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Epithelial Precancerous
Lesions
Karynne O. Duncan, John K. Geisse, &
David J. Leffell
Histopathology
The typical erythematous AK has characteristic
architectural and cytologic histopathologic features. All of the abnormalities are confined to the
epidermis, although dermal solar elastosis is usually
present and an inflammatory dermal infiltrate may
also be seen. The classic histopathologic findings
include foci of atypical, pleomorphic keratinocytes along the basal cell layer and protruding as
buds into the papillary dermis. The basal cell layer
appears more basophilic because of crowding of
the atypical keratinocytes. Overlying these foci of
abnormal cells, one often sees irregular acanthosis,
hyperkeratosis, and parakeratosis. There is notable
sparing of the adnexal epithelium, with orthokeratosis overlying these structures, which gives rise to
the characteristic pattern of alternating orthokeratosis and parakeratosis (see Fig. 113-3B). Cytologically, there is an increased nuclearcytoplasmic
Chapter 113:
5-Fluorouracil
5-FU therapy has been a mainstay of topical
treatment for AKs since the 1960s (see Chapter
220). 5-FU is a pyrimidine analog that inhibits the
enzyme, thymidylate synthase, thus, interfering in
DNA synthesis and ultimately resulting in apoptosis
and tumor cell death. 5-FU acts selectively to cause
cellular destruction in actinically damaged cells but
not in normal skin. 5-FU treatment of sun-damaged
skin usually causes a brisk inflammatory reaction,
which is felt to contribute to its overall efficacy.
Although many different treatment regimens have
been proposed and used with topical 5-FU, the
historical standard FDA-approved method consists
of twice-daily application of 5-FU cream or solution to the entire affected region, typically for 24
weeks. Spot treatment of specific AK lesions is not
recommended but is a common practice. There is
also some evidence that concurrent treatment or
pretreatment with topical tretinoin is more effective than 5-FU alone for AKs on the extremities.51
Therapy should be continued until the treated area
demonstrates erythema, erosion, crusting, and necrosis, at which time treatment should be discontinued. Different strengths (1%, 2%, 5%) and vehicles
(cream or solution) of topical 5-FU are available.
More recently, a 0.5% micronized 5-FU cream has
become available and FDA approved for treating
AKs. It can be applied once daily for 4 weeks. The
choice of which topical 5-FU formulation to use
depends on physician preference, individual patient
characteristics, and the number and location of AKs
being treated.
Imiquimond
The second agent available for topical field treatment of multiple AKs is imiquimod cream (see
Chapter 220). It works by inducing both the innate
and adaptive arms of the immune system to recognize and destroy AKs. It is available in 5%, 3.75%
and 2.5% formulations. First approved in 1997 by
the FDA for the treatment of genital and perianal
warts, it was approved in 2004 for the treatment
of nonhypertrophic AKs on the face and scalp in
immunocompetent adults. It is also approved for
treatment of superficial BCC (see Chapter 115).
The FDA-approved regimens for the three different strengths of imiquimod are outlined in Box 1132. Treatment with imiquimod cream is associated
with adverse reactions, most notably local skin reactions such as erythema, scabbing, flaking, erosion,
weeping, and vesicle formation. Such reactions are
actually predictive of better ultimate clearance of
the AKs, as the greatest resolution of AKs has been
seen in patients with the most severe reactions.5658
Systemic absorption is minimal, and overall excellent safety margins have been demonstrated with
the topical administration of imiquimod cream.59
Systemic adverse effects, including interferon-like
side effects such as flu-like symptoms, headaches,
and myalgia, have been infrequently reported particularly when large surface areas are treated.
The short-term efficacy of imiquimod cream
for eradicating AKs has been well studied in the
last several years. The first systematic review and
meta-analysis of short-term randomized controlled
trials evaluating its efficacy and safety has been
published.60 For this meta-analysis, five trials57,58,6163
involving a total of 1,293 patients were selected
for inclusion based on their high-quality scores,
minimal risk of bias, validity, adequate treatment
duration, inclusion of patients with multiple AK
lesions, and use of at-home application. Complete
clearance occurred in 50% of patients treated with
imiquimod versus 5% treated with vehicle alone.
Partial clearance (more than 75% of lesions) was
seen in 65% of imiquimod-treated patients versus
11% of vehicle-treated patients.60
Evidence also supports the use of imiquimod
in the treatment of AKs to promote long-term
immune surveillance and lower recurrence rates.
Stockfleth et al56 followed 25 imiquimod-treated patients from a previous short-term study61 for up to
2 more years. Of these 25 patients (one was lost to
follow-up), 8% (n = 2), 16% (n = 4), and 20% (n = 5)
Diclofenal
The third FDA-approved topical field therapy for
treating AKs is 3% diclofenac gel. Diclofenac is a
nonsteroidal anti-inflammatory drug whose mechanism of action is not completely understood but
is thought to involve inhibition of cyclooxygenase
(COX), a rate-limiting enzyme in the synthesis of
prostaglandins. Diclofenac appears to have greater
affinity for the COX-2 enzyme than for the COX-1
isoform. One theory regarding its role in eradicating AKs relates to the finding that the production of
prostaglandins from arachidonic acid may contribute to UV radiation-induced NMSC. Thus, inhibition
of this cascade by diclofenac may also explain its
efficacy in treating AKs.67
The FDA-approved regimen for diclofenac in the
treatment of AKs is twice-daily application for 90
days. Compared with imiquimod and 5-FU, diclofenac does not cause as much inflammation, irritation, or downtime for the patient. Adverse effects
Chapter 113:
Future Treatments
The future of treatment for AKs is an area of great
interest and research. Investigators are looking at
reformulating existing topical agents to improve
upon efficacy and to decrease adverse side effects.
Older methods are being challenged in clinical
studies with newer regimens that involve sequential or concurrent therapy with existing AK treatments. Another interesting area of research is looking at the various combinations of lesion-directed
therapies with field treatments, and lastly, new
emerging agents are undergoing rigorous clinical
research to establish their efficacy and safety.8789
Epidemiology
Knowledge of the medicinal benefits and poisoning potential of arsenic dates back to ancient
times. Arsenic was introduced into the United
States Pharmacopoeia in 1850, and before its use
was discontinued around 1965, it was employed
medicinally in the United States and Europe in the
form of Fowlers solution, Donovans solution, and
Asiatic pills for treatment of various illnesses such as
psoriasis, asthma, and syphilis. Medicinal exposure
is now basically limited to treatment of tropical diseases, such as African trypanosomiasis, and more
recently to treat various hematologic malignancies.109 Arsenic in opium has been and is still used
for medicinal and recreational purposes in India,
and inorganic arsenic is still found in some traditional Chinese herbal preparations.110 Unfortunately,
these substances can be easily purchased and are
increasingly being used again as homeopathic remedies, resulting in modern day cases of what once
was primarily a disease of historical interest.111,112
Arsenic exposure can occur in a variety of occupations, either by direct exposure to arsenic or
through indirect exposure from contaminated water and landfills. In 1973, it was estimated that more
than 1.5 million workers in the United States were
potentially exposed to arsenic in the workplace.113
History
The association between arsenic exposure and
skin cancer was first noted by Paris in 1822.115 ArKs
were first described on the palms and soles of
individuals in the late 1800s. In 1898, Dubreuilh
categorized ArKs as precancerous lesions.5 The relationship of arsenic ingestion to palmar and plantar
ArKs and to skin cancer has been documented in
several studies that examined wide-scale exposure
to known sources of arsenic.116 In particular, chronic
arsenicism and an increased risk of skin cancer have
been attributed to drinking water that contains
more than 0.6 mg of arsenic per liter.114 The US Environmental Protection Agency has set a maximum
arsenic contaminant level at 50 g/L.116 Ingestion
of as little as 400 mL of Fowlers solution can be
associated with signs of chronic arsenicism.113 A
compilation of the results of 12 reports that linked
malignancy with the ingestion of inorganic arsenic
found that skin cancer occurred in 70% and an
internal malignancy in 6.3% of ingesters.117
Clinical Findings
ArKs typically begin as pinpoint papules that are
more easily felt than seen. They develop into small,
20-mm, punctate, yellow, keratotic papules most
commonly seen on the palms and soles in areas of
constant pressure or repeated trauma (eFig. 1136.2A). They preferentially arise on the thenar and
lateral borders of the hands, the sides of the fingers,
and sometimes on the dorsal aspects of the fingers,
overlying the joints. Although it is unusual, ArKs can
be found on more widespread body areas such as
the trunk, extremities, eyelids, and genitalia. ArKs
may also present as slightly elevated, erythematous,
scaly, or pigmented plaques. ArKs on the palms and
soles are more likely to be seen in individuals with
chronic arsenicism caused by medicinal exposure
than in those with arsenicism due to occupational
exposure. Also, individuals with arsenical-related
cancer are more likely to have palmar and plantar
ArKs. The mean latency period for the development
of ArKs varies considerably from 9 to 30 years.121
Other cutaneous neoplasms associated with
chronic arsenicism include BD or SCC in situ, SCC
(see Chapter 114), and BCC (see Chapter 115). Mean
latency periods for the development of BD and
SCC can also be as long as 40 years.121 With arsenic
as the carcinogen rather than UV radiation, these
neoplasms, like ArKs, are distributed in more widespread, random, and nonphotodamaged areas. Arsenical BD often begins as a small flesh-colored to
Chapter 113:
Histopathology
The histopathologic features of ArKs are essentially the same as those of AKs. No reliable histopathologic criteria can distinguish between the two.
Some cases of ArKs are characterized by marked
vacuolation of the epithelial cells and keratin horn
formation. Also, solar elastosis is usually absent, and
a chronic dermal lymphocytic infiltrate is commonly seen. Likewise, arsenic-related BD, BCC, and SCC
are histopathologically indistinguishable from their
nonarsenic-induced counterparts.
ArKs may be mistaken for other types of punctate
keratoses, such as disseminated punctate keratoderma, Darier disease, corns, and verruca vulgaris.
Disseminated punctate keratoderma usually appears earlier in life. It has also been reported that
upon removal of the keratinous plugs in punctate
keratoderma, small crater-like pits are left behind,
whereas no pits are seen on removal of the keratin
plugs in ArKs. Darier disease presents with characteristic lesions elsewhere. Corns are usually not so
numerous and not so common on the hands. Warts
often demonstrate evidence of thrombosed capillaries upon removal of the surface keratin.
A diagnosis of ArKs and chronic arsenicism should
be considered when numerous characteristic
keratoses are seen on the palms and soles or when
multiple lesions of BD, SCC, or BCC are found on
an individual, especially when these lesions are
in nonsun-exposed regions of the body. In most
patients with such neoplasms, palmar and plantar
keratoses will also be present. Such patients should
be questioned about previous occupations, living
conditions, and environmental and medicinal exposures to elicit a history of potential arsenic exposure
anywhere from 10 years to 40 years previously.
Biopsy of any changing ArK, erythematous nodule,
plaque, or ulcer on the body should be performed
to ensure that BD, BCC, or progression to SCC is
not present. In addition, laboratory tests to order
include a complete blood count, renal and liver
function tests, hair and nail analysis to measure arsenic concentration, and nerve conduction studies
if a sensorimotor neuropathy is suspected.
Clinical Findings
Prolonged exposure to infrared radiation and to
sources of heat can clinically produce the characteristic lesion of erythema ab igne, which manifests as an erythematous to brownish, fixed, thick,
reticulated patch on the skin overlying the area
that has been habitually exposed to heat (see Fig.
75-21). It differs from livedo reticularis in that it is
more brownish, usually nonblanchable, and fixed.
The sites of predilection are the back and abdomen
from exposure to hot water bottles and heating
pads or blankets, and the lower legs from exposure
to fires or heating units as sources of warmth and
most recently the anterior thighs from chronic
exposure to laptop computers.128 After many years
of such exposure, TKs may appear within these
Histopathology
The histopathologic features of TKs are similar to
those of AKs, including alternating hyperkeratosis
and parakeratosis, keratinocyte atypia, sparing of
the appendageal units, and, interestingly, even
dermal elastosis and vascular ectasia. In one study,
biopsy specimens from erythema ab igne patches
without apparent TKs showed evidence of keratinocyte atypia.129 Merkel cell carcinoma has also been
reported to arise alongside SCC within a patch of
erythema ab igne.130
Hydrocarbon Keratoses
Etiology and Pathogenesis
Hydrocarbon keratoses (HKs), also known as tar
keratoses, pitch keratoses, and tar warts, are precancerous keratotic skin lesions that occur primarily
in persons who are exposed occupationally to
polycyclic aromatic hydrocarbons (PAHs). SCC and
Clinical Findings
HKs present as small, oval-to-round, gray, flat
papules that are easily removed without bleeding. These papules can then become larger and
Chapter 113:
Histopathology
Histopathologically, HKs appear similar to AKs
and ArKs, as previously described. Often, HKs show
more of a progression to full-thickness atypia or a
bowenoid appearance. In early HKs, it has been said
that distinction between benign and malignant
epidermal changes can be difficult.
or without electrosurgery are probably reasonable treatment options for HKs at other cutaneous
sites. Prevention is the key for workers exposed to
PAHs in their occupations. Long-term follow-up of
individuals with previous known PAH exposures
is essential for early diagnosis and treatment of lesions and for early detection of internal malignancy
in those at risk.
CHRONIC RADIATION
KERATOSES
Chronic radiation keratoses (CRKs) are precancerous
keratotic lesions that may arise on the skin many
years after exposure to ionizing radiation. They
have been described in persons exposed to medical
ionizing radiation, including grenz ray therapy for
benign skin disorders, such as acne vulgaris and
tinea capitis; in medical personnel, dentists, and
physicians who have X-rays over many years115; in
other professionals who handle radioactive materials in their workplaces; on the fingers of persons
who unknowingly wore gold rings contaminated
by radioactivity (eFig. 113-6.3)135; in survivors of
the atomic bomb in Japan136; and in the victims
of nuclear accidents such as the one in Chernobyl,
Ukraine.137 For the purpose of the following discussion, radiation refers to ionizing radiation; thus, the
UV and infrared spectra of radiation are excluded.
Clinical Findings
The primary neoplasms resulting in the skin from
exposure to ionizing radiation are CRKs, BCCs, and
SCCs. Cutaneous melanomas and sarcomas rarely
occur. CRKs and BCCs are seen more commonly
than SCCs, but any given CRK can potentially evolve
into invasive SCC. The site and penetration of the
ionizing radiation determine which type of tumor
develops; palms, soles, and mucosal surfaces are
said to be favored locations for CRK. The neoplasms
that develop are often multiple, heal poorly, and recur frequently.115 CRKs usually develop within areas
of chronic radiation dermatitis or in persistent ulcerations arising in such chronically damaged areas of
the skin, but they can also develop on previously
irradiated areas of the skin that clinically appear
normal. They appear as hyperkeratotic papules
or plaques (see eFig. 113-6.3). The latency period
from the time of exposure to the development of
CRKs and radiation-induced skin cancers is typically
long, having been reported to range up to 56 years.
Histopathology
Histopathologically, CRKs display keratinocyte
dyskeratosis with hyperchromatic nuclei and abnormal mitoses. The dermis often demonstrates findings consistent with long-term radiation-induced
changes, such as hyalinization of the collagen
bundles, thickening and occlusion of deep dermal
blood vessels, endothelial cell atypia, and destruction of the pilosebaceous units.
History
In 1828, Jean-Nicholas Marjolin described chronic
ulcers that arose from scar tissue, without referring
to them as malignant.139 Today, the term Marjolins
ulcer is synonymous with malignant transformation of chronic ulcers, sinus tracts, and burn scars,
although the term is used most frequently to
describe malignant changes within burn scars. It
is estimated that 2% of burn scars will undergo
malignant degeneration. Most burn scar carcinomas are SCCs, but cases of BCC, melanoma, sarcoma,
and malignant fibrous histiocytoma have also been
reported.140 Two types of Marjolins ulcer have been
described: an acute form and a chronic form. The
acute type develops within 1 year from the time of
injury, whereas the chronic form develops longer
than 1 year after the injury.141 The average latency
period from injury to onset of malignancy for
the chronic form is 36 years, with a range of 175
years.142 The latency period is inversely proportional
to the patients age at the time of the burn injury.
Pathogenesis
The pathogenesis of a premalignant keratosis or
a carcinoma arising in a chronic scar is not known.
Proposed mechanisms for malignant degeneration within a burn scar include production of a
carcinogenic toxin with the burn injury; immunologic privilege within scarred tissue that allows
unchecked tumor growth; chronic irritation leading
to malignancy; multistep carcinogenesis involving initiation, promotion, and progression; and
burn-induced DNA damage leading to malignant
transformation. Characteristics of the burn scar that
predispose to malignant transformation include a
prolonged healing phase, repetitive trauma, and
graft rejection.
Clinical Findings
CSKs present as hyperkeratotic papules, plaques,
or erosions within the scarred skin (eFig. 113-6.4). In
terms of burn scars, two clinical types of carcinoma
Chapter 113:
have been described. The more common presentation is of a flat, ulcerative, indurated lesion with
elevated borders and surrounding induration. The
less common type is an exophytic, papillomatous
lesion resembling granulation tissue.141 Bleeding,
pain, and a foul odor may also be present. Typically,
chronic and recurrent ulcerations have been present in the burn scar before malignant degeneration,
and the malignancy often develops at an ulcer margin. One important fact about burn scar carcinomas
is that usually only a portion of the ulcer undergoes
malignant transformation. The remaining ulcer
persists as a nonhealing wound, and thus the rate
of false-negative results from biopsies of the ulcer
is quite high.140 Sites of predilection for burn scar
carcinomas are the extremities and areas overlying
joints, presumably because of repeated trauma in
these areas.
Histopathology
Histopathologically, most scar keratoses range
in pattern from several atypical keratinocytes to
full-thickness epidermal atypia or in situ SCC. The
majority of burn scar carcinomas are of the well-differentiated squamous cell type. When the diagnosis
is based on histopathologic features, scar keratoses
may be confused with pseudoepitheliomatous
hyperplasia, a benign reactionary process.
REACTIONAL KERATOSES
Reactional keratoses (RKs) are premalignant
keratotic lesions that may arise in a variety of longstanding inflammatory processes such as cutaneous lupus erythematosus, necrobiosis lipoidica,
porokeratosis, erythema elevatum diutinum, granuloma inguinale, epidermolysis bullosa variants,
pemphigus vulgaris, lichen sclerosus, lichen planus,
and chronic deep fungal infections. Clinically, RKs
present as hyperkeratotic papules or plaques. As
with other precancerous keratotic lesions, a continuum from RK to SCC in situ to invasive SCC may
be seen. Once invasive SCC has appeared, there is a
significant risk that metastatic disease will develop,
similar to that with scar keratoses. The main diagnosis to consider in the clinical and histologic differential is pseudoepitheliomatous hyperplasia.
PUVA KERATOSES
Psoralen plus ultraviolet A (PUVA) keratoses are
precancerous keratotic lesions that arise in individuals exposed to PUVA for the treatment of a
variety of cutaneous conditions. UVA light alone is
thought to play a role in skin cancer formation, but
the combination of UVA with psoralen is associated
with a dose-dependent increased risk of premalignant keratoses and other cutaneous malignancies,
such as SCC, melanoma, and, possibly, Merkel cell
carcinoma (see Chapters 112 and 238).
PRECANCEROUS LESIONS OF
THE LOWER ANOGENITAL TRACT
The term intraepithelial neoplasia (IN) is defined as
a precancerous squamous epithelial lesion of the
lower anogenital tract. The terminology of these
precancerous lesions has been confusing, with various names such as squamous intraepithelial lesion
(SIL), erythroplasia of Queyrat (EQ), genital Bowen
disease (GBD), bowenoid papulosis (BP), and SCC in
situ being used in the past. It is now recommended
that the following terms be used, as outlined
in eBox 113-5.1. All of these INs have a disease
spectrum ranging from mild-dysplasia to severedysplasia, but with no evidence of invasion into the
dermis. For the purposes of this chapter, only vulvar
intraepithelial neoplasia (VIN), anal intraepithelial
neoplasia (AIN) and perianal intraepithelial neoplasia (PaIN), and penile intraepithelial neoplasia (PIN)
will be discussed. Because most dermatologists
consider BP to be a distinct clinical entity, with a
classic presentation in mostly younger individuals,
a better prognosis, and a greater chance for spontaneous regression, this entity has been discussed
separately under Section Viral-Associated Precancerous Lesions.
VIN is a precursor lesion of vulvar SCC. The original
classification of VIN, dating back to 1986, identified
three grades of VIN (VIN1, VIN2, VIN3), based upon
the degree of atypical cells within the vulvar squamous epithelium. This was analogous to the CIN
spectrum. In 2004, the vulvar oncology subcommittee of the International Society for the Study of
Vulvar Diseases (ISSVD) proposed a new classification system for VIN, designating the term VIN be
used only for high-grade lesions (formerly VIN2 and
VIN3) that have the potential to progress to vulvar
SCC. Thus, the older designation of VIN1 has been
eliminated, primarily because such VIN1 lesions are
thought to represent benign, reactive or HPV-related effects, and not precancerous lesions.171
Epidemiology
The incidence of VIN is increasing globally. It is primarily a disease of younger women, who comprise
about 75% of all cases.172 The incidence of vulvar
cancer is also increasing, but at a slower rate.
Clinical Findings
On examination, VIN, usual type can present with
a variety of clinical appearances, such as an erythematous, well-defined plaque; a verrucous white
plaque; grouped pigmented papules or plaques;
erosions or ulcers. These lesions are most often
multifocal and may demonstrate extensive involvement of the perineum and the adjacent skin. Over
50% of patients with VIN, usual type, have associated CIN. Individual lesions of VIN, differentiated
type may present as an erythematous or hyperkeratotic plaque; a verrucous papule or plaque; or as a
nodule or ulcer.
Approximately half of all patients with VIN are asymptomatic and the abnormal lesion is discovered
on a routine gynecological examination. Symptomatic patients typically present with pruritus as their
main complaint. Other symptoms may include pain,
burning, dysuria, bleeding, discharge, a palpable
lesion, or a persistent ulcer. Any suspicious lesion
should be biopsied. A punch or excisional biopsy
is preferred, in order to determine the depth of
the lesion and to not miss invasive SCC. A patient
who has multiple or multifocal lesions will require
multiple biopsies. Histopathologically, VIN is charac-
Chapter 113:
Differential Diagnosis
The clinical differential diagnosis includes other
inflammatory disorders, such as lichen sclerosus,
lichen planus, candidiasis, condyloma acuminata,
and perhaps melanoma in those cases of pigmented lesion presentation.
Treatment
The main goals of treatment are to prevent the
progression to invasive SCC; to relieve patient
symptoms; and to retain as much of the vulvar
anatomy and function as possible. Unfortunately,
there are few, sufficiently powered, long-term,
randomized trials looking at the management of
VIN. Available treatment options include surgical
excision, partial or total vulvectomy, laser ablation,
and field treatments such as topical 5% imiquimod
and 5-FU creams. Treatment with 5% imiquimod
has been shown to be effective in treating VIN and
is preferred by many experts over topical 5-FU, if
topical therapy is chosen.175179 Obviously, any treatment discussions would be handled in conjunction
with the patients gynecologist. Lastly, any patient
in whom VIN is diagnosed will require a complete
gynecologic exam because of the high risk of associated CIN.
The treatment of VIN with currently available HPV
vaccines is an exciting, ongoing area of research.180
A recent study, using an HPV 16 vaccine in females
with the usual type of VIN, showed that at 1 year
15/19 patients had a partial (n = 6) or complete (n =
Prevention
Prevention of VIN and progression to vulvar SCC is
now a reality. It is believed that approximately twothirds of VIN could be prevented in younger women
with the prophylactic use of the currently available
HPV vaccines180,182,183 (see Chapter 196).
Clinical Findings
Patients with AIN may be asymptomatic or may
present with localized symptoms, such as pruritus,
pain, bleeding, tenesmus, and discharge. On physical exam, AIN can present in a variety of ways. The
dermatologists role is to inspect the perianal skin
for suspicious lesions, such as well-demarcated erythematous pink plaques, grouped hyperpigmented
papules or plaques, verrucous papules or plaques,
and persistent erosions or ulcers. Findings of such
suspicious lesions should prompt an excisional or
punch biopsy, as well as referral to a specialist in
this field of medicine for complete anal exam with
high-resolution anoscopy and cytologic exam. Females should also undergo a complete gynecologic
exam to rule out CIN.
No formal AIN screening guidelines have been
formulated or accepted, but regular screening for
AIN is recommended for all HIV-positive individuals;
all MSM; females with a history of high-grade cervical, vulvar, or vaginal IN; and perhaps immunosuppressed patients, such as transplant recipients. Such
patients should be screened by physicians who are
experienced in the diagnosis and management of
AIN. Dermatologists should identify such high-risk
patients and perform perianal examinations periodically.
Histopathology
The histopathology of PaIN is basically that of SCC
in situ. AIN and CIN share similar histopathologic
features, as described using the 2001 Bethesda
classification.184 High-grade AIN2 and -3 are evident
when the abnormal epithelial basaloid cells replace
more than half of the entire epithelium.
Treatment
The treatment goal in AIN is to prevent progression to anal SCC, but there is a lack of good evidence that screening for and treating high-grade
AIN can prevent this progression. There is also
limited data on the efficacy of treatments for AIN.
Many experts recommend that individuals with
high-grade AIN receive treatment, but again, no
definitive algorithms exist. True, high-grade AIN is
best managed by an expert in this field of medicine.
Treatment options for PaIN include similar treatments as described for other cutaneous SCC in situ
lesions.
A recent literature review to assess the efficacy of
5% imiquimod in treating AIN found that five cohort and case reports have been published to date,
all limited to HIV-positive MSM.184 A pooled analysis
of these studies demonstrated a complete response
of 48%, with about a 36% recurrence rate.185
Prevention
Prevention of AIN is an exciting possibility with
the advent of HPV vaccines, but this is still undergoing investigation. Clinical studies are also underway
to see if HPV vaccines can induce regression of
high-grade AIN.186
PIN is a precancerous lesion that may progress
to invasive SCC of the penis. Older, synonymous
terms for this in situ carcinoma of the penis are BD,
GBD, EQ, and BP, but many experts in this area now
recommend that PIN be the preferred name for this
condition.
Epidemiology
The exact incidence and prevalence of PIN are not
known. It is thought to be uncommon in the Western world, but it has been increasing significantly
in some developing countries. Of all the penile
cancers, in situ SCC and invasive SCC are the most
common entities, with SCC representing the majority of invasive penile cancers (~95%).148,187
Chapter 113:
Clinical Findings
PIN and penile SCCs most often originate on the
mucosal surfaces of the penis, such as the glans,
coronal sulcus, prepuce, urethral meatus, and the
mucosal surface of the foreskin. Less than 5% of
PIN and such cancers arise on the shaft of the penis.
The clinical presentation of PIN is variable and depends upon the anatomic site of involvement. The
mucosal presentation has historically been called
EQ and the shaft presentation has been called GBD.
PIN presenting on the mucosal sites often presents
Histopathology
Histopathologic examination of both the EQ and
GBD variants of PIN are mostly similar and that
of SCC in situ. However, in the EQ variant there is
often epithelial hypoplasia, fewer multinucleated
and dyskeratotic cells, and many more plasma cells
in the dermal infiltrate. Histopathologic studies of
penile SCC cases have observed a sequence from
low-grade PIN to high-grade PIN in many (62%)
cases.190
Treatment
Therapeutic measures for treatment include wide
local excision, Mohs micrographic surgery, laser ablation, and topical 5-FU and 5% imiquimod cream
though evidence for use of the two latter topical
therapies is limited to small series and case studies.
Each case must be individualized and based upon
patient characteristics and preferences, PIN type
and size, physicians skills set, and optimal treatment with the most preservation of anatomy and
function. Life-long surveillance of patients with all
forms of PIN is essential to ensure early detection of
recurrence. Patients should also be advised to initiate partner screening for CIN, VIN, and AIN.
Prevention
LEUKOPLAKIA
Physical examination
OL can occur as an isolated single lesion, as multiple separate lesions, or as diffusely outlined lesions.
It is recommended that OL lesions be described
and documented by the size in centimeters of
single lesions and the cumulative sizes of multiple
lesions.206 The exact location should also be documented. OL lesions found on the floor of the mouth,
on the lateral or ventral tongue, and possibly on
the soft palate have been thought to have a greater
ERYTHROPLAKIA
(ERYTHROPLASIA)
Etiology and Pathogenesis
The etiology and pathogenesis of OE are not well
understood. It is still unclear whether or not OE
develops de novo or from a preexisting lesion of
OL. The greatest risk factors for its development
are thought to be tobacco and alcohol use. It is
Chapter 113:
Histopathology
Histopathologic examination of a lesion of erythroplakia usually reveals findings of SCC in situ, areas
of dermal invasion, or various degrees of dysplasia.
Partial or sampling biopsies of erythroplakia may
unfortunately miss focal areas of invasive SCC. In
one study of clinically homogeneous OE, histopathologic examination revealed that 51% of cases
demonstrated invasive carcinoma, 40% showed severe dysplasia or SCC in situ, and 9% demonstrated
mild-to-moderate dysplasia.221
For severely dysplastic or in situ carcinoma lesions of erythroplakia, surgical excision or Mohs
micrographic surgery is generally recommended,
because the entire lesion can be removed with the
most thorough histopathologic confirmation of adequate margins. The proper management of mildly
or moderately dysplastic OE lesions is less clear,
with some advocating excision and others promoting a more conservative, observational approach.
Other treatment modalities, such as laser ablation,
cryosurgery, and electrodesiccation, have also been
used, but their roles in treating OE are even less
clearly defined. Given the high malignant transformation rate of these lesions, it is difficult to advocate any nonexcisional ablative therapy. Regardless
of the treatment method used to remove the lesion,
all patients should be followed at regular intervals
to be evaluated for recurrence or for the development of a not uncommon second primary lesion in
the oral cavity or aerodigestive tract. Exposure to
carcinogenic stimuli, such as tobacco and alcohol,
should be discontinued.