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

70 TUMORS OF THE EYE AND OCULAR ADNEXA

Figure 4–32. Conjunctival foreign bodies simulating melanoma.

noted that it is often difficult to correctly diagnose a conjunctival melanoma, since the cells can have bizarre shapes and there can be marked inflammation surrounding the lesion. Others have queried whether some presumed conjunctival nevi that later appear to undergo malignant degeneration may actually be undiagnosed melanomas in the radial growth phase.176 Using several markers, such as S-100, HMB-45, NKI/C3, there is not good enough differentiation to delineate benign and malignant pigmented conjunctival lesions. Preliminary work using an antibody toward MAGE-3, Mab57b, showed reasonable specificity between benign and malignant pigmented lesions but only 44 percent of sensitivity.177 More recent studies have shown that even in expert centers, there is diagnostic uncertainty in these indeterminant cases.178

The clinical as well as the histologic differentiation of nevi from melanomas may be confusing. Most

commonly, conjunctival nevi are present at birth and arise at the limbus.179 Often, nevi appear to grow at puberty as a result of the increased pigmentation of the nevus cells. Conjunctival nevi and melanomas can be amelanotic (Figure 4–34A and 4–34B). Alternatively, nevi can occasionally be red. Kantelip and colleagues reported a Spitz nevus in a 15-year-old boy that was at the limbus, red and 6 mm in size.180

If the clinical diagnosis of a conjunctival pigmented lesion is not definitive, a biopsy should be performed. Incisional biopsy followed by definitive therapy does not alter the patient’s prognosis.181 Some authors have also advocated tear cytology.182 In atypical cases of either a possible amelanotic melanoma or melanoma versus a nonpigmented lesion, HMB-45, a monoclonal antibody that is positive for both benign and malignant melanocytic processes, can be useful.183,184

Acquired melanosis of the conjunctiva, an entity first defined by Reese, can be difficult to differentiate from melanoma.163 Some authors have suggested that “primary epithelial melanosis” might be a better term, but it has not had wide acceptance. Usually, the onset of acquired melanosis of the conjunctival epithelium occurs in early middle age. Patients who develop malignant degeneration are, on average, slightly older than those with benign acquired melanosis.181

Patients initially develop patchy brown areas of conjunctival epithelial pigmentation (Figure 4–35); occasionally, the lesion can secondarily involve the cornea or lid (Figure 4–36A). The clinical course of acquired melanosis is varied.173 New areas of con-

Figure 4–35. Limbal conjunctival acquired melanosis.

junctival involvement may develop as other sites lose pigmentation. Total spontaneous regression occasionally occurs, whereas other patients develop malignant degeneration. Approximately 17 percent of the patients followed up by Reese developed areas of malignant degeneration.173 Figure 4–36B illustrates malignant degeneration of the case shown in Figure 4–36A. Figures 4–37A and B demonstrate another case of malignant progression in a patient with primary acquired melanosis. Histologically, the progression of acquired melanosis to invasive melanoma has been well delineated.184,185

Zimmermann classified acquired melanosis into four stages. In stage I, there is minimal junctional activity. In stage Ib, there is marked junctional activity, with nesting of the nevus cells. Stage II can be divided into cancerous melanosis with minimal invasion (IIa) or marked invasion (IIb). The histologic changes noted on biopsy are important prognostically, even if no malignancy is noted.184 Folberg and colleagues demonstrated that approximately 50 percent of primary acquired melanosis cases with basal atypical cells later developed into invasive melanoma.156,185 A particularly difficult form of primary acquired melanosis to diagnose is a tumor that arises out of a primary melanosis sine pigmento.186 Most cases of corneal melanomas probably arise from either the limbus or from an unsuspected primary melanosis sine pigmento.172,186,187

Unfavorable prognostic signs in conjunctival melanoma include tumor thickness, location, (involvement of caruncle, palpebral conjunctiva, or fornix), diffuse melanomas, multifocality, more malignant

cell type, lymphocytic infiltration, the presence of marked cytologic atypia, cell proliferation, pigmentation of the lid margin, and pagetoid spread (Table 4–1).158,175,188–193 In a Danish retrospective study of 55 cases with a minimum follow-up of 10 years, the 5- and 10year survival rates were 86 percent and 73 percent, respectively. The local recurrence rate at 5 years was 5 percent, and at 10 years 42 percent.194 In a French series, in 49 of 56 patients who had surgery plus external beam radiation, the overall survival was 77 percent at 5 and 64 percent at 10 years. Tumors that arose de novo had a worse prognosis.195 In another series of 61 patients reported from Yugoslavia, tumor thickness was the most important predictor of survival in multivariant analysis. Other important factors were mitosis, pigmentation, and inflammation.195 Most series have shown that tumors > 1.8 mm thick have a poor prognosis, but some have not.175,180,189,192 In some cases, melanomas that arose from the nevi had a better prognosis than those that

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Figure 4–36. A, Secondary spread of conjunctival acquired melanosis onto the lid. B, Malignant degeneration in the same case, with vertical growth phase in bulbar melanoma.

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B

Figure 4–37. A and B, Malignant progression in multiple areas in a patient with PAM.

arose de novo or from acquired melanosis, but this is not evident in other series.158,196

Almost 20 percent of patients with acquired melanosis develop malignant transformation. If the patient has a relatively small area of PAM that is easily resected at the limbus, it is probably prudent to

do so in a young person. In patients with diffuse involvement, an incisional biopsy in the thickest area or one with inflammation should be performed along with careful serial examinations. The presence of new vessels, discrete tumor thickening, inflammation, or spread of diffuse disconnected pigment suggests malignant degeneration.

Management

Optimal management of acquired melanosis is uncertain. There are no randomized prospective clinical trial data on which to base management decisions, and there have been no statistically significant data demonstrating the superiority of any therapeutic modality in the management of conjunctival melanoma. In general, patients with relatively thin melanomas that are localized on the bulbar conjunctiva do quite well (see Table 4–1). We excise suspicious conjunctival lesions in the office and send the specimens for pathologic examination. If the clinical appearance of the lesion suggests a melanoma, given its thickness, lack of cysts, and epithelial origin, we remove it under frozen section control in the operating room. If the margins are free of tumor, even if there is no clinical evidence of scleral extension, the base and resection margins are treated with double freeze-thaw cryotherapy. The techniques used in conjunctival surgery are discussed at the end of the chapter.

Some authors have advocated various forms of radiation therapy.197–201 Radiation is relatively effec-

tive in controlling local disease; however, its effect on conjunctival melanoma metastases is unclear.202 We use radiation to treat diffuse conjunctival melanomas arising from acquired melanosis when they cannot be surgically resected and the patients refuse exenteration. In a few such cases, we have saved the eye; however, most had enough ocular damage from wide-field irradiation so that only a limited function was achieved (Figure 4–38). Slightly better results have been described by Zografos and colleagues with protons, cobalt, and cryotherapy.203 Other investigators have used approximately 100 Gy of beta radiation to treat more localized melanomas, with good results. Lommatzsch noted that 31 of 45 conjunctival melanomas could be controlled with 90Sr beta applicators.199 As is the case with uveal melanomas, tumor shrinkage is often delayed for 2 to 4 years, and complications including cataract, conjunctival telangiectasia, keratitis, anterior uveitis, neovascular glaucoma, and loss of the eye can occur. Approximately, 12 percent of conjunctival melanomas treated with radiation develop a significant ocular complication, including loss of the eye.198 In Lommatzsch’s series, 11 of 65 patients died, 4 with proven metastases.199

Contraindications for radiation therapy include bulky tumors in the fornix, tumor involvement of the palpebral conjunctiva and lid, and recurrent melanoma previously treated with radiation.

Cryotherapy is usually used as an adjunct in the management of conjunctival melanomas. Not much data are available on this technique, even though it has been used in ophthalmic oncology since the late 1960s.13,204 Limited data indicate that in conjunction with surgery for local disease, cryotherapy is as effective as ionizing radiation and is associated with fewer complications. Cryotherapy can have significant complications, including trichiasis, ptosis, loss of lashes, symblepharon, and paresis of the recti muscles.205,206 The use of this modality for benign acquired melanosis is uncertain. Jakobiec and coworkers have reported results in 5 such patients with acquired melanosis without malignant degeneration.207 Severe corneal changes and cataract occurred in 1 patient. While cryotherapy can destroy nevoid as well as melanoma cells, it does have significant complications, and the value of intervention in patients

with benign disease is uncertain.206 Cryotherapy in an area of acquired melanosis usually destroys all pigmentation. The technique may be effective even when melanoma has superficially involved the sclera.207,208 It has been the author’s experience that if the tumor is limited to the conjunctival epithelium, it is useful to elevate this layer with a 30-gauge needle using topical anesthesia before freezing the tumor. The author believes that this technique decreases the morbidity to both Tenon’s capsule and the eye that otherwise might occur with this therapy. The author also places a symblepharon conformer for 5 to 7 days if a wide area of conjunctiva has been treated with cryotherapy to prevent adhesions.

Experimental treatments with heat have been reported, but sufficient data are not available to determine their utility.209 Several reports using mit- omycin-C, analogous in dose and schedule with that used for conjunctival squamous cell carcinoma have been reported with melanoma. Frucht-Pery and Pe’er treated a patient with PAM with atypia, without progression over 7 months. Starting in 1995, Lomatzsch and colleagues treated 14 patients, 9 with melanoma and 5 with PAM. With local excision, they received 0.02 percent mito- mycin-C for 4 to 6 weeks.214 Two cases developed progression. Finger and colleagues reported 10 cases treated at 0.04 percent qid. Six of the 10 had been treated after the excision in cryotherapy, and all developed transient conjunctivitis, with 1 developing epithelial defect. Those tumors which had a

Figure 4–38. Diffuse conjunctival melanoma treated with widefield radiation. Loss of goblet cells and secondary xerophthalmia has resulted in loss of visual function.

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Figure 4–39. Bulky, diffuse conjunctival and eyelid melanomas.

nodular component were resistant to treatment, and 4 which were treated with topical mitomycin-C all recurred. Exenteration is necessary for some conjunctival melanomas that have intraocular or orbital extension, diffuse, bulky fornix involvement (Figure 4–39), or recurrence after irradiation.215 The intraocular pattern of conjunctival melanoma invasion is not pathognomonic; often, it appears as a flat, diffuse choroidal tumor (Figure 4–40) or as a pupillary irregularity (Figure 4–41).

Prior to exenteration, a complete metastatic evaluation should be performed. In addition, as several

authors have pointed out, inspection of the nasal sinuses with the endoscope to detect possible extension down the nasal lacrimal duct should be performed. This includes a general physical examination, serum liver function tests, and chest and abdominal computed tomography (CT) or magnetic resonance imaging (MRI) evaluation.

The effect of exenteration on the natural history of conjunctival melanoma is unclear.216 The surgical techniques for exenteration are shown in Chapter 8.

Conjunctival melanomas can metastasize to the conjunctiva, sinus mucosa, local cervical nodes, submandibular or preauricular nodes, intra-abdomi- nal nodes, subcutaneous tissues, liver, bone, parotid gland, and brain.2,197,216,219 In a large series Paridaens and co-workers noted that 27 percent of treated patients had recurrences in the previous site, lymph node involvement developed in 11 percent, 5 percent had orbital recurrence, and 3 percent developed sinus involvement.220 Tumor-related mortality from conjunctival melanomas is affected by the extent, location, cell type, lymphocytic invasion, mitotic rate, and thickness of the tumor (see Table 4–1). There is a slight tendency for women to have a better prognosis than men, but this is not statistically significant.175,221 Larger, more diffuse, and thicker tumors have a worse prognosis. Patients with diffuse malignant degeneration of acquired melanosis probably have a worse prognosis than those with localized tumors.155,175 In the largest series of 256 consecutive invasive primary conjunctival melanomas, Paridaens and co-workers studied prognostic factors with multivariate analyses. Tumors in unfavorable

locations, which they defined as palpebral conjunctiva, fornices, caruncle, and lid margins, had over twofold higher mortality, compared with those melanomas on the globe.220 Similarly, patients with mixed tumors had three times higher mortality than those with pure spindle melanomas, and lymphocytic invasion was associated with a fourfold increased death rate. Multifocal tumors on the surface of the eye were associated with a fivefold increase in mortality. Unlike other smaller series, Paridaens and colleagues employed Cox modeling to adjust for effects of multiple parameters on survival.220 They noted that some factors that appeared to be important in univariate analysis lost their significance when multivariate analysis was performed. As an example, when all tumors were considered, melanomas arising from PAM had a worse prognosis; however, this effect was lost when location and cell type were considered. Tumor location, lymphocytic invasion, and cell type were important prognostic parameters when all melanomas were considered together. In tumors in favorable locations, cell type, lymphocytic invasion, multifocality, and advanced age were also prognostically significant. In tumors in unfavorable locations, only thickness > 4mm, compared with < 1 mm, added to prognostic risk.220

Fuchs and others have also found that tumor location is important for survival.222 As previously noted, Folberg and colleagues have found that the pagetoid spread in PAM-derived melanomas is also an important prognostic indicator for the development of metastases.223 In this series, gender, age, and whether the tumor arose from an area of PAM, de novo, or from a nevus was not prognostically significant.220 This group did not find evidence of nucleolar organizer regions associated with prognosis.224 In a combination of several large series, the 5-year tumor-related mortality with conjunctival melanomas has been approximately 17 percent, and the 10-year mortality has been

approximately 30 percent.151,154,158,175,189,193,194,220,225

There is controversy regarding the use of systemic adjunctive treatment in high-risk cutaneous melanoma. In some studies, the use of interferon alpha-2b has increased the relapse time and overall survival, while in other studies, this has not been demonstrated.225 There is significant morbidity with

this agent, and its efficacy in either conjunctival or uveal melanoma has not been demonstrated.

CONJUNCTIVAL KAPOSI’S SARCOMA

KS of the conjunctiva has become a common tumor in patients with acquired immunodeficiency syndrome (AIDS).226 This neoplasm was first described in 1872 and has most commonly occurred in the lids or conjunctiva of elderly Italian or Jewish men. Before 1980, there were approximately 30 reported cases.227,228 In Africa, the prevalence of this tumor paralleled the prevalence of malaria with its immunosuppression. The tumor also occurs in other immunosuppressed populations.229 As discussed in the section on lid tumor pathogenesis, human herpes virus-8 (HHV-8) is important in the etiology of this tumor.230 The role of the herpes virus in the etiology of this tumor would fit with the epidemiology of the disease.230 The clinical presentation with a reddish or bluish, relatively diffuse, vascular conjunctival lesion is almost pathognomonic in a patient with AIDS.2331–232 Approximately 75 percent of patients with ocular involvement exhibit oral lesions.233 The author has never seen a patient with conjunctival KS who does not have the diagnosis or symptoms of AIDS. Three publications cite rare cases of patients with AIDS in whom KS was the first manifestation of the disease.234 A typical example is shown in Figure 4–42. Occasionally, these tumors present as a focal mass (Figure 4–43). This vascular malignancy is very different in appearance from a benign conjunctival vascular malformation (Figure 4–44).

Figure 4–42. Typically, Kaposi’s sarcoma in the conjunctiva are multifocal, diffuse, and reddish lesions.

Figure 4–43. Solitary conjunctival Kaposi’s sarcoma in an AIDS patient.

Fortunately, with the use of multiple protease inhibitors, the incidence of KS lesions of both the lid and conjunctiva has markedly diminished. KS lesions respond rapidly to a number of therapeutic modalities, including cryotherapy, surgery, irradiation, and chemotherapy with vinblastine.233–238 The patient shown in Figure 4–43 received 6 megavoltage (MeV) electrons with excellent results (Figure 4–45). In our experience, equivalent results are obtained with a single fraction of photon irradiation with less morbidity than using cryotherapy, intralesional chemotherapy, or surgery.233

CONJUNCTIVAL LYMPHOID LESIONS

The conjunctiva can be involved by a number of benign or malignant lymphoid lesions, including lymphoid hyperplasia, pseudotumor, leukemia, and various types of lymphoma. It is estimated that conjunctival lymphoid tumors account for between 0.2 and 1 percent of all ocular tumors. Lymphoid lesions char-

Figure 4–45. Lesion shown in Figure 4-42 after low-dose superficial electron irradiation.

acteristically present as a salmon-colored, subconjunctival infiltrate (Figure 4–46). Occasionally, diagnosis of a lymphoma can be difficult, and these can simulate a conjunctivitis or a scleritis.239,240 While usually lymphoid lesions involve the bulbar conjunctiva, occasionally they will present with involvement mainly with the palpebral conjunctiva.241 Differentiating between benign and malignant lymphoid infiltrates can be exceedingly difficult; one large series with a 5-year follow-up showed that it is often not possible to distinguish between the two.242 Scarring of the overlying conjunctival epithelium is more common with benign processes (Figure 4–47); it is not usually seen in malignant lymphomas (Figure 4–48).

Less common lesions that have involved the conjunctiva include plasmacytoma, acute monocytic leukemia, Hodgkin’s disease, Burkitt’s lymphoma, T- cell lymphoma, mycosis fungoides, and large cell lymphomas.243–251

Figure 4–47. Scarring over a benign lymphoid process.

The laboratory diagnosis of lymphoid lesions is by standard histology, immunohistologic marker studies, and, in some cases, Southern blot or polymerase chain reaction (PCR) technique. These newer diagnostic modalities are discussed in Chapter 26.

Localized lesions can be excised (Figure 4–49). Fraunfelder and colleagues reported the use of cryotherapy in a diffuse mixture of lymphoid lesions. Thirty-nine out of 42 responded with two treatments, and 41 of 42 with a third treatment.252 Diffuse malignant lesions isolated to the ocular adnexa are treated with 30 to 40 Gy of irradiation. If the lesion involves only the conjunctiva, after being biopsied, it is irradiated using either orthovoltage (approximately 250 lev) or electrons with appropriate shielding (see Chapter 2) (Figure 4–50A and B). If orbital involvement is present, megavoltage photon irradiation is used (see Chapter 26). Isolated conjunctival small cell lymphomas respond rapidly to irradiation, and in our experience and that of most others, less than 10

percent develop widespread disease on long-term follow-up.253 In the study by Coupland and co-work- ers, however, they noted no difference in the incidence or development of systemic lymphoma between conjunctival or orbital lymphomas.254 As discussed in the chapter on orbital lymphoma, orbital tumors generally have a higher likelihood of developing widespread disease; in another series, this was not been observed.254 In the more poorly differentiated lesions, the risk of systemic disease is substantially higher.255,256 Pre-existing systemic lymphoma was present in approximately 10 percent of our cases, but it was not always diagnosed.

All patients with conjunctival lymphomas should have a thorough evaluation, including complete blood count (CBC), plasma protein electrophoresis, body scans, and bone marrow biopsies. In benign lymphoid lesions that are symptomatic and involve a diffuse area, low-dose irradiation with 10 to 20 Gy is used, with shielding of the cornea and lens. A case of conjunctival–anterior orbital pseudotumor (diagnosed with Southern blot and monoclonal antibodies) is shown before and after low-dose irradiation (Figures 4–51A, B, and C). In rare circumstances, other therapies have been employed. Cellini and colleagues reported an HIV-positive patient with conjunctival lymphoma who responded to a short course of interferon.257

CARUNCLE LESIONS

Most lesions of the caruncle are benign. In two large series, < 10 percent of these tumors were malignant.

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Figure 4–50. A, Conjunctival lymphoma involving the superior conjunctiva and anterior orbit before radiation. B, Appearance after receiving 40 Gy of photon irradiation.

In a series from the Wilmer Institute, nevi accounted for 43 percent of caruncle lesions, followed by papilloma (13%), sebaceous gland hyperplasia (8%), and nonspecific inflammation (4.5%). The most common malignancies were squamous cell carcinoma of the conjunctiva, sebaceous gland carcinoma of the lid, and conjunctival melanoma.258 There have been four cases reported of primary basal carcinomas of the caruncle.259 Other rare lesions include a mucoepidermoid carcinoma of the caruncle.260 These lesions are managed like conjunctival squamous cell carcinoma or melanoma, with one exception. We find that better cosmetic results are obtained when a mucous membrane graft is used to cover the surgical defect than either a primary closure or autologous conjunctiva (Figure 4–52). The surgical technique for obtaining a mucous membrane graft is discussed in Chapter 3.

A number of less common lesions may involve the caruncle, including oncocytoma, which characteristically is a striking cherry red, and, rarely, ade-

nocarcinoma.261–264 A caruncular nevus is shown in Figure 4–53, a sebaceous gland carcinoma in Figure 4–54, a squamous cell carcinoma in Figure 4–55, and a melanotic melanoma in Figure 4–56. In the last case, despite clear surgical margins, this had orbital recurrence as shown on the axial T1-weighted MRI scan in Figure 4–57. Santos and Gomez-Leal have described 113 caruncular lesions with a similar histologic patterns of distribution. In their referral base series, only 114 out of 2,624 conjunctival biopsies involved the caruncle.265

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Figure 4–51. A, Conjunctival-anterior orbital pseudotumor diagnosed with monoclonal antibodies and Southern blot technique prior to treatment. B, Post resection with tumor regression. C, Appearance after receiving 20 Gy of photon irradiation.

Figure 4–52. Mucous membrane graft used to cover caruncular defect after excision of sebaceous carcinoma.

RARE CONJUNCTIVAL MALIGNANCIES

Rare types of conjunctival malignancies are so uncommon that definitive statements about management cannot be made. Several case reports have included descriptions of primary tumors such as leiomyosarcoma, malignant fibrous histiocytoma, and metastatic carcinoid. In addition, a paraneoplastic syndrome involving the conjunctiva and producing pemphigus has been described.271,272 Rare conjunctival malignancies include mucoepidermoid carcinoma of the conjunctiva and spindle cell carcinoma of the conjunctiva.151,153 Metastases to the conjunctiva rarely occur, and they have been described with a number of tumors, including melanoma, metastatic rhabdomyosarcoma, lung cancer, larynx, and uveal melanoma.

Figure 4–54. Sebaceous gland carcinoma of the caruncle.

CONJUNCTIVAL SURGERY

The control of tumor margins in the surgical resection of conjunctival malignancies is difficult owing to the limited amount of tumor tissue available for frozen section analysis, problems of accurate orientation, and difficulty in assessing the deep, scleral surface or the corneal margin. Adjunctive double freeze-thaw cryotherapy is routinely used by us in all our conjunctival melanomas and carcinomas because of these inherent limitations regarding accurate histologic sampling of margins, especially the deep surface if some tissue is used for horizontal margin assessment.