Lid malignancies are quite common and most often develop in sun-exposed older males. Approximately half of all malignancies involve the skin, and 9 to 15 percent of cutaneous malignancies involve the lid. About 1,300,000 basal cell carcinomas and squamous cell carcinomas are diagnosed yearly in the United States.1 It is estimated that 60,000 cases of eyelid malignancies are diagnosed yearly.2–8 Forty percent of skin neoplasms are basal cell carcinomas; in the periorbital region, basal cell carcinoma is the most common cutaneous malignancy and accounts for 85 to 95 percent of lid tumors.2,3

The frequency of various types of tumors depends on the geographic location. In contrast to the above figures, in China, the basal cell carcinomas accounted for only 38 percent of 3,510 cases.9 Even among the Asian populations, however, there are variations. For example, a study from Singapore noted that basal cell carcinomas accounted for 84 percent of eyelid tumors.3 In a small population-based study from Florida of non–basal cell or squamous cell carcinomas, the incidence of other eyelid tumors was 1.8 per million Caucasians over the age 20 years; in contrast, it was less than 0.3 in African American patients.10

Increased solar exposure is considered to be responsible for the increased incidence of cutaneous tumors.11,12 In a small area of England, the diagnosis of cutaneous basal cell carcinoma, squamous cell carcinoma, and melanoma increased from 153 to 235 percent over the last 10 to 15 years.13

EYELID TUMORS: PATHOPHYSIOLOGY

The pathogeneses and pathophysiologies of eyelid malignancies are varied. The etiology of rarer malig-

nancies are poorly understood. In contrast, the events leading to the induction and development of Kaposi’s sarcoma (KS), squamous cell carcinoma, sebaceous cell carcinoma, basal cell carcinoma, and malignant melanoma are beginning to be understood on a molecular level as well as from epidemiologic data that have been known, in some of these tumors, for over 100 years.

Solar radiation, especially the ultraviolet B (UV-B) spectrum (290 to 320nm) is crucial in the development of squamous cell carcinoma, basal cell carcinoma, and melanoma. Both epidemiologic and laboratory data demonstrate different patterns in each of these neoplasms. Shorter wave length UV light is blocked by ozone. Sun exposure and latitude have been shown to be important in all three skin cancers, as have lighter skin color, poor tanning, and blue eyes.8,14,15

While both squamous cell carcinoma and basal cell carcinoma are associated with cumulative sun exposure, the correlation is not as strong with the latter neoplasm; similarly, other epidemiologic features, such as proximity to the equator, exposure to UV-B, and increased patient age, are not as tightly correlated with basal cell carcinoma, compared with squamous cell carcinoma. While the incidence of squamous cell carcinoma is increased 20to 30-fold in immunosuppressed patients, it is only modestly increased for basal cell carcinoma.18 In cutaneous malignant melanoma, intermittent intense UV exposure (as opposed to cumulative exposure for basal cell and squamous cell carcinomas) is a principal epidemiologic parameter.19 As a result melanomas arise more often in indoor workers and in skin areas that are only intermittently exposed to the sun.

2 TUMORS OF THE EYE AND OCULAR ADNEXA

That solar-induced DNA damage was important in the etiology of skin cancer was initially demonstrated by Cleaver, who showed that there was deficient DNA repair in patients with xeroderma pigmentosum who have > 1,000-fold increased incidence of skin malignancies.20 Probably, UV-B interaction with epithelial DNA is the initiating event in the induction of skin malignancies. Solar radiation is absorbed into proteins, purines, and pyrimidines that have unsaturated chemical bonds. The frequencies of these DNA damaging events and alterations in DNA repair are both important in tumor induction.21,22 Cellular cytotoxicity secondary to UV radiation does not result in mutation, but a lower level of nonlethal damage often does. The most prevalent DNA damage is the induction of dimerizations between adjacent pyrimidines, termed cyclobutane pyrimidine dimers; other pyrimidine (6 to 4) pyrimidone photoproducts are probably less important in the induction of human epithelial malignancies.23 The relative importance of various sites of UV mutations in the DNA of epithelial cells is uncertain. Tumors could develop under either positive influences of oncogenes or loss of normal tumor-sup- pressor genes. As an example, p53, which has been demonstrated to be altered in almost 50 percent of epithelial tumors, has been termed the guardian of the genome. Its role is to assess intracellular DNA damage and prevent faulty DNA replication. If there is grave alteration of the cellular DNA, normal p53 routes that cell into apoptosis (programmed cell death). In cells with reparable DNA defects, p53, through a series of other gene interactions, temporarily shuts down the DNA cell cycle until the defect is repaired. Several groups have demonstrated UV alterations in the p53 tumor suppresser gene in skin cancers.22 Other workers have also shown UV-induced alterations in Ha-ras and N-ras oncogenes.24,25

The relative importance and role of alterations in DNA repair function for the development of skin cancers is not clear. As patients age, there is diminution of DNA repair capacity and increased mutations.26,27 Decreased DNA repair is noted in young patients who develop basal cell carcinomas, compared with age-matched controls.26 Several pathways of DNA repair exist. Two major pathways are nucleotide and base excision repair; the former is responsible for removal of pyrimidine dimers and has

been well characterized.28 As mentioned, nucleotide excision repair is abnormal in several syndromes associated with skin malignancies, including xeroderma pigmentosum.20

Apparently, unique to basal cell carcinoma pathogenesis, in contrast to other eyelid malignancies, is an abnormal increased expression of the PTCH2 gene, termed the human patched gene. This gene was first noted in basal cell nevus syndrome (Gorlin’s syndrome). Mutations disrupt its regulation, with resultant overexpression, which seems to be a necessary component for the development of basal cell carcinoma.29,30

The estimated incidence of malignant eyelid tumors is approximately 19.6 per 100,000 per year for males, and 13.3 for females in a study reported from a predominantly Caucasian population in Minnesota.31 Basal cell and squamous cell carcinomas have a propensity for the lower eyelid, although the reason for this is uncertain.32 Lindgren and associates were unable to demonstrate a gradient UV exposure between the lower and the upper eyelids.33

There is a paucity of data on the pathogenesis of sebaceous gland carcinomas. This tumor accounts for between 1 and 6 percent of eyelid tumors. It is much more common in the Chinese population.34 In a small study of seven women with this tumor from Virginia, those with invasive disease had abnormalities of p53, and at least in one case, the molecular form of the p53 abnormality with G:C/T:A transversion was observed which is often associated with bulky carcinogens.34

In squamous cell carcinoma of various body sites, UV damage to p53 has been documented.35 There are several other alterations that may be important in the development of squamous cell carcinoma. A cytoplasmic factor, which translocates the nucleus, Rel/NF-kB is activated by UV-B and suppresses apoptosis. In a transgenic mouse model, the inhibition of Rel/NF-kB signaling resulted in increased development of squamous cell carcinomas.36

As discussed in the next chapter, with the development and widespread use of protease inhibitors, the incidence of KS has markedly decreased in patients with acquired immunodeficiency disease. Several early studies demonstrated that KS had an epidemiology suggestive of an infectious agent

independent of the human immunodeficiency virus (HIV).37 A number of investigations have now shown that human herpes virus-8 (HHV-8) is important in the classic form of KS as well as in that associated with immunodeficiency.38 There are several enigmas regarding KS—whether these cells are truly neoplastic or result from a chronic inflammatory response, and to what degree HHV-8 is the transforming virus for this process.39

The incidence of cutaneous melanoma in the United States has been projected to be 1 in 75 by the year 2000;40 it rose by approximately 120 percent between 1973 and 1994.41 Several investigations have demonstrated alterations in both familial and sporadic melanoma. As discussed in the introduction to this book, p16 INK4a is coded in the area of chromosome 9q21. This factor, which is important in the control of cell cycling, has been demonstrated to be abnormal in both in the familial and sporadic cutaneous melanomas.42,43

In cutaneous and uveal melanomas, as well as in most other human malignancies, the relative importance and order of the genomic changes that have been described, and at what phase during malignant transformation and tumor progression each genomic change affects the neoplasm’s development, are uncertain. Using a variety of techniques, a number of chromosomal gains and losses have been demonstrated in cutaneous melanomas.44 When melanomas progress from the radial to the vertical growth phase, there appears to be clonal derivation of those more malignant cells. It appears that alterations on chromosome 9 and chromosome 10 occur early on in melanoma progression, whereas increases on chromosome 7 are a later event.

Clinical Diagnosis of Eyelid Tumors

Malignant lid lesions can mimic a number of benign conditions, and growing lid tumors usually require biopsies to classify their nature. As a general rule, any growing lid lesion, recurrent sty in the same location, or chronic rodent ulcer should be biopsied. Other clinical signs suggestive of lid malignancy include localized loss of eye lashes, a pearly telangiectatic change in an area of cutaneous disturbance, an area of diffuse induration, or rarely a scirrhous, retracted area.

Table 1–1. SIMULATING LID LESIONS

Inclusion cyst Papilloma Senile keratosis

Keratoacanthoma Inverted follicular keratosis Benign keratosis

Pseudoepitheliomatous hyperplasia Dermoid cyst

Malherbe’s calcifying epithelioma (pilomatrixoma) Sebaceous adenoma

Benign sweat gland tumors (syringoma, porosyringoma, myoepithelioma, mixed tumors)

Amyloidosis

Intravenous pyogenic granuloma of the ocular adnexa Necrobiotic xanthogranuloma

Malacoplakia

Table 1–1 lists a number of benign simulating lid lesions. Clinically typical benign lesions, such as a seborrheic keratosis, can usually be merely watched. However, when a probable benign simulating lesion shows growth, a biopsy should be done to establish the histologic diagnosis. Often, even expert clinicians cannot make a correct diagnosis without a biopsy. Two excellent examples of these problems are typified by the cases shown in Figures 1–1 through 1–3. The patient in Figure 1–1 had rapid onset and growth of his lower lid lesion over a 6- week period. The time course is most consistent with a keratoacanthoma, but this benign lesion can occur in association with either local or distant malignancy and requires histologic data to differentiate it from a squamous cell carcinoma.45,46 Histologically, this was a benign keratoacanthoma and regressed rapidly after biopsy. The patient in Figure 1–2A showed a similar time course and was clinically followed up

Figure 1–1. Biopsy proven keratoacanthoma; lesion enlarged to size shown in approximately 6 weeks.

4 TUMORS OF THE EYE AND OCULAR ADNEXA

elsewhere. The lesion continued to expand (see Figures 1–2B and 1–2C) and, on biopsy, was found to be a squamous cell carcinoma. Sometimes, the clinical behavior is in contrast to the histologic features. Grossniklaus and colleagues reported three such cases of apparent keratoacanthomas, in which all were invasive and one later invaded the central nervous system.47 Some keratoacanthomas behave as a variant of a squamous cell carcinoma.

A

B

C

Figure 1–2. A, Squamous cell carcinoma, initially thought to be a keratoacanthoma. B and C, Axial CT with computer reformatting demonstrates an invasive carcinoma initially believed to be a keratoacanthoma.

Figure 1–3. Diffuse amyloid infiltration of the upper lid.

Figure 1–3 demonstrates diffuse upper lid infiltration due to amyloid. Figure 1–4 shows a cutaneous horn, histologically, due to a benign papilloma. A number of other benign lesions can clinically simulate a malignant neoplasm.48 More often, rare benign lesions have been present for many years and have a tenuous history of growth.49–51 Rarely, an inflammatory process can simulate malignant epithelial tumor, and cases of nodular fascitis, Kamura’s disease, isolated Langerhan’s cell histiocytosis, and discoid lupus in the eyelid have been described.52–56

Similarly, some malignant lesions can appear relatively innocuous. The lesion in Figure 1–5 was the first manifestation of systemic lymphoma. Figure 1–6 shows minimal lower lid signs in a diffuse sebaceous gland carcinoma. Alternatively, the clinical pattern of some malignancies can simulate other neoplasms. Figure 1–7 demonstrates a pigmented basal cell carcinoma. Pigmented lid neoplasms are much more frequently basal cell carcinomas than malignant melanomas.

Table 1–2 lists the most frequent lid malignancies. There is essentially no morbidity with a small, superficial, incisional biopsy.57–59 Several generations of ophthlamic surgeons have reported on false-

Figure 1–4. Cutaneous horn part of a benign papilloma.

Table 1–2. LID MALIGNANCIES

(in order of frequency in the author’s experience) Basal cell carcinoma

Sebaceous gland carcinoma

Squamous cell carcinoma (or its variant, adenoid squamous cell carcinoma)

Malignant melanoma Kaposi’s sarcoma Adnexal carcinoma Metastatic tumors Lymphoma

Mycosis fungoides

Malignant sweat gland tumors (mucinous sweat gland adenocarcinoma, malignant syringoma)

Malignant Merkel cell neoplasm

Figure 1–6. Minimal clinical findings in a diffuse lower lid sebaceous gland carcinoma.

positive and false-negative diagnostic rates in cutaneous eyelid lesions. In a study from Cincinnati, these authors noted that of 864 lesions, there was a false-positive diagnosis rate of malignancy of 8.5 percent and a false-negative rate (in lesions that were thought to be benign and turned out to be malignant) of approximately 2 percent.60 As discussed in Chapter 3, even much larger areas of the lid removed with a “laissez faire” technique often have a reasonable cosmetic appearance, and an incisional biopsy with forceps and scissors or scalpel should not produce a cosmetic deformity. Small cytology series with the diagnostic use of hemato- porphyrin-induced fluorescence and Doppler laser have been reported, but results have not yet shown great clinical utility.61,62

BASAL CELL CARCINOMA

Basal cell carcinoma is the most common malignancy of the lid. The first reported case was in l827.

Over 60 percent occur on the lower lids, and in descending order of frequency, the medial canthus, upper lid, and lateral canthal areas may be involved.63 This neoplasm can present as a nodular, diffuse (morpheaform), ulcerative, or multicentric lesion.64 Typically, nodular tumors account for approximately 60 percent of basal cell carcinomas of the lid and present as a chronic, indurated, nontender, raised, pearly, telangiectatic, well-circumscribed lesion with an elevated surround and a depressed, craterlike center (Figures 1–8A through 1–8D). Unfortunately, in 10 to 40 percent of basal cell carcinomas of the lid, clinically indistinct margins are noted.3,63 Often these morpheaform or multicentric basal cell carcinomas present with either an ulcerative pattern (Figures 1–9A through 1–9C) or demonstrate a relatively uniform area of induration with lash loss (Figure 1–10). In addition to being more likely to have clinically nonapparent spread, morpheaform lesions are more likely to have deep invasion than other types of basal cell carcinomas.65 Occasionally, basal

6 TUMORS OF THE EYE AND OCULAR ADNEXA

cell carcinomas can have a mixed pattern, and that was noted in one series in approximately 12 percent of the cases.66 Figure 1–11 shows medial canthal basal cell carcinomas with orbital invasion. Orbital involvement is manifested clinically as a fixed nonmobile tumor and/or a frozen globe. A rarer form of basal cell carcinoma is a cystic lesion which can cause clinical confusion.65

The management of basal cell carcinomas is discussed in Chapters 2 and 3. The majority of tumors can be eradicated with preservation of ocular function and good cosmesis. Rarely, some may regress spontaneously; however, there is little data on this feature that can be used to make a decision on the management of a primary lesion.67 The basal cell carcinomas most difficult to manage are morpheaform tumors, neoplasms that are not freely moveable (that finding is suggestive of underlying bone invasion), medial canthal tumors (since they have a greater tendency for orbital invasion), and tumors with orbital extension. Treated basal cell carcinomas require long-term fol-

A

B

Figures 1–8. A and B, Typical nodular basal cell carcinomas with nontender, raised, pearly, telangiectatic border and crater-like center.

low-up.68 Only 50 percent of recurrences are detected within 2 years of treatment; in a large meta-analysis, even after 5 years, there was an 8.7 percent recurrence rate. In addition, as many as 20 percent of patients who were previously treated for a basal cell carcinoma develop a new primary within 1 year of initial therapy.49,68 Patients with a nonmelanomatous skin cancer are also at increased risk of cancer mortality, although the mechanism is uncertain.69

Overall, approximately 2 to 4 percent of basal cell carcinomas are sufficiently advanced to require orbital exenteration.70 Howard and co-workers noted that only 13 of 622 eyelid epithelial carcinomas had orbital invasion at the time of initial presentation.71 In the subgroup of basal cell carcinomas, the mean

A

B

C

Figures 1–9. A to C, Ulcerative basal cell carcinomas with diffuse involvement of lid.

duration of the eyelid lesion prior to discovery of orbital involvement was almost 10 years, and most were recurrent tumors with a morpheaform pattern.71 Rarely, intraocular invasion can occur in basal cell carcinoma.72,73

Metastases from basal cell carcinomas are exceedingly rare. The first report was in l894; approximately 130 cases have been described.74–76 Metastases are associated with tumors that have deep invasion, usually spreading to the lymph nodes, lung, and bones. In one report of 5 cases, 3 originated from the lid area.75 The risk of basal cell carcinoma metastases is < 1 percent.77 Overall, three-quarters of cutaneous cancer deaths are due to melanoma; in one study, only a third of the remaining quarter was due to basal cell carcinoma.78 In the group of patients who died from basal cell carcinoma, the mean age was 85 years, and 40 percent had refused surgery.78

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 diffi- cult79,82–86 (4) Even histologically, the tumor can be misdiagnosed, especially if lipid stains (such as oil- red-O) or monoclonal antibodies are not used or if tissue is improperly prepared.81 A recent study by Sinard showed that a combination of antibodies, including those to EMA, BRST-1, and Cam 5.2, were useful to distinguish sebaceous gland carcinoma from other eyelid malignancies.87,88 (5) Frozen-section control of tumor margins has an error in this malignancy of up to 25 percent, especially if there is a pagetoid component.89

The cell of origin in these tumors is not certain in 50 to 60 percent of cases; the remainder arise most commonly from the meibomian gland, anterior to the gray line from the glands of Zeis or Moll.79 This

Figure 1–10. Morpheaform basal cell carcinoma diffusely involving lower lid; note telangiectasia and lash loss.

tumor is more common in the Asian than in the western races. Ginsberg found only 142 cases in the entire western literature prior to l968.90 In the United States, the reported incidence is approximately 0.5 to 5 percent of lid tumors, while in China, it accounts for over 10 percent of lid carcinomas.80,91 In most series, female patients outnumber males.89 It is most common in older patients, with a mean age at diagnosis in the mid-60s, although it has been described even in children as young as 3.5 years old.92

Unlike basal cell carcinoma, sebaceous cell carcinoma has a predilection for the upper lid. This location is affected two to three times more frequently than the lower lid.80,84 In contrast to basal cell and squamous cell carcinomas, which usually arise from a more superficial portion of the cutis, sebaceous gland carcinomas that arise most commonly from the meibomian gland are less prone to ulcerate. In over 50 percent of cases, the tumor presents as either a pseudochalazion or a chronic ble- pharoconjunctivitis.93–95 The tumor can present as a focal mass, a multicentric tumor, or a diffuse lesion

Figure 1–11. Medial canthal basal cell carcinoma invading orbit. The globe is frozen.

8 TUMORS OF THE EYE AND OCULAR ADNEXA

Table 1–3. POOR PROGNOSTIC FACTORS IN

SEBACEOUS GLAND CARCINOMA

Invasion: vascular-lymphatic (8 of 9)*, or orbital (13 of 17)* Diffuse involvement of both lids (5 of 6)*

Multicentric origin

Tumor diameter > 10 mm (No deaths in 25 cases with tumors

<6 mm)

>6 months symptoms (38% mortality)

*Tumor-related mortality/number of cases with this pattern

with pagetoid spread.80,83,95 The latter two types of sebaceous carcinomas are associated with a poorer prognosis (Table 1–3). Typically, these tumors may have a superficial and yellowish appearance due to their origin and lipid content.

Figure 1–12 demonstrates a typical presentation of a sebaceous carcinoma, and this clinical pattern accounts for almost 50 percent of cases. The patient was believed to have four recurrent chalazia in the same location of the lower lid. A small sebaceous gland carcinoma, unsuspected before a cautious ophthalmologist biopsied a chalazion, is shown in Figure 1–13. In the pagetoid pattern, there is often involvement of both lids as well as the conjunctiva.83,96 Figure 1–14 shows another small tumor arising from the lower eyelid. Figure 1–15 illustrates a case initially believed to be chronic keratoconjunctivitis and then felt to be a squamous cell carcinoma of the conjunctiva, until histologic data were available. The patient shown in Figure 1–16 was initially referred to the author by a head and neck surgeon; the patient presented with a parotid mass and a history of four recurrent chalazia in the same location in the lower lid. Figure 1–17 demonstrates a large sebaceous carcinoma of the upper lid.

Figure 1–13. Very small sebaceous gland carcinoma diagnosed when a cautious ophthalmologist biopsied an apparent chalazion.

The prognosis with sebaceous gland carcinomas is dependent on multiple factors (see Table 1–3). As mentioned above, some of the recent decrease in tumor-related mortality is due to earlier diagnosis. In the author’s experience, patients with recurrent chalazia who have had metastases at initial presentation had been observed for over 4 years. In most series with long-term follow-up, almost 30 percent of cases eventually metastasized; as shown in Table 1–3, risk factors have been relatively well delineated, and this author has personally not seen a small sebaceous gland carcinoma metastasize after surgical resection. Tumors < 6 mm in diameter generally have an excellent prognosis. Lower survival rates are observed in tumors > 20 mm in diameter, and tumors less histologically differentiated with highly infiltrative growth, pagetoid spread, or multicentricity.84 This latter factor may result in tumor recurrence, even with histologic evidence of clear mar-

gins. Approximately 30 percent of sebaceous gland carcinomas recur after resection.90,97

Systemic extension of a sebaceous gland carcinoma of the eyelid occurs by contiguous growth, lymphatic spread, and hematogenous seeding. Most commonly, these lesions spread into the orbit, to the preauricular or submandibular nodes, or the parotid gland. Less commonly, there is involvement of the cervical node,5 lung, pleura, liver, brain, pericardium, lip, ethmoid sinus, or skull.79,80,84,90,98 Some patients with regional nodal metastases remain alive for long periods of time, and radical neck dissection for isolated cervical node disease is often indicated.84

Sebaceous gland tumors can be associated with the Muir-Torre syndrome.99 This is an autosomaldominant disease with either a benign or malignant sebaceous gland tumor in association with an internal malignancy, generally of the gastrointestinal

tract. Usually, the sebaceous tumor precedes the internal malignancy by several years.99 A few cases of Muir-Torre syndrome with ocular involvement have been reported.100,101

SQUAMOUS CELL CARCINOMA

Squamous cell carcinoma of the lid is relatively uncommon. It accounts for approximately 1 percent of lid malignancies in Caucasians, although in the Chinese, the incidence of this tumor was approximately 19 percent.102 In a series of 5,392 lid tumors examined at the Wilmer Institute, 31 (0.5 percent) were squamous cell carcinomas.103 Some series have noted a slightly higher incidence—up to 4 percent— of eyelid tumors in Caucasians.104 The ratio of basal cell carcinoma to squamous cell carcinoma of the lid is approximately 39:1, except in transplant recipients.105,106 There is no pathognomonic clinical pre-