1.1.

Latar belakang

The sebaceous glands are microscopic glands in the skin that secrete sebum. In humans, they are found
abundantly in the face and scalp although they are distributed throughout all skin sites except palms and
soles. Sebaceous glands are associated with the hair follicle, arising at the junction of the inferior portion
of the follicle infundibulum and the isthmus. Sebaceous gland proliferations include senile sebaceous
gland hyperplasia, sebaceoma, sebaceous adenoma and sebaceous gland carcinoma.

First described by Allaire in 1891, sebaceous gland carcinoma (SGC) is a highly malignant and potentially
lethal tumor of sebaceous glands. High recurrence rates and tendency for local spread and distant
metastases make correct diagnosis and prompt appropriate treatment extremely important for these
patients. Mean delay from onset of the lesion to diagnosis still ranges from 1 to 2.9 years. However,
progressive education about this disease has reduced the mortality rate from 50% to around 2–10%,
according to more recent reports.

Sebaceous gland tumor of the eyelids may arise from the meibomian glands, glands of Zeis or glands
associated with the caruncle. They are included in the list of tumors of the epidermal appendages, so
called adnexal skin structures. Sebaceous gland carcinoma (SGC) might be the second most common lid
malignancy after basal cell carcinoma (BCC). Its multifocal origin and pagetoid spread give it an unique
place among eyelid malignancies.

Sebaceous glands are located in the periocular skin, caruncle, and eyebrow skin follicles. The tumor is a
very rare, slow growing, and commonly found in elderly population with female predisposition. Mean
age at diagnosis is mid-sixties; however, the tumor has been reported in children as young as 3.5 years
old. It is rare in Caucasians and common in oriental Asiatics. The reported incidence of SGC varies from
0.5 to 5% of all lid carcinomas in USA and 28% in China. SGC most commonly arises from the meibomian
glands anterior to the gray line, occasionally from the glands of Zeis or Moll, and from sebaceous glands
in caruncle; however, the cell of origin may not be certain in 50–60% of cases. In contrast to basal cell
carcinoma (BCC) or squamous cell carcinoma (SCC), SGC is two to three times more common in upper
eyelid due to more number of meibomian glands there. Five percent cases may have simultaneous
involvement of both eyelids due to intraepithelial spread and/or spontaneous development of multiple
primaries.

On one hand it can mimic as benign lesion as blepharoconjunctivitis, whereas on the other extreme it
can have widespread local and fatal distant metastases. Immunohistochemistry, molecular biology, and
electron microscopy have greatly improved the diagnosis, management, and prognosis of SGCs overall.
Surgery, chemotherapy, and radiotherapy all contribute to the treatment of SGC.

2.1 Anatomi dan Fisiologi Permukaan Okuli dan Adnexa

The ocular surface and its adnexa comprise the cornea, the conjunctiva with bulbar, fornical and
palpebral parts, the main lacrimal gland, and the glands of the eye lids, i.e., Meibomian, Moll, Zeis, and
accessory lacrimal glands as well as the nasolacrimal system; the latter consists of the upper and lower
puncta, the paired lacrimal canaliculi, the lacrimal sac, and the nasolacrimal duct. The nasolacrimal ducts
collect the tear fluid from the ocular surface and convey it into the nasal cavity, whereas all other
structures contribute to formation of the preocular and cornea tear film. The tear film serves to protect
and lubricate the ocular surface, allowing for protection of the cornea and consistent clarity of vision.
The preocular tear film contains water, protective antimicrobials, cytokines, lipids, and mucins, and is
divided into three components: a lipid, an aqueous, and a mucus component. The lipid component is
secreted by the Meibomian glands in the eyelid and forms the superficial layer of the tear film. The
aqueous component contains electrolytes, water, and a large variety of proteins, peptides, and
glycopeptides, and is secreted primarily by the lacrimal gland as well as the accessory lacrimal glands
(glands of Krause, glands of Wolfring) of the lids. The mucus component is the product of conjunctival
goblet and epithelial cells, corneal epithelial cells, and acinar as well as excretory duct cells of the
lacrimal gland, which have recently been shown to produce mucins. The mucinous layer helps to spread
the lipid and aqueous layer across the cornea.

2.1.1 Permukaan Okuli

The surfaces of the ocular epithelia, both corneal and conjunctival, provide a specialized and important
interface between the tear fluid and the epithelium that stabilizes the fluid layer. That interface includes
the undulating membrane ridges on the apical cell’s apical membrane, termed microplicae, and
emanating from their apices, a layer termed the glycocalyx. Membrane bound mucins (MUCs 1, 4, and
16) of corneal and conjunctival epithelial cells are present in the glycocalyx layer. Soluble mucins
(MUC5AC) from conjunctival goblet cells, as well as MUC5B and MUC7 from lacrimal glands, are in
solution in the tear film. Both MUC5B and MUC7 have been shown to bind bacteria and contribute to
innate immunity of the tear film. Besides MUC5AC, conjunctival goblet cells secret the trefoil family
factor peptides (TFF peptides) TFF1 and TFF3. The TFF peptides are, together with mucins, typical
constituents of mucus gels that influence the rheological properties of the tear film, promote migration
of corneal epithelial cells, have antiapoptotic properties, and induce cell scattering. Conjunctival and
corneal epithelial cells are able to react against pathogens by the production of inducible antimicrobia
peptides (a kind of body-own antibiotics). In addition, in certain disease states the corneal cells are able
to produce TFF3.

2.1.2 Kelenjar Lakrimal

The lacrimal gland is anterior in the superolateral region of the orbit, and is divided into two parts by the
levator palpebrae superioris muscle, the anterior palpebral segment, and orbital portion of the gland.
The lacrimal gland consists of acini that consist of a luminar lining of columnar epithelial cells that are
surrounded by a basal layer of myoepithelial cells and an enclosing basement membrane. The human
lacrimal gland is a tubulo-alveolar gland of serous type. Intercalated and 6−12 interlobular ducts drain
the secretions into the conjunctival fornix beneath the temporal bone. The tubules discharge without
any characteristic excretory duct system (histological distinction from serous salivary glands) into the
interlobular ducts. The connective tissue between the acini contains accumulations of lymphocytes as
well as many plasma cells mainly secreting IgA and being part of the eye-associated lymphoid tissue
(EALT). As already mentioned, the lacrimal gland produces electrolytes, water, as well as a large variety
of proteins, peptides, and glycopeptides; of these, recent research regarding tear film rheology and
innate immunity focus on production of different constitutively and inducible antimicrobial peptides,
such as beta defensins, surfactant proteins A and D, as well as mucins MUC4, MUC5AC, MUC5B, and
MUC7 which are secreted by the lacrimal gland into the tear film.

2.1.3 Kelopak Mata

The “skeleton” of the eyelid is a collagen plate called the tarsus. It contains a row of branched alveolar
sebaceous glands, unrelated to the eyelashes. These tarsal or Meibomian glands have punctated
openings along the free edge of the eyelid close to its posterior margin. They produce a lipid material
whose synthesis is dependent on neuronal, hormonal, and vascular factors. This lipid material is fluid,
spreads easily, is a surfactant as well as an aqueous barrier, and must remain functional after a blink. To
satisfy these requirements, the Meibomian lipids have a specific composition. Even after delivery, it may
be modified by lipases produced by ocular bacteria, and modifications in the lipid components can lead
to unique disease states. Sexual hormones, especially androgens, seem to play a decisive role in
Meibomian physiology.

Near the anterior margin of the eye lids there are two or three rows of cilia – the eyelashes. In the
middle of the lid is the cross-striated orbicularis oculi muscle. The fiber bundles of its palpebral part
overlap one another like tiles on a roof. Orbicularis action is triggered by the facial nerve leading to time-
shifted lid closure from temporally to nasally and at the same time moving the tears to the medial cantal
region and “lacrimal lake”. The tendon of the cross-striated levator palpebral muscle is inserted into
anterior one-third of the tarsus with extension to the skin layer to help define the eyelid crease. The
smooth tarsalis muscle originates and lies on the posterior surface of the levator muscle and inserts into
the superior tarsal margin. The tone of the latter muscle is determined by autonomic nervous supply,
and responds to neosynephrine stimulation. This contributes to the elevation of the upper eyelid. Its
action is specifically demonstrated with retraction of the upper eyelid associated with thyroid eye
disease. The apocrine ciliary glands (Moll’s glands) open close to the eyelashes. These apocrine glands
are active from birth, in producing agents against pathogenic microorganisms in the eyelid shaft and on
the ocular surface, i.e., lysozyme, beta-defensin-2, adrenomedullin, lactoferrin, and IgA. In the
conjunctival fornix the eyelid also contains small accessory lacrimal glands (Krause’s glands, Wolfring’s
glands). Although much smaller, these glands are histologically comparable to the main lacrimal gland.
They contribute to the tear film as basal aqueous secretors.

2.1.4 The Lacrimal Functional Unit

The cornea possesses the richest sensory innervation of the body to detect noxious stimuli. The
trigeminal sensory neurons (CN V) that innervate the eye vary in their chemical composition and
electrophysiological properties, and can be classified according to the stimuli that activate them
preferentially: mechanical forces; temperature; or irritant chemicals. Different classes of noxious stimuli
(mechanical injuries, heat, extreme cold) activate the population of sensory fibers of the ocular surface
to a different degree and evoke unpleasant sensations of distinct quality.

It is recognized that the tear film is secreted reflexively by the “lacrimal functional unit” which is
composed of the ocular surface tissues (cornea and conjunctiva, including goblet cells and Meibomian
glands), the lacrimal glands (main and accessory), and their interconnecting sensory (CN V) and
autonomic (CN VII) innervation. This reflex secretion is initiated by subconscious stimulation of the
highly innervated ocular surface epithelia.

2.2. Anatomi dan Fisiologi Duktus Nasolakrimalis

Tear fluid is drained by the nasolacrimal ducts into the inferior meatus of the nose. The lacrimal
passages consist of a bony passage and a membranous lacrimal passage. The bony passage is formed
anteriorly by the frontal process of the maxilla and posteriorly by the lacrimal bone. The membranous
lacrimal passages include the lacrimal canaliculi, the lacrimal sac, and the nasolacrimal duct.

The upper and lower canaliculi are lined by pseudostratified and stratified columnar epithelium and are
surrounded by a dense ring of connective tissue, as well as by muscle fibers of the lacrimal portion of the
orbicularis oculi muscle (Horner’s muscle), which surrounds the deep portion of the medial canthal
tendon and the dome of the lacrimal sac. The lacrimal sac and the nasolacrimal duct are lined by a
double-layered epithelium and are surrounded by a wide ranging vascular system comparable to a
cavernous body. The double-layered epithelium is composed of a superficial columnar layer and a deep
flattened layer of basal cells. Both layers sometimes appear as a pseudostratified epithelium. Kinociliae-
lining single epithelial cells are a common finding in the lower part of the nasolacrimal duct; however,
most epithelial cells are lined by microvilli. In addition to the epithelial cells, goblet cells are integrated in
the epithelium as single cells or form characteristic intraepithelial mucous glands.

2.2.1 Mekanisme drainase

Drainage of tears involves a number of different mechanisms. Physical factors, such as gravity,
respiration, and evaporation, have been suggested. A decisive role is played by capillary attraction, aided
by contraction of the lacrimal portion of the orbicularis muscle with blinking, as well as distension of the
lacrimal sac by the action of the orbicularis muscle.

The mucin diversity of the epithelium of the nasolacrimal ducts together with TFF peptides that are able
to influence the rheological properties of tear fluid have already been mentioned. Besides antimicrobial
defense, these components are necessary epithelial secretion products to enhance tear transport.
Disorders in the balance of single mucins and TFF peptides are described in Chap. 2.

The lamina propria of the lacrimal sac and nasolacrimal duct consist of two strata: underneath the
epithelium, loose connective tissue containing a thin layer of elastic fibers and many lymphatic cells,
sometimes arranged in follicles, as well as a rich venous plexus situated under the loose connective
tissue that is connected caudally with the cavernous body of the nasal inferior turbinate. Collagen
bundles and elastic and reticular fibers between the blood vessels of the rich venous plexus are
arranged in a helical pattern and run spirally from the fornix of the lacrimal sac to the outlet of the
nasolacrimal duct, where they contribute biomechanically to tear outflow during blinking. Specialized
types of blood vessels are distinguishable inside the vascular tissue and are comparable to those found
in a cavernous body.

The blood vessels are specialized arteries (barrier arteries), venous lacunae (capacitance veins), veins
(throttle veins), and arteriovenous anastomoses. They facilitate closure and opening of the lumen of the
lacrimal passage by swelling and shrinkage of the cavernous body. Swelling occurs when the barrier
arteries (arteries with an additional muscular layer) are opened and the throttle veins (veins whose
tunica media contains a muscle layer of helically arranged smooth muscle cells) are closed. Filling of the
capacitance veins (widely convoluted venous lacunae) occurs at the same time as closure of the lumen
of the lacrimal passage. In contrast, closure of the barrier arteries and opening of the throttle veins
reduces the blood flow to the capacitance veins, simultaneously allowing blood outflow from these
veins with resultant shrinkage of the cavernous body and dilatation of the lumen of the lacrimal
passage. Arteriovenous anastomoses enable for direct blood flow between arteries and venous lacunae;
thus, the subepithelially located capillary network can be avoided, and rapid filling of capacitance veins
is possible when the shunts of the arteriovenous anastomoses are open. While regulating the blood
flow, the specialized blood vessels permit opening and closing of the lumen of the lacrimal passage,
effected by the bulging and subsiding of the cavernous body, and, at the same time, regulate tear
outflow.

The presence of the cavernous body is lacking in nearly all textbooks of anatomy and is therefore
unknown to most nasolacrimal surgeons as well as radiologists; however, it is densely innervated.
Epiphora related to emotions such as sorrow or happiness occur not only by increased tear secretion
from the lacrimal gland and accessory lacrimal glands, but also by closure of the lacrimal passage. This
mechanism acts, for example, to provide protection against foreign bodies that have entered the
conjunctival sac: Not only is tear fluid production increased, but tear outflow is also interrupted by the
swelling of the cavernous body to flush out the foreign body and protect the efferent tear ducts
themselves. Moreover, it can be assumed that the valves in the lacrimal sac and nasolacrimal duct
described in the past by Rosenmüller, Hanske, Aubaret, Béraud, Krause, and Taillefer could be caused by
different swelling states of the cavernous body and must therefore be considered as speculation.

The cavernous body of the efferent tear ducts actually plays an important role in the physiology of tear
outflow regulation and can be influenced pharmacologically. Interestingly, administration of a
decongestant drug or insertion of a foreign body at the ocular surface both prolong the tear transit time
significantly, but by different mechanisms. Application of a decongestant drug simultaneously with
insertion of a foreign body shortens the tear transit time significantly compared to the effect of the
decongestant drug alone, but there is no significant difference compared with application of a foreign
body alone. The tear transit time is independent of the side (right or left) and gender, and whether the
eyeglasses are worn or not, or whether the person is suffering from a common cold or not.

2.2.2 Absorption of Tear-Fluid Components

Recent animal experiments have indicated that components of tear fluid are absorbed in the
nasolacrimal passage and are transported into the surrounding cavernous body that is subject to
autonomic control and regulates tear outflow. Under normal conditions tear fluid components are
constantly absorbed into the blood vessels of the surrounding cavernous body. These vessels are
connected to the blood vessels of the outer eye and could act as a feedback signal for tear fluid
production, which ceases if these tear components are not absorbed.

2.3. Sebaceous Gland Carcinoma

Sebaceous gland carcinoma is one of the most dangerous eyelid tumors for five reasons. (1) It often
masquerades as a recurrent chalazion, sty, or chronic blepharoconjunctivitis, and the correct diagnosis
may be delayed until the tumor has metastasized. (2) The incidence of metastases is as high as 41
percent, although earlier diagnosis has resulted in decreased tumor-related mortality.79–81 (3) Because
it may have intraepithelial pagetoid spread and/or multicentric pattern, delineation of tumor margins,
even with excellent paraffin-embedded sections, can be difficult (4) Even histologically, the tumor can be
misdiagnosed, especially if lipid stains or monoclonal antibodies are not used or if tissue is improperly
prepared.

2.3.1. Epidemiologi
SGC represents 1–3% of all malignant tumors and 0.6–10.2% of eyelid tumors. Such a large range is
explained by the different prevalence of SGC among different ethnicities. SGC can occur in either the
periocular location or at extraocular sites with the periocular sites accounting for 75% of all SGC.
Periocular SGC usually arise from the meibomian glands, the glands of Zeis and the sebaceous glands of
the eyelid skin, with the former being most frequent. SGC arise two to three times more frequently in
the upper eyelid than its lower counterpart due to the presence of more meibomian glands in the upper
eyelid compared to the lower eyelid.

Other periocular sites include the eye-brow, caruncle, lacrimal gland and conjunctiva. The rate of SGC
varies according to the ethnicity of the population. In Caucasians, SGC are rare accounting for less than
1–5.5% of eyelid malignancies. On the contrary, in the Chinese and Japanese population, SGC is the
second most common eyelid malignancy with the highest reported rates being 39% and 37.5%
respectively. Similar studies in the Indian population and in Singapore report rates of 31.2% and 10.2%
respectively.

The reason for higher rates of SGC in the Asian population could be genetic or racial in nature.
Alternatively, the rates of SGC could be higher due to the lower incidence of other eyelid malignancies.
The absolute incidence in non-Caucasians is unknown. SGC is considered to be a tumour of the older age
group, mostly arising between the sixth and eighth decades of life, although it can occur in younger age
groups as well. Some reports suggest a female preponderance while others report no gender
predilection.

The overall incidence of SGC is increasing significantly. In 2012, it was 3.2 (male) and 1.6 (female) per 1
million person/years, versus 1–2 cases per 1 million individuals/year estimated in 2009, making it the
third most common eyelid malignancy after basal cell carcinoma (BCC) and squamous cell carcinoma
(SCC) globally.

2.3.2. Etiologi

The aetiology of SGC is largely unknown. Several risk factors have been associated with this tumour.
Asian race is reported to be significantly associated with SGC. However, recent reports suggest a
contradictory observation of the tumour being more common in whites thus suggesting the role of
sunlight exposure. Muir–Torre syndrome (MTS), a rare genodermatologic disorder characterized by
autosomal dominant non-polyposis colorectal carcinoma, sebaceous gland tumours and visceral
malignancies is a risk factor for SGC. Other reported associations include Rb and p53 mutations, HIV and
HPV.

2.3.3. Patofisiologi

Two important features differentiate sebaceous carcinoma from other periocular malignancies. First,
unlike single origin of other tumors, sebaceous carcinoma appears to arise from multifocal origins.
Second, unlike radial spread of basal cell and SCCs, SGC tends to spread superficially in a pattern known
as pagetoid spread. This spread may lead to the erroneous histologic diagnosis of epithelial dysplasia or
carcinoma in situ. Immunohistopathology shows that the cells occur in irregular lobular masses with
distinctive invasiveness. The cytoplasm is pale, foamy, and vacuolated. This feature of foamy cytoplasm
is seen only in sebaceous carcinoma. The nuclei are hyperchromatic, and the cells stain positive for lipid
such as oil red O stain. The ultrastructural features of SGC include desmosomes, tonofilaments, and
intracytoplasmic nonmembrane bound lipid. Occasionally bizarre and atypical tripolar mitotic cells may
be seen. Immunohistochemical reaction aids in the diagnosis of SGC. Molecular biology of SGC suggests
dysplasia if there is no expression of p53 or invasiveness, if there is hyperexpression of p53.

2.3.4. Presentasi Klinis

The tumor typically arises in the sixth–seventh decade of life (57–72 years), but cases in younger age
groups have also been described. History of periocular irradiation represents a documented risk factor,
while gender predilection is still an object of debate. Clinical associations with Muir–Torre syndrome
(MTS), immunosuppression, familial retinoblastoma, human immunodeficiency virus, and human
papilloma virus infection have also been reported.

According to the Surveillance, Epidemiology, and End Results (SEER) study from 2002 to 2012, SGC can
be classified into two groups: ocular type and extraocular type. Extraocular sites account for only a
quarter of the cases of SGC, predominantly located in areas of skin covered by hair, such as the head,
trunk, and genitalia. The analysis of extraocular phenotype is beyond the scope of this review.

Ocular SGC arises mainly from the Meibomian glands of the upper eyelid (39–50% of cases), due to the
presence of a greater number of glands compared to the lower eyelid. It can also arise from the glands
of Zeis of the eyelid margin (10%), at the caruncle (\10%), or in the skin of the eyebrow; around 12%
were multicentric with no obvious source of origin. The clinical appearance of ocular SGC is highly
heterogeneous; it often mimics other ocular benign conditions, such as chalazion, posterior blepharitis,
superior limbic keratoconjunctivitis, keratitis. SGC can be confused also with other malignancies,
including SCC, BCC, or Merkel cell tumors.

Classically, this lesion appears as a firm, painless, indurated thickening of the eyelid, with a yellow hue
due to the high concentration of intracellular lipids. Upon eyelid eversion, the lesion appears as a
multinodular protruding or fungating mass. Madarosis, unilateral blepharoconjunctivitis, forniceal
shrinkage due to diffuse infiltration of the palpebral or the bulbar conjunctiva, and invasion of the
cornea are generally associated with the intraepithelial spread of tumor cells.

Multiple SGCs represent a common feature of the MTS, an autosomal dominant condition characterized
by sebaceous tumors (sebaceous adenoma, basal cell epithelioma with sebaceous differentiation, and
sebaceous carcinoma) associated with gastrointestinal, endometrial, and urologic malignancies. Tumor
staging is assessed using the TNM (tumor node metastasis) definitions as provided by the American Joint
Committee on Cancer (AJCC) recommendations.

2.3.5. Diagnosis

Diagnosis is frequently difficult due to two main reasons; (1) in early stages the external signs are quite
subtle, resembling a benign lesion such as a chalazion or chronic blepharoconjunctivitis and (2) the
presence of yellowish material within the tumor gives it resemblance to SCC.

Thus, due to high index of suspicion, it becomes mandatory to include SGC in the differential diagnosis
of most eyelid masses and recurrent, nonresponding eyelid inflammatory conditions. A delay in clinical
diagnosis of SGC can be attributed primarily to its ability to masquerade as more common benign eyelid
conditions. This often leads to delayed management with increased morbidity and mortality rates.[20]
The actual reported sebaceous carcinoma-related mortality is about 6%.[7]
2.3.6. Diagnosis Diferensial

The list for SGC includes; congenital sebaceous gland hyperplasia which is common on face or scalp or
acquired sebaceous gland hyperplasia which is common on face or forehead. Adenoma sebaceum of
Pringle is another diagnosis to consider. It is found in tuberous sclerosis and commonly located in the
nasolabial fold and cheek areas. Sebaceous adenoma is common on the eyebrows and eyelids.

SGC is included in the group of simulating lid lesions (inclusion cyst, papilloma, senile keratosis,
keratoacanthoma, benign keratosis, dermoid cyst, and amyloidosis). Wali and Al-Mujaini: Sebaceous
gland carcinoma of the eyelid Occasionally, SGC may diffusely infiltrate conjunctival epithelium. This may
resemble lesions such as chronic blepharoconjunctivitis, superior limbal keratoconjunctivitis or cicatricial
pemphigoid, and BCC. The tumor may mimic chronic inflammation and even grow bacteria on repeated
cultures but does not improve with antibiotics. Conjunctival scrapping may reveal the underlying SGC
pathology. Due to such mimicking, SGC is one of the forms of masquerade syndromes. Diffuse
intraepithelial sebaceous carcinoma closely resembles SGC in its rarity and indolent course; however,
the former is not an obvious primary tumor of the eyelid and may not require exenteration. Papilloma
simulates SGC and sometimes may be differentiated only by histology.

2.3.7. Penatalaksanaan

The mainstay of treatment of SGC is surgical resection followed by eyelid reconstruction. Careful
analysis of the margins may be carried out with wide local excision (WLE) and frozen section or Mohs’
micrographic surgery (MMS), although it might occasionally be complicated by the multifocal nature of
the tumor. A surgical margin of 5–6-mm in WLE and a 2-mm margin in MMS are recommended. In the
setting with no frozen section or MMS control, another useful management protocol for SGC is excision
with 3- to 5-mm surgical margins, paraffin section control, and delayed reconstruction.

Map biopsies should be taken from 17 sites: four clock hours of the limbus, three from the upper and
lower forniceal conjunctiva, three from upper and lower tarsal conjunctiva, and one from the caruncle.
After a complete review of all biopsies, pagetoid disease can be addressed with cryotherapy, mitomycin-
C in cases with limited involvement and in cases with diffuse pagetoid spread or associated orbital
involvement, and orbital exenteration may be indicated. Obtaining clear margins is an important goal of
orbital exenteration; clear margin status, however, is not always associated with lower risk of recurrence
in patients with SGC and orbital invasion.

Different non-invasive imaging techniques have been used in the attempt to precisely localize the lesion,
to exclude a potential orbital spread, to follow its progression, or some combination of these. Computed
tomography is well tolerated, can be rapidly obtained at most medical centers, and gives clues to the
specific diagnosis. Magnetic resonance imaging (MRI) signal intensity and pattern of contrast
enhancement allow to distinguish between similar appearing lesions. Recently, advanced imaging
techniques such as MRI diffusion-weighted imaging (DWI), 18-FDG-PET CT, and MRI PET are being used
in the pre-therapeutic workup and monitoring of patients with eyelid and orbital malignancies, including
SCG. The DWI technique aids in the distinction of benign and malignant lesions by quantifying different
apparent diffusion coefficient (ADC) thresholds and represents a promising tool in the correct staging of
the disease.
Due to the tendency to give locoregional lymph node metastasis, the use of sentinel lymph node biopsy
(SNLB) as a part of tumor staging has been advocated for this malignancy. SLNB allows for the
identification of micrometastases and influences the AJCC stage of the tumor as well as the treatment
approach. The procedure is effective, reliable, and associated with very low risk (e.g., temporary
weakness of the marginal mandibular branch of the facial nerve).

SNLB or at least strict regional lymph node surveillance is recommended in patients with tumors of 10
mm or more in greatest dimension. Radical neck dissection is indicated in SGC patients with regional
lymph node metastases, followed by radiation therapy.

Radiation (50–66.6 Gy) administered as a primary treatment on the tumor site is effective in achieving a
prolonged survival, a better tumor control, and a more cosmetic preservation of the eyelid, or as an
adjuvant treatment following orbital exenteration. Adjuvant reirradiation with modest doses (30–45 Gy)
may be considered in tumor recurrences to provide disease control and long-term survival. In very
advanced cases with or without locoregional lymph node metastasis, neoadjuvant chemotherapy with 5-
fluorouracil and carboplatin/cisplatin may allow local resection of advanced tumors otherwise requiring
more invasive procedures.

Finally, recent studies on expression of estrogen, progesterone, and androgen receptors may suggest a
potential role of hormonal therapy in the treatment of SGC. Future larger-scale studies are needed to
evaluate their utility in locally advanced or metastatic disease.

2.3.8. Prognosis

The overall mortality rate of SGC is 5–10%, being as high as 29% in certain populations, owing to early
recurrence and metastatic spread. A recurrence rate of 11–36% in 5 years and an 18–30% 5-year
mortality has been reported with WLE of 5–6-mm margins, and 38% of these recurrences are locally
invasive [76]. On the contrary, MMS has been shown to be associated with lower rate of recurrence
(7%), with a metastatic rate of 4%.

Snow and colleagues have reported an overall metastasis rate of 8% (4/49) in a review up to 2002; the
higher risk is carried by advanced tumor. Metastatic sites include lung, regional lymph nodes, liver,
brain, and bone. The time from diagnosis of ocular SGC to metastasis may range from 0 to 62 months.
According to a recent study published by our group, locoregional lymph node metastasis was noted in
23% of patients, while systemic metastasis in 14% and death due to metastasis was 10% over a mean
follow-up period of 29 months.

Clinical prognostic risk factors include medial canthal involvement, location at both upper and lower
eyelids, multicentric origin, orbital invasion, duration of symptoms[6 months, and tumor size 10 mm].
The T category, as defined by the AJCC, and a prolonged interval from symptoms appearance to the
correct diagnosis have also a role in the overall prognosis. Histopathologically, a pagetoid infiltrative
pattern of the skin and conjunctiva, vascular or lymphatic invasion, non-lobular growth pattern [90], and
poor differentiation is associated with worse prognosis. Human telomerase RNA (hTR) has been shown
to be a marker of undifferentiated disease.

On the contrary, tumors originating from the glands of Zeis and those associated with MTS have a better
prognosis. The factors predictive of locoregional lymph node and systemic metastasis are medial canthal
involvement, lateral canthal involvement, tumor basal diameter [10 mm, and perivascular invasion]. The
factors predictive of death due to metastasis are medial canthal involvement and tumor basal diameter
(10 mm).