topical steroids are required.
lie
The family members and contact persons should be simultaneously examine<
and treated, even i f t h e y h a v e n o s y m p t o ms. A l l c a r p ets sh oul d b e v a c u u m ed
clothing laundered, bed linens and tow els washed in hot w a ter in the second day o
Cg
treatment and again after 1 week. Items that cannot be washed may be professionall~
pL
dry cleaned or sealed in p l a stic bags fo r 1 w e ek . Excess scales in cr u sted scabies
should be removed to ease the penetration of topical scabicidal agents and decreas~
the burden of infestation.

ch

PEBK.'ULOSIS
CII

capias

There are 3 types of human lice: Pediculus humanus

(head louse), Pediculus humanus corporis (body louse), and Pthirus
al l
pubis (crab louse). Head l o use i nfestations are seen i n

Lceas.

socioeconomic groups and in school children and are not a sign of

poor hygiene, as the parasites survive underwater r'or up to 6 hours.

Body lice mainly affect the homeless. Pubic lice generally are spread
as a sexually transmitted disease (STD). Head and pubic lice infest
hair, laying their eggs at the base of hair shafts. Body lice infest
clothing, laying their eggs on fibers in the fabric seams. All 3 types
take periodic blood meals by piercing the skin of the host with their
anterior mouthparts.
Head lice spread through crawling from one person's hair to another's but als(

through a shared hairbrush. Lice cannot jump or fly from one person to another. Seal)
pediculosis manifests by scalp p r u r i t us. It l e ads to excoriations, secondary bacterial

infections (impetigo) and regional lymph node enlargement. Head lice are found most
commonly in the retroauricular and occipital scalp. Females lay eggs and produce)
biologic clay to form nits that attach the eggs to the hair shaft. Nits (egg-cases) are sees
just above the level of the scalp (they need body warmth to incubate) but also several
millimetres from the scalp, the latter being nonviable and indicating chronic infection
Nits look similar to the dandruff, but have a regular ovoid form and they adhere to th(

r 8-1i
hairs (Fig.5.5). Blacks have a lower incidence of infestation by the head louse but may
frenzy h,rs
scalp infestation by P. pubis.
but

nzer

expe
rience

cape

Body lice live and lay eggs on the seams of clothing and only moves onto the

urs, li

y to take blood meals at night (Fig.5.6). Nits are also found in the seams. The adult

i), no
toes
s alsi
eks i~

ferna]e body louse, unlike the head louse, can survive as long as 10 days away from the
h~ a n body wi t h out a blood meal.
Intense itching and papulo-vesicles caused by an allergic reaction to louse bites

il.

are common symptoms of body lice infestation. At sites where insects bite blue-grey
~acules appear, called maculae cerulea. They are pathognomonic for infestation with

iicalb
shor

l ,ce and are caused by t h e en zymes in t h e l o use saliva that b r eaks d ow n h u m a n

b i]jrubjn t o b i l i v e r d in . A s a result o f s c r a tching, t h e p a t i ent h a s e x c oriations,
ljchenifications and melanoderma, condition called "vagabond's disease".
Body lice are vectors of epidemic typhus, trench fever.
nine<
smed
Crab lice (pubic lice) are most frequently transmitted by d i r ect physical

iay o contact with an infected indivi d ual and adapted to liv ing on thick and curled hair of
snail)
cabiei
ere asi

p ubic, axilary, beard, and eyelash regions. Like head l i ce, the female crab lice f i x

their eggs to hair shafts with a cement material. They appear light-brown (Fig.5.7,
5.7a). Intense pruritus, maculae cerulae and n i t s i n t h e a f f ected areas are h i g hly
characteristic for the crab lice infestation.
Treatment of pediculosis:
Body hce: wash clothing and bed linen in hot water and dry wi th h i gh heat; dry

cleaning also effective to kill lice and nits.

Head and pubic lice:
cleaning of h a i r a c cessories, towels, bedding, clothing ar e essential t o p r e vent
reinfestation; plain white vinegar helps dissolve the cement away from the nit and aid
in mechanical removal of nit with fine-tooth combs. Removing nits after treatment is
not necessary to prevent spreading, as these contain dead eggs.
pediculicides as 1st line treatment:
o p e r m ethrin, pyrethrine not very effective for nits and may develop resistance
o m a l a thion (solution, spray) effective against both lice and nits
o m e r c u ric oxide ointment useful for eyelash infestation
o b e n zyl alcohol solution 5%
o p e d i culicides as 2nd line treatment: hexachlorocyclohexane (Lindane lotion,
it als(

ScalI
teria
most

cream, shampoo 1%); neurotoxic for children and pregnancy

3rd line treatment (oral): ivermectin, albendazole, levamisole.

TICKS

duce <
Ticks, Ixodes species (Fig.5.8) are common in w o o ded areas and are vectors of
. seer
vera'. Lyme disease caused by the spirochaete Borrelia burgdorferi.
Lyme disease is divided into three stages:
ction
to th< 1) acute illness: erythema migrans at the site of the tick bite appears 1 day-1 month after
the tick bite and develops an annular shape greater than 5 cm in diameter (Fig.5.9);
headaches, fever, myalgia and arthralgia may associate;
49

2) d i ssemination phase: secondary annular skin l e sions, migratory arthritis, cardiac

arrhythmias and meningitis; antibodies to the spirochete are developed;
3) l at e chronic phase, 2-3 years after untreated initial i n fection: destructive chronic
arthritis, acrodermatitis chronica atrophicans and neuropathy.
Treatment: doxycycline 100 mg bid or amoxiciline 500 mg tid for 3 weeks.

C UTANEOUS LARVA M I G R A N S
h o o k w o rms (a n aglostoma duodenale, strongyloides stercoralis) g i v e
usually
a ccidental i n fection i n h u m an s t h a t a r e d e ad-end h o sts. Th e i n f ection i s
encountered in barefoot beachgoers/sunbathers after contact with warm, moist, sandy soil
ide
etc. that contain animal feces contaminated with parasitic eggs. The larvae penetrate the
Larvae o f

s kin and m i g rate through a t u n nel i n t h e e p i dermis and u p per de rmis, giving the a l a
dis.
characteristic sign of erythematous, slightly elevated, serpiginous (snakelike), advancing
fail
lines (2 cm/day) (Fig.5.10). Intense pruritus is associated. Erythema, urticaria plaques,
yea
vezicles/bullae may also appear.
The treatment of choice: thiabendazole ointment 5-10% for early, localized lesions reg
or tablets for widespread lesions. Alternatives: mebendazole, albendazole, ivermectin as
oral treatment.

inf i

inc
im.
be1
sta

ca1

sp
ke

(F
le!

bl
lil
af

Pl
a1

s(

50

.rdiac

Chapter 6

.ronic

VIRAL INFECTIONS

WARTS (VERRUCAE)
give
ually
y soil
:e the

g the
ncing
.ques,

~ art s

a r e b e n i g n e p i d e r ma l n e o p l asms c a u sed b y v ir u s e s o f hu m a n

papillomavirus (HPV) group. Currently, more than 100 types of HPV have been
>gentjfjed, with a tendency of certain HPV types to occur at particular anatomic sites.
+arts are transmitted by di rect or indirect contact, and predisposing factors include
djsruption to the normal epithelial barrier. Treatment can be difficult, w it h f r equent
f ajlures and r e currences. Many w a r ts, h o w e ver, r e solve s p ontaneously w i t h i n 2

y ears. Probably cell-mediated immunity (CMI) p l ays a significant role in

.sions
tjn as

wart

w ith C M I de f i c i ency a r e p a r t i c u l arl y s u s ceptible t o H P V

regression; patients
i nfection and a r e n o t o r i ously d i f f i c ul t t o t r e at . A s m a l l s u b set o f H P V t y p e s,
i ncluding t y pe s 16 , 1 8 , 3 1 , 3 3 a n d 3 5 i s a s s o ciated w i t h t h e d e v e l o pment o f
rnaijgnancjes, m ost c o m m o nl y s e e n i n per s i s t en t g e n i t a l i n f e c t io n a n d i n
j~rnunocompromjsed p a tients. I n fection w i t h

H P V 6 a n d 1 1 i s a s s o ciated w i t h

benign lesions and low-grade intraepithelial neoplasia.

C linial manifestation depends on th e H P V t y p e i n v o l ved an d t h e i m m u n e
status of the patient.

Common warts (verruca vulgaris) a ppear as h y p e rkeratotic, yellowish

cauliflower-like papules (verrucosities) with a rough, irregular surface, smaller than 1

cm in diameter, most frequently on the hands (Fig.6.1., 6.2, 6.3). They may resolve
spontaneously in children. Common w arts have to be di fferentiated from seborrheic
keratoses, actinic keratoses and hypertrophic lichen planus.
Plantar warts may be: a) deep, solitary or scattered over the sole of the foot

(Fig.6.4), or b) more superficial and grouped together (mosaic warts, Fig.6.5). The
lesions are round, sharply d efined, with r o ugh k eratotic surface that covers several
black dots produced by th r ombosed capillaries. Plantar warts are frequently painful
like calluses and corns, but these develop in areas of friction over bony pr ominences

and appear without capillaries, as uniformly thickened skin (calluses) or with painful
central plug of keratin (corns).
Plane warts (f l at w a r t s) a re t i n y , f l e s h-coloured f l a t o r s l i g h t ly e l e v a ted
papules that are smooth, usually localized on the face and dorsa of the hands. Children
d w o men ar e m o s t f r e quently a f f ected (F ig.6.6). I n oculation o f t h e v i r u s i n t o
scratches and abrasions cause frequently disposition of these warts in l i nes (pseudo-

Koebner sign)
Viral papiloma are long, narrow, frond-like and flesh-colored elevations that

grow rapidly, usually on the face (Fig.6.7, 6.8, 6.9)

51

Genital warts (condyloma acuminata) are one of t he m ost common sexuall~

transmitted disease (although min or). They are caused by certain types of HPV th p~
can also cause cervical and penile cancer. Among the strains in the genital area (aboq
40), 13 are high-risk (strains 16 and 18 cause 70% of all genital cancers) and the other!
are low-risk, sometimes yielding changes in pap smears but not progressing to cance!
(6 and 11 cause about 90% of genital warts).
The virus is transmitted through d i rect genital contact. Extremely unl ikely i,
transmitted through shared clothing, bed sheets etc. The incubation may be anywher!
from 1 week to more than 1 year and lesions become apparent after additional month <
or years.
Condylomata appear as d i screte small p a p u les w i t h s m o ot h s u r f ace, skin.
colored, brown or w h i t ish (w hen m acerated), that becomes papillomatous and late!
acuminated ( v egetations) w i t h w e t a s p e ct. T h e l e s ions measure on e t o s e v er<I
m illimeters diameter but t h a y m a y a l s o p r esent as p educulated papilomas, up t !
several centimeters diameter, with f oul smell (Fig.6.10, 6.11). They are located on th!

external genitalia, perineum and perianally and may extend in the adjacent cutaneous!
areas like inguinal fold, mons pubis and also mucosal areas like vagina, uretra an)
anal canal.
Giant condylomata acuminata (Buschke-Lowenstein tumor) i s a ssociated wi Q
low-risk HPV types 6 and 11 and extensive growth as large cauliflower-like tumor an<
deep infiltration. It i s b enign bu t t r a nsformation i nt o sqarnous cell carcinoma mal
occur.

High-risk HPV type (HPV-16) is associated with squamous cell carcinoma ir

situ t ha t

m a y p r e sent a s m u l t i p l e b r o w n - red p a p u les o n t h e e x t e rnal g e n italia

perineum and perianally (Bowenoid papulosis)or eroded plaques on penis shaft or vulv<
(Erythroplasia of Queyrat). Biopsy is warranted to exclude malignancy.
Genital warts should no t b e c o nfused w it h c o n dyl oma l ata f rom secondary
s yphilis, a l t h ough t h e t w o di s e ases ma y a s sociate. M o l l u scum c o n t agiosum i !
frequently located in the genital area but has a different clinical aspect.
Oral warts results from d i g i t al or o r a l-genital sexual transmission, as small

fl

soft, white or pink papules or plaques. Transformation in oropharyngeal cancer mal

occur.

Therapy

There is no specific antiviral therapy to cure HPV infection. Treatment is aime(

at destruction of the warty growths rather than elimination of the virus. HPV infectio!!
is usually self-limited but l i f e l on g subclinical infection may be also possible. Mosl
sexual partners are likely to be sub clinically infected with HPV (no exophytic lesions)
Use of condoms may, in some cases, reduce transmission of the v i rus to u n i n fecte

<

partners.
Local destructive therapies
salicilic acid, tricloracetic acid, glutaraldehyde or formaldehyde
cryotherapy with l i q uid n i t r ogen, repeated every 1-4 weeks for approx.3 month(
(using a cryospray or a cotton bud applicator on a stick, until the lesion is frozen),
paring plantar warts is a valuable adjunct to cryotherapy
52

:ually

electrosurgery requires local anesthesia

~ that

l aser is an expensive treatment, reserved for l a rge or r e fractory w a rts; mu l t i p l e

treatments may be required.
Cytotoxic therapy

about
)ther'

ely i<

> odophylotoxin 0.5% solution (Condyline) - t h e m ost active constituent of t h e

plant extract p odophyllin w hich i s n o lon g e r u s e d d u e t o its tox i c i t y ;
>odophylotoxin is a self-applied treatment, more efficient that podophyllin an d

vhere

contraindicated in pregnancy

onto'

5-Fluorouracil cream (5-FU)

ancet

Topical immunomodulators

.ver al

irniquimod 5% stimulates the innate immune response to produce cytokines (IFN~, TNF-a, IL 1 2); it w o r k s w el l o n m u c osal sites, while on c u taneous areas its
penetl ations is i n creased by s alicylic acid p r e parations or c r y o therapy; l o nger

ap ta

periods of treatment are usually needed, e.g. 3-6 months

in

s jnecathechins 15% o i n t m ent c o n t ains g r een-tea l eaf d e r i ve d c a t echins w i t h

immunostimulatory and antiproliferative properties
HPV vaccines
The new vaccines Gardasil and Cervarix are designed to elicit vi r us-neutralizing
antibody responses to prevent initial infection with the HPV types represented in
the vaccine, HPV 16 & 18 (that cause cervical pre-cancers) and HPV 6 & 1 1 (that
cause genital warts). It is recommended for w o men and men 9-26 years old, who
have not contacted HPV infection. The research continues to develop therapeutic
vaccines that elicit the immune responses against established HPV infections and
HPV-induced cancers.

skin
latet

the
scout
a and
witl
~1 and

. may
ma is
italia,
vulvB

n.dary

MOLLUSCUM CONTAGIOSUM

im is

It is caused by a pox v i r us. Hemispheric, firm, u m b i licated papules that are

flesh-colored, white or translucent, usually 2-6 mm in diameter, arranged in groups or
small, widely disseminated are very characteristic for molluscum contagiosum. The papules
may are filled with a white material containing virus-infected degenerated cells.
In children transmission occurs from nonsexual skin contact and the lesions are

frequently localized on the face, neck and trunk (Fig.6.12).In early adulthood (age 1530 y) molluscum contagiosum occurs as a sexually transmitted disease (minor) and is
aimed localized perigenital, on the lower abdominal wall, inner thighs, buttocks (Fig.6.13)
'ctios
The goal of the treatment is the destruction of the lesions. The central hard core
Mosl of the lesions is removed with a sharp curette or squeezed out then 1% alcoholic iod is

ions), applied. Cryotherapy, imiquimod cream or podophylotoxin can also be used.

:ected

MILKER'S NODULKS
ont
>zen,,

The disease, caused by parapox virus, is a zoonosis in cattle. In humans, it is an

occupational disease, contracted after contact with th e u d d ers of i n fected cows. The
incubation takes 5-7 days and then hard hemispherical yellowish-brown or r e d dish-

53

blue nodules, 0.5 cm in d i ameter, appear on the mi l k er's fingers, hands or forearms
(Fig.6.14). The initial target aspect (a papulovesicular lesion with a r ed centre, white

ring, and red periphery) is followed by weeping (loss of epidermis over the centre),
crusts and regression. Fever, lymphangitis and r egional lymphadenopathy may
a ssociate. The c o urse i s u s u ally s e lf-limited, r u n n in g f r o m 3 - 6 w e e ks. T o a v o i d
secondary infection, local disinfecting agents can be applied.

ORE
It is t r ansmitted b y c o ntact w i t h i n f ected sheep or g o ats, causing m i l k er'8
nodule-like lesions. No human-to-human transmission occurs.

HERPES SIMPLEX
Herpes simplex viruses (HSVs) are double-stranded DN A v i r u ses that cause
acute skin infections characterized by grouped vesicles on an erythematous base. HSV

type 1 (HSV-1) is commonly known to cause herpes labialis and keratitis, whereas HSV
type 2 (HSV-2) is commonly known to cause genital herpes, but in reality these
antigenic types can locate anywhere on the body.
T ransmission of H SV can occur even d u r in g asymptomatic periods of v i r al
shedding. HSV-1 is spread through di rect contact with contaminated saliva or other
secretions, while HSV-2 is spread primarily by sexual contact. Contact must involve
m ucous m embranes o r a b r aded s k in . V i r u s r e p l i cates at m u c o cutaneous site o f
infection and then travels to the sensory dorsal root ganglia where remains latent (nonv
infectious state) until reactivation.
t
Viral shedding an d p o s sible t r ansmission occur d u r i n g p r i m ar y i n f e ction,
during subsequent recurrences, and during asymptomatic periods.
Once a patient has become infected by herpes virus, the infection remains for
life. HSV-1 infection is acquired by early childhood, and almost 80% of adults have

positive HSV-1 serology but only a small part of them (20%) have clinically apparent
outbreaks during their lives. The seroprevalence for HSV-2 varies from 13% to 40% in
the adults worldw i de, but more than half of these do not experience clinically apparent
outbreaks, while they still have episodes of viral shedding and can transmit the virus.
The HSV-2 infection is one of the most rapidly increasing sexually transmitted disease.
Primary herpes simplex infection is c l i n i cally m o r e s e vere than r e current
outbreaks. However, most primary HSV-1 and HSV-2 infections are asymptomatic and
may never be clinically diagnosed. Incubation is 3-7 days. Clinical forms of p r i m ary
herpetic infection:

p r i mary orolabial herpes (HSV-1 more frequently) - t he m ost common is

h erpes l a b i alis, m i g h t be sev e r e w i th
gingivostomatitis and odynopfagia, anorexia

f ev e r , i ntense p a i n , e r o d e d

p r i mary genital herpes (HSV-2 most frequently) - occurs 2 days-2 weeks after
exposure with p ainful eruption, sometimes with f ever, malaise and inguinal

lymphadenopathy

arms
v'hite

etre),
may
!Void

ker's

'.ause

pr i ~ a r y c utaneous herpes -with HSV-1 frequently on the face, or on the fingers

{herpetic w h i t l ow ) i n c h i l d ren w h o s u c k t h ei r t h u m bs, i n d e n ta l w o r k e r s
(before the spread of gloves) or with HSV-2 after digital-genital contact.
he r p etic keratoconjunctivit is -may cause corneal ulcers
ec g eflla herpeti curn
it is a rapid, widespread cutaneous dissemination of HSV
infection in areas of dermatitis or skin b arrier di sruption (atopic dermatitis,
burns); it occurs especially in c h i l dren, usually w i t h H S V-1 and can be li fet hreatening; i t a p p e ars a s m o n o m orphic, d i s crete 2- 3 m m e r o s i ons w i t h
hemorrhagic crusts
ne o n a tal H S V -2 h e r pes - m a n i f ests w i t h in t h e 2 " d w e ek f r o m b i r t h a f t e r
exposure to HSV during the vaginal delivery; the risk is higher if the mother
acquires a HSV-2 infection in the third semester of pregnancy; the infection in
newborn clinically r anges from l ocalized skin, mu cosal, or eye i n fections to
encephalitis, pneumonitis, septicaemia and death.

Recurrent herpes simplex

About 20% of HSV-1 and 50% of HSV-2 infections are recurrent. They tend to

HSV
HSV

occur at or near the muco-cutaneous site of inoculation, within the distribution of the

these

sensory nerve. Stimuli that in d uce recurrences are, most frequently, febrile diseases

viral
other
rolve
te of
',non:tion,
is for
have
arent
)% in
arent
rirus.

for herpes labialis (cold sore) (Fig.6.15) and intercourses or menses for herpes
genitalis (Fig.6.16). Other f a vouring f a ctors a re t r a uma, u l t r aviolet r a d iation,
extremes in temperature, stress, immunosuppression, or h o r m onal f l u c tuations (at

menses).
Recurrent clinical outbreaks are milder than the primary infection and have a

prodrome of pain, itching, tingling, burning, or paresthesia. A group of clustered

vesicles appear on an er ythematous base, eventually t ur n i n t o p u stules or erosions

then form a crust and usually resolve in 10-14 days (Fig.6.17, 6.18).
Individuals exposed to HSV may have asymptomatic primary infections and
experience an initial clinical episode of herpes months to y ears after th at. Such an
episode is
not as severe as a true primary outbreak.
Recurrent herpes simplex can trigger episodes of erythema multiforma.
Diagnosis of herpetic infection:
1. Detecting the virus from infected cells in symptomatic patients by

.ase.
rrent
. and

giant cells

mary

3n iS

cytologic examination (Tzank smear) scraped cells from the base of the
erosion show i n t r anuclear inclusion bodies and m u l t i nucleated epithelial
direct fluorescent antibody assay (DFA) test detects the HSU antigen and
distinguishes it from varicella zoster virus (VZV)
pol y m e r a se chain reaction (PCR) detects HSV DNA i n s p e cimens from

oded

the skin, mucosa, cerebrospinal fluid etc; most sensitive

virus culture the gold standard, used for typing
Type- specific serologic tests for asymptomatic or unrecognized patients with

after
uinal

genital herpes wh o serve as reservoirs for H S V t r a n smission or f o r s exual

p artners of p a t i ents w i t h g e n i tal h e r pes; t hese tests d etect a n t ibodies t o

glycoproteins G1 for HSV-1 and G2 for HSV-2

Treatment

or IIl

HSV infections are usually self-limited. H o w ever, antiviral t h erapy shortertl

alIl

t he course of th e sy m ptoms and m a y p r e v ent t r ansmission. Oral, i n t r avenous an) p

topical antiviral medications are available for treatment of HSV and are most effectiv< bastI
if used at the onset of symptoms (during the prodrome). Antiviral therapy is virustat>~ freQ'
blocking the virus replication; it is not viricidal and is not curative, since HSV remain~ invk
latent in sensory ganglia.
the
Oral antiviral therapy with acyclovir, valacyclovir or famcyclovir can be give~ for
at the time of th e episode or as chronic suppressive therapy. Intravenous acyclovp ca
may be u se d i n s e v ere f o rm s o f h e r p e ti c i n f ections o r i n i m m u n o c ompromise]
individuals. Topical treatments are less effective than oral therapy.
Dru
Acyclovir

First clinical e isode

Recurrent

i s o des

Su r e ssive thera
400 mg x 2/day for up to 1 year

200 mg x 5/day, for 10 days

200 mg x 5/day, for 5 days

Valacyclovir

1 g x 2/day, for 10 days

500 mg x 2/day, for 3 days

1 g /day for up to 1 year

500 mg / day for up to 1 year

Famcyclovir

2 50m x 3 / d a

1 x 2/da , f or l day

250 mg x 2/da for u

for 10da s

(followed by reevaluation)

t o 1 year

Table 2. Dosage recommendations for antiviral therapies in patients with genital herpes.

Imiquimod i s

a t o p i cal i m m u n e r e sponse m o d i fier ( s t i m ulates th e i n n at<

i mmune r e sponse), w h il e I s o p r inosine i s a non-specific i m m u n ostimulant o r a lly
administered. Both may be used to reduce the frequency of recurrences.

HERPES ZOSTER (SHINGLES)

Zoster is a common, predominantly cutaneous and neurologic disorder causei

by the varicella-zoster virus (VZV).

VZV i s

a DN A

v i r us th a t i s tr a n s m i t te d t h r o u g h h i g h l y c o n t a g iouI

respiratory droplets or by direct contact. The primary infection with VZV is varicell8
usually in childhood. After the cutaneous lesions heal, the virus remains dormant h
dorsal root ganglia or cranial sensory ganglia often for d ecades. More then 90'/o 0
the adults h ave serologic evidence of V Z V i n f e ction. Because circulating specifil
antibodies develop, the person wil l no t d evelop varicella after a subsequent contac
with the vi rus, but this mi ght reactivate later on (in 10-30% of the individuals) an)
cause a localized recrudescence called herpes zoster or shingles. When reactivated
f
t he virus m i g r ates down th e sensory nerves to th e skin an d l e ads to i n j ur y o f t h
keratinocyte nuclei and subsequent intracellular edema, producing the characteristi( fa
fr
vesicles.
Shingles is a dermatomal disease manifesting in 1 posterior spinal or crania s

sensory ganglia (ganglionitis) with pain (nevritis) and characteristic unilateral lesion.'
(vesiculization) on the skin innervated by this sensory nerve.
The triggers of this reactivation have not been precisely determined, but could
be malignancies, particularly of l y m p h oreticular system, acute or chronic infection
emotional stress, or the factor remains undiscovered. Recently, a genetic susceptibilit)
to zoster has been demonstrated.
56

Most pf the patients present prodromal sensory phenomena with pain along 1
~pre sk1n dermatomes 1-10 days before skin lesions appear. This pain may simulate
.ortegapr @lore
in pf different other etiologies and can result in incorrect diagnosis.

~s an~ pa]n 0

The clinical aspect is typical: vesicles (2-4 mm) grouped on an erythematous

fectiy<
e and associated pain confined to one unilateral dermatome (Fig.6.19, 6.20), most
usta'
frequently pn the thorax or abdomen. The eruption stops abruptly at the midline of the
.main<
;nvplved dermatome. Regional lymphadenopathy may appear. Initially the content of
the vesicles is clear, but subsequently becomes cloudy and dries up in a few d ays to
give>
fprm crusts. The condition resolves within 2 w e eks wi thout v i sible sequels. Scarring
jr clove|
can pccur if secondary infection or necrosis complicates the evolution (Fig.6.21).
)mise]
Cpmplicated forms of herpes zoster.
]. I n i m m u n osuppressed individuals herpes zoster is pluridermatomic or even
disseminated (varicelhform) with n u m e rous extradermatomal vesicles that
1 year

may be hemorrhagic or necrotic (Fig.6.23).

postherpetic neuralgia may develop, usually in elder patients, defined as the
persistence of pain for w e eks, months, years after the cutaneous lesions
have resolved.

3. Other less common postherpetic sequels include hyperesthesia,or more

rarely, local anesthesia or in v olvement of m o tor f i b res with mu scle palsy
innatt

oral)

cause

agiou
ricella
1ant it
30% 0

pecifi i
'.onta(
.s) an(
ivated
of th
teristi i

and subsequent atrophy.

4. I n t r i g eminal zoster the ophthalmic d i v i sion is most frequently i n v o lved
(zoster o p h t almicus, Fi g .6.22). O c ular i n v o lvement wi t h co n j u n c tivitis,
keratitis and iridocyclitis is heralded by zoster rash on the tip, side or root
of the nose due to involvement of the nasociliary branch of the ophthalmic
d ivision. O p h t halmic i n v o l v ement r e q u i res i m m e diate r e ferral t o t h e
ophthalmologist innorder to prevent vision loss.
5. Ra msay Hunt s yndrome defines herpes zoster infection t hat i n v o l v es the

geniculate ganglion of facial nerve (CNVII) and sometimes other nearby

cranial nerves, like CN VIII, IX, V an d V I ( i n o r der of f requency). It
presents with vesiculation and ulceration of the external ear and ipsilateral
anterior 2/3 of the tongue and soft palate, ipsilateral facial paresis. Vertigo,
h earing loss, ti nnitus, headaches or d y s arthria ma y a l s o d e v elop. T h e
overall prognosis is good, but complete recovery of the facial nerve occurs
in less than 50% of patients.
Treatment
Systemic treatment w i t h o r a l o r i . v . a c y clovir o r d e r i v a tives (v alaciclovir,
famciciovir, penciclovir) has to be started as early as possible, ideally wi t hin 72 hours
pm the onset of symptoms. It shortens the duration of zoster, prevents or reduces the

crania severity of postherpetic neuralgia. The dose for acyclovir is 800 mg x 5/day for 7-10
lesion

: coun
etio%
tibilitI

"ays; valacyclovir 1000 mg x 3/day for 7 days.

A cute pain du e t o d e m i elinisation of t h e n e r ves is t r eated w it h v i t a mi n 8
preparations in combination with analgesics. Glucocorticoids are sometimes used early

' h e disease to reduce acute pain (by anti-inflammatory effect) but care has to be
taken in severe cases of zoster when dissemination of viral particles is possible.

57

Postherpetic n e u ralgia can be a l l e v iated w i t h a n t i e p ileptics ( g abapenti>

carbamazepin), tricyclic antidepressants (doxepin, amitriptiline) and capsaicine crea>
(depletes neurotransmitters like P substance at involved nerve endings).
A ntibacterial treatment i s o nl y n e cessary in p a t i ents wh o ar e a t r i s k f r y >
infections to protect them against secondary bacterial infection.
Topical t r eatment u se s w e t a n t i septic d r e ssings with 1 % z i n c s u l p h at~
cloramine 8 or cyclohexidine to dry lesions and control secondary infections. After t
vesicles have dried up, softening antiseptic ointments are indicated.
A vaccine for p r evention of z o ster (Zostavax) was approved in 2 006 in t$,

>,

Unites States for persons older than 60 years, including those with previous episode <
zoster or who have chronic medical conditions. It is a live, attenuated strain of VZ)
the same strain as in varicella vaccine, but much more potent.

58

senti',
crea@
; frog

mph ate
'ter th
in th(
ode o>

Fig.6.1. Common wart

Fig.6.2. Diseminated common warts

E VZW

Fig.6.3. Periunghial warts

Fig.6.4. Deep plantar wart

Fig.6.5. Mosaic plantar warts

Fig.6.6. Plane warts

Fig.6.7. Filiform wart

Fig.6.8. Filiform wart

5 ,1

002

Fig.6.9. Keratotic 61iform wart

-j

Fig.6.10. Genital warts

Fig.6.11. Genital warts

Fig.6.12. Molluscum contagiosum

Fig.6.13. Molluscum contagiosum

Fig.6.14. Milker's nodul

Fig.6.15. Labial herpes

Fig.6.16. Genital herpes

wc,

0 ) '4'!

Fig.6.17. Cutaneous herpes simplex

Pig.6.18. Herpetic whitlow

')

Fig.6 20. Herpes zoster

Fig.6.19. Herpes zoster (initial lesions)

Fig.6.21.
Scarring after herpes zoster

Pig.6.22. Herpes zoster ophtalmicus

'

p<' j c '
')
).

g 6 23. Variceliform herpes zoster

Fig.6.24 Varicela

()allI

nm)
T.p(
d( t<
COIl.'

to i'
ver

lbn
lynI

higl
P I'0

huf
h Ll I
no
ill'( i

PII

intl

t rl
infj
do

Chapter 7
SEXUALLY TRANSMITTED DISEASES (STD)

SYPHILIS
Syphilis is a chronic systemic venereal disease caused by the spirochete Treponema
p<ilidg~ a facultative anaerobic organism of the tissue, not the blood. It is very small (5-15
coiled like a c orkscrew w it h u n i f orm t u r ns, bending and r o t atory m ovements.
T ppllidgm is difficult to s tain. Dark-field microscopy is the method of c hoice for T.p.
detection and differentiation from other saprophytic spirochetes by shape and movements.
Syphilis is t r ansmitted f ro m i n t i m ate contact w it h i n f ectious lesions (sexual
contact most common), by blood transfusions, or transplacentally from an infected mother
to her fetus. Transfer via smear infection plays only a minor part, because T.pallidum is
very sensitive to drying, temperature fluctuations and pH variations.
rapidly p enetrates intact m ucous membranes or m i c roscopic skin

T.pa
llidi

abrasions and multiplies at the p ortal of entry. The infection remains localized until
regional ganglia face the multiplication of T .p., but after a few w e eks T.p. enter the
lymphatics and blood to p r oduce systemic infection. In this early phase the patient is
highly contagious, but as the disease progresses and the immune response becomes more
prominent, the patient becomes less contagious.
Antigens of T. p allidum i n d u ce a h y p e r sensitivity r e s ponse in t h e h o s t o f

humoral (synthesis of antibodies), and cellular (delayed, T-cell mediated) type. The
humoral response results in I g M a n d I g G s p ecific anti-treponemal antibodies and
nonspecific reagin antibodies. The cellular reaction results in mononuclear infiltrates
around Treponema, responsible f or t h e c u t a neous a nd v i s c eral m a n i f estations. In

primary syphilis a unique infiltrate appears at the portal of entry of treponema and
results in the chancre formation. In secondary syphilis the im m une reaction is more

intense and explains the formation of the macules and, specially, the papules. In the
tertiary syphilis, the immune reaction is exaggerated and produces giant
infiltrates corresponding t o g u m m a . T h e t r e p onemas w i t hi n t h ese
d estroyedbut some persist in a l a tent state in th e l y m p h atic ganglia
from time t o t i m e , y i el d s m al l e p i sodes of bacteriemia an d t h u s

inflammatory
i n f i l t r ates are
and m u l t i p l y
t h e r e c u rrent

cutaneous and/or visceral eruption.

The immune reaction in syphilis is incomplete, for example it may prevent the
forInation of a primary lesion (chancre) on subsequent infections with T paliidum, but it is
~nsficient to clear the organism. Nevertheless, there is some efficiency of the immune
spse, as only 15-20% from th e i n fected and u n treated patients develops tertiary
yphilis Also, some heal spontaneously but they remain contagious for a number of years,
until then.

I
'a

Syphiiis is characterized by episodes of active disease (primary, secondary, tertiary

'"'ges) interruPted by Periods of latency. The current classification of syPhilis is as follows:
63

Acquired syphilis
o E arly syphilis
pr i m a ry syphilis

secondary syphilis

early latent syphilis

L a t e syphilis

tertiary syphilis

lab

IW

late latent syphilis

o P arenchymal syphilis (cardiovascular syphilis, tabes dorsalis, general paresis)
Congenital syphilis
o
o

P
t,

lymf,

E a rly congenital syphilis

L a t e congenital syphilis

nod<

Acquired syphilis is distinguished from the congenital syphilis; the former occam
through exogenous transfer and u sually b egins w it h a p r i m ar y c h ancre (except th~
clas
transfusion syphilis, where the spirochete enters the bloodstream directly, thus the chancrt
i s lacking and secondary syphilis occurs from t h e b eginning), w h ile th e l a tter is ; ( s e r
ofT
consequence of the transfer of the spirochetes through the placenta to the foetus from @
infected pregnant mother.
ch
Known as a great imitator, syphilis can be a diagnostic challenge because of h
(tra
wide-ranging clinical presentations.

Acquired Syphilis

Primary Syphilis (stage I)

Primary syphilis occurs 3 weeks (incubation period) after the contact with z
infected individual and is marked by the development of the chancre at the portal of entrI

(sy
my

and regional lymphadenopathy.

The chancre is usually single. It starts as a small indolent papule and in a few day,
it reaches its c h aracteristic aspect: round-oval erosion, 4-8 m m i n di a m eter, w it} asp
cartilaginous consistency on p alpation (pathognomonic character!), smooth, lacquere< Up

surface and sharply delimited edges (Fig.7.1). The classic lesion is usually painless an( ite
heals in 4-8 weeks even without therapy, leaving no scar. It differs from the chancroi(
which has undermined margins.
Clinical forms of chancres:
giant chancre or microchancre
multiple chancres - when simultaneous entry sites occur
successive chancres - when further infection occurs during the incubation time; <
soon as sufficient specific immunity develops, no other chancres appear
phagedenic chancre with necrotic tissue extending to the depth, heals with scat
occurs when contaminating bacteria associate.
Chancres are most often located in genital regions, but extragenital chancres can b
encountered:
genital chancres:
t
o i n m e n : on the glans penis and coronar sulcus, penis shaft, scrotum or pubj
area; when the chancre is on the prepuce, and the prepuce is drawn back, j:

will flip over all at once, being too hard to bend (a dory-flop phenomenon)

the

be
air

fa'
m

sy
ra
fi

in women, on the major and minor labia, clitoris or urethral opening; in vagina
it is often overlooked

extragenital chancres: in the oral cavity (Fig.7.2),on the lips, on the nipple, in the
perianal region, or enywhere else(Fig.7.3)
The chancre may complicate with:

ay~osis(tight prepuce cannot bedrawn over the glans penis)

.sis)

paraphymosis (prepuce, after being retracted behind the glans penis, is constricted
there and can not be brought into place again)
iant edema).
One week after the chancre, swollen lymph nodes (syphilitic bubo) develop in the
lymph drainage region that is inguinal, if the primary lesion is genital (Fig.7.4). The lymph

elep
hantiasis(g

nodes are hard with freely movable and of normal color overlying skin. Regression of the

occur! swollen lymph nodes occurs within 2-8 weeks.

pt t4
hancrt
r is ~
)m th

. ofig

The primary syphilis has two substages: 1) seronegative, 2) seropozitive. The

ciassica] serum tests are nonreactive in th e f i rst 2-3 weeks after the chancre appears

(seronegative primary syphilis). In this case the diagnosis of syphilis is based on detection
of T.pallidum by dark-field microscopy.
Syphilitic chancre should be differentiated from: genital herpes, candida balanitis,

chancroid (jagged border, yellow exudates, painful), lymphogranuloma venereum

(transient, indurated, painless), fixed drug eruption, squamous cell carcinoma.
Secondary Syphilis (Stage II)

ith a!
f entrv

iv de!
, witl

In secondary syphilis spirochetes flood the entire body via the blood and lymph
(syphilitic septicaemia) causing general symptoms: micropoliadenopatia, fever, malaise,
myalgia, headache, pain in the long bones and visceral manifestation.
The cutaneo-mucous manifestations in t his stage are called syphilids. Initially
t hese are symmetrical macules, more or l ess generalized, and l ater p apules w it h a

tendency for asymmetry and grouping in cocardiform, serpiginous and corymbose

aspects. The syphilids almost never itch and they commonly heal without scars or atrophy.

guerec Up to 25% relapse within the first 1-2 years. The secondary syphilis lasts 2-6 months until
ss aS

incroi(

it enters the latent phase. The serum tests are reactive and T. Pallidum can be detected in
the lesions, thus secondary syphilis is contagious, especially the eroded lesions.

Cutaneous secondary syphilids:

Macular syphilids (roseola) are the earliest manifestation of secondary syphilis,
.me; $

beginning about 6 weeks after the chancre (9 weeks after infection), when the chancre may
already be regressing. Roseola are discrete macules, 2-10 mm diameter, pale-red, round,
not clearly demarcated, symmetrically located on th e fl anks and shoulders. They are

h scl

neither scaly, nor itching and regress spontaneously in a few days (Fig.7.5). They are so
faint that might not be observed by the patient.

Macular syphilids should be differentiated from pityriasis rosea, primary HIV

infection, drug eruption.
Papular s y p h i l i d s

p pubi'
~ack,!
)n)

c a n o c cu r t o g e ther with th e

r oseola (maculopapular
syphids) or may follow them after a short latency period. The papules are round, of a
a+-"am or coppery shade, 2-5 mm in diameter, slightly raised but with a palpable
f' infiltration (Fig.7.6, 7.7). Papular syphilids tend to be initially d isseminated and
65

symmetrical, but later localized, asymmetrical, hypertrophic, sometimes confluent, q

arranged in patches, rings, corymbose or serpiginous patterns. Without treatment, tg
lesions resolve over several weeks to months. Relapses occur especially in the first year,
Variations from the above described picture may be observed:

hll

coul
len t i c ular syphilids disseminated, with smooth, shiny surface, like in lichen planus v\Thl
pap u l o -squamous syphilids disseminated, covered by adherent scale, like in guttat, dev'

psoriasis
mfll
pal m a r a nd p l a n tar s yphilids characteristic site of i n v o l vement; coppery, flat
indurated papules with squamous collarette (Biett) or hyperkeratotic surface (Fig.7,~ oth

de

7.9);

split papules at the oral comrnissures or in the crease of alae nasi

hypertrophic papules and papulo-erosive syphilids, with their large variant

condyle,sp

lata occur in intertriginous regions, especially about the genitalia and anus, sometirnq;
in axillae and g r oins; they are broad f lat (1-3 cm) p a pules wit h s m ooth, moist
s
weeping, gray-white surface and characteristic foul smell; they are highly contagiou

(Fig.7.10, 7.11, 7.12). Condyloma lata in should be differentiated from

acuminate (due to HPV) and squamous cell carcinoma.

condyle;

se
Mucous patches are the most infectious lesions of secondary syphilis. They aa fl

M lcosal secondary
syphilids

an

painless, superficial, silvery-gray erosions with red periphery, located on:

the lips, oral mucosa, tongue (Fig.7.13), palate, pharyngs (syphilitic sore throat)
laryngs (syphilitic laryngitis with hoarsness or aphonia), tonsils (angina syphilitica);
glans penis, inner prepuce, vulva and vagina (Fig.7.14), anal canal.
]n

Other manifestations of the secondary stage:

Pigment metabolism disorders - several small hypopigrnented and depigment6
patches on the sides of the neck, also called leucoderma syphiliticum or Venus' collar
Disturbances of hair growth with two patterns, both completely reversible

pa t c hy hair loss (syphilitic alopecia) with a mouth-eaten appearance on the seal~

eyebrows, beard or other parts of the body

di f f u se alopecia
Visceral manifestations in

s econdary syphilis i n clude hepatitis, nephropathI

(proteinuria, acute nephrotic syndrome), gastrointestinal involvement (gastritis, proctiti~

ulcerative colitis), p eriostitis, osteomyelitis, p o lyarthritis, ocular involvement (opti
neuritis, iritis, uveitis).

Latent syphilis
It is characterized by reactive serologic tests for syphilis in the absence of tb
clinical signs. The l atent period o ccurs after th e l esions of secondary syphilis has
involuted and may last for a few months or continue for the remainder of the person's lif(
Sometimes, syphilis starts as a latent form (no anamnestic chancre or syphilids).
For treatment reasons, it is important to distinguish between:

early latent syphilis: up to 1 year from the infection

late latent syphilis: after 1 year from the infection

66

II

Tertiary syphilis (stage III)

nt. ot
nt, tlt,

Tertiary syphilis is a n o n-contagious but highly destructive phase of syphilis,

year,
bus
plttatt

h;~ usually develops within 3-10 years of infection in 15-20% of untreated patients. The
cours of syphilis is dependent on the cellular immune response. Tertiary syphilis occurs

hen a cellular hypersensitivity reaction (type IV, tuberculin type) to the treponema
develops in th e h o st, l eading t o a s m a l l n u m ber o f o r g anisms an d a l s o t o l o c al
ammatory infiltrates in affected tissues.
The typical lesions in this phase are tubers and gumma, located in skin or any
organ. The cutaneous lesions tend to b e l ocalized and g r ouped, asymmetrical,

destructive and heal with atrophic scarring.

The nontreponemal serum tests (VDRL) are positive in about 75% of cases and the
dyioyyg specific treponemal tests (TPHA, FTA tests) are positive in all cases.
.ctime.

Cutaneous tertiary syphilis

moist

Tuberous syphilids located on the face, scalp, limbs, are firm, reddish-brown, 3-5

:agio'

Iylom; miilimeters dermal tubercles, grouped in characteristic circular, serpiginous patterns with
tendency to ulceration.

Syphilitic gumma appears as painless, single, isolated subcutaneous firm nodule or

several nodules grouped in circles or arcs. After weeks or months, central necrosis occurs, with
<ey @ fluctuation, perforation, drainage of a purulent fluid and a deep punched-out ulcer with steep sides
and gelatinous, necrotic base. It heals with smooth, white scars with peripheral hyperpigmentation.
:hr oat) It is most &equently located on the anterior shins, face, forehead and buttocks.

ica);

Mucosal tertiary sy phi lis

Nasal septum, the hard and soft palate, the tonsil region or the tongue can be

involved by tuberous syphilids and syphilitic gummata (Fig.7.15).

nente<

Tertiary lesions of internalorgans

. scalp

Eye: gummata in the iris; optic nerve atrophy; Argyll-Robertson sign: small reflex
pupil that reacts normally to accommodation but not to light.

Gummata in bones (saber tibia), lungs, testes, liver.

Cardiovascular syphilis

opathi

Occurs 10-30 years after infection and is mainly represented by aortitis resulting
tocfiti~ from thickening and hardening of vasa vasorum with consequent necrosis of elastic tissue

(optI and fibrosis of proximal aorta. This is manifested by aortic insufficiency (altered aortic
valve function), coronary disease and ultimately aortic anevrism (weakened aortic walls).

Neuro syphilis
of 8
Central nervous system involvement can occur at any stage of infection. Most
s ha>' n it is asymptomatic but can be detected by testing the cerebrospinal fluid (CSF) for
n's IEE~ mononuclear pleocytosis, non-specific and specific treponema tests. It is divided into early

and late forms (not directly correlated with early and late syphilis).
Early neurosyphilis
Meningeal neurosyphilis appears up t o 1 ye a r a f t er i n f e ction w i t h h e a dache,
vomiting, neck stiffness, cranial nerve palsies, seizures.

67

Meningo-vascular neurosyphilis a ppears 5-10 years after infection with hemipares< ~ p

and hemiplegia, as a result of infarction due to syphilitic endarteritis.
s
Late (parenchymatous) syphilis occurs more than 10 years after infection and I,
due to direct invasion of the cerebrum by treponemas.
Tabes dorsalis degeneration of the dorsal roots of the spinal nerves and posterio,
c olumns of the spinal cord; it presents with the specific tabetic dissociation of pain ~ ~

tactile sensations (which are lost, resulting in deep ulcers of the feet), from temperature, in p
sensation (preserved), with ataxis wide-based gait, foot slap and areflexia.
typiC
General paresis is caused by degenerative changes in the brain, corresponding to tb,
mnemonic p aresis: personality, affect, reflexes (hyperactive), eye (Argyll-Robertso>

pupils), sensorium (illusions, hallucinations), intellect (memory, judgment) and speech.

diffe

Congenital syphilis

Congenital syphilis arises from intrauterine transfer of T.pallidum to th e fete, use

from the m other w it h i n fectious syphilis after the 4th m o nth o f g estation, when @
anti
placenta becomes permeable for T.pallidum.

If the mother has a recent syphilitic infection (highly infective), syphilitic stillbi <

m ay result in the 7th-8th month of pregnancy, or fulminating early congenital syphib; e p

may develop until the child reaches 2 years of age. If the mother has an old syphilitic aug

infection (low bacteriemia), the child will be apparently healthy (latent congenital syphilis)
or will develop late congenital syphilis after the age of 2 years.

Plas
bec

Early congenital syphilis manifests in the neonate or subsequently up to 2 years pi

age, corresponding essentially to the acquired secondary syphilis of the adult. There ar< neg
spo
also specific manifestations:
ind'

syphilitic pemphigus of the new-born bullous eruption of palms and soles

rhinitis syphilitica abundant, muco-sanguinolent nasal secretions which i m pas

sucking and can lead to the perforation of the nasal septum

fals

wit
syphilitic laryngitis hoarse weeping of the infant
pe r i nasal, perioral and perianal infiltrative syphilids (papular syphilids) that caus~
depressed radiating linear scars, called Parrot's grooves

osteo-articular signs: Parrot's pseudoparalysis with immobile forearm, due to the pais
caused by osteochondriti.s syphilitica with epiphisiolysis in the ulnar region

hepatosplenomegaly, generalized lymphadenopatia, nefritis, meningitis

Late congenital syphilis m anifests after 2 years of age, in juveniles or adults,

corresponding essentially to the aquired tertiary syphilis of the adult, with tuberous an <

pos

(sy
tre

tre
gummous syphilids.
Many cases (60%) of late congenital syphilis are latent (no clinical manifestation<
but reactive serum tests). In any case of unexplained seropositive latent syphilis, not only
acquired syphilis but also congenital syphilis has to be considered. In these cases, stigmas
(sequels of active syphilitic lesions) are present:
bone abnormalities:
o s y p h i l itic saddle nose (depression of the nasal root due to destruction of th<

cartilage/bone)
o s aber shins (anterior tibila bowing)
o "Olympian brow" (bulging of the frontal bone region),
68

>resjl

parrot's grooves (radial periorih.cial scars at sites of previous fissures)

nd ls

Hutchjnson's triad (interstitial keratitis, inner ear deafness and Hutchinson's teeth =
small, oblique, barrel-shaped upper incisors that tapper towards the tip; crescentic

otch of jncisal edge).

teria'

I,abogatory diagnosis of syphilis

l and
ature

Dark-f jeld microscopy is essential in early syphilis with moist lesions (the chancre

:o the
rtson

h.

fete
n. the

jmary syphilis, the condyloma lata in secondary syphilis) where

mpfprim

T.pa/lidum with

j cal mov'ements i s f o u nd . D i r ect f l u orescent antibody t es t ( D F A T-TP) fo r t h e

ident f cat on of T. Pattldum ln lesions ls another option.
Serologic diagnosis aims to identify antibodies to T.pallidum in the serum of the
syphilitic Patient. According t o t h eir P roPerties, antibodies against T.Paltidum are of
djfferent types: precipitating antibodies - used in VDRL test, agglutinating antibodiesused jn TPHA test and immobilizing antibodies - used in TPI test.
Nontreponemal or n o nspecific reactions de tect a ntibodies against l i p o i dal
antjgens (reagins) of T.pallidum. In these tests cardiolipinic antigen (extracted from ox

lbjrth

heart, rich in phospholipids) is used as it cross reacts with similar phospholipids in the

Phill

treponemai wall. Antibodies in the serum of the patient and cardiolipin antigens form

hiijtic
)hilisj

aggregates that can be directly seen in tubes.

Most widely used are Venereal Disease Research Laboratory (VDRL) and Rapid
plasma Reagin (RPR) tests. These are initial screening tests all over the world, as they
b ecome positive 5-6 weeks after infection, shortly b efore the chancre heals and ar e

arsof generally strongly positive throughout the secondary phase. They usually become
.e are negative during early an d e f ficient therapy. Results may also become negative
spontaneously in the third p hase of syphilis. A f o r f old decrease in the antibody titer
indicates successful treatment, while a fourfold increase indicates relapsenor reifection.
.'np all

The reaction has high sensibility (rare false negative results) and low specificity (many
false-positive results). Biologic false-positive test denotes positive VDRL/RPR tests in persons

with no history or dinical evidence of syphilis and with negative treponemal tests. Most of

p~

these tests are of low titres. Acute false-positive VDRL/RPR revert to negative in less than 6
months and can result from pregnancy, vaccinations and infections (infectious mononucleosis,
hepatitis, measles, varicella, influenza, lymphogranuloma venereum, malaria). Chronic falsepositive VDRL/RPR persist more than 6 months and is found in connective tissue diseases

(systemic lupus erythematosus), chronic liver disease, rheumatoid arthritis, tyroiditjs.

s ana

Any positive nontreponemal test result should b e c onfirmed w i t h a s p ecific

treponemal test. All patients with syphilis should also be tested for HIV infection.
Treponemal or specific reactions detect antibodies directed against specific

>tlON

treponemal antigens:
TEA (T r e ponema pallidum h e magglutination) t est: s pecific a ntitreponemal

t onl)'
~mal
7

>f tl>e

antibodies in the patient's serum are agglutinated by antigen-coated erythrocytes.

FTA (Fluorescent treponemal antibody) test - antitreponemal antibodies are fixed on
treponemal antigens. Visualisation of this reaction is possible using fluorescein-linked
anti-human immunoglobulin (indirect jmmunofluorescence).
The IgM FTA-ABS test detects antitreponemal IgM antibodies that occur in congenital

and recently acquired syphilis. Treated or older spontaneously healed syphilis

produces IgG class a ntibodies. Constant t i t res o f I g M a n t i b odies i n dicate t h e
Psjstence of T.p. in the body, thus the need of treatment.

69

Enzyme-linked immunosorbent assay (ELISA): the visualisation of antibody+specg,

antigen complex requires an enzyme-labelled antiglobulin.
The treponemal tests become positive a bit earlier than nontreponemal tests aq,

qu

remain positive for life. Therefore they confirm syphilis even in late phases, when g, year1
nontreponemal tests tend to become negative. TPHA i s u n suitable for monitoring th,
O'P
course and treatment of syphilis. VDRL test can be used as a screening test and ii, S8
quantitative form is suitable for monitoring treatment, measuring significant falls in titer.

Treatment
Penicillin is the most effective agent in all stages of syphilis thus it remains g
drug of ch oice. It p enetrates into all b od y fl u i d s an d p asses the cerebro-spinal @g
placental barriers and kills T.palhdum by blocking the synthesis of the microbial cell wg
T.pallidum divides about every 33 hours and the treatment has to be long enough to catg
all the treponemas: at least 2 w e eks w it h c onstant penicillin serum concentration ~
recommended for early syphilis and 3-4 weeks in late syphilis.

Early syphilis (seronegative/seropositive primary syphilis, secondary syphili~

early latent forms) and preventive treatment for sexual contacts of syphilitic patients: 2i
2.4 mil.I.U. penicillin G benzathine (Moldamin, Retarpen), that is 1.2 mil I.U. i.m. in ea6
buttock on the 1st and the 7th day of treatment.
Late latent and tertiary syphilis: 3x 2.4 mil.I.U. penicillin G benzathine divided op
the 1st, 7th, and 14th day of treatment.
In case of syphilitic patients with penicillin allergy oral tetracicline (not to be use)

in children and pregnant women) or erythromycin 500 mg every 6 h, for 15 days in earll
syphilis and 30 days in late syphilis can be used.

Herxheimer reaction
When treponemas are abundant (late I stage, II stage, early congenital syphilis), on
systemic toxic effects appear within 8 h a f ter the first dose of penicillin because hig1 ba
number of microorganisms are destroyed and fever up to 40'C, shaking chills, malaise, (b
headache and intensification of syphilitic rashes may develop. Increased inflammation i
vital structures may have serious consequences, as in aortic aneurysm (aortic rupture an)

sudden death) or CNS involvement (paralyses). Herxheimer reaction in pregnancy ma~

induce premature labor and fetal distress.
In order t o m i t i g ate the sym p t oms of H e r x heimer r eaction, small d oses 0!
penicillin G ( 2 5 000 IU ) w i l l b e a d m i n i stered ev ery 6 h o u r s i n t h e f i r s t d a y Ol
treatment, w it h w a t e r-soluble i .m . o r i . v p r e d n i solon f o r m u l a ti ons. Every p a tienl
should remain u n der m e d ical observation fo r several h o ur s after th e f i rst d ose ot

penicillin. The use of retard penicillin (benzathine-penicillin) reduces the risk ol

Nu

Herxheimer reaction.
Herxheimer reaction has to be distinguished from drug reactions to penicillin.

Ten

Treatment of sex partners

Ulc
AP

Sexual partners of persons with syphilis should be identified and treated, even i
seronegative. At-risk partners are those exposed for u p t o 3 m o n ths before plus th~ Ad
duration of the primary lesions, up to 6 months before plus the duration of the secondary
lesions, or up to 1 year before for latent syphilis.

70

specific

$ggpipgicat tnpn'ttpnng
Every patient who has been treated for syphilis should be followed up u s ing a

!Sts anc

<tative
nontreponemal test (VDRL) at 3, 6, 9 and 12 months after treatment and then
quantt
a

hen ge
arlyyfor
year
or 3 years. It may take 8-12 months for four-fold decrease in titer. The longer lasting the
ing the
the longer it takes for serological tests to normalize, if at all. Persistence of reactive
and i((
t titer,

syp

~
te
seruIyl
eSs ts after 12 months requires retreatment with penicillin and prednisolon.

DIPPKRKNTIAL DIAGNOSIS OI' GKNITAL ULCER DISKASKS

Iins the
Ial anc

I,ymphogranuloma venereum (LGV), STD that usually occurs in tropical and

.11 wa!! subtropical countries is caused by Chtamydha trachomatis, L1-L3 serotypes and evolves in 3
to catd stages:
ation !t
painless shallow, rapidly healing genital ulcer, without scarring
painful unIlateral lymphadenopathy (buboes), 2-6 weeks after the ulcer, with classical
wp~
groove sign (femoral nodes above and below the inguinal ligament); fistulae and sinus
ents: 2i

Ided otj

tracts result with a purulent discharge and finally depressed scar;

genito-ano-rectal syndrome occurs many years after the infection (perirectal fistulas,
abscesses, stenosis in the genital tract and rect, genital elephantiasis)
Treatment:

be usee

needle aspiration of involved buboes, for pain relief and prevention of ulcer formation
Tetracycline hydrochloride 4x500 mg/day, Doxycycline 2x100-200 mg/day, or

in eacl,

in ear]I

Erythrom
ycin 4x500 mg/day, for 21 days

Chancroid (soft chancre, ulcus molle) is a sexual transmitted disease (STD) caused
by Haemophitus ducreyi (gram-negative coccoid-bacillary rod). Clinical picture consists of
r philis) one (or more) painful soft genital ulcer with undermined margins and yellowish-gray
se hip base, surrounded by erythema. After 1-2 weeks, painful inguinal lymph nodes enlarge
malaise (bubo) and spontaneously rupture with fistula formation.
Treatment:
ation!t
Ceftriaxone 250 mg i.m. single-dose
ure an(

Azithromycin 1 g orally, single-dose

Erythromycin 2g/day for 7 days
Ciprofloxacin 500 mgx2/day for 3 days.

.cy IYlst

oses s.'
day 0:
paties
Bose 0'
risk 0'

3,

even I
)lus 8
-ondar,

!! All open sores facilitate transmission on HIV.

Disease

HSV

Nnntlrer,

Clusters of erosions
on labia and enis

Ten rter ness

Tender

Ulcer
Appenrartce

Uniform size, clean

base, erythematous

LOMtlogt

border

A<em
pathy

Tender

hilis

LGV

Chancroid

One or two,
o nva ' a a n d e n i s

Ulcer lasts 2-3 weeks,

on labia and enis

One/two,may coalesce,
on labia and enis

Little / no
tenderness

Painless

Clean, indurated
base
Rubbery, mildly
tender

Ulcer spontaneously
heals at time of
fluctuant adeno athy
Fluctuant inguinal
nodes, groove si

Ta hei.3 Differential diagnosis of genital ulcers of STDs.

71

Can be large, ragged,

necrotic base,
undermined ed es
Very tender, fluctuant
in i n a l nodes

The ce'
Qy cull
Gonorrhea is a sexually t r a nsmitted i n f ection of mucous m e mbranes th,, phase
wofneI
commonly m a n i fests a s urethritis ( i n male), cervicitis (in f emale), proctitis

GONORRHEA (BLENORRHEA)

conjunctivitis. If untreated, infections at these sites can spread retrogradly, leading to lo~
complications. Sometimes resistant subepithelial gonococcal "nests" can be preserved apt
with
act as starting point for relapses in patients and reinfection of partners.
Neisseria gonorrhoeaeis a Gram-negative diplococcus shaped like a coffee bean 9@

urethr

Invos

grows in pairs with adjacent concave sides seen on Gram's or methylene blue stain sm@,
uni-/bilayered epithelia, wg POStg
examination. Go nococcushas a special affinity f o r
N.gho
pavimentous and multilayered epithelia are resistant to infection.
squ
Gonorrhea is transmitted almost exclusively through sexual intercourse. Only tt
the e
exceptional cases an extragenital infection occurs, e.g. as a smear infection through da~I
towels. Infected adults can infect children sleeping in the same bed.

Gonorrhea causes asymptomatic infection (in 10% of men and 50% of worn@
especially in r e ctal and p h aryngeal infection), local symptomatic mucosal infection
sometimes with complications, and systemic dissemination.

ostl

folds

Direct mucosal infection

a. I n men.
Anterior gonorrheal urethritis is the most common clinical form of gonorrhoea i
men, involving the columnar epithelium of the urethra up to the external sphincter of th;

bladder.
The acute form has an incubation of 2-3 days, a florid stage of 2-3 weeks andI
regression stage of 4-6 weeks, when th e d i scharge diminishes. Untreated, symptom;
disappear in about 6months. First symptoms are dysuria, prickling and heat in the ureth
on urination. The next day a v iscid, creamy yellow discharge appears with numerov
intracellular gonococci at microscopic examination.
The chronic form manifests after the 6th-7th week with discrete viscous

discha
rge

("good morning drops" ) and no symptom during the daytime. The morning urine is clem
but contains whitish filaments discharged from the ureflual folds, mucus, epithelial cell~
leukocytes and bacteria.
In about one quarter of infected men, the symptoms are less pronounced, simila,
to those of non-gonococcal urethritis. H ow ever the cause of urethritis is often impossibl
to differentiate on clinical grounds alone.
Posterior gonorrheal urethritis may start 10-14 days after infection and spree
distally, as the orifices of the excretory ducts of the prostate, seminal vesicles, and ducts
deferens open into the posterior urethrae. The bladder is not infected, as its transition>
epithelium is not susceptible to the gonococci.
The patient has distressing desire to urinate every 5-10 minutes,
t(1
but voids eve'
time just a few drops. Hematuria and pain at the end of micturition are characteristic.
b. I n W omen
Gonococcal cervicitis is usually symptomatic in w o m en, with m o re acute ant

uruletn

intense symptoms than in chlamydial cervicitis. Increased green/yellow muco-p

vaginal discharge from the cervical orifice and dysuria are the most common symptoS-'

The ce

is red and swollen. In time, the columnar epithelium is destroyed and replaced

bycu
cubic
1 pr even flattened epithelium that is less favorable for gonococci, so that in chronic
> se the disease becomes less symptomatic, but gonococci are still found. Symptom-free
.s thy pl!!ase
omen with chronic cervical gonorrhea are a frequent source of infection.
Es
wome
to lpq!

Gonococcal urethritis u sually accompanies cervicitis. The posterior part of t h e

ethra is affected (the anterior third is coated with squamous epithelium). It manifests
ed ar!i ure

with dysuria (stinging pain or burning on urination) and scant urethral discharge.
an tQ! involvement of the trigonal region of the bladder produces tenesmus.
! sme@

wN

Gonoc
occal v ulvovaginitis

o c curs o n ly i n pr ep u b e rtal g i r l s, p r e g nant o r

ostrnenppausal women, wh o h av e fl at , u n i l ayered vaginal epithelia, susceptible to

N<INnorrhoeae infection. Except of t h ese situations, the v agina i s l i ned b y s t r atified

)nly ~, sqQampus epithelia. The vagina is red, edematous, with abundant purulent discharge, and

1 da+ the examination is extremely painful.

Gonococcal bartholinitis occurs occasionally due to the inflammatory ocdusion of the

vom@ ostium pf the excretory duct and manifests with painful cherry sized pseudoabsces of the labial
CtlOIg

folds and purulent discharge when pressure is applied to the gland.

Local extension of gonococcal infection

of the anterior gonorrheal urethritis:
hoeam

r oft'

dorsal lymphangitis or thrombophlebitis: hardening and swelling of the dorsal lymph

or venous channels of the shaft of the penis
gonococcal perigrethritis: the c onnective t issue a round t h e u r e t hra i s i n v a ded,

becoming a hard and painful cord

) and !

nptom!
uretIU;
merou~

perigtrethral abscesses: Morgagni lacunae intraepithelial, microscopical abscesses,

observed only by u r e throscopy ; g l a nds of Li t t re larger paraurethral abscesses,

s chary

palpated as painful rice-sized nodules along the urethra; glands of Cowper(cherrysized glands behind the scrotum) boil-like perineal abscess
phimosis and paraphirnosis(the last is a surgical emergency that can lead to the glans
necrosis)

is cle8!

urethral strictures late complication, can lead to acute urine retention

al celh

similr
iossibl!
spread
duclN
sitio5

s ever

of the posterior gonorrheal urethritis:

epididymitis: the gonococci migrate up to the vas deferens, reach the epididymis with
unilateral tenderness and edema, high fever, high sedimentation rate and neutrophilic
leukocytosis. The testis itself is spared and is of normal size. The complication of the

epididymitis is oligospermia and if bilateral, azoospermia and loss of fertility.

acgte orhitis: the involvement of testis
prostatitis with pain in the intestinal region and during defecation
seminal vesiculitis with accidental ejaculations, tenesmus, blood in ejaculation

of the gonococcal cervicitis:

~cute salpingitis or pelvic inflarnrnatory disease manifests usually immediately after a

Jte N'

menstrual period, w it h l o wer abdominal pain, abnormal adnexal mass on pelvic

examination, associated with fever, leukocytosis, elevated ESR or C-reactive protein
level. It may result in l ong-term consequences of infertility, chronic pelvic pain or

uruler

ectopic pregnancy.

>ptpS'

73

acute perihepatitis (Fitz-Hugh-Curtis syndrome) results in women, after migration ~,

gonococci from the faloopian tubes via the peritoneal cavity to the upper abdorne<
Pain in the right upper quadrant mimics acute colecystitis.
pelvic peritonitis re sults from t he s preading of t he i n f ection to t he p elvis and I,
characterized by nausea and vomiting.

Extragenital direct gonorrhoea

Pharyngeal gonorrhea wi th r e d d ening, swelling o f t h e m u c osa an d s l igI,,
II
dysphagia occurs in men or women after oral sexual exposure. However most of the forg,
are asymptomatic and p h aringeal gonorrhoea remains undetected and r epresents @
important source of infection.
Rectal gonorrhea occurs after anal intercourse. It is asymptomatic in at least 50<,
of cases but may result in goconococal proctitis (rectal pain, pruritus, tenesmus, rectp

discharge and bleeding).

Goncoccal ophtalmia represented years ago an important cause of blindness. ],
moanifests with p u r u lent conjuctivitis and, i f l e f t u n t r eated, can rapidly p r ogess ~~

keratitis followed by permanent corneal opacification.

In newborn it is caused by inoculation of N.gonorrheaduring delivery through@

infected birth c anal. Prophilactical application of 1 % s i l ver n i t r ate o r e r y thromycII
ointment immediately after birth currently reduces the rate of ophtalmia neonatorum.
In adults i t r e sults f ro m s e lf-inoculation o r u n u sual sexual p r actices. Earl~
recognition and local antibiotic are essential to avoid blindness.
I

Disseminated gonococcal infection (gonococcemia)

It occurs through hematogenous bacterial spread that is favored by menstruatior
(most cases appear immediately after menses) and pregnancy. Clinical picture include
arthritis-dermatosis syndrome:
po l y a r t hralgia with fever, pain, tenderness, decreased range of motion, usually at lary

joints: knees, elbows, wrists, ankles; erythema overlying the tendons; endocarditi<
meningitis
skin rash: scattered necrotic pustules due to embolic septic vasculitis on the distr
portion of the extremities, but also on the trunk.
Laboratoryexamination in gonorrhea
Is based on identification of N.gonorrheaby:
Gram smear Gram-negative (red) diplococci within neutrophils, which differer from ne

pathogen Gram-positiveNeisseriaspecies (blue); used for urethral cad 'endocervical secretion

not for pharyngeal or recto-anal exudates, where there is a large number of other bacteria
culture on special media most specific, gold standard for gonocccal infec'tion
DNA probe antigen detection test fromI. mucosal secretion or from u r ine sampk
C.
more sensitive than culture for extrager6tal secretion. Chlamydia can be identified fry'
the same specimen collection tube.
Treatment of gonorrhea
N.gonorheaehas a remarkable capacity to alter its antigenic structure and adapt b
chaqges of the microenvironment, thus it has become resistant to numerous antibiotic!

74

3n of
meq
Ld ia

lllght
orrrg

:s
500I,

ectg
ss. It
ss tp

h an
lyQn

S+ifpnamldes were used in 1930, penicillin until 1976, fluoroquinolones - ciprofloxacin,

flpxacjn, levofloxacin, since 1993 were efficient orraly as a single-dose, and also offered
or>pxa
t,~amydial activity w h e n g i ven f o r 7 d a y s, bu t n o l o n ger u sed s ince resistant
~ gonorrhea strains appeared. Fluoroquinolones remain an alternative treatment option
p py fp r d i s seminated g o nococcal i n fection i f a n t i m i crobial s u sceptibility c a n b e
ented. Ampicillin and Am oxicillin are also no longer reliable in the treatment of
pnprrhea. Currently 3'~ generation cephalosporines are the antibiotics of choice:

ceftriaxone 250 mg i.m as single dose (preferred);

cefixime 400 mg p.os as single dose
cefuroxime axetil 1g, single oral dose
cefpodoxine 400 mg, single oral dose
Alternatives:

ceftizoxime 500 mg, i.m. single-dose

cefotaxime 500 mg, i.m., single-dose
Spectinomycin 2 g, i.m. single-dose reserved for multiresistant strains
Azithromycin 2 g, single oral dose effective but widespread use not recommended

because rapid emergence of resistance; an option in allergy to cephalosporines

Since the infection w ith

Ch lamydia trachomatisi s frequently concomitant wi t h

gpnprrhoea, doxycycline 100 mg twice a day, orally for 7 days or a single oral dose of

Early

Azithromycine 1g has to be associated, unless Chlamydia testing excludes coinfection.

Condoms, if properly used, provide effective protection against transmission and
acquisition of gonorrhoea. All p atients should be instructed to r efer sex partners for
evaluation and treatment.

ation

DISEASES CAUSED BY CHLAMYDIAE

.Ud6

Chlamydiae are Gram negative bacteria that preferentially infect squamo-columnar

larg<

epithelial cells. They are obligate intracellular microorganisms that need to be provided

ditla,

with energy for metabolism from a host cell.

Chlamydia trachomatis is one of the 4 species (including C.puerorum, C.psittaci,

distal

C.pneumoniae) in the genus Chlamydia. There are 18 serovars (serologically variant strains)
of Chlamydia trachomatis: A, B, C cause trachoma (a serious eye disease that can lead to

b lindness), D-K a r e associated w i t h g e n i ta l t r a c t i n f e ctions and L 1 -L 3

lymphogranuloma venereum Nicolas-Favre.
non.
'e6on

nplal
from

c a u se

Chlarnydia has a unique biphasic life cycle that is adaptable to both intracellular
and extracellular environments. In the extracellular milieu, it exists as an inactive spore

called elementary body (EB). Once inside a susceptible host cell, inclusion bodies are
need. Since only the intracellular forms of chlamydia are susceptible to antibiotics, only
drugs with good intracellular penetration will successfully combat the infection.
Chlamydial genitp-urinary infecbpns, caused by C.trachomatis serovars D-K, are
manifested a s c e r v i citis, salpingitis, e n d ometritis, u r e t hritis, epididymitis,
conjunctivitis, and neonatal pneumonia.
Chlamydia c auses the most common n o n-gonococcal urethritis, together wi t h

.pt ta

"aplasma urealyticum, Mycoplasma hominis and Trichomonas vaginalis.Non-gonococcal

ptiC5

"'ethritis has longer incubation period than gonococcal utrethritis, is asymptomatic or

75

s ubacute. Th erefore, d i agnosis i s d e l a yed u n t i l p o s i t i v e screening r e sults o r ,

symptomatic p artner i s d i s covered. A s y m ptomatic p atients act a s a r e s ervoir fo,
chlamydial infections.
The clinical aspects in men include urethral discharge, urinary frequency and/0.
urgency, dysuria, scrotal pain/tenderness, perineal fullness (related to p r ostatitis); >
women mucopurulent endocervical discharge, easily i n d uced endocervical bleed~(
intermenstrual bleeding, dysuria, and abdominal pain.
Diagnosis:

cytologic diagnosis evaluates endocervical scrapings for intracellular inclusions, b,.

interpretation is difficult and both sensitivity and specificity are low.
isolation in tissue culture (40-72 hours) and then detection of intracytoplasmatic inclusipg,
by Giemsa stains or immunofluorescent staining with m onoclonal antibodies; hi~~
specificity (100%) and sensitivity; expensive; swabs need to be taken invasively frog
urethra or cervix
antigen detection d etects the ribosomal RNA by h ybridization with a DNA p r o b f..
simpler, less expensive, high sensitivity but lower than cell culture; other technique>
direct fluorescent antibody (DFA), ELISA

detection of chlamydial genes by DNA amplification tests e.g. polymerase ch~

reaction (PCR) in urine or self-administered vaginal swab specimens

serologic tests are valuable in L G V, b ut n ot i n c e rvicitis, urethritis, where positivf
results reflecting a possible anterior infection, the antibody titers are low and thf.r~
may be a cross-over reactivity between C.trachomatisand C.pneumoniae
Treatment is indicated when the diagnosis is established or suspected, in sexua
l
partners o f t h e p a t i ents an d f o r p a t i ents b eing t r e ated f o r g o n o coccal i n fection
Recommended drugs are:
azithromycine 1 g p.os, single dose

doxycycline 100 mg x2/day p.os for 7 days

Alternatives

erythromycine 500 mgx4/day, p.os for 7 days - in pregnancy

ampicillin 500 mgx3/day, p.os for 7 days in pregnancy
ofloxacin 300 mgx2/day p.os for 7 days
levofloxacin 500 mg once daily for 7 days

AQUIRED IMMUNODEI'ICIENCY SYNDROME (AIDS)

atient

This syndrome is a complex of aquired infections and tumors occuring in p

with T-cell deficiency due to the HIV virus.

The most common route of infection is sexual contact. Other routes of infection art
sharing of needles and syringes contaminated with blood among drog users, injuries vriII
contaminated instruments in health care workers and physicians; by transfusion of blop<
and blood p r oducts or b y t r a nsplantation of o r gans; pre- and p erinatal infection c
newborns by HIV-positive mothers.
HIV is a RNA-virus and is a retrovirus because it has an enzyme called revere
transcriptase that copies the viral RNA to the DNA in the cells of the host. Target cells fo'
HIV are CD4+ cells such as CD4+ lymphocytes, monocytes, macrophages, Langerhap'
76

or
rr for

ceIls
sI ~iia
g cells, keratinocytes and any other cells in the human body. Increased destruction
f
$
cells
results in impaired immune response and in the proliferation of opportunistic
o

sections
and malignancies.
e
d/or
rs)

HIV infection evolves in 3 stages after an incubation of 1-3 weeks:

acute viral HIV infection starts asymptomatic or with flu-like illness (10-20% of cases):

headache,

edlQL

sor e

thr o at ,

mal a ise, pe r sistent lym p h adenopathy,

hepatosplenomegaly, maculo-papular exanthema. Anti-HIV antibodies are detectable

by ELISA by 3-4 weeks.

s. but

2nd stage - starts when a specific immune response against HIV has been mounted
and has controlled the initial viremia. It may last at least 1 year but can be over 10

usrorrr

years; in some patients may persist indefinitely (at least 20 years so far)

; higg

generalized lymphadenopathy

frog
o
robe.

.iquea

char'rr
>sitivj.
there

c o m p letely asymptomatic o r w i t h p r o g ressive weight l o ss, m alaise, and

t h e patient is source of infection for others

o C D4 positive lymphocyte counts drop progressively as they are sequestered in

the lymph nodes.
hard stage
AIDS (overt disease) severity is directly related to the decline in CD4+ T
cells below 200/pl (normal 500-2000), which causes diminished function of T cells, B
c ells (hypogammaglobulinemia), macr ophages and N K
c e l l s a n d l e ad s t o
opportunistic infections, neoplasms and dementia.
Opportunistic infections are caused by microorganisms that take advantage of the
decreased immune response in order to develop:

ction

fungal (o ral a n d oe s ophagial c a ndid osis, wid espread p i ty riasis v e rsicolor,

dermatophytosis, proximal white onychomycosis, deep mycoses)
viral (disseminated CMV i nfection, herpes simplex not healing after 1 m o nth,
multidermatomeric o r v a r i celliform h e r pes z oster, o r al, g e nital o r w i d e spread
cutaneous warts, mollusca contagiosa; Epstein-Barr virus induces hairy leukoplakia
that appears early in HI V i n f ection, as asymptomatic white plaques with hair-like
projections on the lateral aspects of the tongue
mycobactevia, atypical

bacterial (stafilococci, streptococci, treponema pallidum)

ectopavaziteinfections (norvegian scabies)
Non-infectious HIV-related disorders

atientr

on arr
s wiS
blood

seborrheic dermatitis with exaggerated presentation or resistant to treatment

psoriasis severe forms; tends to worsen with decreased immunity status
Tun ol's:
Kaposi sarcoma (hemorrhagic disseminated angiosarcoma) associated with human

herpes virus type 8 (HHV-8) that can be t ransmitted by infected semen or saliva; the

ion 0<

lesions start on the upper part of the body, characteristically on the face, intraorally
induding gingiva and the hard palate, with purple/red macules that increase in size

everI

and become raised and tender, some of them nodular and ulcerated (Fig.8.13, 8.14). In
HIV-related Kaposi sarcoma, l y m p h no d e s a r e i nv o l ve d ( w i t h se c o ndary

.lls for
.rhaNr

lymphedema), gastrointestinal tract and lungs.

lymphomas (associated with Epstein Barr virus)
77

squamous cell carcinomas especially in men having sex with men and infected witI
HPV condyloma acuminatum in anogenital region

Paraclini c examination

HIV screening should be encouraged as part of routine physical examination @g

by ELISA. Western-blot test is used for confirmation.

Laboratory tests that help in staging HIV infection are:
o C D 4 T-cell count indicates the risk of acquiring opportunistic infectio~

+
average

The reference range for

C D 4 c o unts i s 5 00-2000 cells/pL. A

seroconversion, CD4 counts tend to decrease (around 700/pL on
and under 200/pL is considered AIDS-defining.
o

Q u a ntitative v i ral l oad assays in p e r ipheral bl ood m easure the v i rg

replication rate (even if this occurs in the lymph nodes rather than in th<

peripheral blood), which is related to progression to AIDS and death.

The treatment of HIV infection aims to reduce viral multiplication and to treat 0~
prevent opportunistic infections. Anti-retroviral therapy suppresses viral loads to @
undetectable level so that CD 4 count r ises and the r isk o f o p p ortunistic infection g
reduced. Viral eradication is impossible as the virus is integrated in the DNA of the hog

lymphocytes.
The prognosis of HIV infection is poor. The average time from diagnosis to deaf
is one decade, with individual variability.

78

ioQs,
A.fter

rage)

Fig.7.1. Primary syphilis

Fig.7.2. Chancre of the soft palate

virg
n tge
L

.'at o(
3Il is

host
3.eath

Fig.7.3. Extragenital chancre

Fig.7.4. Syphilitic bubo

Fig.7.5. Secondary syphilis

Fig.7.6. Secondary syphilis

(macular syphilids)

(papular syphilids)

Fig.7.7. Papular syphilids

Fig.7.8. Plantar syphilids

79

Fig.7.9. Palmar syphilids

Fig.7.10.Secondary syphilis (condilomalag)

Fig.7.11. Secondary syphilis (condiloma lata)

Fig.7.12. Intertoe condiloma lata

22 12 2002

Fig.7.13. Mucous syphilids

Fig.7.14. Mucous syphilids

Fig.7.15. Soft palate perforation after guma

Fig.7.16. Kaposi sarcoma

80

Chapter 8
ALLERGIC SKIN DISORDER S
Allergic diseases are determined by hypersensitivity reactions which may be
late)

t body or cell-mediated. The basic immunological reactions were classified by Gell and

Cpombs in four groups.

Humoral allergic reactions (antibody mediated)
IgE-dependent reactions (Type I, Gell-Coombs classification)
In the sensitization phase, antigens induce the formation of specific IgE antibodies
adhere to the surface of mast cells. When the antigen contacts again the organism,

spedfic IgE antibodies already fixed to the mast cell surface react with the circulating
antigens inducing the release of mediators from the granules of the mast cells (histamine,
prostaglandins, l e u kotriens, k i n i ns). V a so dilatation r esults, w i t h a n inc r ease i n
and exudation of serum, chemotaxis of eosinophils.
In a sensitized organism, the Ig-E dependent reaction becomes clinically manifest

per
meability

within a few minutes to a few hours (immediate reaction).

Urticaria, angioedema (Quincke's edema), anaphylactic shock, reactions to insect

bites and stings are clinical manifestations of the IgE-dependent reaction and can,
sometimes, be fatal.
Cytotoxic reaction (Type II, Gell-Coombs classification)
The antigen (often drugs) is bound to a cell surface. Binding of the specific
antibody leads to activation of the complement and generation of inflammatory mediators

with cell damage. Immunohemolytic anemia, thrombocytopenia or pemphigus vulgaris

are clinical manifestations of cytotoxic reaction.

Immune-complex reaction (type III Gell-Coombs classification)

oa

This type of r eaction involves the deposition of a n tigen-antibody complexes

mainly in the vascular walls with the activation of the complement cascade. This leads

to chemotaxis of polymorphonuclear neutrophils and release of lysosomal enzymes,

responsible for the vasculitic lesions. There are 2 types of immune-complex reactions:

Arthus type (manifested in leucocytoclastic vasculitis) and serum-sickness reactions

(manifested by widespread vasculitic lesions in skin, kidneys, joints, erythematous or
urticarial exanthem, l y mphadenopathy, p olyarthralgia, polyserositis a nd a c u t e
nephritis).
Cell mediated reactions

Cellular allergic reactions of delayed type (type IV Gell-Coombs)

Exogenous or endogenous antigens react with sensitized T ly m phocytes and a

delayed allergic reaction occurs 24-48 hours after reexposure.

a. delayed reaction of eczema type d evelops after the contact of the skin wi t h

allergens, in 2 stages:

81

Induction o f sensitization. Small m o l ecules (nickel, cobalt or d i c h r o mate) art,

called haptens or incomplete antigens because they have to be conjugated tto
epidermal proteins to form f ul l antigenic structures. These antigens are take<
up and processed by antigen-presenting Langerhans cells that migrate to tpe
regional l y m p h n o d e . A n t i g ens ar e p r e sented t o t h e T ly m p h o c ytes
s
conjunction with class II histocompatibility antigens (HLA-DR). As a responseI
T lymphocytes proliferate to form antigen-specific memory T cell clones, unde>
the control of the suppressor cells. The induction of sensitization to a contag
allergen takes 5 to 7 days and, once realized, it is long lasting (years, decades

or life-long).

Reaction phase. In a sensitized person, re-exposure to very low concentrations of q

specific allergen stimulates memory T c el l c l ones that p r o liferate and r eap,
Various cytokines (IL-2, IFNs etc) will be released at the site of the contact with
a llergen, leading to eczema type reaction w it h i n creased permeability o f + t

vessels, lymphocytic exocytosis and epidermal spongiosis followed by interstitial)

vesiculization. The clinical manifestations appear 24-48 hours after re-exposur
xpos\Q'q
and represent allergic contact dermatitis.
b. D e layed reaction of tuberculin type occurs when the antigens enter the skin
through vascular system. They r eact w i& . p r eviously sensitized ly mphocyte~

which release lymphokines and lymphotoxins, leading to an inflammatory cellul@

reaction with vasodilatation, increased permeability, edema and the clinical aspeg
of allergic exanthems (morbilliform, scarlatiniform, rubeoliform drug reactions,

fixed drug reactions).

URTICARIA
Urticaria is a h eterogeneous group of d i s eases with a c o m mon s kin r e action
pattern, i.e. the development of skin urticarial lesions (wheals/hives) and/or angioedema.
The typical features of wheal:
a central swelling of variable size, white to pink, with smooth surface, well defined'

borders, almost invariable surrounded by a reflex erythema (Fig.8.1)

associated with itching or burning sensation
a fleeting nature, with quick development (within minutes) and complete resolutios

within 24 hours (generally 2-8 hours).

There are several clinical variants of wheals, sharing the typical features:
erythematous plaques (urticaria rubra) due to the vasodilatation (Fig.8.2)

pale plaques (urticaria porcellanea) as a result of edematous compression of th<

surface blood vessels(Fig.8.3)
small, papule-like lesions (pseudo-papular urticaria)
palm size or larger lesions (urticaria gigantea)
joined wheals with policyclic borders (urticaria circinata)
annular configuration with healing of the center (urticaria annularis - Fig.8.4)
If the wheals remain fixed for longer than 24 hours, the diagnosis may be urticari

vasculitis (Fig.8.5,type III hypersensitivity reaction) or bullous pemphigoid (autoimmune<

disease).
82

Angioedema (Quincke's edema) is a deeper form of u r t icaria, characterized by

~den pronounced localized edema of the lower dermis and subcutis. The edema is not

en

haply delimited, it is nonpitting, sometimes painful rather than itching and its resolution

he

~ fake up to 72 hours (Fig.8.6).

Angioedema is most apparent in the head and neck (face, lips, floor of the mouth,

se,
ler
let

les

fa

+ e and l arynx), external genital organs, hands and feet. In advanced cases it can
tongue
<ass to complete airway obstruction by laryngeal edema and death. It may also
proP
,nvo
nvp]Qe
v the gastro-intestinal tract, with edema of the intestinal wall leading to colicky
bdorninal
pain, nausea, vomiting and diareea.
a
Classification of urticaria
Spontaneous urticaria:

Lct,

the
the
tial
1re

Acute spontaneous urticaria: up to 6 weeks of wheals/angioedema;

Chronic urticaria: continuous/recurrent episodes of wheals/angioedema over a 6-week

period.
Inducible urticaria

Q1l

tea

Phisi cal urticaria (defined by the triggering stimulus):

Dermographic urticaria (urticaria factitia) (Fig.8.7) - rubbing or writing

on the skin, induced by mechanical share forces that produce an initial red

line (capillary dilatation), followed by broadening erythema (axon-reflex

arteriolar dilatation) and the formation of a linear wheal in 1-5 minutes

(transudation of fluid/edema) termed the triple response foLewis. The

lesions are intensely pruritic.

Simple dermographism, without pruritus, appears in about 5% of

healthy population and i s c onsidered an exaggerated physiological

Lan

response.
White dermographism is a misnomer (false dermographism, not
urticaria), in f act a b l anching response to skin s troking explained by
capillary vasoconstriction. It is more pronounced in persons with atopy.
Cold contact urticaria - wh e aling w i t h in m i n u t es of rewarming after
cold exposure. It can be elicited by r a i ny, w i nd y w e a ther or c ontact
with cold objects; can be congenital, or associated to cryoglobulines or
cryofibrinogen. Cold u r t i caria r equires HC V d e t ermination, because
c ryoglobulins ar e i n d i r ect m a r k er s o f h e p a t i ti s C . S w i m m i n g o r

red

ion

jumping into cold water may be particulary dangerous, resulting in

anaphylaxia.

Heat contact urticaria - elicited by localized heat

Solar urticaria e licited by U V a n d / or v i s ible l ig ht; w h e als on s u n
exposed areas, in up to 30 minutes after exposure
Delayed pressure urticaria wheals within 3-12 h latency elicited by sustained
pressure under the waistband of tight clothes, under the elastic part of socks,
on buttocks sitting for a long time, feet in tight shoes, soles after prolonged
walking or climbing a ladder;

Vibratory urticarialangioedema - elicited by j o gging or t he u se oi

vibrating machinery e.g. pneumatic hammer, lawn mowers, motorcycles.

Special types of urticaria:

Aquagenic urticaria - elicited by water

Cholinergic urticaria elicited by increased body temperature due g

physical exercise, elevated environmental temperature (warm bath), fever<
emotional stress or eating spicy f o od; i t

i s d i s t inctive clinically witi

multiple, transient, small (2-3 mm) papular wheals, surrounded by @,

obvious flare
Contact urticaria elicited by contact with urticariogenic substances

Classification of angioedema:

allergic angioedema often associated with urticaria

drug-induced angioedema (non-allergic angioedema) due to A CE inhibitors, Dpi

associated to urticaria

aquired angioedema (AAE) - rare

o a ssociated w it h l y m p hoproliferative diseases of
consumption of C1-inhibitor)
o

B ty p e ( i n creased

a u t o i m mune process (auto-antibodies against the C1-inhibitor)

heredita~ angioedema (HAE) rare, inherited, autosomal dominant, deficiency of thy

C1-esterase inhibitor
The deficiency of th e C1-esterase inhibitor of t h e c omplement system allo<vs
u ncontrolled activation o f t h e c o m p lement cascade w it h t h e release of k i n i n-like
mediators. Increased vascular permeability results with subcutaneous and mucosal edem,

AAE and HAE are nonhistaminergic angioedema and are no longer considered subtype>
of urticaria, due to their different pathomechanisms.

Pathogeny of urticaria/angioedema
Allergic urticaria (20% of cases):
o I g E-dependent (type I hypersensitivity reaction)
o a u t o immune mechanism: autoantibodies against IgE or IgE receptor (iD
chronic urticaria)

Non-allergic urticaria (80% of cases): direct mast cell degranulation by alterin[

membrane properties and secondary release of histamine, i n d uced by radiocontrast

media, drugs (agiotensin-converting enzyme i nhibitors, aspirin, AINS), fool

preservatives and food (fish, sea fruits, all types of berries, red wine)
Treatment
Patients should be informed that usually the disease has a self-limiting duration.
E tiologic therapy attempts the removal of t h e eliciting f a ctors, w h enever

identified. History should focus on medications (aspirin, NSAID, angiotensin-converting<

enzyme inhibitors), food allergens (animal proteins: meat, milk, eggs) and foo|i
pseudoallergens (fish, seafood, strawberries, nuts and food additives like tartrazin<,
sodium benzoate), contactants (latex, medication, tomato, plants), infections (bacterisi

infections of the nasopharynx, H.pylori, bowel parasites), exposure to arthropods, physicsi

precipitants (pressure, cold, sun, water), and family history. Acute spontaneous urticaria i~
84

se oI

usua> ycaused by food and drugs, while chronic spontaneous urticaria may be associated

:les,

tpgronune disorders (e.g., systemic lupus erythematosus).

to autoi
Symptomatic therapy is aimed at palliation of pruritus and discomfort, by:
1. First hne therapy n on-sedating anti-H1 antihistamines (compete with histamine for
histamine receptor, reduce vascular permeability): l oratadine (Claritine),

ue t0

desloratadine (Clarinex, Aerius), fexofenadine (Telfast, Allegra), cetirizine (Alerid),

levo-cetirizine (Xyzal), ebastine.
Second line therapy: The dose of non-sedating antihistamine may be increased up to 4

feve,
Wlg

times.
Classic, traditional anti-H1 antihistiamines may be associated in the evening, for
sedative a n d
an t i c holinergic e f f ects. T h ese a r e hy d r o x y zine ( A t a rax)

promethazine, dyphenhydramine (Benadryl),

ethylenediamine, propylamine and phenothiazine.
I10f

3 Third-line therapy (drugs added to H1 antihistimies):

leukotriene receptor antagonist (LTRA) Montelukast
Ciclosporin in severe disease, refractory to an y d ose of antihistamine; high
incidence ofadverse effects
Q malizumab IgG monoclonal antibody that inhibits IgE from binding to t h e
surface of basophils and mast cells; this removes and deactivates free circulating
IgE, preventing the activation of basophils and mast cells

ec5$$

of the
~liow~
.n-jil(e

den
)types

c l o r pheniramine, a l k y lamine,

oral glucocorticoids should be administered only in short course (3-7 days): for
exacerbations of chronic urticaria unresponsive to H 1 a n f i histamines. Topical
glucocorticosteroids are not indicated in urticaria.
Phototherapy UV-B and UV-A for 1-3 months lowers the number of mast cells in
the upper dermis; indication: chronic urticaria and symptomatic dermographism
induction of tolerance in cold urticaria, cholinergic urticaria, solar urticaria (UVA treatment), physical urticaria
4. Local treatment only achieves some symptomatic relief of pruritus using antihistamincontaining lotions or gels, alcoholic solution with menthol 1%.
Anaphylaxis is a "serious allergic reaction that is rapid in o nset and may cause

terin)
intr@I

foo<

death. Anaphylaxis typically involves multiple organ systems. The signs and symptoms, in
order of frequency, are:
cutaneous: flushing, pruritus, urticaria, angioedema
respiratory: nasal congestion, rhinorrhea, throat pruritus, laryngeal edema,

choking, wheeze, cough, dyspnea

gastrointestinal: cramping, abdominal pain, nausea, emesis, diarrhea
cardiovascular: dizziness, tachycardia, hypotension, collapse
other: anxiety, mental confusion, lethargy, seizures
The emergency treatment in anaphylaxis:
First line therapy:

ion.

weve
ertisf
foo<

cter>a

lysi<>
.ariaI'

v'

0 . 5 ml of epinephrine intramuscularly in the anterior-lateral thigh; may need

to be repeated every 5-15 minutes

Adjunctive therapy:
85

i . v . soluble glucocorticoids (hemisuccinate) are indicated up to 1000 mg, 0,

metilprednisolon 60-80 mg; further oral treatment with 40-80 mg prednisoloqp
o b r onchodilator ( P2-agonist): albuterol nebulised solution every 20 minutes 0,

continuously when brochospasm appears

o

H 1 a n t ihistamine(diphenhydramine) 50 mg i.v. or oral solution; alternate<

second generation less sedating antihistamine

o H 2 a ntihistamine (Ranitidine) 75-150 iv

Additonal steps
o p l a ce the patient in recumbent position if tolerated, with elevated lower legs

o o x ygen therapy
o i v fl u i d s in large volumes (volume resuscitation)
o p r o m p t transfer to an acute care facility

DERM A TITIS OR ECZEMA

Dermatitis (Anglo-American term) and eczema (in Europe) are synonyms used tp
pru r i t i c noninfectious
describe e p i dermal i n t o l erance r eaction o r

infl
ammatory

dermatoses. They are extremely common (in 15-25% of all patients with skin diseases).
Classification
a. Ac c ording to the clinical aspect and evolution:
o Ac u te e czema:erythematous plaques unclearly d e marcated, with o o z in~

surface and covered with vesicles (Fig.8.8). Histology shows spongiosis with
o

formation of interstitial vesicles.

Su b a cute eczema:after the acute phase the oozing diminishes, the lesion i

covered by crusts. Histology shows acanthosis and parakeratosis.

o

Ch r o nic eczemais c h a racterized by s c a les and l i c h enification ( F ig.8.9),

Histology s h o w s a c a n thosis, hyperkeratosis w i t h pa r akeratosis an<
inflammatory inflltrates in the dermis.

b. Ac c ording to the etiopathogenesis,

eczema can be exogenous, endogenous and mixt

Contact dermatitis/eczema (Exogenous eczema)

There are two types of contact dermatitis:
a. Irritant (toxic or orthoergic) contact dermatitis is a nonspecific inflammator)t
response of the skin to agents that cause direct skin-damage in all persons, without T-cell
immunity involvement. The lesion has sharp margins, according to the contact area and

healing starts promptly when the offending agent is withdrawn (Fig.8.10).

Clinical forms:

acute: appears after a single exposure to corrosive agents that cause immediatt.'
death of e p i d ermal cells, destroying th e b a r r ier f u n c tion o f t h e s k in , e.g.

physical (UV, X-rays) or chemical irritants (alkaline/acid solutions, organi(

I
solvents)
cu mu l a t i v e e ffect o f r e p e ated e x p o sures t o l o e
concentration of contact irritants (water, soap, detergents causing "housewife'~
eczema", organic solvents, w o un d s e cretions, amm oniac i n u r i n e c a usin)
chronic: a p pears by a

diaper dermatitis)

31re

p, Allergic contact eczema: is a T-cell immune response of delayed type resulting

~ cutaneous contact with an allergen to which the patient has previously developed a
e<fic sensitivity. After the allergen contact the skin for the first time sensitization is
speci
.duced
within 5-7 days (induction phase). Lesions occur 24-48 h hours after a subsequent
u
ntact (reaction phase). They tend t o

s p r ead ar ound th e c ontact area and a lso on

cbstant body regions (Fig.8. 1 1 ), because the contact allergen is transported through the
blood to o t her a r eas o f t h e s k in , w h e r e i t e n c o unters sensitized T - l y m p hocytes.
Memory T cells persist in the dermis even after allergic contact dermatitis clinically

resolves
The causes of contact allergic reactions include nickel (Fig.8.12; earrings, necklace,
etc)' chemicals in rubber gloves; dyes added to textiles; fragrances; topical corticosteroids;
topical antibiotics: neomycin.

Atopy and atopic eczema (Endogenous eczema)

Atopy is a t endency to develop specific allergic disorders like atopic eczema,
Btp

tory

.11lg

vith
n lI

8.9j.
arrd

allergic bronchial asthma, hay fever, allergic rhinitis and allergic conjunctivitis, due to a
genetic predisposition to increased production of IgE immunoglobulins.

Atopy is characterized by a v ariety of i m munoregulatory and skin barrier

abnormalities:
increased serum level of IgE and specific IgE to foods, aeroallergens and bacteria
deficient c h emotaxis o f
t he ne u t r o phil s a n d ma c r o phages c ausing f r e quent
staphilococcal, viral (e.g. eczema herpeticum) and fungal infections;

T-helper 2 (Th2) immune response is activated, with increased type II cytokine

response (IL-4, IL-5, IL-10 and IL-13) and T-helper 1 (Thl) response is inhibited with
decreased type I cytokine response (IFN-y). IL-4 and IL-5 stimulate B lymphocytes
which produce elevated IgE levels; IL-10 and reduced IFN-y i n hibit d elayed-type
cellular immune response, explaining f requent staphylococcal, viral ( e.g. eczema

herpeticum) and fungal infections

defective lipid (ceramide) production in the epidermis results in xerosis and then
deffective barier function with increased entry of antigens
tOIy

Clinical signs of atopy: pale, dry skin (xerosis), dry hairs, dry and fissured lips,
keratosis pilaris, Dennie-Morgan folds (increased folds below the eye), hypersudoration,

-cell

low skin temperature, recurrent keratoconjunctivitis, cataracta, white dermographism,

aIlCl

poor response to i.d. histamine, irritability.

Urticaria and acute anaphylactic reactions to food (peanuts, eggs, milk, soy, fish,
and seafood) occur with increased frequency in patients with atopic dermatitis.

iate

e,g
%111C

low
ife'>

Clinical manifestations of the atopic dermatitis

Intense pruritus and dry skin (xerosis) are the hallmark of all stages. The pruritus
Is worse at night and the skin shows eczematous changes and lichenification with location

and morphology that change with age.

Infantile atopic dermatitis b egins a bout t h e 3 r d mo n t h o f l i f e w i t h pr u r i t i c
e rythematous plaques, vesicles and scales (eczematous) that are ill-defined on t h e
cheeks, scalp and extensors of the lower legs, with sparing of the napkin area. The
Itching i s v ery i n tense, interfering w i t h t h e s l e ep. Scratching i s f o l l o wed b y
87

superinfection. The lesions may gradually heal up to 2 years or may be followed b>
atopic eczema of the childhood.

2. A t opic eczema of th e c h ildhood can e i t her d e velop f r o m t h e i n f a ntile a top<

dermatitis or appears in children after the age of 2 to puberty. As a result of chrorri<
rubbing an d s c ratching, th e l e sions become l i chenified ( t hickened) w it h l i n e@
excoriations. The distribution of the lesions changes from the extensor surfaces to th~
flexures, particular antecubital and polpliteal fossae (Fig.8.73). Eyelids, ear lobes, tir~
nape of the neck, dorsum of the feet and hands may also be affected.
3. A t opic eczema o f

t h e a d u lts s t a rts a t p u b e r t y. T h e s k i n i s dr i e r a n d t h ~

lichenification is more intense. The lesions may be symmetrical or localized to sorrr<

predilection sites (circumscribed neurodermitis) (Fig.8.9). Flexural folds are aisp

involved in adult stage, along with the face, eyelids, upper arms, back, dorsa of thq
hands, fingers, feet and toes. Chronic hand eczema might be the only manifestatjprr
of adult atopic dermatitis.
The condition is worsened by sweating, contact with organic solvents and wool.
Complications in atopic dermatitis:
bacterial infections: impetiginization, staphilococcal infections
viral infections: eczema herpeticum, warts, molluscum contagiosum

fungal infections: chronic persistent trichophytosis

occupational irritant contact dermatitis of the hands (hand dermatitis) is very common
in atopic patients, favored by water, detergents, solvents; the skin of the hands is dq
and thickened
erythroderma
frequent drug sensitisation

Mixt Eczema (Exo-/Endogenous)

Some types of eczema occur in persons with a tendency to react with allergi<
manifestations to exogenous/endogenous antigens. These forms of eczema are chronir,,
relapsing, may disseminate at some distance where similar eczematous plaques appear
and may lead to erythroderma.
Nummular eczema
It i s m o r e c o m mo n i n me n , m o s tl y b e t w een 5 0-70 y ears, p r esenting @
disseminated round-to-oval, usually sharply d emarcated, "coin-shaped"

erythem
atous

lesions, with overlying scaling (Fig.8.14) or oozing with crusting. The lesions art

distributed symmetrically on the legs, but they may occur on the trunk, hands or feet. Tirr,'
sharp margins make them look like psoriasis, while central clearing makes the clinic<i
differentiation from tinea corporis difficult.
Focal infection can be associated (chronic tonsillitis, chronic prostatitis, intestinal

dismicrobism, H.pylori gastritis); venous insufficiency and stasis dermatits could explaIrr
the envolvement of the lower legs.

Dyshidrotic eczema (Pompholix)

It is recurrent palmo-plantar vesiculous dermatitis.
The etiology is b elieved to b e m u l t i factorial, related to v a r i ous endogenou~
conditions (50% of c ases associated w it h a t o pi c d ermatitis) an d e x ogenous factor~

88

drugs, bacterial o r

~pic
)ltd
lQ@

thy

f u n gal a n t igens through a d e l ayed t y p e c el l m e d i ated

action),
Fungal infection of th e f eet can cause palmar p ompholyx an d a n t imicotic
reac
1
eatrnenf of the primary site resolves the recurrences. Emotional stressexacerbates
trea

Jyshidrotic eczema.
It js characterized by crops of vesicles and/or bullae located strictly on the hands
d feet (lateral aspects of the fingers/toes, palms and soles, sometimes extending to the
p>ck of hands and feet) that will ti pically resolve with desquamation and no rupturing

(F;g 8 15, 8.16). Burning pain and intense pruritus are associated. Dyshidrotic eczema may
thy
)I@a

also

the

tie

disseminate on the trunk or face (id reaction).

Stasis dermatitis (gravitational eczema, varicous eczema)
It occurs mostly after the age of 50 on the lower extremities in patients with venous
hypertension and edema du e t o c h ronic venous insufficiency, heart failure or o t h er
conditions that cause swelling in the legs.
Stasis dermatitis starts at the medial ankle and gradually involves the lower leg up
to the knee. Itching then vesiculous, oozing erythematous plaques are the first signs
(Fig 8.17), later lichenification and hyperpigmentation secondary to scratching. Edema is
resent at the beginning, but in chronic cases of stasis dermatitis, there is gradual

<suan p
non

cia

tightening and sclerosing of the skin. Dermal fibrosis is the hallmark of advanced stasis
dermatitis. In severe cases, the skin breaks down with oozing, crusted areas and ulceration
which may heal with shiny scars or complicate with superintection.
O ther ty pes o f a l l e rgic d e rmatitis ma y a s sociate, l ik e s ensitisation t o t h e

microorganisms present in the venous ulcer (microbial eczema) and/or to the drugs used
topically on the ulcer (allergic contact dermatitis).

Id reaction (autoeczematization)
Is a generalized acute allergic reaction to intense inflammatory diseases of the skin

.rgic
mic,

pear

a5
too5

are
The
ical

caused by fungi (dermatophyte, candida, bacteria) or some antigen created during the
inflammatory processes.
Id r eaction o c c urs 1- 2 w e e ks a f t er t h e p r i m a r y i n f e c t ion o r d e r m a t i t i s
exacerbated due to infection, scratching or innapropriate treatment. The eruption has
acute onset at distant sites from the primary in fection, is symmetrical and extremely
p ruritic, with m a culo-papular o r p a p u l o -vesicular lesions. The i n f ectious agent i s
absent in the id lesions. It resolves as the inflammation that initiated it resolves.
Etiology of id reactions:
stasis dermatitis id reaction on the forearms, trunk and/or face (Ftg.8.18, 8.19)
allergic contact dermatitis id reaction at long distance from the contact area (Fig.8.12)

inflammatory tinea pedis id reaction on the sides of the fingers (pompholyx)

kerion id reaction as symmetrical small follicular papules on the upper trunk

final
)laia

ioU5

tof5

Microbial eczema (infective eczema, paratraumatic eczema)

It is provoked by the superantigens of staphylococcus aureus and streptococcus on
t"e skin. Area of advancing erythema with microvesicles is seen around infected wounds,
Ulrs, bacterial dermatoses, scars (Fig.8.20). Superantigens can activate multiple clones of
lymphocytes, even without prior senzitisation.

Microbial (infective) dermatitis should be distinguished from infected eczema

( erna complicated by secondary bacterial or viral infection).
89

F'

Seborrheic dermatitis
Seborrheic dermatitis needs three factors to develop: individual susceptibility
sebaceous secretion and the yeast Malasseziafurfur.
Seborreic dermatitis exhibits erythematous patches with greasy flakes on the scalp,

ears, eyebrows, nasolabial folds and the middle of the chest, with itching (Fig.8.21,8.22)
Dandruff is a m i l d f o r m o f seborrheic dermatitis, presenting with small w h ite fl akes
confined to th e scalp, w it h o r w i t h out i t ching. Seborrheic dermatitis is w orsened ~

neurological disorders (Parkinson disease, polynevritis), HIV infection, obesity, emotional

stress, myocardial ischemia.
In neonates, seborrheic dermatitis manifests with redness and greasy scaling o~
the scalp and folds during the first 3 months of life. It may complicate with erythroderrnia
desquamativa (Leiner's disease) that associates fever, diarhea and anemia.
Asteatotic eczema (eczema craquele)
It is f avored by x e rosis, decreased sebaceum and sweat secretion in e l derly
personsI excessive use of soaps that reduce the normal cutaneous hydro-lipidic film,
degreasing agents (solvents, cieansers), diabetes mellitus, hepato-renal conditions oy

cancer. Pruritus is the first clinical sign, cracks and polygonal fissures appear on the shins,
I
arms and back of the hands (Fig.8.23), redness, and scales.

Treatment of eczema
Exposure to trigger factors has to be reduced in atopic dermatitis: detergents,
soaps, toiletries containing alcohol and astringents, extreme temperature changes, stress,

infectious agents (staph.), intense activity (sweating), irritant clothing (wool), food (peanut
butter, eggs, fish and seafood, milk, soy and chocolate), aeroallergens (e.g.dust mites,
animal dander) and contact allergens.
Preventing and treating xerotic skin is important in atopic dermatitis to reduce
itching and th e f r equency between the fl ares. Restoring the cutaneous barrier with
ceramid-containing creams is particularly helpful i n i r r i t ant contact dermatitis, also.

Soaps and detergents should be replaced with syndets (like Dove, Neutrogena, Eucerin
etc) that have a pH similar to the skin (approx. 5.5). Bathing daily in lukewarm water
with mild, unfragranced cleanser should be immediately followed by application of
moisturizers/emollients (e.g. Trixera, Atoderm) to m a x i m ize m oisture retention and
I
provide a barrier to irritants, pathogens and antigens.
Topical treatment
In acute eczema or acute flares of atopic dermatitis topical therapies targeting the

immune system dysfunction are the mainstays of treatment.

Wet dressings with mild antiseptics (kalium permanganicum 1/10.000, zinr

sulfate 1/1000, silver nitrate 1/6000, or in v er y sensitive patients NaCl solution) ar<
recommended for oozing lesions. Besides being antiseptic, wet dressings also reduce
inflammation b y v a s oconstriction du e t o t h e c o o l in g e f f ect an d b y m e c h anically
removing the bacteria.
in
ec z e m a ar e topical
Topical
i m mu n o m o d u lators recommended
corticosteroids (TCSs as first-line treatment) and topical calcineurin inhibitors (TCIs).
Topical corticosteroids exert anti-inflammatory and immunosuppressive effects
through regulation of

p r o i n flammatory cy t okines and cells. The potencies of TCSS

90

<ge from very mild to very strong and they are chosen according to the severity of
rang
the d]sease and th e

Lp,
2),
'es

a r e a o f t h e b o d y t h a t i s a f f e cted. C l o betasol p r o p i onate

(perrnovate) is a potent formulation, mometason furoate (Elocom), methyprednisolon

eponat (Advantan) and hydrocortison butirate (Locoid) have medium activity and
acepo
hydrocortisone
h
ro
is th e w e akest TCS. The l o n g -use of T CSs (m ore t ha n 3- 4 w e eks
<ontinuously applied) is limited by the cutaneous side effects:
cutaneous atrophy after potent formulations

ial

striae, skin fragility

on

steroidic purpura on the arms, legs; telangiectasia most striking on the face,
after fluorinated formulations (Fig.8.24)
steroid acne, steroid rosacea (Fig.8.25) and perioral dermatitis are induced or

aggravated
hypertricosis
rly
or

microbial, viral and fungal infections are favoured through depression of the local

immune response
healing of the wounds is suppressed by inhibition of the collagen synthesis, thus
dermatocorticoids applied on the ulcers will increase their depth (Fig.8.26)
S ystemic side effects like suppression of th e h y pothalamic-pituitary axis w i t h
ibition of growth in children may appear after potent TCSs on more than 30% of the

body surface,
for long periods.
its,
'.Ss,

rut

Tar (coal tar, ichtiol, oleum cadini) can be associated to topical steroids as it

decreases inflammation, especially in t hickened, scaly plaques (e.g. Flumethasone

es,

pivalat with coal tar - Locacorten tar). When lichenification appears dermatocorticoids
are applied u n d e r oc c l u siv e d r e s sings o r dep o t co r t i c o id s ( m i c r o cristalline

lee

triamcinolon - Volon A, bethametasone diproprionate - Diprophos) are infiltrated

sublesionally.

ith
SO,

ter

of
nd

Topical calcineurin inhibitors block the inflammatory cascade produced by the

pathologic T cells in the skin, preventing expression of proinflammatory cytokines and
t he proliferation o f T c e l l s . T acrolimus 0 .03% an d 0 .1% o i n t ment ( P r otopic) an d
Pimecrolimus 1% cream (Elidel) are now available. They are indicated as continuous
followed by non-continuos treatment in chronic eczema to reduce the incidence and
severity of flares and prolong the time between flares. The most common side effects
are stinging, burning or itching immediately after application.
Systemic treatment
Oral corticosteroids are used for short periods in severe flares of acute eczema if
the topical treatment is not efficient or in widespread eczema.

Systemic antibiotics are generally used in superinfected eczema, and also to

tee

.lly
cal

cd
'.Ss

eliminate bacterial superantigens that cause the flares of the microbial eczema. Antibiotics
he no effect without the clinical evidence of infection. Only l a boratory evidence of
Saeus without c l i nical m a n ifestation i s n o t e v i d ence of clinical i n f ection, since
aphylococcal organisms commonly colonize the skin of patients with atopic dermatitis.
H1 antihistamines of sedative type reduce the pruritus.

UV light (UVB and PUVA-therapy) help reduce inflammatory activity in the skin
(ibits Langerhans cells and lymphocytes).
Ciclosporin, azathioprine, metotrexate can be recommended in very severe cases.
91

PRURIGO
Prurigo is a severely itching skin condition characterized by dome-shaped papule,
topped with a small vesicle. The vesicle is transient because it is immediately removed p
scratching, so that a crusted papule is more frequently seen.

>
I

Acute prurigo of childhood (strophulus infantum)

It appears in children of 2-8 y ears, predominantly i n

s u m mer an d f a ll, as ~

recurrent reaction to insects, with severely itching seropapules of 1-2 cm on the limbs ~d

trunk. When bulla is formed, prurigo is called strophulus bullosus (Fig.8.27). Aft',
causes
s cratching, h a r d , e xcoriated a n d cr u s te d p a p u l e results. S u perinfection
impetiginization. Depigmented and hyperpigmented spots result after healing.
Treatment: adequate room desinsection or admission to a clinic will lead to heal~~
in most cases. Sedative oral antihistamines, topical powder or zinc lotion can result.

Subacute prurigo
It is a chronic inflammatory dermatoses encountered more frequently in wome~
between 20-30 years of age. Insects seem to play no role. It is frequently associated with:

diabetes mellitus (prurigo diabetica)

pregnancy {prurigo gestationis)
liver diseases (prurigo hepatica)
menses (prurigo dysmenorrheica)
hormonal influences (contraceptives)
gastrointestinal disorders (hypoacidity, chronic gastritis, enteral candidiasis)
focal infections
Clinical findings: symmetric papulo-vesiculous lesions on the extensor surfaces Of
the extremities, upper part of the anterior and posterior thorax. Atrophic scars result,

hyperpigmented or more often depigmented and surrounded by hyperpigmentation.

Chronic prurigo
It is described as multiple, intensely pruritic, excoriated nodules, erupting on thr
extensor surfaces of the limbs secondary to itching or rubbing. The individual lesions art.'
generally symmetric, 3-20 mm, firm, erythematous or brownish papules or nodules that
evolve slowly (F ig.8.28).The pruritus is characteristically p a r oxystic: i n termittent,
unbearably severe and relieved only by scratching to the point of damaging the skin, with

bleeding and scarring.

The cause of prurigo nodularis is not known, but multiple factors are supposed to
contribute: atopic dermatitis, anemia, hepatic (including l i ve r C i n f e ction) o r r ene~
dysfunction, l y m phoproliproliferative diseases, p s y chiatric c onditions, H I V
immunodeficiency conditions. The majority of patients have a positive history for atop)'

(atopic dermatitis, asthma, hay fever).

Treatment is challenging, as lesions may not heal completely. The treatment 0~
choice is i n t r alesional o r t o p i cal ( u n d er occlusive d ressing) corticosteroids. Oth
treatments are: PUVA ( p soralen+UVA) o r c r y o therapy. Systemic treatment i n cludt'~
antihistamines, antidepressants, anxiolytics, Dapsone, Thalidomide.

92

DRUG ERUPTIONS
The undesirable side effects of the drugs can mimic a wide range of derrnatosis. A
r eactiorl should be considered in any patient who is taking medication and wh o
drug rea
d denly
develops a symmetric cutaneous eruption. Medications that are kn own f o r
sud
e
aa a

and
kfter
l13ea

sing sidn reactions more frequently are antimicrobials, non-steroidal antiinflammatory

causing
s (NSAIDs), cytokines, chemotherapeutic agents, anticonvulsivants and psychotropic
drugs

agen s. Drug eruptions may be produced by i mmunological or nonimmunological

rocesses. Immunosuppression due to HIV i n creases 10-fold the risk of d rug eruption,
process
including severe reactions.

Immunologically mediated d r u g eru p t i on s a r e non - d os e r e l a ted and

unpredictable; they are classified in 4 groups (Gell and Coombs):
Igp dependent reactions (urticaria, angioedema, anaphylaxis). Anaphylaxis combines
(urticaria, angioedema) with systemic manifestations such as hypotension and
metr
'r:

tachycardia and in severe cases cardiovascular shock with death. All these types of
reactions appear within minutes after drug administration, faster and more frequently
after parenteral drugs as compared to oral ingestion. Anaphylactoid reactions, as seen

with radiographic contrast media, may mimic clinically IgE-induced histamine release,
but are secondary to a non-immunologically release of histamine.
cjtotoxic reactions (the drug antigen is fixed on some cells, antibody-antigen reaction
activates the complement and cytolysis results) e.g. hemolytic anemia after penicillin

therapy, post-drug purpura

une complex reactions: serum sickness syndrome caused by treatments with
as Ot

.suit,

heterologue serum or depot penidllin; leukocytodastic vasculitis (Fig.9.29) that appears 721 days after the onset of therapy, with red macules quiddy followed by palpable purpura
and hemoragic vesicies associated with constitutional symptoms (fever, arthritis)

delayed hypersensitivity reactions: allergic contact dermatitis (after topical use of

neomycin, rivanol, antibiotics), exanthematous reactions, photoallergic reactions (after

doxicycline); they begin 7-20 days after medication is started.

a are
tent,
with

Non-immunological drug reactions are dose-related and predictable and are called

side-effects:
d yschromia: argyria blue-gray d i scoloration o f s k i n a n d n a i l s d u e t o s i l v e r
treatments; brownish colour caused by antimalarics, melasma caused by estrogens

direct degranulation of mast cells (opioids, contrast substances)

enar
tOIrIr
xt or
tther

ader

anaphilactoid drug reaction after aspirine (affects the arachidonic acid metabolism

resulting in synthesis of leucotriens)

imbalance of the intestinal flora (candida infections after antibiotics)
m etabolic disorders (hiperlipemia and c u taneous xanthoma after t r eatment w i t h

isotrebnoin)
Herxheimer reaction due to bacterial endotoxins released from destroyed treponema;

symptoms resolve with continued therapy.

opecia after retinoids, antimetabolite chemotherapeutic agents (cyclophosphamide)
hypertricosis (minoxidil, fenitoin)
skin necrosis: cumarins (warfarin, heparin)
93

Clinical forms of drug eruptions

Acne caused or aggravated by lithium or corticosteroids

Drug-induced pemphigus: captopril and D penicillamine

Lupus like eruptions: hidralazine, penicilline, griseofulvin

Psoriasiform eruptions caused by betablocant drugs
Fixed drug eruption: recurs at t he s ame s ite ( fi x) a f ter e ach exposure to d r y )
(sulphamids, AINS, analgetics). One or a f e w c i r cular, red-violaceous, edemato~
plaques (sometimes with central bu lla) t hat t u r n t o b r o w n a f ter 3-6 w eeks ar<

characteristic (Fig.8.30, 8.31). Secondary hyperpigmentation lasts for months. Han@

feet and genitalia are the most common location, but oral, perioral lesions or on tg<
trunk can also appear.

Stevens-Johnson synd.rome (SJS) and toxic epidermal necrolysis (TEN or LyeII

syndrome) presenting with disseminated, large vesiculo-bullae with atypical targetpjf

aspect (2 zones of color), significant mucous membrane involvement with p ainful

erosions and ulcerations, constitutional symptoms. Stevens-Johnson syndrome can >q

caused by drugs and infections (especially Mycoplasma) and sloughing occurs on le%
than 10% of the body surface (Fig.10.13, 10.14, 10.15). TEN is due to drugs and is <
severe skin reaction that starts with painful skin then sloughing over more than 30% o(

the body surface area (Fig.10.16).

Erythema nodosum symmetrical, tender, bruise-like nodules, 1-10 cm diameter,
located on the anterior aspects of the legs; they last 1-2 weeks, then slowly involute
(Fig.8.32); it i s a r ea c t ive p r o c ess, often s e condary t o in f e c tion (s t reptococcu>,

M.tuberculosis), but also due to drugs (contraceptives, sulphamids), inflammatory

bowel diseases, sarcoidosis, pregnancy.
Livedo-like dermatitis (Nicolau) appears after an intramuscular injection (benzatin<
penicillin, NSAIs) that causes embolic obstruction of small arteries or arterial spasm. It
is manifested with intense pain and a livedoid patch with dendrites that ulcerates an(
heals in months.
Photosensitisation

o p h ototoxic reactions: usually predictable, appear in any persone who receive

a sufficient dose of phototoxic drug together with sufficient exposure to V~
radiation. Clinically they l ook l i k e exaggerated sunburns, limited to sun.
exposed areas, but a p pear a f ter a s h o r ter-than-expected exposure time,

Responsible drugs: tetracyclines (doxycycline), NSAIDs, fluoroquinolones,

o

amiodarone, phenothiazines.
p h o t oallergic reactions: cell-mediated hypersensitive reactions due t o N
radiation that converts the drug into a photoallergen. Clinically, the lesions ar<
p ruritic and resemble eczema or lichen planus. They appear initially on st .
exposed areas, then spread on non-exposed areas and tend to be more chroni<
than ph o t o toxi c r e a c tions. R e s p onsible dru g s : thi a z id e di u r e tic>
sulphonamide antibiotics, phenothiazines.

lrug
:ous
are
nds
the

Fig.8.1. urticaria

Fig.8.2. Urticaria rubra

Fig.8.3. Urticaria porcelanea

Fig.8.4. Urticaria anularis

Fig.8.5. Urticaria vasculitis

Fig.8.6. Angioedema

yell
toi(I

nhl

abc
less

isa
%oj
'ter,
lute
'Qls,

torl
itine

n. It
anti

ives
UV
iuG'

ime,
ines,

onir

)S

k,

'.tlesi

Fig.8.7. Dermographism

Fig.8.8. Acute eczema

95

Fig.8.9. Chronic eczema (neurodermitis)

Fig.8.10. Acute iritant contact

dermatitis to plasture

Fig.8.11. Acute alergic contact dermatitis

to topical NSAID

Fig.8.12. Acute alergic contact dermatitis

to nickel with id reaction

Fig.8.13. Atopic dermatitis

Fig.8.14. Nummular eczema

Fig.8.15. Dishidrotic eczema

Fig.8.16. Dishidrotic eczema

96

Ai!

i'
tT

Fig.8.18. Id reaction to stasis dermatitis

Fig.8.17. Stasis dermatitis

I
C

Fig.8.19.Chronic id readion mith

lichenification after to stasis dermatitis

Fig.8.20. Paratraumatic dermatitis

Fig.8.21. Seborrheic dermatitis

Fig.8.22. Seborrheic dermatitis

/
Fig.8.24. Erythema and telangiectasia
after fluocinolon

Fig.8.23.Asteatotic eczema

97

Fig.8.25. Steroidal rosacea

Fig.8.26. Superinfected steroidal ulcers

Fig 8.27. Prurigo strophulus

Fig.8.28. Prurigo nodularis

Fig.8.29. Leukocytociastic vasculitis

Fag.8.30. Faced drug reacbon

Fig.8.31. Fix drug reaction after Fenobarbital

Fig.8.32. Erythema nodosum

98

Chapter 9
DISEASES OI' CONNECTIVE TISSUE
The teim collagen diseases" was created by Klemperer in 1941. He observed that
in t e connective tissue of th e p atients w it h l u p u s erythematosus, scleroderma and
derirlatomyositis an eosinophilic homogenous substance is present. He called it fibrinoid"
because it was like fibrin. Later this group of diseases was called autoimmune, because of
the presence of autoantibodies in the serum.
Autoonmunlty is caused by loss of immune tolerance to self" (antigens of the
b dy) due to a genetic anomaly of the i m m une system or due to autosensitisation to
tiip dified self antigens transformed in n o n self" af ter contact with exogenous factors

(physical, chemical, microbial, viral).

LUPUS ERYTHEMATOSUS (LE)

There are two main forms of lupus erythematosus: chronic cutaneous and acute
systemic. Cutaneous form may progress in less than 5% of the cases into the systemic form.

Cutaneous lupus erythematosus

Chronic cutaneous LE (discoid LE) is a photosensitive autoimmune dermatosis
that produces scarring and atrophy. There is no visceral involvement and the serologic
abnormalities are uncommon.
The exact pathophysiology of CLE is not well understood. It probably occurs in

g enetically predisposed individuals, where a heat shock protein is induced in t he

keratinocyte following UV light exposure or stress. This protein may act as a target for the
T-cell mediated cytotoxicity.

Clinical findings
The most characteristic elements of chronic cutaneous LE are: erythema, scales and

scarring atrophy. The disease begins with persistent erythematous papules or plaques
(Fig.9.1) that are sharply delimited and raised (with palpable infiltrate). Then adherent
thick scales appear. The scales have characteristically carpet tack aspect, that describes
multiple small keratin plugs corresponding to the follicular openings (follicular plugging)
attached to the underside of scales. The lesions progress centrifugally and may merge.

solution of th e

a c t iv e l e s ion r e s ult s i n at r o p h y a n d s c a r r ing (F i g .9.2, 9 . 3).

Hyperpigmentation, hypopigmentation (Fig.9.4) and telangiectasia may associate in old
~eorLs leading to poikiloderma. The course is chronic, lasting for years to decades.
Most of the lesions are photodistributed on the face (often on the cheeks with
biittfly-shaped distribution; forehead, nose), on the ear, scalp, the V cf the chest, but they
cae also found on the trunk and extremities. The scalp is commonly involved and
Piiianent alopecia may result (pseudopelade-Fig.9.5). The vermilion of the lips is often
~ffected, with epithelial thickening, erosions.

99

There are two subsets of chronic cutaneous LE: localized on the head and neci,
and widespread on the trunk and limbs, regardless of whether lesions are seen on tg~
head or neck (Fig.9.6). The patients with l a t ter form o f t en have haematological any
serological abnormalities, are m o r e d i f f i cult t o t r e a t an d m o r e l i k el y t o d e v elop
systemic LE.

Clinical forms of chronic cutaneous LE:

di sc o id LE - low number of lesions with fix dimension and thick scale
centrifugal LE - many lesions with centrifugal spread and thinner scale
LE t u m i d us with edematous lesions and no visible scales
ver r u c ous LE wartlike lesions on the extensor arms

LE p r o fundus (lupus panniculitis) with painful nodules deep in the subcutis, th@

result in depressed scars

Complications of CLE are: inesthetic scars, mutilation (worm-eaten appearance 0~
the nose and ears), permanent alopecia and in time, squamous cell carcinoma.

Laboratory endings are usually normal, but AN antibodies can be found (10% pf
cases, mostly in disseminated forms) and anti-native DNA (dsDNA, in less than 5%, reflef

systemic LE).
Histopathology shows vacuolar alteration of th e basal cell layer, atropN
epidermis, hyperkeratosis and follicular plugging. Around the dilated blood vessels an<
skin adnexa dense lymphocytic infiltrate is present.
is
u s e d to
Immunhistopathology

confi rm

t he

disease.

Di r e f

immunofluorescence shows positive immunoglobulin IgG and complement deposits g

the dermal-epidermal junction i n b ot h l e sional and n o n-lesional exposed skin. Th
nonlesional and nonexposed skin i s n egative in i m m u n o histopathology in CL E but

positive in SLE (lupus band test).

Treabnent
Topical therapy is successful for small lesions. Sun-protective measures (protectiv
clothing including hats, broad-spectrum sunscreens and behaviour changes like limi~
sun exposure to mornings and late afternoons, avoiding sunbed use, replacing fluorescent

bulb with compact bulb) are essential. Smoking appears to worsen CLE.
G lucocorticoids ( t o pical, i n t r alesional) ar e t h e standard m e d i cal t h erap~,
Superpotent drugs and occlusion are used in hypertrophic lesions, medium-potent on th
face, foams on the scalp. The intralesional injection of corticosteroid crystalline suspensioo
=
(triamcinolone acetonide = Volon A, o r b e thametasone dipropionate Diprophos) t
effective but has the risk of cutaneous atrophy.
Topical calcineurin inhibitors are an alternative to topical corticosteroids, as thg'
do not result in skin atrophy, but the follicular plugging limits drug penetration and th
response in chronic lesions.

Superficial cryotherapy has also proved useful.

Systemic therapy

Antimalarial drugs (hydroxychloroquin-Plaquenil 200-400 mg/day or chloroquine

phosphate 250-500 mg/day) are recommended for several weeks to limit the effect of U>'
on the keratinocites. The most important side effects are corneal clouding and retinopath)
i
(ophtalmological checks are required before and during the treatment).
Systemic glucocorticoids are r arely e ffective, w h il e i m m u nosuppresants, lik
metotrexate, azathioprine and mycophenolate mofetil are more successful.
100

cia

he
ld

Dp

Systemic lupus erythematosus

TMs is a heterogeneous connective-tissue disease affecting several organs and
a ssociated w it h a u t o antibodies against n u clear a n t igens. I t a f f ects m o r e

sys
ffrequ
equently young women (men/women ratio 1 / 1 0).

The etiology is unknown. Interactions of genetic anomalies of the immune system and

tat
pn

expgen
xp<npus factors (UV radiations) are responsible for the disease. It is assumed that UV
ad,at pn dters the nat ve DNA in such a way that tl is recog e d as forelg and induces the
ra
fprrnatipn pf autoantibodies. Genetic T cell defects of the suppressor cells are responsible for
the fact that the B cells form autoantibodies in an uncontrolled way. The immune complexes
that are deposited in the vessel walls of the skin and internal organs activate the complement
resulting in immune complex vasculitis, nephritis, endocarditis and arthritis.

casca
de

Clinical findings
The patient, frequently a

y o un g w o m an, p r esents facial erythema, tiredness,

<eneral malaise, fever and swallen, painful joints.

Skin findings are present in only 80% of cases, the rest representing lupus sine lupo
(lupus patients without skin lesions). Symmetric diffuse erythema occurs on the face and
IUC

exposed areas of the chest (I'ig.9.7). There is a butterfly-like aspect on the face, with malar

Xld

ermnences and nasal bridge involvement. Morbilliform, scarlatiniform (Jig.9.8) or livedolike exanthems may develop on the trunk, patchy or diffuse erythema on the palms and
spies, felangiectatic blood vessels at the fingertips and along the nail folds, with subungual
hemprrhages, even gangrene and ulcerations due to th e angiitis. Skin lesions can be
transient for several days or weeks and they wax and vane in several hours with sun
exposure. The lesions are not scarring.
Joint in v olvement w i t h a r t h r algia an d p e r i p heral p o l y arthritis i s f r e quent.
Myalgias and polymyositis are signs of the muscular involvement
Renal involvement may exist in the form of focal nephritis, nephrotic syndrome,

:ct
at

'he
)ut

ive
Jlg
.nt

nephrosclerosis with hypertension, ending in renal insufficiency.

Involvement of other organs: pericarditis, endocarditis, polyserositis, polyneuritis,

uveitis, pneumonia, hepatospelnomegaly, aseptic bone necrosis.

Laboratoryfindings
ion

tg
the

|ne

'JV

non-specific changes:
o a n e mia, leukocytopenia, thrombocytopenia
o t h e ESR is significantly raised (100 mm/more in the 1s~ h)
o e l ectrophoresis sh ow s h y p o albuminemia, i n c reased a l ph a 2 gl o b u l ins,

hypergammaglobulinemia with polyclonal IgG

o t h e C-reactive protein and RF are frequently positive, immune complexes and
cryoglobulins can be present; the complement level is usually low
o p r o t einuria, hematuria and urine casts reveal nephritis
o f a l se positive serological syphilis reactions (VDRL, RPR) in 10% of cases, due
to antophospholipid antibodies responsible for thrombosis, fetal loss

immunological changes:
o

a n t i n uclear antibodies (ANA) positive in m ore than 95% of patients, but

non-specific for SLE; may be positive in 10-15% of healthy persons;

o a t b . anti-native double-stranded DNA (anti-dsDNA) very specific for SLE

101

o Sm

a n t igen, which is part of the RNAse-resistant fraction of the extractable

nuclear antigens (ENA) strongly specific for SLE

o

are neutrophili<
L E - cell p h e n omenon and L E -cell t e st . T h e L E ce l l s
granulocytes containing phagocytosed basophilic nuclear material resulted
from th e d e struction o f t h e n u c l eus b y t h e a n t i nuclear factors. LE-cell
material is ',
phenomenon is rosette formation, when th e a l t ered n u clear
surrounded by neutrophils
l u p u s band test is specific for SLE and demonstrates the deposition of IgG @
the basement membrane in unaltered skin which is not exposed to sunlight. g
diseased skin the test is positive in both systemic and chronic LE.

Course and prognosis

The formerly very poor prognosis, often with fatal outcome within a few weeks up
to 2 years, has improved since the introduction of corticosteroids.

Treatment
Systemic
Advise patients to avoid exposure to the sun.
Systemic corticosteroids are the mainstay of therapy for systemic disease. Initial]y

high doses are given (over 1g/kb/d, usually 100-150 mg prednisolone). After cutaneous,
clinical and paraclinical response (ESR) is obtained, the dose is carefully reduced to
individual maintenance dose that must be continued for years. Adverse effects of systemic
osteoporosis,
corticosteroids must b e a d d r essed: d i abetes mellitus, o steonecrosis,

hypertension, stigmata of Cushing syndrome, gastritis, gastric ulcer.

u s e d (azathioprine = IMURAN,
Additional
immun o s uppressives a re
cyclophosphamide) because of steroid-sparing effects.
Antimalarial drugs (hydroxichloroquine) also have steroid-sparing effects and are
used as first-line therapy especially in patients with skin lesions.

Intravenous IgG (0.5-1 g/kb/d for 4 days) have recently become important in
controlling recalcitrant disease.

Topical

UV sunscreens, topical c alcineurin i n h i bitors, c orticosteroids i n

ointments are used as an adjunct to systemic therapies.

creams or

DERMATOMYOSITIS
D ermatomyositis (DM) i s a systemic a u t oimmune

d i s order with s evere,

inflammatory myopathy and characteristic cutaneous involvement, but also with frequent
involvement of i n t ernal organs, mainly t h e p u l m onary, gastrointestinal and c ardi
systems. It occurs more often in 30-60y females.

Clinical findings

>

The skin symptoms are accompanied by muscle disease. In the absence of the s
involvement one speaks of polyrnyositis.
The pathognomonic skin lesions in D M

a r e t h e h eliotrope rash and Gottro~

papules. The heliotrope rash is a periorbital violaceous erythema with or without

ed'~

of the eyelids (Eig.9.9). Gottron papules are violaceous-red, flat-topped papules an

102

ues located over bony p r o m inences, particularly th e m etacarpophalangeal joints,

)Ie

4c
ell

terphalangeal joints, wrists, elbows and k ees

irtterp
Other characteristic but not pathognomonic cutaneous findings include:
violaceous-red or h y p erpigmented macular p atches: in a d i s t ribution
'lar to that of Gottron papules (Gottron sign-Fig.9.10), on the nape of the neck,

symm
etric

upper back and shoulders (Shawl sign), on the V of the neck and upper chest (V sign),
on the latera] thighs or hips (Holster sign), linear extensor erythema on the legs, thighs,
upper arms and forearms, hands and feet, facial erythema in a malar distribution or

at

more extensively with perioral sparing

In

poikilodermia results from chronic evolution of macular violaceous erythema in sunexposed areas and consists of mottled hyperplgmentatlon and h y p opi g e n t atlon.
telangiectasia and skin atrophy with or without scale
periunghial erythema, nail-fold telangiectasia, cuticular overgrowth
caicinosis cutis (dystrophic calciflcation) - firm, yellow or flesh-colored nodules in the

LlP

subcutis {Fig.9.11) and muscles

lly
Ila,

to
Inc

ns,

photosensjtlvlty
pr u r i tus
Muscle findings are characteristic: increased fatigability, proximal symmetrical

tnUscle weakness and tenderness of the limbs. Patients may have difficulty in r a ising
hands (combing), squatting or rising from this position and climbing. Involvement of the

respiratory muscles leads to dysphagia and dyspnea.

Systemic findings include interstitial pneumonia, arthralgias and o p ortunistic
infections.

Laboratory findings
ire

mildly raised ESR, leukocytosis with l y m p h openia and eosinophilia; occasionally

positive rheumatoid factor; negative LE factor, ANA and syphilis serology
muscle enzyme levels are increased and m easure the l evel o f d e struction: CPK

(creatine phosphokinase), GOT (glutamate-oxalate transaminase), LDH

( l actate

dehydrogenase), ALD (aldolase); serum creatine is raised and excreted in urine

electromyogram (EMG) demonstrates fibrilation and small polyphasic potentials
musde biopsy shows inflammatory infiltrates in the connective tissue between muscle
fibers and degenerative lesions with l oss of t h e c r oss striations in t h e m u scles,
homogenization and destruction of the muscle fibers, resulting in sclerosis.
An evaluation for a possible malignancy should be performed, as dermatomyositis
may be a paraneoplastic disorder (carcinomas of t h e d i g estive tract, l u ngs, female

genitalia).
re,
iac

Evolution, prognosis
DM can be acute in more than half of the cases in children but rarer in adults; it
rt have a polycyclic evolution i n 1/ 3 o f t h e cases or i t can b e c hronic. In case of
Paraneoplastic disease, dermatomyositis improves after removal of the tumor, but recurs
with recurrence of tumor or metastases.

Treatment
'On
trta
I
g(l

S ystemic glucocorticoids (0.5-1 mg/kb/d t apered t o 5 0 % o ve r 6 m o n th s a n d

"'scontinued in 2-3 years) are the treatment of choice. Steroid-sparing immunosuppressants
an be associated, like Metotrexate {weekly low dose), Azathioprine (2-3 mg/kb/d), pulse
103

Cyclophosphamide, Cyclosporine, recently biologics and intravenous immunoglobulin

Sun avoidance and sunscreens are recommended.

SCLERODERMAS
Sclerodermas are chronic diseases in which, after an inflammatory phase, sclerosis
of the skin develops. There are two groups of sclerodermas: localized or circumscribed
scleroderma and progressive systemic scleroderma.

Localized. or circumscribed scleroderma (morphea)

Localized scleroderma is characterized by excessive collagen deposition leading to

thickening of the dermis, subcutaneous tissue or both. Different clinical f orms of localized
scleroderma may be distinguished according to the size, form and depth of the sclerotic
changes in the skin.

Morphea (plaque form)

One or several lesions, 1 cm to more than 20 cm in diameter are found on the trunk
or limbs. The lesions start as erythemato-violaceous plaques and enlarge slowly. The
typical mature lesion is a sclerotic, firm plaque, shiny, waxy or ivory, without hair and
sweat glands, surrounded by a blue-violet erythema, called lilac ring" that later becomes

hyperpigmented (Fig.9.12, 9.13). The plaque softens and the dermis becomes atrophic,
sometimes hyperpigmented after months/years.
Guttate morphea
It is characterized by small (<1 cm in diameter) scattered yellowish-white sclerotic
lesions (white spots disease).
Linear scleroderma
Is characterized by unilateral, linear, band-shaped lesions along the length of an
extremity, causing restricted movement; circumferentially on a finger or a limb, leading to
amputation of a digit; or paramedian on the frontoparietal region, from the eyebrows up
into the scalp. The latter is also called coup d e sabre" because the linear, atrophic
depression with permanent alopecia resembles the stroke from a sw o rd. This form is
deeper than the plaque and guttate forms, involving the underlying tissue (muscles or
bones or even the cerebral substance).
Etiology may be l i n ked to i n f ections like Borrelia burgdorferi (after tick bite),
Epstein-Barr virus, varicella etc at least in some cases.
Course. Morphea typically has a benign, self-limited c o urse, with sp ontan
resolution over 3-5 years. Unlike systemic scleroderma, morphea lacks sclerodactily,
Raynaud phenomenon and internal organ involvement.
Treatment
Topical treatment is based on glucocorticoids that can be applied as ointments or
injected intralesionally (triamcinolone acetonide suspension) in early lesions to reduce
inflammation. Topical calcipotriene, tacrolimus or i m i quimod can also be used under
oclusion. Physiotherapy with heat treatment and massage is useful.
Systemic treatment with penicillin is recommended in extensive and active forms
Systemic corticoids might be helpful in the inflammatory phases of morphea, but they
104

have l'ttle
itte benefit for established sclerosis. Broadband UVA (320-400 nm), or better UVA1
0 400 nm) penetrate deeper into the dermis than UVB and is particularly eHective in the
(340-4
treatment of morphea.

progressive systemic scleroderma (systemic sclerosis)

T his i s

a chronic systemic a u toimmune

d i sease o f t h e c o n n ective t i ssue

by cutaneous and systemic manifestations. The pathogenesis of the disease

characterjzed
er
unologic system disturbances and vascular changes that lead to increased
inclu es
collagen
ag deposition in skin and other tissues.

Clinical findings
Skin lesions
The disease starts slowl y w i t h v a s omotor d i s o rders - ac r ocyanosis',cutis
rrnorata 2 and the most characteristic Raynaud syndrome. The Raynaud syndrome
marmor
ecedes
prece
e the development of skin and systemic sclerosis by 1-15 years, it is caused by
episodic vascular spasm i n

t h e f i n g ers an d i t e v o l ves i n a t y p i cal t h r ee-stage

sequence of painful ischaemia, local cyanosis, and arterial vasoplegia. The skin color
changes from white to blue and red, and intense pain associated through the spastic

crisis (15-30 min).

Skin sclerosis is acral at the beginning. Sclerodactily appears progressively as
sbght erythematous swelling of the fingers and turns into extremely tight, stretched and
~ax-like skin. The mobility of th e hands and feet is greatly restricted because of the
sc}erotic shrinkage of t h e s ki n r e sulting i n b en t an d c o m pletely i m m ovable fingers

(Fig.9.14).Small painful necroses at the fingertips are often found (rat-bite necroses), with
mutilated terminal digits.
The face shows loss of facial expression, the nose becomes pointed, the lips are
narrow, the mouth becomes small and r ound ( m i crostomia) with r a dial grooves. The
mobility of the face is restricted. Sclerosis may slowly become generalized, on the trunk

and limbs (Fig.9.15).

Involvement of internal organs:

digestive tract: the esophagus (most frequently involved) looses peristalsis and shows

atonic dilatation in scintigraphic examination

lungs: massive fibrosis
heart: diffuse, interstitial, myocardial fibrosis and cor pulmonale
kidneys: fibrosis of the interlobular arteries and atrophy. The first sign is proteinuria,
and then progressive insufficiency with malignant hypertension develops.

CRESTsyndrom
e is a particular form of scleroderma manifested with calcinosis,

Raynaud, esophagus involvement, sclerodactyly and telangiectasia (Fig.9.16).

Laboratory f'indings: increased ESR, hypoalbuminemia, hypergammaglobulinemia

and C reactive protein. Antinuclear antibodies are positive in over 90% of cases, and
anticentromere antibodies in 70-80% of cases.

> aii symmetric, permanent blue-red color of the skin in cold environment due to reduced oxygenation
reticulated blue color of the skin due to obstruction of superficial vessels and secondary stasis in other vessels
tt are compensatory dilated; it does not blanch on pressure

105

Treatment
The therapeutic approach depends o n

t h e p r e sentation o f t h e d i sease and

complexity of symptoms. In systemic sclerosis the treatment is symptomatic

in Raynaud syndrome - v a soactive drugs: calcium-channel blockers, vasodilators
(pentoxifyllin, xantinol n i cotinate, intravenous prostaglandins), and i n h i bitors o{'

thrombocyte aggregation (aspirin); smoking cessation is adviced

glucocorticosteroids (antiinflammatory and immunomodulatory action) in moderate
dosage (40 mg p r ednis oneevery second morning), cytostatics (azathioprine,

cyclophosphamide)
antisclerotic drugs: D-penicillamine can arrest the disease in early inflammatory forms
Side effects: drug-induced pemphigus, renal d a mage, h ematological c h anges,
P enicillin i n fusions are better t olerated, and t h e

degradation product (penicillamine).

Topical treatment r efers t o
heparinoids to promote circulation.

a ction ma y o c cur t h r ough t h e

p h y s iotherapy, ointments w it h

106

n i t r o glycerin or

II

Fig.9.1. Chronic lupus erythematosus

Fig.9.2. Chronic lupus erythematosus

Fig.9.3. Chronic lupus erythematosus

Fig.9.4. Atrophic scar after chronic LE

Fig.9.5. Scarring alopecia in chronic LE

Fig.9.6. Diseminated chronic LE

>>g 9.7. Systemic lupus erythematosus

Fig.9.8.Systemic LE

107

Fig.9.9. Heliotrope rash in dermatomyositis

Fig.9.11. Calcinosis cutis in dermatomyositis

Fig.9.13. Morphea

Fig.9.15. Systemic sclerosis

Fig.9.10. Gottron sign in dermatomyositis

Fig.9.12. Morphea

Fig.9.14. Scierodactily with vasculitis

in systemic sclerosis

Fig.9.16. CREST syndrome

Chapter 10
BUI.GUS DISEASES

PEMPHIGUS VULGARIS
Pemphigus vulgaris (PV), the most severe and frequent autoimmune bullous
disease, is mediated b y c i r culating autoantibodies directed against k eratinocyte cell
The disease usually affects people between 40 and 60.

surface.

Pathogenesis:
IgG a u t oantibodies t o

de s m osomes ( i n f a c t to des m o g lein I

transmembranar proteins that belong to

and

III,

d esmosomes) are produced. Desmoglein-

autoantibody complexes initiate an immunologic inflammatory reaction that destroys the

d esmosomes resulting i n l o s s of cell-cell adhesion, a p rocess called acantholysis.
lntraepidermal acantholytic blisters are formed in the lower part of the prickle cell layer

(medium blisters) within a few hours.

1

Clinical findings:
Mucous membranes are typically affected first in PV, preceding cutaneous lesions
for about 4 months. Blisters develop most often in the mouth. These soon rupture and

painful, slow-healing erosions result with peripheral extension and epithelial shedding

(Fig.10.1,10.2).
On normal appearing skin flaccid blisters filled with clear fluid arise. They
are fragile an d

s o o n p r o d u c e p a i n fu l e r o s i on s w i t h p e r i p h e ra l e x t ension and

shedding of the epithelium. Crusting develops while the margin o f

t h e b l ister

advances (Fig.10.3). T he lesions have litt le tendency to epithelisation but w h e n t h i s

happens, characteristic hyperpigmented macules result (Fig.10.4). As new lesions

a ppear, the e r u p t ion b e comes p o l y m o r p h ous, w i t h b l i s t ers, erosions, crusts an d

hyperpigmented macules.
The skin fragility might be revealed in two ways: a) firm and repetead sliding
pressure with a f i nger separates the upper layers of normal-appearing epidermis,
producing bulla (Nikolskysign); b) pressing on the top of a blister may spread the content
into clinically unaffected skin (Asboe-Hansen signor blister's migrating sign).
Lab tests
Blister smear cytology (Tzank test): acantholytic cells are found on a smear taken from

the base of a freshly opened blister, in May-Griinwald-Giernsa stain; these are

epidermal cells with a round shape because they lost desmosomes
Histopathology: suprabasal cells separate from t h e b a sal cells t o f o r m b l i sters;
acantholytic cells are found in the blisters (Fig.10.5).

Immunology:

109

d i r ec t i m m u n o fluorescence (DIF) o n p e r i l esional s ki n d e t ects Ig G a r i d

complement on the surface of keratinocytes, resulting in a fluorescent networl,
aspect throughout the epidermis

i n d i r ect imm unofluorescence(IDIF) using the patient's serum and m o nkey

esophagus demonstrates circulating antibodies IgG against desmosomes. The
titre of the circulating antibodies correlates with the disease activity.
Pemphigus vulgarls
IgG 8, C3

blister urlthin the epidermis

floor lined by basal cells
acantholybc cells in blister fluid
intercellular IgG & Ca by direct
immunofluorescence

Pemphigoid
subepidermal blister
eosinophil infiltrate in underlying dermis

IgG 8 C3

basement membrane IgG & Ce by

direct
immunofluores cence

Dermatitis herpetlformh
subepidermal blister
neutrophil infiltrate in underlying dermis
dermal papillary Ig A by direct
Immunofluorescence

IgA

Graphic 10.1. Diagram showing histology of typical bullous autoimmune dermatosis

Course
The untreated disease usually leads to death within 1-3 years because of cachexy,
as water, electrolytes and proteins are lost and oral erosions hinder feeding or because of
superinfections.

Tfeatfnent
The aim of th e treatment is to i n duce disease remission by reducing antibody
production.
ail]
Since the introduction of glucocorticosteroids and imunosupressive drugs, over'
mortality has been reduced by more than 50 %. Most of the mortality is now linked to the

side effects of therapy. Minimal drug doses required for disease control should be used in
order to minimise side effects.
T reatment o f
pe m p h i gu s i s started wit h

h i g h s t eroid d o ses (1-2 r ng

prednisolone/kg) in order to in duce rapid remission. After remission of cutaneous and

mucous lesions is achieved (4-8 weeks), the dose is slowly tapered to a sufficient
maintenance dose (5-15 mg prednisolone daily) that will be for life. If the dose is reduced
too fast, recurrence can occur. As the treatment is in many cases for life, side effects such as
l
diabetes rnellitus, g a stric h y p e rsecretion or u l c eration, h y p e rtension, t i e ombosis
osteoporosis and activation of tuberculosis or candidosis may occur. Although steroiddependant, this treatment prolongs these patients' life with 20-25 years.
110

Immunosuppressants should be considered early in the disease, as steroid-sparing

ents when complete remission is attained. Azathioprine and mycophenolate mophetil

are first-line agents.

~ o un d

ca r e i nc l u d e s g e n t l e c l e a n sin g w i th

anti s e p ti c a g e n t s a n d

n onadherent dressings to p r o m ote healing, m i n i m iz e t r a um a t o

s u r r o u n d in g s k i n

and Prevent scarring.

OTHKR FORMS OF PKMPHIGUS

Pemphigus vegetans
Is a rare form of pemphigus that involves predominantly skin folds (axilla and
;Aghinai regions, the lip commissures, vulva and anal areas), scalp and face. In these
areas the blisters are rapidly b r o ken, thus barely seen, and v egetations and crusts

develop. The target is desmoglein 3 (lower epidermis, suprabasal). This form is more
resistant to therapy.

Pemphigus foliaceus
Is a benign variety of pemphigus characterized by acantholysis in the upper
layers of the epidermis resulting in s uperficial blisters (Fig.10.6). The target is
desmoglein 1. The blisters are not evident but extensive scales, crusts and erosions on
an erythematous base are observed mainly i n t h e s o -called seborrheic areas (face,
scalp, upper part of the trunk). Mucosal areas are respected and the N i k olsky sign is

positive.

Pemphigus erythematosus
It is a v a r i ant o f t h e p e m p h i gu s f o l i aceus that can be p h o t oactivated. The
target i s d e s m o g l ei n 1 . It has ov e r l a pe d f e a t u r e s o f lu p u s e r y t h e m atosus

( circulating AN A a n d I g G d e p o sits a t t h e d e r m o-epidermal j u n ction) a n d

pemphigus (superficial a catolysis an d I g G d e p o sits i n t h e i n t e r keratincyte
substance). Prognosis is favorable.

Paraneoplastic pemphigus
Is a rare form o f p e m p h igus, associated wit h c ancer elsewhere in th e body,
most commonly l eukemia or l y m p h oma. The most common cl i nical presentation is
intractable erosive stomatitis that can be confused with severe herpes simplex infection
O r erythema m u l t i f o rma. Systemic t h erapy p r o v i des t e m p orary r e l ie f u n l ess t h e
primary tumour is not treated.

Drug-induced pemphigus
Thiol-drugs (D-penicillamine, captopril, enalapril, piroxicam) and non-thiol
ugs (penicillin, cefalopsporins, quinolones, carbamazepin) may i n duce bullous
eruption similar to pemphigus.

BULLOUS PKMPHIGOID
Bullous pemphigoid i s an autoimmune, subepidermal blistering disease that
fcts people over 65 years and rarely involves mucous membranes.

111

pe>

It is characterized by IgG autoantibodies directed against the hemidesmosorrtg

prtl

antigens (minor and major bullous pemphigoid antigens - BPAG1 and BPAG2)
Subepidermal bullae result when hemidesmosomes are destroyed (Graphic 10.1, 10.2).

mI

Bullous pemphigoid may have a paraneoplastic character.

orI

Clinical findings

coI

Tense, large bullae with clear content associated with i n t ense pruritus arise
or m or e o f t e n o n s y m m e tric
spontaneously e i t h er o n apparently n o r m a l s k i n

CO'

erythematous plaques, slightly elevated (urticariform). The lesions appear mostly 0>
the flexural areas: neck, axillae, inghinal fold, and upper abdomen. Later the blisters

may show hemorrhagic content and bloody crusts (Fig.70.7, 10.8). Nikolsky apd
Asbboe-Hansen signs are negative. Oral l e sions rarely occur. The general state of

health is good.

it

trrterrrrrergerte gterrtertts
rtK6 f Kt4 tgt

gsset e4rg eytrrytesrs

p
igry/y .r/y'- r r ,'.',,Pr.~gz

'

. ~- irtsrtrre ~gPAG t~

f rl~ r r
rtrerrrbrsrre
Arrretrrtstrrgtitemerrts -.,
tttgltgI r.r t t.. l l i

tt :~

:: "'; , ",. " :

~r, l

igg l

'hertsrrrerrrbterre trrroteirrs
grrg Q trttegrlrr y
grsset terrrrrre
f4e8rttrr tf'f
Arrrehcrr irrg fibrils
f@rrttagerr Vltt

g.rrtreeetltrrirr r

rrretrisef gre
rter'Irr le

Arretrrrrrflrrgr trtsrtrre
tCottsgerr tV, Usrrrtrrrrirr'f

Graphic.10.2. Connections between basal keratinocytes, basement membraneand

derm1s.
Lab exufns

Tzank test is negative. The histopathology shows deep subepidermal bulls

without a cantholysis (G raphic 10.7). DIF f r o m n o r m a l -appearing p e r i lesional sknt
shows deposits of I g G an d c o m p l ement C 3 i n a l i n ear b an d a t d e r m al-epidermal
junction. IDIF and ELISA techniques show circulating autoantibodies in the patient' s

serum that target the bullous pemphigoid antigens (BPAG) 1 and 2 i n

t h e skin

basement membrane.
The course of b u l l ous pemphigoid i s u s u ally c h r onic w i t h r e m issions over
months an d y e a rs. W i t h ou t t r e atment t h e m o r t a l it y r a t e i s l o w e r t h a n t h a t Ut

pemphigus vulgaris.
As in

infla
mmatory

<

o t h e r autoimmune d i s o r d ers, t r e atment i s d i r e c ted a t r e d u c irt

ed
r esponse and a u t oantibody p r o d u c tion. Th e m o s t c o m m o nl y u s e

medications are antiinflammatory dr ugs (glucocorticosteroids in lower doses than irt

112

ernphigus vu l garis, are u s u ally s u f f i cient t o i n d u c e r e m ission, e.g. 0.5-1 m g / k b

rednisolon) an d i m m u n o s u p p ressants ( a zathioprine, mycophenolate m o p h e t il,

etotrexate, cyclophosphamide). As compared to pemphigus vulgaris, patients with

bulious pemphigoid ar e n o t c o r t i co-dependent, systemic steroid b e in g n e cessary
only in recurrences. Recent evidence shows that strong topical corticosteroids may
c ontrol cases wit h l o c alized l e sions w h i l e a v o i d in g s y stemic s id e e f f ects o f o r a l
corticosteroids.

HERPES GESTATIONIS (PEMPHIGOID GESTATIONIS)

Is the bullous pemphigoid of the late pregnancy. The original name is a
misnomer, as it is not a herpetic infection but somehow the clinical aspect resembles
;t The immune response seems to be t r i g gered by I g G a u t o antibodies to p aternal
antigens in amniotic basement membrane.

The eruption resembles bullous pemphigoid and appears periumbilical in the

2nd or 3rd tr imester of pr egnancy. Sometimes neonates from these mothers show a
similar eruption. The d i sease heals spontaneously bu t i t m a y r e cu r i n s u b sequent

pregnancies.

DERMATITIS HERPETII'ORMIS DUHRING-BROCQ

Dermatitis herpetiformis is a n

a u t oimmune blistering disease associated with

gluten-sensitive enteropathy. Gluten is found i n w h eat, barley, rye and k a muth. This

autoimmune disease occurs in genetically predisposed individuals whose immune system

mistakenly perceives gluten as a foreign invader and attacks it. IgA antibodies to gliadin (a
protein in gluten) are formed. They cross-react with enzymes normally present in the gut,

tissue transglutaminase (tTG), and in the skin, epidermal transglutaminase (eTG). IgAeTG complexes deposit at the tips of papillary dermis to cause endothelial cells activation
and accumulation of n eutrophils w it h subsequent lesions of dermatitis herpetiformis.
These deposits may resorb after 10 years of gluten-free diet.
Gluten-sensitive enteropathy is asymptomatic in m ost patients, but 90% show
abnormalities at the endoscopic examination (villus athrophy, lymphocyte infiltration in

the jejunum).

Clinical findings
The symptoms of dermatitis herpetiformis appear in early adulthood (20-30
years old).
Intense itch and burning sensation located tipically symmetric on the extensor
arms, knees and buttocks are followed by erythematous, pseudo-urticarial plaques with
herpetiform vesicles (small, clustered) or bullae. The pruritus is so intense that often
patients present with erosions or crusts in the absence of vesicles which have ruptured
due to excoriation (Fig.10.9). The oral mucosa is usually not involved. The Nikolsky sign

iegative
Symptoms of celiac disease may be associated (abdominal p ain, l oose stool,

fatigue).
113

L,ab exams
Tzank test is negative.
Biopsy taken from the edge of the lesion shows neutrophil deposits in the

derma
l

papillae and deep, subepidermal bulla, without acantholysis (Graphic 10. 1).
DI F of normal-appearing perilesional skin shows granular deposits of IgA and C3 ~

the dermai papillae, the standard criterion for the diagnosis ot herpettform dermatitis
ID I F or ELISA of the patient's serum shows the presence of IgA autoantibodies against
gliadine or the endomysium in smooth muscle tissue.

Course
Dermatitis herpetiformis is a benign disease with recurrent eruptions and periods
of several months with few or no symptoms, related to the amount of ingested gluten.

Treabnent
Gluten-free diet ( i ncluding m a ize, rice, mi llet, teff, sorghum, bu ckwheat) is
necessary in p atients with g l uten-sensitive entheropathy. Oats are also generally not
recommended, as they induce symptoms in a small minority of celiac patients. N o ncereals as amaranth, quinoa are allowed. I o d inated salts, sea fish and drugs containing
iodine have to be avoided, as they may exacerbate the disease.

Sulfones (DAPSONE, 100 mg daily) are the primary drugs in the treatment pf
dermatitis herpetiformis. They act b y i n h i b ition o f n e u trophil m i g ration. Immediate
(within a few hours) improvement of pruritus and skin lesions after first dose of treatment
is another diagnostic criterion. Side effects: methemoglobinemia, anemia, hemolysis. Other
sulfonamides that can be used: sulphapyridine, sulphametoxypyridazine.
Absolute gluten restriction in the diet is the best treatment, making the reduction
of Dapsone dosage possible or even eliminating the disease from the skin and gut mucosa.
Topical t r eatment a i m s t o relieve th e b u r n in g i t c h in g s e nsation. T o pical
corticosteroids could be apllied.

EPIDERMOLYSIS BULLOSA AQUISITA

Epidermolysis bullosa aquisita (EBA) is a very rare disease with tense blisters

at sites of trauma and IgG autoantibodies to type VII collagen (anchoring fibrils).
These fibrils attach th e b asement m e mbrane t o t h e u n d e r l y in g d e r mi s an d t h eir
destruction results in subepidermal blisters, within lamina densa.

EBA is not inherited and usually presents in adult life (50-60 years old), unlike
epidermolysis bullosa (EB) which is inherited blistering disease that is present from birth.
Clinically is characterized by blisters, scars and millia at trauma-prone areas such
as the hands, feet, knees, elbows and buttocks. Mucus membranes may also be involved

(oropharyngeal, nasal, ocular) with possible sequels esophageal strictures, conjunctival

scarring, blindness). The scarring nature of EBA can lead to nail destruction and hair loss.
Skin biopsy shows subepidermal blister and direct immunofluorescence detects

linear C3 and IgG deposits along the basement membrane, like in bullous pemphigoid
Indirect immunofluorescence detects in the patient's serum IgG circulating autoantibodies
to type VII collagen, on of the skin basement membrane component. Split skin technique i~
114

ed to differentiate EBA (IgG autoantibodies are located in the lower part of the basement

>embrane, that is lamina densa and sublamina densa) from bullous PemPhigoid (IgG
utpantibodies to the hemidesmosome are localized in the upper lamina lucida).
The treatment is similar with that in bullous pemphigoid.

PORPHYRIA S
Porphyrias represent a group of disorders caused by inborn defects in the haem
Qjpsynthetic pathway. This causes elevation of certain porphyrins or their precursors in the

tissues, urine, or stool. The principal sites of porphyrin synthesis are the erythropoietic
system, liver and kidney.
Porphyrin b iosynthesis starts with th e c ondensation of s uccinate and g lycine

resulting in delta aminolevulinic acid (dALA) and porphobilinogen. Four molecules of

pprphpbjlinogen form th e p orphirins. After decarboxilation and oxigenation processes

pro t o porphyrin v ia uro p o rphyrinogen and

pprphpbilinogen transforms i n
cpprpporphyrinogen. The heme is formed by incorporation of iron into protoporphyrin,
catalyzed by ferrochelatase (Grapht'c 10.3). The individual steps in heme biosynthesis are
catalysed by specific enzymes. Enzymatic disturbances in porphyrin metabolism lead to

porphyrias.
Sectittyl CeA

Rttt Z'041$
ALA ttyttthaee

O'A dehydro'eee-detit:iery perphyria

ALA de'r ytlrare re

Acttte itttertrtittertt ttartthyrie

Vreiterphyrittegett I
Ureprtrphy..inegen Il strnti:are

Cnrrteniinl erythrnpeietie porpLyrig [Cfpj

Uraparphyrirtalett ttt
Urepnrphyrinegendeertrhnxy'nte

perphyrtn eetenee tncen

Cattrattertehyrlttegelt
Cep&pe'phy':rtegen ex ciJK

Hereditary eettrettertthyria
ttretetttartthyritteeett

Vrelepe"phyrineger. err c'ate

ttr@letpertthyt ta
ter.rrri:.elntnte

prntnporphyrn'.

Haettt

Graphic 10.3. Biosynthesis of haem and the porphyrias

115

There are two main groups of porphyrias:

manifested with abdominal pain and neurological signs due to superproduction of

porphyrin precursors (dALA and porphobilinogen)

photosensitization due to accumulation of porphyrins in the skin that are activated by
UV light resulting in free radicals which induce blisters.

Porphyria Cutanea Tarvia

Porphyria

c u t a n ea tarda ( PCT)

r e sults f rom

h e p a t i c deficiency of

uroporphyrinogen decarboxylase. This is the most common form of porphyria seen by the
dermatologist. Types of PCT:
fa m i lial PCT - autosomal d o minant d i s order w here more t h a n 9 0 % o f t h e

elbo
deIIl

of cc

uroporphyrinogen decarboxylase is deficient

sporadic PCT the deficiency of uroporphyrinogen decarboxylase is about 50% and is

usually compensated, but becomes manifested when hepatic disease is associated
(ethanol, oral contraceptives, hepatitis, hepatic tumors, and environmental exposure to

polyhalogenated aromatic hydrocarbon compounds).

Clinical ff.'ndings
The first manifestations usually occur after th e age of 30, m ore frequent in
males.

The most common presenting sign of PCT is fragility of skin exposed to sun and
mechanical trauma, leading to erosions and bullae typically on hands and forearms,
occasionally on feet, face, and ears. Crusted lesions heal with hypopigmented atrophic

scars, milia (keratotic cysts-Fig.10.10) and patchy hyperpigmentation. Hypertrichosis

pre(

appears over m a la r a n d t e m p oral a r eas an d t h e f a c e b ecomes hy p erpigmented.

Sometimes extensive sclerosis and t h i ckening o f t h e s k i n o n t h e c h est an d b a ck

by I
invl

develops.

Laboratory findings
The excretion of urinary porphyrins is massive and urine appears beer-brown with

red fluorescence in UV light (Wood's light). Evaluation of the iron profile (serum ferritin
level), liver enzymes (transaminases, AT) and screening for hepatitis viruses are required.

tarl

pur

(Fig
epi(

Treatment
Systemic
Sun, alcohol, estrogen and hepato-toxic agents must be avoided. Treatment of

clas

chronic hepatopathy has to be associated.

Therapeutic phlebotomy reduces iron levels (250-500 ml blood weekly and

then every 2-4 weeks until haemoglobin drops to 10 microgm/dl or until the serum
iron drops t o 5 0 m i c romg/dl). H ig h l e vels of i ro n i n h i b i t u r o p o r p h i r i n ogendecarboxylase and disturb haem synthesis. In patients in w h o m p h l ebotomy is not
convenient or is contraindicated, alternatives for iron mobilization are: Chloroquine
i n l o w d o ses 125 m g t w i c e w eekly f o r 8- 1 8 m o n t h s or c h el atin g a g ents

(desferrioxamine).
Topical

hy
SllII

8, i

Superinfected blisters are treated with antiseptics.

116

ha

ERYTHEMA MULTIFORME
It is an acute self-limited eruption with iris or target lesion as a hallmark. It occurs
s type IV hypersensitivity reaction characteristically induced by herpes virus infection.
The typical target lesions have symmetric acral distribution (hands, forearms,
elbows, knees and feet) and mild or n o m u cosa involvement. They are round, sharPly
dejnarcated, palpable, expanding to maximum 2 cm over 1-2 days, bright red with 3 zones

af colour {Fig.10.11). The lesions subside in 2-3 weeks without scarring but usually recurr.
According to the aspect of the target, there are two clinical forms:

erythemato-papulous
form (erythema-iris): small papule in t h e c e ntre, raised
edematous and pale intermediate ring, and violaceous periphery

ve sicuto-buttous
form (herpes iris): central vesicle, surrounded by a cyanotic zone
and a margin of small herpetiform vesicles.

Treatment
Recurrent EM is typically related to episodes of recurrent herpes simplex infection
and can be prevented by continuos antiviral therapy.

STEVENS-JOHNSON SYNDROME AND TOXIC EPIDERMAL

NECROLYSIS
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare and
present as dermatological emergencies, potentially life-threatening. They are characterized
by targetoid lesions with full-thickness epidermal necrosis and with mucous membrane

involvement.
Oral, genital and ocular mucosa involvement precedes the cutaneous lesions and is
manifested by painful erosions, ulcerations and crusts in almost all the cases.
The cutaneous lesions begin on the face and upper trunck and differ from classic

target lesions of EM by a) having only 2 zones of color (targetoid lesions): central dusky
purpura or central bulla, w it h s u rrounding macular erythema that is p o orly d e fined

{Fig.10.12); b) typicall flat aspect, with the exception of central bulla. Areas of denuded
epidermis are dark red with oozing surface.
D epending o n

t h e e x t ension o f t h e e p i d ermal d e tachment, th e f o l l o w i ng

classification has been proposed:

SJS - less than 10% of the body surface detachment (Fig.10.13, 10.14)
overlapping SJS/TEN confluent lesions, epidermal detachment of 10-30% of the

body surface
TEN more than 30% epidermal detachment (Fig.10.15); the mortality rate can

approach 40%
C learing

o f the

les i on s t a k e s 3 - 6 w ee k s, with s ubsequent h y per-or

hypopigmentation. Nearly al l

c ases of SJS/TEN are d r ug-induced (trimetoprim-

supfamethoxazole, NSAID, allopurinol, carbamazepine etc), but viral infections (hepatitis

~. influenza), microbial infections (streprococcal, mycoplasma), autoimmune disease (LES)

"ave also been reported.

117

Treahnent
TEN should be treated in an intensive care unit. Principles of management of

SJS/TEN:
withdrawal of the causative drug
r esulting i n fl u i d s h i f t s and
fluid r e placement because of epidermal loss
dehydration
nutritional supplementation because massive protein loss through denuded s~
wound care debridement of necrotic epidermis, application of antiseptics and
biologic dressings, avoiding silver sulfadiazine as sulfonamides are frequent
inciting drugs; broad-spectrum antibiotics are not recommended.
Systemic glucocorticoids are controversial, as some believe they may predispose to
superinfections. Intravenous Ig and cyciosporine have shown some benefit in reducing the
mortality rate.
Because the high mortality rate in TEN and treatment arrest progression when
administered early enough, the early recognition of this entity is very important.

118

'

. ['I

Fig.10.1. Pemphigus vulgaris

Fig.10.2. Pemphigus vulgaris

4i-'"
*

Fig.10.3 Pemphigus vulgaris

Fig.10.4. Hyperpigmented macules after

pemphigus vulgaris
~

' RCF

cb

'

'6 e~ ~

g ~Q
OQO

gg ~

~ O Oy Q ~
,~,'I

~P a~~ ~

0ea ~~g

Fig.10.5 Acantholytic bulla

(hematoxylin-eozin stain)

Fig.10.6.
Pemphigus foliaceous

Fig.10.7. Bullous pemphigoid

Fig.10.8. Bullous pemphigoid

119

Fig.10.10. Milium cysts in porphyria

cutanea tarda

Fig.10.9. Dermatitis herpetiformis

Fig.10.12. Stevens-Johnson syndrome

after Didofenac

Fig.10.11. Erythema multiforma

Fig.10.14. Stevens-Johnson syndrome

Fig.10.13.Stevens-Johnson syndrome

il
h

Fig.10.16. Toxic epidermal necrolysis

Fig.10.15. Stevens-Johnson syndrome

120

Chapter 11
ERYTHEMATO-SQUAMOUS SKIN DISEASES

PSORIASIS VULGARIS
Psoriasis is a common, chronic, relapsing inflammatory disease with a strong genetic
basis. Kith a morbidity of 1-2%, psoriasis vulgaris is one of the most common skin diseases.
The disease is much less common in the tropical and subtropical climates than in temperate
zones. The white races are most frequently affected, while psoriasis is practically nonexistent

in red skinned people (Eskimo and American indians).

Pathogenesis
The inflammatory mechanisms are most probably initiated and maintained by the T
cells and cytokines (interferon y, TNFa) in the dermis. These result in increased epidermal
increased mitotic activity and DNA synthesis in the basal cells) and increased

pro
liferation(

djfprentiation (decreased epidermal transit time from 30 to 7 days, increased and defective
keratinisation, named hyperkeratosis and parakeratosis).
Both genetic and environmental factors are involved in th e pathophysiology of

psoriasis:

' f

'

ld
ph d
dp
8
probability of a child having the disease if one parent has psoriasis is about 16%, about

%6

i&

50% if both parents have psoriasis and only 7.8% when neither parent has psoriasis

o H L A -Cw6 antigen is associated to type I psoriasis with early onset (<40 years)
and increased familiar occurrence, but not to type II psoriasis with late onset

(>40 years)
o p s o r iatic arthropathy is frequently associated with HLA-B27 antigen
environmental factors (non-genetic):
o l o cal factors:

t rauma: p h y sical, c h e mical, e l e ctrical, s u r g ical, i n f e ctive a n d

inflammatory types of injury, even excess scratching

sun/artificial light: generally considered beneficial for p soriasis,

o

however, a small minority find aggravation due to summer sunlight

s y s temic factors:

infections: streptococcal infection is linked to guttate psoriasis (throat

culture in patients with pharyngitis is recommended); HIV increases
psoriatic activity
drugs: beta-blockers, lithium, withdrawal from systemic corticosteroids

psy c h ogenic/emotional factors: stress increases severity of the disease

alcohol, smoking
e n d o crine: hormonal changes influence the evolution improves during

pregnancy, flares after parturition; peaks at puberty and during menopause

121

Clinical findings
The primary lesion in psoriasis is a red and sharply marginated palpable plaque
that soon becomes incompletely covered by multilayered, dry, silvery-white or micaceous
scales. The number of the lesions can range from a few to many at any given time and the
s ize varies from one to several centimetres (Fig.11.1). The
lesionsmacules
are symmetric
an t e y
' mented
result (Fig.11.2j

usually do not itch. After regression, temporary hypopigmented ma

and then the skin becomes completely normal.
Clinical signs:

scraped off they detach from the lesion as small

: 'f h
1
candle phenomenon: i t e sca es are scrape
flakes, like wax flakes scraped from a candle
g off the scales, a
last cuticle phenomenon: if one continues scraping, after removin

moist sheet appears (the lowest layer in the epidermis above the dermal papillae)
focal bleeding phenomenon (Auspitz sign): after removing the last epidermal layer
spotty bleeding occurs, as enlarged dermal capillaries within unequally elongated
dermal papillae are eroded
Kobner phenomenon: psoriatic lesions often appear after injuries (surgical scars) thi' s sign is specific for psoriasis, but also for lichen
Fig.11.3, burning, insect b't
i es et c);
planus (where lichen lesions appear)
The psoriadc lesions are frequently localized on the scalp, knees, elbows (Fig.11.4),
'
when lesions are spread over all
sacra1region an d trunk.. Ps oriasis is generalized or universal
. ). Mucous membranes
are left ((Fi'g..11.5).
anatomical regions and just some areas or normal skin

'p
(ips,
(li
s, glans
anspenis with circinate erythematous plaques) are rarely affected.
o atica. The nail l ate might
.

T he nails are more frequently affected in psoriasis arthr p

'

inhea
d size
' (ps
ps o riatic pitted nails), yellowish patches (psoriatic oil
present depressions up to p'
spot) or hyperkeratosis with irregular thickening resembling onychomycosis (psoriatic
dystrophic nails) (Fig.11.6).

Particular morphologicalforms ofpsoriasis:

uttate

soriasis: disseminated d r o p -sized p s oriatic l e sions; q ui te

common in

.)

streptococcal infections, particularly in children and young adults ( ig.

aspects: coin-sized (nummular psoriasis-Fig.11.8), arge,
se
plaque
l
psoriasiswi'th several
ular
h ' 1 p soriasis) lesions with a clear centre ( annu ar
irregular lesions (geograp
(
ica p
rs
pso riasis)I with polycyclic margins (gyrate psoriasis)
surfaces and aaffects
the ty pically
i n v o l ved e x tensor
spears
e
p
'
psoriasis inversa:
ma a nd/or
'

'

intertriginous areas with minimal scales (axillae, inguinal folds, inframammary and or

intermammary creases -Fig.11.9)

Histopathology

Hyperproliferation of keratinocytes leads to irregular thickening of the epidermis

(acanthosis), with elongated rete ridges and dermal papillae. Above the tops of the papillae, the
nl

fe

11 1 ers thick. Abnormal differentiation of the keratinocytes is

manifested as parakeratosis in the thickened corneum layer and loss of the

stratum granulosum.
with p e r i vascular chronic in fl ammatory
The d ermis shows v asodilatation
infiltration. Neutrophylic leukocytes migrate from the dermis (exocitosis) and extend up to

form microabscesses in the horny layer (Munro abscess).

122

Special forms of psoriasis

a. Pustular psoriasis
I s an uncommon f or m o f p s o riasis consisting of w i d espread pustules on a n
erythematous base. It results from the confluence of the Munro microabscesses into the

rnacropustule Kogoj. Culture from the pustule's content is negative (sterile pustules).
Clinical forms of pustular psoriasis:

pustular palmo-plantar psoriasis (Fig.11.10) aggravated by smoking, it is commonly

resistant to treatment
acroderrnatitis continua H allopeau involves the f i ngers and t o es, causing nail

destruction and atrophy of the distal falangs (Fig.11.11); it may remain confined to the
original site up to many years or spreads proximally to the hand, feet, limbs.
generalized pustular psoriasis (Fig.11.12) - can be pustular from the beginning, or it can
complicate other forms of psoriasis. The eruption is often triggered by infections, drugs
(antimalarials, lithium and w i t h drawal of systemic glucocorticoids), strong irritating

topicals (tar, anthralin, steroids under occlusion), or it is idiopathic. Generalized pustular

form may have a poor prognosis, especially in older patients.
b. Psoriatic arthritis
Psoriatic arthritis is a chronic inflammatory arthritis that is commonly associated with

psoriasis (10-15% of the patients with psoriasis). It is most frequently a seronegative (negative
rheumatoid factor) oligoarthritis with asymmetrical distal joint involvement. Joint findings
may include dactilitis (painM swelling of the distal interfalangeal joints of the fingers and toes
with the aspect of sausage digits" Fig.11.13); enthesopathy (inflammation of the insertion
point of tendon into bone); tendonytis and spondylitis. The bone is severely destructed in
advaced stages with osteolysis and erosions that cause restrictions in movement.
In the absence of overt psoriatic skin lesions, a careful examination of the scalp, the
gluteal crease, the umbilicus, the axillae and the nails may aid diagnosis of psoriatic arthritis.
c. Erythrodermic psoriasis
This is a severe form, characterized by the extension of the psoriatic lesions over
the entire skin (red man"), which shows deep inflammatory reddening with scaling and
slight lymph node enlargement (Fig.11.14). Pruritus can be intense. Water, protein and

heat loss is an aggravating factor. These cases require appropriate fluid and protein
supplements. Erythroderma can be triggered by drugs or excessive UV exposure.

Course
The guttate psoriasis is an acute form in w h ich the cutaneous lesions disappear
spontaneously in a few w e eks without treatment, or represent the initial stage of the
chronic plaque-type psoriasis. Once cleared, patients with guttate psoriasis usually have
hmited or no evidence of psoriasis for prolonged periods.

Plaque psoriasis is a chronic disease with a relapsing course. It is impossible to

predict the duration of the active disease, the time or the frequency of relapses, or the
duration of a remission. The disease is rarely life-threatening, but often is intractable to
treatment, with relapses occurring in most patients. With age, the relapses are more and
~ore frequent, becoming annual, and then the lesions are permanent.
Psoriasis is linked to other disorders, particularly to cardiovascular disease (longstanding psoriasis is a risk factor for coronary arterial disease) and metabolic syndrome
123

(obesity, dyslipidemia, high blood pressure, increased glucose tolerance) but also to
rheumatoid arthritis, diabetes, Crohn's disease and streptococcal infections.
The quality of life is very much affected in psoriatic patients, related to dry and

peeling skin, fissuring (especially at the fingers), embarrassment about appearance, the

rom

adverse effects and high cost of therapy. The mortality rate in psoriasis is low, related tp

associated disorders (cardiovascular disease) or to its therapy: liver and lung fibrosis f
metotrexate, PUVA-induced skin cancers with metastasis.

Treatment
Psoriasis is a chronic skin condition w it h a n

i n h erited predisposition, so the

treatment is not curable and must be considered for long term.

Experience shows that low-calories diet can be favourable. Alcohol is considered a
risk factor for psoriasis and smoking aggravates palmo-plantar pustular psoriasis.

Three basic treatment modalities are available for the management of psoriasis.
These can be used alone or in combination.

1. Topical therapy
is generally suitable for plaque psoriasis. Many topical agents are used
sequentially over t i m e o n t h e s ame p atient ( a r o t ational therapeutic approach),
lowering the adverse effects of each drug. Clearing of th e scale is observed first,
followed by the flattening of the plaque. Sometimes perilesional white ring precedes
psoriatic lesion regression (Fig.11.16). Resolution of erythema may take 6-8 weeks and
then transitory hypopigmented macules result before the skin turns to normal.
Kerutolytics (5-10% salicylic acid, 5-10% urea) are recommended alone at the
beginning of the treatment to remove the thick scales. As scales continuously reappear,
keratolytics will be combined after a few days with anthralin, corticosteroids or other
drugs that reduce the turnover of th e k eratinocytes. Keratolytics are followed by

prolonged bathing for a soaking effect. Sea bathing is even more favourable.
Anthrulin (dithranol) reduces oxidative metabolic processes, decreasing the rate of
epidermal cell proliferation. It is one of the most effective topical reductor, but irritates and
stains the skin, cloths and bedding. The desirable irritant effect is confined to slight

reddening of the skin (crisophanic erythema, Fig.11.15). Increased irritation (vesicles,

oozing) may favor evolution of plaque psoriasis into erythroderma or pustular psoriasis.
Because it is irritating, it should not be applied on the face, scalp and folds. There are two

different methods of application: a) prolonged contact method 0.5% preparations, for 2-4
hours; b) short contact method -1-2% preparations, for as much as 1 hour.
Topicul corticosteroids in creams, ointments, foams, sprays and lotions are the
eks
most used topical agents. High potency steroids can be used for maximum 4 wee

(Clobetasol/Dermovate) and continued with medium potency preparations (Elocom,

Advantan). If stopped abruptly, they have a rebound effect. Topical steroids are
quickly effective but psoriasis usually recurs rapidly after the end of treatment. Sid<
effects: skin atrophy, purpura, hypertrichosis, telangiectasia, striae distensae, steroid
acne and pyoderma. To reduce the incidence of adverse local effects, two weeks of
continuous treatment can be followed by pulse therapy on weekends.
d
Culcipotriene is synthetic vitamin D3 a nalogue that in hibits proliferation an
promotes differentiation of the keratinocytes and has immunosuppressive effects on
lymphoid cells. For best results it is combined with strong topical corticosteroids, e.g
with betamethasone in Daivobet, with fewer side effects and steroid sparing effects.
124

Tazarotene (Tazorac) is a topical retinoid derivative, available as 0.05 and 0.1%

gels, particularly useful for scalp lesions. It modulates keratinocyte proliferation and
differentiation and su pp."esses inflammation. M a y b e c o m b i ned w i t h t o p i c al
corticosteroids to increase effects and decrease irritation that commonly occurs when
used alone.
Tacrolimus and pimecrolimus are topical calcineurin inhibitors (macrolactams)
and can be u sed w h en c orticosteroids are contraindicated (thin l e sions prone to
atrophy or s teroid acne). The burning sensation associated with t h e ir u se can be
avoided by prior treatment with a corticosteroid.
Crude coal tar (pix lithantracis) and tar extracts have antimitotic effect. Bath oils
and shampoos are available, often combined with salicylic acid. They are effective but
have an o f fensive odour. C oal ta r i s a s sociated w it h f l u m ethasone pivalate in
I.ocacorten Tar formulation. It can be used in occlusive dressings.
Phototherapy is now frequently used in extensive and widespread disease and if lesions
are resistant to t o p ical therapy. UV r a d i ation r educes DNA sy n t hesis, decreases
cellular proliferation and induces local immunosuppression. While sunlight usually
improves psoriasis, burning o f t h e s k i n m a y c a use K oebner p h enomenon and
e xacerbation o f p s o r iasis. Climatotherapy combining sea b athing w i t h U V a r e

especially effective.
Artificial UV light is produced by fluorescent bulbs in short-wave UVB (280-320

nm) or long-wave UVA spectrum (320-400 nm). The whole body can be exposed to UV
in special phototherapy cabins but there are also small devices for limited affected

areas (scalp, palms, and soles). There are different types of phototherapy:
narrow-band UVB of 311 nm, more effective than broadband UVB
PUVA photochemotherapy combines the oral administration of a photosensitizing

agent (8-methoxypsoralen Oxoralen) with UVA irradiation

excimer laser UVB therapy delivers high-dose light to limited plaques
Systemic therapy is i n d i cated when t o p ical t herapy a nd p h o t otherapy have b een
unsuccessful or in complicated forms (erythrodermic psoriasis, generalized pustular

psoriasis, psoriatic arthritis):

Methotrexate is a folic acid antagonist with immunosuppressing effects through
inhibition of DNA synthesis in tissues with high rates of turnover (such as psoriatic

plaques); the weekly dose is 10-20 mg orally, divided in 3 doses at 12h interval.
Methotrexate can induce anemia, leukopenia, liver (elevated transaminases) and lung

fibrosis or aggravate kidney disease. Methotrexate has to be stopped when leukocytes

are under 3000/mm', haemoglobin is under 10g% or transaminases rise above normal
values.
Retiwoids are vitamin A d e r i v atives that control t he a bnormal keratinisation.
Etretinate (Tigason) was first used and t hen i t ' s m or e active derivative acitretin

(Neotigason). Side effects: transitory hyperlipemia and teratogenity. Contraception is

m andatory i n f e r t ile w o men fo r t h e t r eatment p eriod an d o n e m o r e y e ar. Th e
combination of retinoids with PUVA (Re-PUVA) is very efficient.
Cyclosporin inhibits the activity of T h e lper lymphocytes and proinflammatory
epidermal cytokines. Side effects: renal toxicity. It i s v ery expensive. It can not be
combined with UVA, as it enhances the risk of cutaneous carcinogenesis.
125

Biological therapies are relatively new systemic therapies that provide selective
intervention at key steps in the pathogenesis of the disease:
inhibit the initial cytokine release and the Langerhans cell migration
prevent further T-cell activation and eliminate pathogenic T-cells (alefacept)
block cell-to-cell interactions that lead to T -cell activation and m i gration into
tissues (efalizumab, a humanized monoclonal antibody)
alter the balance between T-cell types
inhibit the proinflammatory cytokines: infliximab, adalimumab (both anti TNFg
monoclonal antibodies) and etanercept (TNFa Ig-receptor protein) inhibit alfa-

tumour-necrosis factor (TNFa).

PARAPSORIASIS
Parapsoriasis is a group of erythematosquamous diseases that clinically resemble
psoriasis, but are different in respect to pathogenesis, histopathology and response to treatment.
There are two types of parapsoriasis with different variants:

Pytiriasis lichenoides (Guttate parapsoriasis, Mucha-Haberman disease)

Is a rare disorder of unknown etiology with two clinical presentations:

pityriusis lichenoides et variolifonnis aclta (PLEVA): sudden onset of multiple

reddish-brown or purpuric papules that rapidly progress to pseudovesicles with
central necrosis and heal with varioliform scars. Sometimes high fever is associated
with coalescent necrotic ulcerations (Fig.11.17).

pityriasis lichenoides chronicu (PLC): small, benign-appearing papules, covered by

fine scales, similar to frosted glass
In both presentations, the lesions appear symmetrically on the trunk, buttocks and
proximal extremities. Lesions of PLEVA and PLC are often found together. They may selfinvolute over weeks or have an ondulatory evolution for m o nths or y ears. Pytiriasis

lichenoides is considered a self-limited self-healing lymphoproliferative disease.

Treatment
Phototherapy (sun exposure, PUVA, UVB) may result in clearing. Oral antibiotics

like tetracycline and erythromycin may have an immunomodulatory activitiy.

Parapsoriasis en plaques
Large plaque parapsoriasis and small plaque parapsoriasis are 2 diseases caused
by T-cell infiltrates in the skin. They differ in respect to the capacity of progressing to

mycosis fungoides (MF), a form of cutaneous T-cell lyrnphoma (CTCL).

as well-circumscribed, slightly scaly,
Small plaque purapsoriusis manifests
elongated fingerlike patches, with less than 6 cm in diameter on the lateral thorax
are asymptomatic,
and abdomen, f o l l owing t h e d e r m atomes. Th e l e sions

occasionally slightly itching. Small plaque parapsoriasis is a benign disease that

can last for several months to years and rarely if ever progresses to malignancy.
Large plaque parapsoriasis manifests as faint erythematous patches > 6 cm
diameter with arcuate geographic borders, on the proximal extremities and trunk

The lesions show thin scales and central cigarette-paper-like atrophy. Large plaque
parapsoriasis can progress in 10% of cases in CTCL. Controversies exist in tb<
126

terminology, as some consider large plaque parapsoriasis to be equivalent to the

early stage of CTCL, the patch stage.
Treutment
In small plaque parapsoriasis, emolients and mild topical corticosteroids reduce

scaliness and pruritus. Phototherapy (UVB, PUVA) can induce remission.

In large plaque parapsoriasis, treatment may prevent progression to MF (CTCL).
Beside mid-to potent topical corticosteroids and phototherapy, chemotherapeutic agents
g<e nitrogen mustard and topical carmustine can be used. Follow-up every 6 months is
recommended. Possible progression should be considered when lesions grow in number

and size, induration or epidermal atrophy develops. These situations suggest a need for
reevaluating by skin biopsy.

LICHEN PLANUS
Lichen planus is a pruritic subacute or chronic papular dermatosis localized on the
skin and mucous membranes.

Etiopathogeny
It is most likely a cell-mediated immunological reaction with u n k n ow n o r igin.

Viral infection (HCV hepatitis), stress, drugs (antimalarials, gold salts, isoniazid) have
been suspected to elicit the disease. Autoimmunity has also been suspected, based on the
presence of lichen planus antigens" detected by immunofluorescent methods.

Clinical f'indings
The name of lichen derives from the typical appearence of aggregated papules that
resembles that of lichen growing on rocks and trees.
The lesions appear first on wrists and anterior calves and then they spread on the

whole body (Fig. 11.18). The typical lesions of lichen planus are violaceous, poligonal
(delimited by the natural skin lines) papules 1-3 mm in size, with shiny and plane surface
that reflects light. Adjacent papules can coalesce to form p l aques. After healing
characteristic hyperpigmented macules remain (Fig.11.19). Pruritus is common. Sometimes
the papules located especially on the anterior shins become extremely pruritic, brown-red

to blue-red, larger and thicker, hyperkeratotic (hypertrophic lichen planus Fig.11.20).

This form is very resistant to treatment.
Characteristic fine, milky-white network can be observed on the surface of the
papules, called Wickham stria and representing focal thickening of the statum granulosum

(Fig.11.21). On sites of skin injury new lichen papules appear (Kobner sign-Fig.11.22).
M ucous membrane i n v olvement i s c o m mo n a n d m a y o c c u r w ithout s k i n
involvement. On the buccal, genital and anal region striated, reticular, arborizing, or

ramifying whitish lesions appear, called leukoplasia, explained by aberrant thickening of

granular layer (Fig.11.23). They are asymptomatic but erosions that may add are painful.
Some of the mucous membrane lesions may develop in carcinoma (facultative precancer).
The nails can be involved and also the scalp, with permanent hair loss.

127

Histopathology

epidermal changes are

The papule i n l i c hen p l a nu s i s d e r m o-epidermal:
a band-like
acanthosis, orthokeratosis and hypergranulosis. Beneath the epidermis
inflammatory infiltrate can be seen. Degenerated basal cells release melanin that is taken

up by dermal macrophages resulting in hyperpigmentation.

Course
Lichen planus is a self-limited disease that usually resolves within 6-12 months.
Recurrences after healing are quite often, even after years. Oral lichen has a mean duration
of 5 years. Hypertrophic lichen planus is usually chronic.

Treatment
Topical steroids with high activity are the first-line therapy of lichen planus. In

hypertrophic forms corticosteroids can be applied under occlusion (covered by plastic

sheets) or, as intralesional injections (triamcinolone acetonide suspension).
Systemic steroids are used for e xtensive disease and m ore r apid r e gression.
Prednisolone 20-40 mg is administered daily for about 3 weeks with slowly reduction of
the doses. Other options are retinoids, such as acitretin (Neotigason), PUVA, UVB.

PITYRIASIS ROSKA
Pityriasis rosea is a common, acute but benign, self-limited inflammatory disease

that appears on the trunk in adolescents and young adults (18-35 years). Pityriasis denotes
fine scales and roseatranslates as rose colour or pink.
The etiology is probably viral, linked to herpes virus type VII. Others consider it
an allergic reaction to a viral respiratory tract infection. It is more frequent in the spring
and autumn. It is not contagious and a single outbreak tends to elicit lifelong immunity.

Clinical findings
The disease begins with a typical, single plaque ( medallion" or herald plaque)
usually on the trunk. It is pink, oval, 2-7 cm in diameter, with pseudoatrophic, slightly
depressed centre, like cigarette paper and with a collaret of fine scale just inside the welldemarcated border. The herald patch is mistaken as ringworm or psoriasis (Fig.11.24).
Within the next 1-2 weeks, symmetrical round to oval scaly patches appear, that
resemble the primary plaque but are smaller. They are found on the trunk, with the long
axes following the rib lines, like a fir tree, but also seen on the neck, upper third of the
arms and thighs. Facial involvement is rare, except in African Americans. The palms and
soles are not i n v o lved an d t h ere i s n o l y m p h adenopathy, w h ich d i stinguishes the
condition from secondary syphilis. The eruption gradually resolves within 6-8 weeks.
Pruritus is commonly m il d an d b ecomes moderate severe with i n appropriate
treatment. The disease is very irritable under some physical factors: frequent hot baths,
rubbing, exercise, leading to atypical forms that have to be differentiated from psoriasis,
urticaria, eczema, secondary syphilis.

Treatment
Topical corticosteroids, antihistamines and UVB can be used to reduce the itching
Systemic treatment is not necessary, because of the spontaneous tendency to regression.
128

Fig.11.1. Psoriasis vulgaris

Fig.11.2. VA6tening psoriatic lesion (1)

3$

Fig.11.3. Koebner sign in psoriasis

Fig.11.5. Gener~

psor i a sis

Fig.11.7. Guttate psoriasis

Fig.11.4. Typical location of psoriatic lesions

Fig.11.6. Nail psoriasis

Fig.11.8. Nummular psoriasis

Fig.11.10. Palmo-plantar pustular psoriasis

Fig.11.9. Psoriasis inversa

"'4.

1
>I

!sE.W

Fig.11.11. Acrodermatitis continua Hallopeau

Fig.11.13. Psoriatic arthritis

Fig.11.15. Crisophanic erythema

Fig.11.12. Generalized pustular psoriasis

Fig.11.14. Erythrodermic psoriasis

Fig.11.16. Perilesional white halo of Vorono~

Fig.11.17 Acute guttate parapsoriasis

Fig.11.18. Lichen planus

Fig.11.19. Hyperpigmented macules

after lichen planus

Fig 11.20. Hypertrophic lichen planus.

Fig.11.21. Wickham striae

Fig.11.22. Koebner sign in hchen planus

Fig.11.23. Leukoplasia in lichen planus

Fig.11.24. Pytiriasis rosea

131

Chapter 12
G ENOI3ERM A T O S E S
Genodermatoses are skin diseases caused by gene mutations or, more rarely by
chromosomal anomalies. Sex-linked genodermatoses result when a gene from a sexual
chromosome is involved. Autosomal genodermatoses result when the mutation involves a
gene from an autosomal chromosome.
The recessive inheritance is caused by genes that are capable of exerting their full
effect only in homozygous state (the patient has mutated genes from both mother and
father). The recessive diseases are rare. The parents do not have the disease, but they have
affected relatives.
The dominant inheritance is caused by a gene that is capable of exerting its full
effect when present on only one chromosome in the pair (heterozygous state). In this case
the mutated gene comes from only one parent, who has the disease. Mutations de novo
can also exist.
T he probability fo r a m u t ated gene to p r o d uce the d i sease depends on t h e
expression of the gene. The frequency with w h i ch a g e ne produces a disease is called
penetrance.

DISORDERS OF KERATINIZATION
ICHTHYOSIS
The Greek w ord

ic h thys m eaning " f i s h" i s c o n s idered the r o ot o f t h e t e r m

ichthyosis that encompasses a heterogeneous group o f

d i seases with a bnormal

differentiation of the epidermis presenting with excessive scaling.

Ichthyosis vulgaris is the most common form of ichthyosis. Most of the cases are
inherited as autosomal dominant genetic disorder but acquired forms also exist, secondary

to systemic diseases, including malignancy (leukemia, lymphoma, multiple myeloma,

hypervitaminosis A, pellagra, chronic renal failure, hypothyroidism, sarcoidosis, leprosy,
dermatomyositis etc) o r t o c e r t ai n m e d ications ( cimetidine, i soniazid, allopurinol,
retinoids). Inherited form appears in early childhood, intensifies up until puberty and then
decreases with age, while acquired form appears at adult age and follows the severity of
the associated systemic disease.
Ichthyosis vulgaris is caused by a defective synthesis in f'Ellagrin, an epidermal
protein responsible for the skin barrier function. Genetic mutation that causes ichthyosis
vulgaris is a major predisposing factor for atopic dermatitis, thus the two diseases are

frequently associated.
T he clinical aspect i s s i m i lar i n b o t h f o r m s o f i c h t h yosis v u l garis an d i s
characterized by symmetrical dryness and scaling of the skin of v ariable severity. The
scales are small (1mm-lcm), polygonal, curled at the edges and more expressed at the
lower a nd e x tensor e x t r emities (F ig.12.1). Palms and s oles ar e i n v olved w i t h
133

hyperkeratosis and accentuated skin m arkings while the flexural areas (neck, axillae,

antecubital and popli

tealfolds) are spared. Keratosis pilaris (follicular hyperkeratosis) is
associated on the cheeks, neck, dorsum of the upper arms, buttoks and thighs. Pruritus,
caused by dry skin leads to scratching and erythema. Symptoms improve during summer

and with age.

Biopsy shows moderate orthokeratosis and reduced or absent granular layer.
X-linked ichthyosis i s t h e s e cond m o st c o m m on t y p e o f ic h t h y osis. It i s
transmitted only to m ales by heterozygous mothers as an X-linked recessive trait. The
cause is a deficiency of steroid sulfatase, leading to delayed dissolution of desmosomes in
the stratum corneum.
Onset is usually before 3 months of age with a "dirty" appearance of the posterior
and lateral neck, upper trunk and extensor surfaces of the extremities due to dark, large
and prominent scales. The flexures, palms and soles are spared. Corneal opacities (which
do not affect vision ) and cryptorchidism predisposing to testicular cancer are frequent
associations. Unlike vulgar ichthyosis, the extent and severity gradually worsen with age.
Skin biopsy demonstrates normal granular layer with hyperkeratosis.

The diagnosis can be established by: a) genetic studies done prenatally; b) the
assessment of the reduced activity of steroid sulfatasein the placenta or after birth in the
peripheral leukocytes; c) l i p oprotein e lectrophoresis w h er e L D L s migrate f aster

demonstrating increased cholesterol sulphate (a substrate of the steroid sulfatase enzyme )

in the blood.
Treatment of ichthyosis is continuous and includes hydration of the skin (alphahydroxy acids, urea) and application of an ointment to prevent evaporation.
There are other forms of ichthyosis that are rare, are apparent at birth and continue
throughout life, showing dramatic aspects:
epidermolytic hyperkeratosis autosomal dominant, with wi d espread denuded
areas and bullae and later development of hyperkeratosis; it improves with age
congenital ichthyosiform erythroderma autosomal recessive; the new-born is

enclosed in a tough, firm membrane collodion-like or "baked-apple"-like which

fissures when stretched; this peels of within 2 weeks, followed by red skin and fine
scales that generalize, including the face and large folds
lammelar ichthyosis autosomal recessive, with collodion-like membrane that
peels of within 2 w e eks, followed by l arge scales with free edges and central
adhesion
Harlequin fetus autosomal recessive; the m o st s evere form w i t h m a s sive
hyperkeratotic plates, limb deformities, rudimentary ears, ectropion and eclabium,
leading to death usually within a week.

DARIER'S DISEASE (KERATOSIS FOLLICULARIS)

Darier's disease is a dominantly inherited disorder of keratinization characterized
by early keratinization (dyskeratosis) and acantholysis mainly at the hair follicles.
It usually appears in young adults as greasy, brown keratotic papules that coalesce
in plaques in seborrheic areas (behind the ears, about the nose, on the forehead, scalp,
1
neck, shoulders, groin, chest and midline of the back). The eruption is symmetrical an
134

becomes worse during summer, especially after sunburns, with malodorous vegetating
growths (Fig.12.2, 12.3). Flat, wart-like papules may be seen on the dorsa of the hands
(Fig.12.4) and shins and punctuate keratosis may be present on the palms and soles. Nails
are fragile, with i r r egular ni cks of t h e f ree edges. Oral and r e ctal m u cosal surfaces
demonstrate s m all , c o b blestone-like p a p u les. H e r pe s s i m p le x i n f e ction b e c omes
widespread and severe in these patients.
Biopsy shows acantholytic dyskeratosis. Acantholysis results from the detachment
at the desmosome/tonofilaments level and is seen as a suprabasal cleft. Dyskeratotic cells
appear as round eosinophilic cells (corps rounds) in the lower layers of the epidermis and

flat, deeply basophilic cells (grains) in the upper layers of the epidermis.
Treatment is not able to cure the disease, but reduces the flares. Moisturizers
containing urea, lactic acid, salicilyc acid or t o pical corticosteroids reduce scaling and
irritation. Oral retinoids (Neotigason) are the drugs of choice for more severe cases, but
toxicity (teratogenicity) limits their use.

BENIGN FAMILIAL CHRONIC PEMPHIGUS (HAILEY-HAILKY

DISEASE)
This form o f

p e m p h i gus i s a n a u t o somal d o m inant i n h erited s ki n d i sease

characterized by acantholysis due to d efective formation of t o nofilaments-desmosome

complexes. In addition to the primary gene defect, contributing factors like sun exposure,
friction and infection (microbian or micotic) are known to exacerbate the disease.
I tching erythematous plaques with v e sicles that break and f o r m c r u sts w i t h

peripheral spread are formed especially in the intertriginous areas (neck, inguinal-Fig.12.5,
axillae-Fig.12.6 and p e r i anal r e gion). Th e e v o l ution i s c h r o ni c w i t h r e l a pses and
remissions.
Treatment includes soothing compresses followed by intermittent use of topical
antibiotics, animicotics and mild corticosteroids.

INHERITED KPIDERMOLYSIS BULOSA

This group of diseases, also called "Mechanobullous disorders" represent rare,
I

gene t i cally determined disorders that have in common blister formation after trauma of
the skin or m u cosa. They usually appear at b i rth o r i n i n f ancy bu t c ause problems
throughout life.
The cause is defective formation of structural proteins responsible for dermoepidermal adhesion. Depending on the level of the cleft, there are 3 main varieties (each

with numerous subtypes) of inherited epidermolysis bulosa (EB):

1. EB s i m p l ex autosomal d o minant; t ra uma r e sults in e p i d e rmal b u l l ae d ue t o
production of defective tonofilaments in the basal cells.
Blisters may be present at birth, but more often when the child starts to crawl and
walk. Sometimes the disease is not diagnosed until increased pressure is generated on
skin surfaces, like marching in the military. Mild blisters and desquamation develop
on hands, knees, feet or other sites subject to repeated trauma and h eal w i t hout
scarring, sometimes with milia (keratin cysts) formation. Usually the mucosa and nails
are not involved.
135

2. Junctional EB autosomal recessive; the bullae appear between the epidermis and
dermis, at the level of lamina lucida due to alteration in laminin 5.
The blisters form l a rge denuded areas with l i t tl e t endency to h eal, m u cous
membranes are severely involved and the teeth are abnormal. A high proportion of
these children die in infancy.
3. Dy s trophic EB
both autosomal dominant and recessive; subepidermal blisters result
due to defective anchoring fibrils (collagen VII) that connect the basement membrane to
the dermal collagen.
The dominant variant is not very severe, showing a tendency to become localized

and less severe with age (Fig.12.7). Bullae heal with scars and milia, while hair and
teeth develop normally.
In the recessive variant hemorrhagic blisters appear at birth and heal with scarring
and formation of w ebs between fingers. Eventually a useless fist results (Fig.12.8),
s ynechia), h a i r
conjunctival
Mucous m e mbranes ( esophageal strictures,
abnormal an d s q u amous ceQ

( pseudopellade-type alopecia) and teeth may be

carcinoma may develop over the scars.

As the clinical and histological picture is not specific to one form o f EB, the
electron m i c r oscopy and
diagnosis is e s t ablished by im m u n o f iuorescence,
immunomapping. Th e l a tter t echnique i n v olves antibodies directed against k n own
oca e at specific sites in the skin i n o r der t o d etect the level of the blister
pro
roteins
eins located
formation.
There is no specific treatment for t hi s group o f d i sorders. Trauma has to be
minimized to prevent new blisters (soft shoes, for infants padded trousers). Emollients

minimize shearing forces. Occupational therapy may

d elay th e d evelopment of

contractures. Specialist dental care is needed. Antiseptic treatment of the wounds prevents
superinfection.
Parents of children with EB should benefit for genetic counselling and should be
informed about the possibility of prenatal diagnosis by fetal skin biopsy at around 9 weeks

of gestation.

136

Fig.12.1. Ichtyosis vulgaris

Fig.12.2. Darier's disease

lb

4P

Fig.12.3. Folicular keratosis

in Darier's disease

Fig.12.4. Wart-like papules in Darier's disease

Fig.12.5. Hailey-Hailey disease

Fig.12.6. Hailey-Hailey disease (axila)

Fig.12.7. Dystrophic epidermolysis bulosa

Fig.12.8. Dystrophic epidermolysis bulosa

137

Fig.13.1. Epidermal nevus

Fig.13.2. Sebaceous nevus

Fig.13.3. Nevus Hammeus

Fig.13.4. Nevus anemicus

Fig.13.6. Aquired

Fig.13.5. Congenital nevus

melano
ticnevi;

histopathologically compound type

Fig.13.8. Dermatoscopical image of

traumatized nevus from Fig.13.7

Fig.13.7. Aquired melanocytic nevi

138

Chapter 13
NEVI (moles, birthmarks}

Nevi are circumscribed malformations during embryonic development.

Classification:
depending on the time they appear
o c o n genital nevi are present at birth or appear later in life
o a c q uired nevi appear after later in life, usually until early adulthood
depending on the type of the dominant cells
o o r g anoid nevi
o n e v ocytic nevi

Organoid nevi
Epidermal nevus ( often zoniform) s hows v e rrucous, skin-coloured or b r o w n

papules that coalesce to form a serpiginous plaque (Fig.13.1). It appears at birth or in the
first 10 years of life and persists indefinite.

Nevus sebaceous of Jadassohn(Fig.13.2) occurs preferentially on the scalp as a

congenital, alopecic plaque that is yellow, soft, elevated and flat, measuring from several
mm to cm. The lesion persists through life. N evus sebaceous can develop into basal cell
carcinoma.
Vascular nevi are represented by:
nevus fl ammeus (F ig.13.3) c ongenital m a l f ormation o f t h e d e r m al b l o o d
capillaries which are dilated; it is present at birth, grows commensurate with the
child and has no tendency to involute; it is unilateral, initially pink-red to purple,

flat (macule) and later evolves into deep-red to purple, raised, thickened plaque,
studded with vascular papules prone to bleeding; treatment: pulse-dye-laser
nevus anemicus (Fig.13.4) congenital disorder characterized by a pale macule
that looks like vitiligo but cannot be made red by trauma, cold or heat and the
number of melanocytes is normal; the vascular structure is also normal but there is
an increased sensitivity to cathecolamines.

Melanocytic nevi (nevocytic nevi)

Nevus cells or nevocytes are round, nondendritic cells that are closely related to
the melanocytes. Melanocytes and nevocytes both originate from the neural crest and are
capable of melanin synthesis, but melanocytes are scattered within the basal layer of the
epidermis, while nevocytes form small groups, known as nests, at the dermoepidermal
junction or in the dermis.
Melanocytic nevi are benign proliferations of m elanocytes, arranged in nests,
either in the form of a congenital, circumscribed malformation / hamartoma (congenital
melanocytic nevi) or a benign tumor (acquired melanocytic nevi). An increased number
of melanocytes, like in lentigo, without arrangement in nests, is not enough to define a
nevus.
The prevalence of nevi is lower in dark skin, where they are specially located on
acral areas, while light-skinned individuals not uncommonly have large nevi (> 1 cm), in

139

high number (> 50), located mostly on the trunk. The number of nevi is high in children with poor
sun intolerance.

Congenital nevi (Fig.13.5)are subdivided into large (> 20 cm), medium-sized (1.5
19.9 cm) and small {( 1.5 cm). They are present at birth (especially the large and medium-

sized) or appear during childhood and puberty (small congenital nevi). Sometimes,
congenital nevi have terminal hairs. The melanocytic nests extend down to the reticular
dermis. Their occurrence is independent of exposure to UV r ays. The high number of
congenital nevi correlates with a higher risk of melanoma.
Nevus Spilus is a variant of congenital nevus with variously pigmented dots that
are rised or flat on a light brow macule.
Sutton nevus (halo nevus) occurs mainly in ch ildren and adolescents as small
congenital nevi with a hypopigmented halo. This is more likely due to an immune reaction
that sometimes leads to complete disappearance of the nevus.
B oth Miescher nevus and U n n a n evus h ave similar h i stopathologically w i t h
congenital nevi presenting with dermal melanocytic nests. Both appear around puberty.
Miescher nevus is a dome-shaped nodule on the face, skin-colored or light brown, rarely
dark-brown and sometimens with terminal hairs. Unna nevus appears usually on the

trunk as papillomatous, soft, occasionally pedunculated skin-colored or brown papule.

Acquired nevocytic nevi, called Clark nevi (Fig.13.6,13.7) appear after the age of 2
until 35-40 years, with increasing numbers throughout childhood and early adulthood and
slowly involute towars advanced years. Their pigmentation is related to the skin color, so
that light-skinned persons have less-pigmented and non-pigmented varieties. The clinical
s pectrum varies from small m acules of fe w m i l l i m etres to p l aques up t o 1 c m , o f
symmetrical aspect. Acquired nevi typically have less than 1 cm in diameter. Clark nevi
appear on the trunk and the proximal parts of the extremities, not on the face or acral
areas. Ultraviolet radiation favors the appearance of acquired melanocytic nevi especially
in children with poor sun tolerance.

Atypical moles or dysplastic nevi are acquired nevocytic nevi that usually appear
after puberty an d a r e c onsidered t o h a v e a h i g h r a t e o f m e l anoma d evelopment.
" Atypical" r e fers t o t h e a b n ormal c l inical aspect, according t o t h e A B CD E r u l e asymmetric, irregular borders, mottled color, diameter > 6m m

a n d e l evated surface.

"Dysplastic" refers to the abnormal histological aspect (atypia of melanocytes). But

atypical mole is sometimes difficult to be clinically distinguished from melanoma and, on
the other hand, histological "dysplasia" in nevi can not predict melanoma development.
Thus the terms "atypical" an d " d y splastic" are controversial and t h ere are opinions
sustaining that they should no longer be used.

Dermatoscopy (epiluminiscence microscopy) is a non-invasive optical method that

allows the o bservation o f p i g m ented structures in t h e e p i d ermis, d ermo-epidermal
junction and upper dermis. These colors and structures are otherwise not visible to the

unaided eye and have specific histopathological correlates. Thus, dermatoscopy improves
the clinical diagnostic accuracy (Fig.13.8).
Histopathology is the gold standard in the diagnosis of melanocytic nevi, thus
only the pathologist is able to establish the correct pathological diagnosis, while 'el
th<
clinician just predicts it, based on the clinical presentation. The nevi cannot be definite y
'

140

distinguished only upon clinical aspect. The nests of melanocytes can be located at the
dermoepidermal junction or in the dermis (papillary or reticular dermis). In interpreting
the behaviour of a nevus, the morphopathological aspect plays a leading role, so that we
will use this criterium to classify nevi.
Malignant transformation of nevi is more frequent in patients with positive family
history of melanoma (inherited risk) or can be triggered by exogenous factors like trauma
Qf the nevi and brutal sun exposure (sun burning).
Clinical features suspicious of malignant changes in a nevus are:
sudden increase in surface area;
borders become irregular, notched and ill-defined

)
)

pigmentation increases, different colors (pink, brown or black) appear

signs of focal regression
p r u r i t us, pain
inflammation
e r o sion and bleeding
irregular surface with macular and papular areas (fried-egg appearance")

Treatment
Patients with multiple nevi need to be educated about the importance of self-skin
examination, watching for new and changing lesions. The entire cutaneous surface should
be examined every year. Not all melanomas will exhibit the classic ABCDE rule (e.g. they
may be less than 6 mm), therefore always be suspicious about changing nevi and consider
an excision and a biopsy to rule out the dev lopment of malignant melanoma.
Intensive sun exposure and UV tanning beds have to be avoided and sunscreens
with SPF at least 30 are to be used on skin areas exposed incidentally to sun. Sun has to be
avoided and/or protective clothing has to be used between 12 a.m. and 4 p.m.
Because melanoma may develop de novo on the skin (on healthy skin, without
previous nevi) and because the risk of any one atypical mole to progress to melanoma is
low (considering the immense number of nevi in the general population ), prophylactic
excision of all atypical moles does not prevent melanoma and is not recommended. The
nevi that must be removed and examined histologically are the ones that change along a
few months and are clinically worrisome for melanoma.

141

Chapter 14
B ENIGN TUM O R S

BENIGN EPITHELIAL TUMORS

B enign ep ithelial t u m or s ca n a r ise f r o m t h e i n t e r f ollicular e p i d ermis, t h e

epithelium of hair follicles, or the epithe

liumof the ducts of the sweat glands.

Seborrheic keratosis (seborrheic wart)

Seborrheic keratoses are the most common benign tumors in older indivi duals.
They usually appear after the age of 40, on the trunk and face. The early lesion appears

as a sharply defined yellow-brown macule (Fig.14.1) which develops a velvety to

verrucous surface, covered by a greasy brown scale, with comedo-like black keratotic
p lugs (Fig.14.2). W it h t i m e , t h e l e s ions b ecome t h i cker an d h a v e a "s t u c k o n "
appearance. Sudden occurrence of a large number of seborrheic keratosis may indicate
development o f a v i s c eral m a l i gnancy, especially a d enocarcinoma o f t h e g a s trointestinal tract (paraneoplasic syndrome Leser Trelat, Fig.14.3).
The lesions do not need to be removed unless annoying or become irritating.
Keratolytic agents can be used (ammonium lactate lotion 12 or 15%, tricloacetic acid
100%), cryotherapy w i t h l i q u i d n i t r o gen o r e l e c trodessication. I f h i s t o pathology
confirmation i s n e e de d t o di f f e r entiate a s e b o r r heic k e r atosis f r o m m a l i g n ant
m elanoma, basal c el l c a r cinoma o r s q u a m ou s c el l c a r cinoma, s u r gery p r o v i d es
histological material and removes the lesion.

Keratoacanthoma
Originates in the pilosebaceous follicle and represents tumor characterized by
the proliferation o f a t y p i c al, h i g hl y d i f f e r entiated s q u amous c e lls. I t r e s embles
clinically and pathologically squamous cell carcinoma (SCC), but it is characterized by
a benign c o urse an d s p o n taneous regression w i t h i n 1 y e a r . K e r atoacanthoma i s
characterized by a rapid growth, within 2-3 weeks, of a dome-shaped nodule of 1-2 cm,
with smooth shiny surface and central crateriform ulceration or keratin plug that may

project like a horn (Fig.14.4).It usually occurs on uncovered sun-exposed areas, like
face, neck, dorsum o f t h e u p per extremities. To d i stinguish keratoacanthoma fr om
SCC, deep excision of the whole lesion is necessary, to observe the symmetric aspect of
the whole lesion. After shave biopsy, keratoacanthoma might look similar to SCC.
Treatment: surgical excision, laser therapy or cryotherapy can be used in small
lesions and radiotherapy i n l a rge and n u m erous t u m ors. Injection of m e thotrexate,
bleomycin under the lesion is another option in inoperable tumors.

Syringoma (hidradenoma)
Are benign neoplasms considered to differentiate along the ducts of the eccrine

sweat glands. They appear as skin-colored, round or flat-topped, small (3 mm) papules
{often mistaken for xanthelasmas or milia), sometimes with cystic aspect. The lesions
143

are multiple symmetrical distributed, on the upper cheeks and lower eyelids (Fig.14.5),
cosmetic reason an d c o n sists of
c hest, l o w er a bdomen, p e n is. T r e atment h a s

electrosurgery, laser therapy or cryotherapy.

b>
bt

cl
hi

Epidermal and pilar cysts

Keratinous cysts have been incorrectly named as sebaceous cysts. There are
two types of keratinous cysts: a) epidermal cysts that result from t he i m p l a ntation of

re
p(

epidermal elements in the dermis, more frequently from the infundibular region of the
o cysts arise from the outer root sheet of the

hair follicle (Fig.14.6a);b) pilar (trichilemma

re
T(

hair follicle at or distal to the level of sebaceous duct (Fig.14.7).

fh

The cysts appear as hemispherical, skin-colored, painless nodules. Epidermal

Si

cysts occur on any part of the skin (face, trunk, scalp scrotum, extremities, fingers),
while pilar cysts occur mostly on th e scalp. A central pun ctum exists in epidermal
cysts, from w h i c h a t h i c k f o u l - smelling cheesy m aterial i s s o m etimes expressed,
while in p i la r cy sts there is no p u n ctum. They are asymptomatic but ma y b ecome

inflamed (Fig.14.6b) or secondarily infected, resulting in pain and tenderness.

ot

Histologically the two variants differ: the epidermoid cyst is characterized by

cornified epithelium with well-defined granular layer and multiple lamellae of keratin;

of

the pilar cyst has a trichilemmal keratinisation pattern that lacks the granular layer.

er

Very rarely, malignant transformation can occur (BCC, SCC).

Treatment: surgical excision.

p(

eI

BENIGN MESENCHYMAL TUMORS

d<
h<

13ermatof ibroma
This is a c o m mon t u m o r o f

t h e e x t r emities, particularly th e l o w e r l e gs. It

usually occurs as a solitary nodule that hardly exceeds the size of 3-8 mm and is firm,

grey-brown, slightly raised, usually set into the skin like a lens or a pastille (Fig.14.8).
Dermatofibroma are characteristically asymptomatic but i t c hing an d p ai n ar e often

noted. A useful clinical sign for diagnostic is the dimple sign: the overlying epidermis
tethers to the underlying lesion with lateral compression.
Treatment: excision, for symptomatic lesions.

Fibroma pendulum (acrochordon, skin tag)

These are small, skin-colored to dark-brown, sessile or pediculated papilomas
that commonly occur on th e n eck, axillae, eyelids and l ess often on th e t r un k an d

groins (Fig.14.9, 14.10). Occasionally, as a result of twisting the pedicle, the lesion
becomes inflamed, tender or even gangrenous. Fibroma pendulum o ften increases in

size with age (Fig.14.11) but mostly with gaining weight or pregnancy. Histologically,
they are characterized by epidermis enclosing a dermal fibrovascular stalk.
Treatment: cryotherapy, electroexcision, l a ser t h e r ap y w i t h or

without

anesthesia, depending on the size of the lesion.

Keloid

of scar

Keloids and h y p ertrophic scars ar e e xagerated g r o w t h s

developing after a deep (dermal) skin injury that can be physical (piercing,
144

t i s s

surgery

cO

(e
uz

bruns etc) or pathological (acne scars, chickenpox). Keloids usually extend beyond the
borders of th e o r i ginal w o u nd , w i t h

c l a w - l ike aspect (the Greek chete, mean crab's

claw) and have no tendency to regress spontaneously (Ftg.14.12). They differ from
hypertrophic scars that d o n o t e x t end b eyond th e i n i t ial i n j ur y a n d m a y p a r t i ally
regress spontaneously within 12-24 months. Both are erythematous and may be tender,

painful and puritic.

Keloids are t r eated w i t h

i n t r a lesional i njection o f t r i a m cinolon su spension,

repeated at 4-6 weeks, as required. Other treatment is p u lse dye laser. Both reduce
TGF-P, know n t o b e i n v o l v e d i n k e l o i d f o r m a t ion. C r y o therapy, i n t r alesional 5f luorouracil an d c a l c i u m-channel b l o ckers ( V erapamil) a l s o h a v e some efficacy.
Silicone sheeting and pressure are adjunctive methods to reduce recurrences.

Hemangioma s
These are benign tumors of blood vessels of the skin, mucous membranes and
other organs, characterized by the proliferation of the endothelial cells.
Infantile hemangioma is present at birth or appears in the first several weeks
o f life. It c h aracteristically g r ow s r a p i dl y d u r i n g t h e f i rst 6 m o n th s o f l i f e d u e t o
endothelial cell p r o l i f eration an d t h e n s l o w l y b u t s p o n t aneously i n v o l u tes ( 70%
completely involute by the age of 7). The skin may return to normal but in most cases
permanent skin changes remain in the form of t elangiectasia, dilated venes, scarring,

epidermal atrophy or hypopigmentation.

It appears as a vascular proliferation of different size (0.5 20 cm) and depth,
d ome shaped, bosselated, plaquelike or t u m o r al. The color i s b r i gh t r e d w h e n t h e

hemangioma is

s u perficial (Fig.14.13), a nd purple o r

b l u ish w h e n d e ep. T h e

consistency i s f i r m , r u b b er y a n d t e n s e an d e x p ands w i t h i n t r a v ascular p r essure

( e.g.when th e b ab y c r i es). R arely, i n f a n til e h e m angioma ca n b e a s sociated w i t h
underlying congenital anomalies.
Treatment: laser surgery with pulsed dye laser is effective in both proliferating
and residual v e ssels f ro m h e m a n giomas; i n v o l uted h e m angiomas with r e si dual
cutaneous defects can be surgically excised. Propranolol works w ell i n l a rge infantile

hemagioma that compress vital organs (eyes), cause high-output cardiac failure or
result in deformation of the face.

Cherry angiomas (late angioma) appear as round, slightly elevated, 0.5-6 mm

ruby-red papules in a d ult p ersons (Fig.14.14). The number of c h erry angiomas
increases with age.
T reatment: e l e ctrodesication, l a s e r ablation,
reassurance and do not request removal.

but

m os t p at i e n t s a c c ept

Pyogenic granuloma (lobular capilary hemangioma)

Pyogenic granuloma i s a b e n ign v ascular t u mo r t ha t r esembles granulation
tissue. It is a misnamed entity, being neither inflectious, nor granulomatous. It occurs
in children and y o ung a d u lts as a gl istening red p apule or n o d ul e t hat g r ow s f ast,
within a few weeks, and is prone to bleeding and ulceration. The head (face, lips), neck
and distal extremities (fingers) are sites of predilection, but lesion can occur anywhere

145

(Fig.14.15, 14.16). The cause of the p y o genic granuloma is n ot k n o w n, b ut t r a u m a ,

hormonal influences, topical and systemic retinoids are implicated.
Clinically, acromic melanoma must be excluded.
Treatment: excision, electroexcision, laser therapy. It i s i m p o rtant to r emove
t he angiomatous pedicle w h ich e x tends deep i n t o t h e d e r m is, since i f i t i s o n l y
removed superficially, recurrence may occur.

146

Fig.14.1. Seborrheic keratosis on the back

Fig.14.2.Seborrheic keratosis

I
,I

'

II

jt

Fig.14.3. Leser-Trelat sign

Fig.14.4. Keratoacanthoma

Fig.14.5. Syringoma

Fig.14.6 Epidermal cyst (b. inflamed)

Fig.14.7. Trichilemmal cyst

Fig.14.8. Dermatofibroma

147

Fig.14.9. Axillary fibroma pendulum

Fig.14.11. Fibroma pendulum of the groin

Fig.14.10. Fibroma pendulum of the neck

Fig.14.12. Presternal keloid

Y.
Fig.14.13. Infantile angioma

Fig.14.15.
Pyogenic granuloma

Fig.14.14. Cherry angioma (red) and

seborrheic keratosis (brown)

Fig.14.16. Pyogenic granuloma

Chapter 15
PRE CANCEROSES
Precanceroses are skin conditions which pose a risk to malignant transformation.

Actinic keratosis (solar keratosis, keratosis senilis)

Actinic keratosis is a thickened scaly growth (keratosis)induced by UV (actinica)
that may progress to squamous cell carcinoma. It appears in fair-skinned persons after
long-term sun exposure, on any chronically sun-exposed area, but mostly on the forehead,
bald scalp, nose, earlobes, dorsal forearms and hands (Fig.15.1). Immunosuppression after
organ transplantation is another risk factor for actinic keratosis. However, actinic keratosis
does not occur without sun exposure.
Initially it is a well delimited thin keratosis that is easier felt, like sand-paper, but
later it enlarges, becomes thicker, with hard, dirty-brown surface. If the adherent horny
layer is tried to be removed, bleeding occurs. Many lesions can appear on one anatomical
area. Sometimes the keratinization is so prominent that a horn-like projection develops,
known as cutaneous horn (Fig,15.2).
After years of e v olution th e b ase of t h e l e sion ma y b e come infiltrated and
squamous cell carcinoma develops.

Actinic keilitis
Actinic keilitis usually develops on the lower lip, related to cumulative life-time
sun exposure. It is characterized by continuously dry an d f issured lip (Fig.15.3), white
patches (leukoplakia) t hat m i gh t p r o g ress t o s q u amous cell c a rcinoma. M a lignant
transformation is announced by infiltration, erosion and ulceration of the lesion.
Treatment of both actinic keratosis and actinic keilitis is warranted as they can be
cured and malignant progression prevented:
sun avoidance between 10 a.m. and 3 p.m., protective clothing, sunscreens
i
medi c al therapies:
o t o p i cal 5-fluorouracil (EFUDIX cream) 2x/day for 4 weeks has cytostatic
effect; it results in temporary intense erythema and erosions over the areas
of actinic keratosis (Fig.15.4)/ actinic keilitis
o i m i q u i mod 2-3 times/week for up to 4 months; immunoregulator
o t o p i cal diclofenac sodium gel 3%, 2x/day for 3 months
o p h o t odynamic therapy (PDT): application of delta-aminolevulinic acid, a
photosensitizer that accumulates preferentially in dysplastic cells of actinic
keratosis, is followed by exposure to light; this will generate oxigen free
radicals and cell death
surgical care
o c r y o therapy with liquid nitrogen or solid carbon dioxide
o e l ectroexcision or electrocauterisation
o s u r g ical excision for cutaneous horn

149

Radiation keratoses
Following prolonged X-ray therapy or

p r ofessional exposure (radiologists)

atrophic skin l e sions w it h t e l agiectasia and h y p opigmentation w i t h i n c reased focal

h yperpig
perpigmentation ma y a p p ear. Six-twelve m onths after i r r adiation, f i brotic, t hick,
adherent erythematous plaques are formed, characteristic for chronic radhodermabbs.
Radiation keratosis presents with f i r m ly a d h ering keratosis that cannot be r e moved
without pain and bleeding and that can transform 20-40 years later into squamous cell
carcinoma.
Treatment: excision.

Xeroderma pigmentosum
Is an autosomal-recessive disorder characterized by a) defective DNA repair after
UV insult; b) sun sensitivity and lentigines before the age of 2; c) actinic keratoses and skin
cancer before the age of 10. Basal cell carcinoma, squamous cell carcinoma, melanoma
often results in an early lethal outcome.

Bovren disease (sqamous ce11 carcinoma in situ)

Bowen disease or squamous cell carcinoma in situ is an intraepidermal carcinoma

with potential lateral spreading. Usually the lesion is unique, asymptomatic with very
slow progression, over months or a few years. The initial erythematous scaly patch may

become hyperkeratotic, crusted, fissured (simulating psoriatis plaques), or ulcerated. After

removing the crust, a red, eroded surface appears (Fig.15.6).
Bowen disease can also occur on mucosa. On the glans penis and foreskin is called

erythroplasia Queyrat. It appears as a persistent sharply delimited red patch without

crusts and scales(Fig.15.7).
Histopathology shows a full-thickness anaplasia of the epidermis with atypical
and disorderly keratinocytes (windblown appearance), under the hyperkeratotic
or
are atypical epithelial cells, with i n d i v i dual
p ar akeratotic k e r atin l a y er . T h e r e
keratinization (dyskeratosis), and atypical mitoses.
Course: chronic, with malignant transformation after some years.

Treatment: 5-flourouracil cream (EFUDIX), cryotherapy with liquid nitrogen,

excision, electroexcision, laser therapy.

Paget disease of the nipple

Paget disease occurs almost exclusively in w omen. It is no longer considered a

precancerosis but a retrograde extension into the overlying

epidermisof an underlying

intraductal carcinoma of the breast.

The initial presentation of mammary Paget disease is typical for a long standing
eczema of the nipple with itching, recurrent small vesicles and excoriations, but unlike
eczema, Paget disease is located unilaterally and th e er ythematous patch is sharply
demarcated and infiltrated. Retraction of the nipple and palpable nodules indicate the
underlying breast cancer.

Histopathology: Paget cells are found in the thickened epidermis (large cells
devoid of desmosomes, with edematous cytoplasm and large oval nuclei).
Treatment: mastectomy with removal of the axillary lymph nodes.
ands
Extramammary P aget d i sease

occurs in

(anogenital and axillary region).

150

a r eas w i t h a p o crine s w eat g i an

Fig.15.1. Actinic keratoses

Fig.15.2. Cutaneous horn

L'

Fig.15.3. Actinic keilitis

Fig.15.4. Erythema after 5-FU

treatment for solar keratoses

Fig.15.5. Radiation keratosis

Fig.15.6. Bomen disease

Fig.15.7. Eritroplasia Queyrat

Fig.15.8. Malignant lentigo

151

Lentigo maligna (melanosis Dubreuilh)

Lentigo maligna is melanoma in situ, characterized by the proliferation of atypical
melanocytes within th e epidermis that can p r ogress to melanoma when th e atypical
melanocytes reach the dermis. Lentigo m aligna is i n d uced by l o n g-term cu mulative
ultraviolet injury. It occurs mainly on the face or lower leg, as brown-black macules and
plaques that increase very slowly in size and change both the contour (extension of one
margin and regression of another) and the colors (from pale and dark-brown to black
colors) (Fig.15.8). Lentigo maligna can be present for 5-15 years before invasion occurs.
Invasion is suggested by slight infiltration and elevation of the surface.

Other precanceroses
o
o
o
o
o

C h r o nic ulcers
B u r n scars
L u p u s vulgaris
C h r o nic lupus erithematosus
E p i d ermolysis bullosa dystrophica

153

Chapter 16
M A LIG N A N T EPITHELIAL TUM O R S

B ASAL CELL CARCIN O M A

Basal cell carcinoma (BCC) is the most common malignant tumor, characterized by
dermal proliferation of cells that closely resemble normal epidermal basal cells. It occurs in
persons aged 50-80 years, with fair skin, especially on the sun-exposed skin regions (face,
ears, scalp, neck, upper trunk). Chronic exposure to UVB radiation is more involved. Basal
cell carcinoma usually arises from clinically normal skin w i thout precursor changes, in
contrast to squamous cell carcinoma, which is preceded by precancerous lesions.
The initial basal cell carcinoma is often a small, grayish-white induration wi t h
telagiectases. At the very beginning, patients observe a small hemorrhagic crust, always in
the same l o cation a f te r r e p eated t r auma ( scratching o r s h a v i ng). T h e t u m o r i s
asymptomatic, without pain, neither spontaneously, nor upon palpation.

Clinical forms:
solid BCC: waxy, translucent papules that grow slowly (in months, years) to nodules
with telangiectases over the surface (Fig.16.1)
ulcerating BCC (ulcus rodens): persistent erosion or ulceration surrounded by a hard
pearly border formed from confluated tiny emisferic nodules with shiny surface (so
called basalioma pearls) (Fig.16.2, 16.3)
superficial BCC (pagetoid) occurs frequently on the trunk as red-brown, fine scaly
patches with pearly nodules at the periphery (Fig.16.4)
pigmented BCC is a brown or black aspect of any type of BCC (Fig.16.5). Distinction
from melanoma, pigmented nevocytic nevi, and seborrheic keratosis is very important
morpheaform and i n f i l t rating BCC are sclerotic (scar-like) plaques with ill-defined
borders that s u rpass the cl inical m argins. I t i s a n a g g ressive for m a n d r e c urs
frequently after excision (Fig.16.6)
basalioma terebrans leads to deep tissue destruction that can affect the cartilage and
the bone (Fig.16.7). This tumor can be life threatening due to erosion, hemorrhage, and
meningeal complications

Histopatho
logy

The tumoral cells resemble normal basal cells with t h eir l arge oval basophilic
nuclei and appear as nodular aggregates in the dermis with a palisade-type arrangement
of the cells at th e p eriphery. The epidermis over the basal cell carcinoma is usually
atrophic and frequently eroded.

Course
BCC has a slow course, over a few years, with tendency to ulcerate. Metastases do
not occur, but the terebrant form may be life threatening or mutilating. The tumour can

155

recur within a treated area because of basal cell carcinoma residues that were not removed,
but new basal cell carcinomas can also arise in predisposed patients. Treated patients
should be followed up l ong enough (5 years) in order to detect recurrences as soon as

possible.

Treatment
Surgical treatment
excision of the tumour with 4 mm margins of normal tissue is the treatment of choice;
plastic surgery methods can be used in large tumours
Mobs chemosurgery method involves histological monitoring of all the outer edges of
the excised tissue. The sections are frozen and examined while the patient is still in the
operating room. Tissue is mapped microscopically, so if any t u m oral nests persist,
further excision is directed to only those areas to spare the normal tissues, repeatedly,
until no malignant cell is found.
radiation therapy i n s e lected patients: elderly o r d e b ilitated patients, aggressive
tumours that have already been treated surgically, patients who refuse surgery
electroexcision and laser therapy are not recommended as no tissue for biopsy can be

provided
Medical treatment
topical cytostatic treatment w it h 5 - f luorouracil o r i m u n o m odulating agents like
imiquimod are used only in very superficial tumours or in patients who refuse other
treatments
Avoidance of exposure to UV is strongly recommended, with protective clothing,
road-brimmed hat and sunscreen during outdoor activities.

SQUAMOUS CELL CARCINOMA

Squamous cell carcinoma (SCC) is a malignant tumour of epidermal keratinocytes that
develops on both skin and mucosa, also on both normal skin and precancerous lesions.
Risk factors associated with SCC are:

o f a ir-skin (burs easily and never tans); SCC can also appear on black skin, usually on
the scalp and is more aggressive, probably because delayed diagnosis
o h i gh cumulative dose of UV (natural or therapeutic-PUVA) or X-ray radiations
o

p r e m alignant lesions: actinic keratosis, cutaneous horn, actinic keilitis, leukoplakia,

chronic ulcers, chronic scars or some forms of carcinoma in situ (Bowen disease,

erythroplasia Queyrat).
o e x p osure to chemical carcinogens (tar, arsenic)
o c h r o nic immunosuppression
o v i r a l infection with certain subtypes of HPV.

Clinical findings
SCC starts with a small, slightly raised, firm and painless warty hyperkeratosis
that grows slowly until 1 cm di ameter, then quickly larger. It can express sometimes a
yellowish paste-like material, like little worms which consist of cornified tumour cells.

Clinical forms:
Nodular squamous cell carcinoma (Fig.16.8)
156

Ulcerated squamous cell carcinoma (Fig.16.9)

Ulcero-vegetant squamous cell carcinoma (Fig.16.10, 16.11)
E xtensive u l c er at iv e n e c r osis occurs af ter m o n t h s an d t h e t u m o u r i n v a d e s t h e

soft tissues, bones, and cartilages. It develops faster (within a few m o n t hs-one year)
than BCC and metastasizes, first in the regional lymph nodes and later on, after years
in internal organs (lungs etc). The lymph nodes are enlarged and hard, then fixed to
the neighbouring tissues, with possible central ulceration and fistulisation (Fig.16.12).
In advanced stages, SCC affects the general state of health, producing haemorrhagia,
anemia, and death.

Histopatho
logy

While SCC in situ i s c onfined to th e epidermis, SCC is characterized b y t h e

proliferation of atypical keratinocytes that invade the dermis. The tumoral cells resemble
those in the prickle cell layer (plasma-rich, large nuclei and visible intercellular bridges),
but they have varying degrees of differentiation and atypia (atypical dyskeratosis, atypical
mitosis, nuclear atypia), with the formation of concentrically layered cornified spheres
within the tumour, so-called horny pearls. Marked stromal reaction with h istiocytes and
mast cells, lymphocytes and plasma cells are present.
Staging of the squamous cell carcinoma
according to the TNM classification system, based on the characteristic of the primary
tumor and on the presence or absence of regional lymph node and metastasis:
o T x : p r imary tumor cannot be assessed
o T O : no evidence of primary tumor
o

o
o
o

o
o
o
o

Ti s : c arcinoma in situ

T l : t u mor < 2 cm in greatest diameter

T 2 : tumor 2-5 cm in greatest diameter
T3 : t u m o r > 5 cm in g r eatest diameter (+metastases in lymph nodes)
T 4 : destructive tumor invading the cartilage, muscle, bone
N x: regionallymph nodes cannot be assesed
N O : No regional lymph node metastasis
N l : r e gional lymph node metastasis

Broders classification according to the degree of differentiation

gra d e I under 25% undifferentiated tumor cells
gr a d e II under 50%;

gr a d e III under 75%;

gra d e IV more than 75% undifferentiated tumor cells.

Prognosis
The prognosis depends on the a) localization: SCC of the tongue, vulva, and penis
have a relatively poor prognosis, b) dimension: up to a size of 2-3 cm can be cured in about
90% of cases and c) the degree of differentiation: greater differentiation, lower tendency to
metastasize.

Treatment
Surgical methods
radical removal of t h e t u mo r m ass w it h a m a r gin o f 4 - 6 m m o f n o r m a l t i ssue,
depending on the TNM stage

157

5.
Mohs micrographic surgery is the treatment of choice with reconstruction by plastic

surgery

electrodessication in low-risk cases

Nonsurgical methods are used in inoperable tumours and metastasizing forms:

radiotherapy
systemic chemotherapy
Patients with a history of SCC should be carefully examined every 6-12 months as
there is an increased risk to develop another carcinoma.

MALIGNANT MELANOMA

node
bone

Melanoma is a malignancy of the pigmented cells (melanocytes) that are

located predominantly in the skin, but also in other organs (eyes, ears, nervous system,
oral and genital mucosa). It is one of th e m ost severe malignant tum ors w it h early
lymphogenous and/or hematogenous metastases, and lethal outcome. The incidence of
melanoma has increased in recent years (more than tr i pled in th e w h i t e p opulation

during the last 20 years in the US).

Risk factors in the development of melanoma include fair skin, intermittent and
intense sun exposure with blistering sunburns in childhood, large number of nevi (more

than 10 atypical/dysplastic nevi; more than 100 common nevi; large congenital nevi),

The h

epidh
meta

p revious melanoma o r m e l anoma i n f i r s t-degree relatives. Melanoma occurs m o re

frequently on the trunk in men and on the legs in women. For dark-skinned individuals,
the most common sites are the plantar areas, followed by nail plate, palms and mucosa.

Melanoma develops in precursor melanocytic nevi, but more than 60% appear
de novo (with no preexisting pigmented lesion). It is very rare before puberty.
Clinical forms of primary cutaneous melanoma

1. Superficial spreading melanoma (SSM) usually occurs in middle-aged people.

Initialy it is a sharply lim ited, flat or slightly elevated patch with variegate colors

(grayish-bluish-black-pink-white) and irregular asymmetric borders (Fig.16.13).

The lesion grows horizontally, and later it becomes infiltrated with p a p ules and

nodules (vertical growing). The prognosis is favorable in early phases.

2. Nodular melanoma manifests as a dark brown to black papule or dome-shaped
nodule with rapid growth over weeks or months (Fig.16.14); it may ulcerate and
bleed with minor trauma; it may be clinically amelanotic! (Fig.16.15)
3.

Le n t igo maligna melanomaoccurs in 10-20% of melanoma cases; it develops mostly

in older individuals (over 65 y) from lentigo maligna which has often been present
for decades with varicolored patches ranging from light to dark or blackish brown,
on the face or arms. It grows slowly over 5-20 years. Dermal invasion (progression to
invasive melanoma) is announced by i n f i l trated changes or small b l ack n odules

thre i

mar
2 CII

defe
mar

dela
Lyrr
of tl

(Fig.16.16). The prognosis is more favourable than in other types

4. A c ral melanoma occurs on the palms, soles, and beneath the nail plate, sometimes
in the mouth and g enital region; on th e n ail p l ate it m a n ifests as a dif fuse nailal
discoloration or a nail band; the spreading of the pigment to the proximal or latera
nail fold (H u t chinson sign) is a hallmark for m elanoma and differentiates it from
subungual hematoma;
158

rs u<
useh

5.

Ac r o mic melanomais a nonpigmented variant that looks like pyogenic granuloma,

BCC or SCC, but grows faster; it occurs more often as a nodular melanoma or as
skin metastasis of the melanoma or visceral carcinoma.

Course and prognosis

Early metastases appear in the surrounding skin (in transit) and regional lymph
nodes. Later, blood-borne metastases occur, particularly to the lungs, liver, heart, brain,
bones and skin.
Clinical staging and 5-year survival rates:
stage I: primary tumor without clinically detectable regional lymph node metastase; >

90%,

stage II: primary tumor w ith clinically detectable in-transit or regional lymph node
metastases;80-40%
stage III: primary tumor with distant metastases; < 20%

Histopathology
The histopathological examination is the criterion standard for melanoma diagnosis.

The epidermis is invaded by large atypical melanocytes, arranged haphazardly at the dermoepidermal junction, with upward migration. Dermal invasion by atypical melanocytes confers
metastatic potential. The stromal inflammatory reaction is pronounced.
Histology offers also important prognostic information:

Levels of invasion (Clark) measure anatomical tumour invasion

o s t age I: epidermal invasion
o s t age II: discontinuous invasion of the papillary dermis
o s t age III: continuous invasion of the papillary dermis
o s t age IV: invasion of the reticular dermis
o s t age V: invasion of the subcutis
Breslow index: tumour thickness in mm, measured from the stratum granulosum to
the deepest tumoral cell

Treatment
Malignant melanomas should be treated by surgery. As far as possible, extensive
three dimensional surgical removal of the primary tumor is performed with a resection
margin that depends on the Breslow index (e.g. 1 cm margins for up to 1 mm thickness or
2 cm margins for 4mm thickness) into the healthy tissue and down to the fascia. The skin

defect must be covered by plastic surgery. Mohs micrographic surgery has also been used
in melanoma with the advantage of providing visualisation of 100% peripheral and deep

margins microscopically.
Prophylactic lymph node excision might confer a survival advantage, compared to

delayed removal of the lymph nodes when lymphadenopathy became clinically apparent.
Lymphatic mapping and sentinel node biopsy were developed to identify the localisation
of the first-draining nodal metastasis (sentinel node).
In extensive lymph node metastases and distant metastases palliative radiotherapy
is used for pain relief.
Cytostatic drugs used in melanoma: dacarbazine (DTIC), vinca alcaloids, cisplatin

used in monotherapy or polychemotherapy.

159

Interferon

alpha an d

i n t e rleukins and al so

s pecific i m m u n otherapy w i t h

melanoma vaccines (based on tumor cell associated antigens) have been used in clinical
trials.

Pro phy laxi s

Early detection and treatment of malignant melanoma are of vital significance
for
melanoma (lentigo maligna,
t he patient. Premalignant conditions that ca n l ea d t o
dysplastic nevi) have to be early treated. As great percent of melanoma appears on normal
skin, the pigmented nevocytic nevi shouldn't be all prophylactically excised. If, however,
pigmented patches appeared after the age of 30 and developed over the course of a few
months, or a mole changes (in diameter, colour, symmetry, elevates) it is advisable to
rophylactic excision.

perform
p

Patients should be f ollowed regularly after a d i agnosis of m elanoma because

m etastasis or recurrences occur mostly in t h e f i rst 3 y ears after the treatment of t h e

primary tumor. Annual skin examination is recommended for life, as a new melanoma can

appear.

160

Fig.16.1. Solid basal cell carcinoma

Fig.16.2. Ulcerated basal cell cardnoma

Fig.16.3. Ulcus rodens

Fig.16.4. Superficial (pagetoid)

basal cell carcinoma

'

Fig.16.5. Pigmented basal cell carcinoma

Fig.16.6. Morpheaform basal cell carcinoma

Fig.16.7. Basalioma terebrans

Fig.16.8. Nodular squamous cell carcinoma

161

Fig.16.9. Ulcerated squamous cell

carcinoma

Pig.16.10. Ulcero-vegetant SCC

and actinic keratoses

(*

Fig 16 11. Ulcero-vegetant SCC

on chronic leg ulcer

Fig.16.12. Necrotized lymph node metastases

from SCC of the right cheeck

Fig.16.13. Superficial spreading melanoma

Pig.16.14. Nodular melanoma

'

'" + t

.P
P !r

Q(

'J

Fig.16.16. Melanoma on lentigo maligna

Fig.16.1S. Nodular melanoma (acromic)

16'2

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