Ординатура / Офтальмология / Английские материалы / Tumors of the Eye and Ocular Adnexa_Char_2001

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have shown that proliferation rates appear to affect the chance of malignant progression.69

The incidence of CIN lesions in an equatorial sunny climate was noted to be approximately 1 to 2.8 per 100,000 people per year.70,71 The strongest risk factor for squamous cell carcinoma of the conjunctiva is past history of cutaneous malignancy. As above, the role of UV radiation has been demonstrated.63,72

Several reports and studies have emphasized that in a patient under 50 years old who presents with a conjunctival squamous cell carcinoma the possibility of human immunodeficiency virus (HIV) infection should be considered.73 It is estimated there is an 8- to 13-fold increased incidence of conjunctival carcinoma in this setting. In addition, immunosuppressed transplantation patients may also have an increased risk of this neoplasm.74

Diagnosis

The pathogenesis and pathophysiology of squamous cell carcinoma is uncertain. As discussed in Chapter 1, UV radiation can produce “signature” mutations in p53, a tumor suppressor gene, that is probably important in the pathophysiology of these neoplasms. Recent work in a transgenic mouse model of cutaneous squamous cell carcinoma has illustrated the importance of the p53 suppressor gene in this tumor.75

In cervical carcinoma, several groups have observed human papillomavirus (HPV) types 16 and 18.76 McDonnell and colleagues noted that 88 percent of 37 CIN lesions had HPV-16, as demonstrated with polymerase chain reaction (PCR) on paraffinembedded tissue.6,17 The HPV oncogenes inactivate both the p53 and Rb proteins and some experimental treatments are being studied in an attempt to alter this process.77,78 Since many of these patients also had evidence of the virus in the contralateral, uninvolved eye, they postulated that HPV was only one of a number of factors important in the initiation and progression of CIN lesions. Other reports have described bilateral conjunctival carcinomas that were positive for this virus.79 There have now been approximately 15 reports, with variable rates of detection of HPV in squamous cell carcinoma.74 What becomes problematic are studies of nonmalignant conjunctival lesions associated with excess solar

exposure, where there are alterations of either p53 or HPV. Tan and associates found that 3 of 8 pterygia specimens were positive for abnormal p53 staining.80 A conjunctival squamous cell carcinoma appears to occur more commonly in equatorial regions, and

older men with high solar exposure appear to have a higher risk of developing it.65,81 This epidemiology would be consistent with the p53 data shown with squamous cell carcinomas involving the skin. Some studies have shown that the E6 and E7 viral proteins interact with p53 and Rb proteins and can form complexes that then inactivate these proteins.82 Several studies have questioned whether HPV is, in fact, a main driving force or a passenger in the development of squamous cell carcinomas.83 Karcioglu and Issa noted that HPV was present in 20 percent of climatic droplet keratopathy patients, 35 percent in scarred corneas, and in 30 percent of conjunctiva biopsies from otherwise normal cataract patients in Saudi Arabia.84

In most series, approximately three-quarters of conjunctival carcinoma cases have occurred in male patients. While children as young as 4 years have been reported with squamous cell carcinoma, the usual age of onset is in the mid-60s.84,85 In the series from the Mayo Clinic, patients with invasive squamous cell carcinoma had a mean age 7.6 years older than those with CIN.65

Most CIN lesions developed at the limbus in the interpalpebral fissure (Figure 4–5) and are amelanotic. The presence of a neoplastic conjunctival lesion distant from the limbus suggests the possibility of a sebaceous gland carcinoma or another tumor.85

Figure 4–5. Conjunctival intraepithelial neoplasm (CIN) usually develops in the epithelium at the limbus.

Occasionally, squamous cell tumors can be pigmented, and nevi can sometimes simulate these lesions.86 In one histologic report, a malignant nerve sheath tumor simulated a conjunctival squamous cell carcinoma.87 We recently managed a patient who had both primary acquired melanosis and CIN in the same biopsy specimen (personal observation).

Whereas CIN lesions usually develop at the limbus and more commonly involve the bulbar conjunctiva, a more subtle CIN lesion may occur in the cornea. Waring and co-workers described a gray limbal intraepithelial plaque in the interpalpebral fissure (Figure 4–6). Often, this sheet of tissue had a characteristic fimbriated margin with isolated clusters of gray spots (Figure 4–7). None of the 17 reported cases of these very early lesions progressed to invasive carcinoma, on serial evaluation.66

Invasive squamous carcinomas have four common clinical presentations: (1) a gelatinous lesion with

intrinsic vessels (Figure 4–8), (2) a leukoplakia lesion (Figure 4–9), (3) a vascular papilloma-like lesion (Figures 4–10 and 4–11), or (4) pagetoid spread onto the cornea (Figures 4–12 and 4–13). Most commonly, if a mass is present (in contrast to a pagetoid flat

Figure 4–8. Gelatinous conjunctival squamous cell carcinoma with intrinsic vessels.

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Figure 4–11. Papillomatous vascular appearance of a biopsyproven conjunctival carcinoma.

lesion), it has intrinsic vasculature, as shown in Figure 4–5. Occasionally, CIN or invasive carcinoma can simulate a pterygium (Figure 4–14). Most often, the

pseudopterygium is either not in the palpebral fissure, or if it is, it is in the temporal location instead of in the more common nasal location. Rarely, the vascular pattern is atypical and may simulate a peripheral corneal degeneration as shown in Figure 4–15. Occasionally, only the cornea appears to be involved by this neoplasm.66–67

Advanced invasive squamous cell carcinoma of the conjunctiva is often misdiagnosed as a chronic unilateral conjunctivitis (Figure 4–16). Consequently, any older patient with a refractory unilateral conjunctivitis should have a biopsy.88–90 Exfoliative cytology is helpful in establishing a diagnosis in patients suspected of having a conjunctival malignancy. As shown in Figure 4–17, a stained specimen scraped from the surface of the lesion may demonstrate typical neoplastic cells with an abnormal

Figure 4–16. Diffuse squamous cell carcinoma of the bulbar and palpebral conjunctiva simulates “chronic unilateral conjunctivitis.”

Figure 4–18. Sebaceous gland carcinoma of the lid presenting as a conjunctival tumor. An epithelial malignancy of the conjunctiva that arises away from the limbus should suggest this diagnosis.

nuclearcytoplasm ratio, coarse nuclear, and chromatin.91,92 In a recent small report from an experienced center, cytology had 100 percent accuracy.93 Some authors have suggested using rose bengal to label dead or degenerative epithelial cells and to delineate the margins of this tumor.94 We have not found this technique sufficiently accurate to be useful. Sebaceous gland carcinoma of the lid can present with mainly conjunctival involvement (Figure 4–18).

CIN may progress to invasive squamous cell carcinoma, although a few have been reported to have undergone spontaneous regression.95 Many CIN lesions do not progress to invasive squamous cell carcinoma.65 Fully developed conjunctival carcinomas often have a pathognomonic appearance of a mulberry gelatinous tumor with fronds of superficial vessels (see Figure 4–8). The histologic features of CIN lesions may appear quite malignant, but the

Figure 4–17. Exfoliative cytology of a squamous cell carcinoma of the conjunctiva. Large malignant nuclei are seen.

risk of metastatic disease is almost zero.1,10,96,97 The recurrence rate of both CIN and invasive squamous cell carcinoma is mainly a function of the completeness of tumor resection. Previous series, often with incomplete tumor removal, have reported recurrence rates ranging from 10 to 64 percent.98 In some studies, the correlation between clear microscopic margins and survival were not as good as in others.99 In the author’s experience, as discussed below, surgical margins have been quite accurate as a means to prevent recurrence.100 The low historic figure of a 10 percent recurrence rate is from a series in which over half the cases had either no follow-up or follow-up for less than 1 year, and most older series had a short-term recurrence rate of approximately 40 percent.85,92,94 Fifty-three percent of incompletely excised CIN lesions recurred versus < 5 percent of lesions that were completely resected.65 In the cases that did recur, the mean interval between excision and recurrence was approximately 22 months.

Usually, recurrences develop at the limbus (Figure 4–19) and spread superficially onto the cornea rather than toward the cul-de-sac. Alternatively, there can be intraconjunctival metastatic lesions. As discussed in Chapter 1, for basal cell carcinomas of the eyelid and probably by analogy germane for these conjunctival neoplasms, these patients are also at risk for new as well as recurrent squamous cell carcinoma of the conjunctiva, although the former hypothesis has not been proven. Rarely, there can be intraocular extension of a squamous cell carci- noma.101–108 Invasion into the globe has been very difficult to diagnose. The author has personally had

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Figure 4–19. Recurrent conjunctival carcinoma in the interpalpebral fissure at the limbus.

Five years later, the patient was tumor free, with a visual acuity of 20/25 in the involved eye.109 The spindle cell variant of squamous cell carcinoma has a higher incidence of intraocular invasion.110,111 In one reported case, this tumor resulted in the patient’s death within 14 months of the initial incision.112 Unfortunately, the appearance of a spindle cell tumor is not diagnostic (Figure 4–22). Rarely, squamous cell carcinoma can be bilateral (Figure 4–23).

Management

Surgery

experience with 6 such cases. In 3, gonioscopic examination showed broad-based synechiae and a “velvety appearing” tumor in the anterior segment. In 1, there appeared to be just anterior segment inflammation, as others have noted.104 Occasionally, cytologic examination of an anterior chamber paracentesis may be diagnostic.103 The fifth case that the author managed presented with a flat anterior chamber after the referring physician had attempted to perform a conjunctival scraping for cytopathologic diagnosis (Figure 4–20). The intraocular penetration was secondary to tumor erosion through the cornea. Another case of focal intraocular recurrence after multiple treatments is shown in Figure 4–21. In the latter case, we were able to resect the tumor with an 18-mm en-bloc scleral-iridocyclochoroidectomy.

As discussed under “Conjunctival Surgery” (see below), the mainstay of treatment of conjunctival epithelial tumors is excisional biopsy with frozen section control. In the author’s personal experience with approximately 100 CINs and invasive conjunctival epithelial carcinomas, < 5 percent recur when frozen sections are used to evaluate margins.100 There are two problems with this technique: (1) it is imperative that accurate orientation be given to the pathologist. We have a life-sized, sterilized ocular pathology form (see Figure 3–1), and all specimens are submitted on it; and (2) while it is relatively straightforward to establish whether the margins distal to the limbus are clear of tumor, the corneal edge usually cannot be accurately sampled, and similarly, the deep scleral surface of the tumor is often not precisely surveyed with standard frozen section control.

Figure 4–20. Intraocular invasion of a conjunctival carcinoma. Intraocular penetration (and subsequent gluing) occurred when the referring physician attempted diagnostic scraping.

Figure 4–21. A case referred for a focal intraocular recurrence after multiple treatments. The tumor was removed with a large iridocyclectomy and a free graft.

Figure 4–22. The clinical appearance of the spindle cell variant of squamous cell carcinoma is not diagnostic. These tumors are more aggressive.

Usually, Bowman’s membrane offers considerable resistance to deep invasion; however, occasionally a lamellar keratectomy is required to completely excise a tumor.55,65,86

We routinely use adjunctive cryosurgery with a double freeze-thaw technique (see Chapter 2) at the scleral base of the tumor as well as on presumably “tumor-free” conjunctival margins. Fraunfelder and Wingfield reviewed 36 patients with squamous cell carcinoma of the conjunctiva who were treated and followed up for more than 3 years. Two of six who were only excised had recurrences, as did 3 of 9 who were treated with only freezing. Excision plus cryotherapy had a recurrence rate of approximately 9 percent.113 Other workers, including ourselves, have had a similar experience.114–116 Rarely, after cryosurgery, a Wesseley ring can occur, last for several months, and produce decreased vision; however, the author has never seen this complication.117

Often with a small carcinoma, the tumor area that has been treated with resection and cryotherapy can be closed primarily. If too large a defect has been created, we cover the muscles with either an autologous conjunctival membrane or a buccal mucous membrane graft, since symblepharon or fibrosis with secondary strabismus can occur, if these areas treated by freezing are not covered with mucosal epithelium.118

A major problem with tumors that involve more than 40 percent of the corneal surface has been posttreatment morbidity and resultant decreased visual acuity. On the basis of the work by Thoft and colleagues, we have treated such patients with limbal grafts after superficial resection and cryotherapy.119,120 A 3 × 5 mm limbal graft is harvested from the contralateral eye and sutured into place at the limbus with four interrupted No. 10-0 nylon sutures. Figure 4–24 shows fluorescein staining 36 hours after removal of a tumor involving most of the corneal surface, cryotherapy, and placement of limbal grafts. Note that > 85 percent of the cornea has been re-epithelialized as a result of the limbal graft. Figures 4–25A and B show a lesion prior to and after resection, cryotherapy, and placement of limbal grafts. Visual acuity improved from 20/100 to 20/20. An alternative approach to reconstruction is the use of amniotic membrane transplantation; however, the long-term experience for this approach for tumors is extremely limited.121 An additional surgical option that has been tried in only a few patients is the use of excimer laser keratectomy to resect the corneal portion of the tumor.122 The problems with this

Figure 4–23. Bilateral conjunctival squamous cell carcinoma.

Figure 4–24. Fluorescein staining 36 hours after complete removal of involved epithelium, cryotherapy and placement of limbal grafts. This figure shows that > 80 percent of the corneal surface had become re-epithelialized by that time.

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A

B

Figure 4–25. A, A large conjunctival— corneal squamous cell carcinoma. B, Removal of the tumor, cryotherapy, and placement of autologous limbal grafts resulted in a good visual outcome.

approach are at least threefold. The major issue is that since it vaporizes tissue, there is no material available for histologic evaluation of the margins or of the lesion itself. A second less important issue is that since these tumors do not grow in a symmetric fashion, sculpting an area with the laser would be somewhat difficult. Third, there is a paucity of data.

Recently, the group in Miami has reported excellent results using only Mohs’ technique (see Chapter 3) under a local anesthesia without cryotherapy. None of 19 patients developed a recurrence with a follow-up between 6 and 60 months.123 In 4 of the 19 patients, however, a second procedure was required, since the initial surgical margins were positive.

We have had one intraocular occurrence that was present at the time of initial surgery, though we failed to recognize it. The patient, who had had her first surgical procedure in a developing country, appeared to have a rough scleral surface as a result of a partial-

thickness sclerectomy. Three months after we removed one tumor with clear margins and treated the resected tumor base with triple freeze-thaw cryotherapy to –30° C, intraocular invasion was documented.

Radiation

Some, generally diffuse carcinomas have been treated with brachytherapy or teletherapy. Lommatzsch reported treating 15 patients with beta irradiation for localized tumors, with excellent results. In 6 patients followed up over 5 years, no recurrences were noted. One patient developed a cataract, but it was bilateral, and 1 developed a partial symblepharon. Two patients developed glaucoma, and 1 case of corneal degeneration also occurred.124

Several other groups have reported radiation therapy results with different forms of brachytherapy (ruthenium-106 [106Ru], iridium-125 [125I], stron- tium-90 [ 90Sr]) in small number of cases.125–129 Radiation doses have varied from 30 to over 100 gray (Gy) in single or fractionated treatments. Cataract occurred in some of these patients and recurrences were reported in 4 of 27 cases in one series.125 90Sr has been used as an adjunctive therapy after surgical resection of conjunctival squamous cell carcinoma. In 131 evaluable cases, approximately 6 percent developed recurrences. Cataract and scleral damage were noted in < 5 percent of cases.130 Scleral damage at lower radiation doses after pterygium repair has been previously reported.131 Possibly, if radiationinduced scleral necrosis occurs, hyperbaric oxygen can be used, although the author’s inclination would be to biopsy the area to ensure there is no recurrent tumor, and then graft the site.132

Topical Therapy

Several evolving experimental therapies are being investigated for CIN and invasive squamous cell carcinoma. Maskin reported a single case of a CIN lesion treated with topical interferon.133 Dausch and colleagues reported a single case with a 26-month follow-up of a patient who had a CIN lesion removed by phototheraputic keratectomy.134 Frucht-Pery and Rozenman reported 3 patients treated with topical mitomycin-C for between 10 and 22 days. After 4 to

12 months of follow-up, none of the 3 had recurrences.135 While they noted no major complications, others have seen severe vision problems when this medicine has been used after pterygium surgery.136

There have been several small series reported with the use of topical mitomycin-C, mainly for intraepithelial disease. A few patients have been treated with 5-fluorouracil with short-term good results.137 A number of authors have reported under 10 patients each, using various concentrations of mytomycin-C, usually either 0.02 percent or 0.04 percent four times a day for either 7 or 14 days. In a follow-up paper by Frucht-Pery and associates, 17 patients with CIN were treated. After one course of therapy, the tumors were eradicated in 10 cases, but in 6 regrowth occurred. In 5 of the 6 cases where there were CIN lesions (the latter was an invasive carcinoma), they were able to eradicate the tumor.138 Wilson and colleagues treated 7 eyes with 0.04 percent mitomycin-C four times a day for 7 days in alternate-week cycles, and 2 of 7 required a resec- tion.139–141 Vann and Karp have treated 6 patients with biopsy proven lesions using 3 megaunits of interferon 2-beta and achieving complete resolution, with a mean follow-up of 7.2 months.142

Management of Widespread Conjunctival

or Orbital Invasion by Squamous

Cell Carcinoma

Unfortunately, a number of invasive conjunctival squamous cell carcinoma patients are initially misdiagnosed as having chronic unilateral conjunctivitis when they actually have a diffuse conjunctival carcinoma involving both the palpebral and bulbar conjunctiva (Figure 4–26). In this group of patients, it is very difficult to retain a functional eye. In one or two heroic cases, we resected the entire conjunctival area and used extensive grafts. We have been able to control the tumors with 50 Gy of radiation; however, as a result of damage to the goblet cells and lacrimal ductules, none of these eyes has retained useful vision, and most required anterior exenteration after they became painful and nonfunctional.143

Orbital or intraocular invasion in these patients is often an indication for anterior exenteration (see Figure 4–20). We have had to perform total orbital exen-

Figure 4–26. Diffuse involvement of both palpebral and bulbar conjunctiva by squamous cell carcinoma.

teration in only a few cases, as orbital involvement is almost always limited to the anterior portion of the orbit. (See Chapter 8 for a discussion of exenteration techniques). In an anterior exenteration, we make incisions distal to the lashes and elevate a myocutaneous flap as shown in Figure 8–71. The entire conjunctiva and globe are removed en bloc, but the muscles posterior to their insertions as well as other orbital structures are left in situ. Hemostasis is achieved with both pressure and cautery. The orbital tissues are closed with 4-0 chromic gut suture. A small Penrose drain is left in place, and the skin is sutured with interrupted 6-0 silk. The orbit is pressure-patched for 48 hours, and re-dressed with another 48-hour pressure-patch after the first dressing change. Thereafter, the bandage is changed daily. Figure 4–27 shows a patient 1 week after an anterior exenteration.

Metastases from squamous cell carcinoma of the conjunctiva are quite rare; only 3 tumor deaths have been reported in the United States, and only 1 of these was documented with postmortem examination.5,62,63 In the world’s literature, there have been approximately 10 cases of tumor-related mortality associated with conjunctival squamous cell carcinoma.3,144

Variants of Conjunctival Squamous

Cell Carcinoma

Some variants of conjunctival squamous cell carcinoma that have a greater tendency to behave aggres-

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Figure 4–27. One week after anterior exenteration for intraocular invasion of a diffuse squamous cell carcinoma.

sively have been reported. Margo and Groden described a case of a CIN lesion with mucoepidermoid differentiation.145 There have been approximately 15 cases of mucoepidermoid carcinomas of the conjunctiva described. There is a high tendency for these spindle cell variants to invade the globe and the orbit, and local excision has been of limited efficacy (see Figure 4–22).110,111,146 In 2 of 6 spindle cell carcinomas of the conjunctiva, reported by Huntington and colleagues, intraocular extension developed.147

Campanella and colleagues report two cases of conjunctival carcinoma in enucleated sockets and hypothesize that the prosthesis may have caused sufficient irritation to promote tumor development.148 The author personally has never seen such a case.

CONJUNCTIVAL MELANOMA

Conjunctival melanoma is an uncommon ocular tumor that accounts for 2 percent of all eye malignancies.149,150 In Sweden, the annual incidence of this tumor is approximately 0.024 per 100,000.151 In an American study of 4,836 cases of melanomas at all sites, 5.2 percent involved ocular structures, and of the ocular structures, 85 percent were uveal and 4.8 percent involved the conjunctiva.152 The estimated incidence of melanoma in the uvea is between 20 and 40 times that in the conjunctiva.149–152

Pathogenesis

The pathogenesis of conjunctival melanomas is controversial. They can arise de novo, from nevi, or from malignant degeneration of acquired melanosis.153–155 Reese believed that most conjunctival melanomas arise from an area of acquired melanosis.156 Although some oncologists continue to believe that conjunctival melanomas arise de novo in approximately 50 percent of cases, most oncologists no longer do.157 Folberg and colleagues reviewed 131 cases of conjunctival melanoma and concluded that 98 (75%) arose from primary acquired melanosis, while 33 were either new tumors or tumors arising from nevi.158 Other workers believe that only 50 to 60 percent of conjunctival melanomas arise from acquired melanosis.

The importance of environmental factors in the etiology of conjunctival melanomas is uncertain. In cutaneous melanomas, sun exposure plays an important role, and melanomas occur more frequently in patients living closer to the equator. Similar, but smaller, data sets are available for both uveal and conjunctival melanoma.63,159,160 Because of the paucity of tissue, there have been few molecular biologic investigations on conjunctival melanoma. In some work in the author’s laboratory several years ago, we did not find increased p53 abnormalities, and others have found similar results.161,162

Diagnosis

Establishing the correct diagnosis in a patient suspected of having a conjunctival melanoma can be difficult. Three general principles are helpful: (1) the patient’s age is a factor; melanomas rarely occur in teenagers and younger children; most occur in middle-aged or older individuals. Fewer than 10 cases of conjunctival melanoma have been reported in children;163–166 (2) conjunctival melanoma is an epithelial lesion. Many of the pigmented simulating lesions, such as melanosis oculi (Figure 4–28), oculodermal melanosis (nevus of Ota), and blue nevi are in the sclera; and (3) conjunctival nevi will often have cystic inclusions visible on slit-lamp examination (Figure 4–29); cystic inclusions are almost never found in melanomas.

The patient’s ocular history is important in differentiating simulating lesions from melanomas. A

history of previous conjunctival inflammation, such as trachoma, the use of certain eyedrops (argyrosis or adrenochrome staining) (Figures 4–30 and 4–31), exposure to radiation or arsenic, and certain systemic conditions, such as pregnancy or Addison’s disease, can produce benign superficial pigmentation.167,168 In Carney’s complex, an autosomal dominant disorder characterized by cardiac myxomas, endocrine disease, and spotty pigmentation, conjunctival pigmentation has been described.169

Simulating Lesions

Lesions that can simulate conjunctival melanomas include nevi (see Figure 4–29), staphylomas, subconjunctival hematomas, foreign bodies (Figure 4–32), and extraocular extensions of uveal melanomas (Figure 4–33). While previously thought

to be uncommon, we have noted that combined nevi are not rare and can closely mimic melanomas.170

Conjunctival melanomas are rare in dark-skinned races.171,172 As is the case with uveal melanomas, African Americans are much less commonly affected by this process. Approximately 5 to 10 percent of Caucasians have limbal conjunctival epithelial pigmentation.173 In contrast, approximately 50 percent of Oriental and Hispanic patients have limbal pigmentation, and it is present in almost 95 percent of black patients.172 Some clinicians have used an overly inclusive definition of primary acquired melanosis (PAM). Gloor and Alexandrakis thought it was present in 36 percent of outpatient examinations in one center.174

Conjunctival nevi may be difficult to differentiate either clinically or histologically from melanomas. Jay reported 43 conjunctival nevi that had previously been histologically classified as melanomas.175 He