Ocular Melanoma Versus Ocular Metastasis: A Diagnostic Dilemma

H&0 CLINICAL CASE STUDIES

Ocular Melanoma Versus Ocular Metastasis: A Diagnostic Dilemma Madhu Midathada, MD Ammar Safar, MD Robert Schaefer, MD Sanjaya Viswamitra, MD Manish Kohli, MD

University of Arkansas for Medical Sciences Central Arkansas Veterans Healthcare System Little Rock, Ark.

Case Report A 54-year-old white male presented with blurred vision in the left eye, diplopia, and pain. External and anterior segment examinations were normal. Ophthalmic examination showed a choroidal tumor in the macular area of the left eye with overlying serous retinal detachment (Figure 1A). B-scan ultrasonography showed a tumor in the posterior pole with subretinal fluid collection (Figure 2A). A-scan ultrasonography demonstrated low to medium internal reflectivity of the tumor, strongly suggestive of melanoma (Figure 2B). Based on the ultrasound and retinal findings (Figures 1 and 2), a diagnosis of intraocular melanoma was entertained. A magnetic resonance imaging (MRI) scan of the orbit and brain also showed a mass in the posterior pole of the left globe without involvement of the optic nerve or extraocular muscles. Systemic staging workup initiated prior to definitive local therapy for the melanoma showed numerous low attenuation lesions in the liver consistent with hepatic metastasis (Figure 3A) and fractures of multiple transverse processes of the lumbar vertebrae suggestive of bony metastases. Bone imaging with a technetium scan also detected a left acetabular lesion. While multiple bone metastases are not uncommon with choroidal melanoma, they do not usually occur at presentation. Therefore, a diagnostic biopsy of a liver lesion was performed. Small, round malignant cells with uniform nuclei (Figures 4A and 4B) negative for melanoma-specific antigen (HMB-45), MART-1, and S-100 protein on immunohistochemistry were observed. Tumor cells were weakly positive for chromogranin and negative

Address correspondence to: Madhu Midathada, MD, Attn: Slot 508, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205-7199; E-mail: [email protected].

Figure 1. (A) Retinal examination showing macular elevation (arrows) caused by the choroidal tumor with overlying serous retinal detachment. (B) Posttreatment resolution of the tumor with areas of loss of retinal pigmentation.

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Figure 4. (A) Computed tomography (CT) scan of the liver showing metastatic lesions (arrow). (B) Posttreatment CT scan of the liver showing partial regression of the lesions.

Figure 2. (A) B-scan of the eye showing a mass in the posterior pole of the left globe with overlying subretinal fluid (SRF). (B) A-scan showing low to medium internal reflectivity of the tumor.

Figure 3. (A) Light microscopy (40X magnification) showing normal liver cells and aggregate of tumor cells (arrows). (B) 400X magnification showing malignant cells staining weakly positive for cytokeratin.

A = anterior; P = posterior margins of the tumor reflection; D = dip.

for synaptophysin, CD56, CD45, CD20, and CD30. AE1/AE3 pancytokeratin stain was focally positive. Based on morphology and immunohistochemical staining patterns, a diagnosis of undifferentiated carcinoma with neuroendocrine features was favored. Despite an extensive workup, a primary lesion could not be found. The patient received systemic chemotherapy with cisplatin and etoposide and local radiation to spinal metastases in order to relieve back pain. Response to treatment was evaluated by fundus examination and systemic imaging. A dramatic improvement in clinical symptoms was observed after initiating chemotherapy. Fundus examination (Figure 1B) revealed tumor regression with overlying retinal scarring. Systemic imaging also demonstrated partial response (Figure 3B). However, duration of these

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responses was limited to 4 months. Fundus re-examination revealed relapse of choroidal metastasis. A change to a taxane-based chemotherapy regimen produced shortterm improvements, but the patient died 12 months after initial presentation. Discussion Ocular melanomas are the most common primary intraocular malignancy in adults, with the majority localizing in the choroid. Due to the location of these malignancies, a pathologic diagnosis is rarely attempted and diagnosis is typically made on the basis of ocular examination and clinical findings. Ultrasonography using A- and B-mode criteria has a high accuracy in the diagnosis of choroidal

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tumors.1 This report highlights a case of choroidal tumor that was presumed to be an ocular melanoma with hepatic metastasis but in fact had a different etiology. It is rare to find an undifferentiated tumor with neuroendocrine features and widespread metastases that presents with signs, symptoms, and patterns of metastasis suggestive of intraocular melanoma. The potential for misdiagnosis in this scenario is high, with the possibility of inappropriate therapeutic planning. In our patient, bony metastases raised suspicion of the diagnosis because ocular melanomas commonly do not present with bone metastases. After histopathologic confirmation of a liver lesion, the patient received chemotherapy typically administered to carcinomas with neuroendocrine features. The pattern of initial chemosensitivity in the eye lesion and systemically in the liver lesions lent further credibility of a metastatic intraocular deposit rather than a melanoma-based lesion. Poorly differentiated carcinomas with neuroendocrine tumors metastasizing to the eye have been rarely reported. Dominant sites of metastasis from neuroendocrine tumors typically involve retroperitoneal lymph nodes followed by mediastinum, liver, and bone.2 We found only 2 case reports of neuroendocrine tumor with metastasis to the eye in published literature.3,4 To our knowledge, the present case is the first description of a nonpigmented, poorly differentiated carcinoma with neuroendocrine features with unknown primary tumor presenting with choroidal metastases. Palliative chemotherapy appears to have local and systemic benefit, although it is unlikely to change overall prognosis.5,6 We propose that a closer coordination between ophthalmologists, medical oncologists, and radiologists is needed in cases of suspected ocular melanomas with unusual patterns of presentation, which will likely reduce the chance of misdiagnosis and improve the initiation of appropriate therapeutic interventions. References 1. Sobottka B, Kreissig I. Ultrasonography of metastases and melanomas of the choroids. Curr Opin Ophthalmol Ophthalmol. 1999;10:164-167. 2. Hainsworth JD, Johnson DH, Greco FA. Poorly differentiated neuroendocrine carcinoma of unknown primary site: a newly recognized clinicopathologic entity. Ann Int Med Med. 1998;109:364-371. 3. Eagle RC, Ehya H, Shields JA, et al. Choroidal metastasis as the initial manifestation of a pigmented neuroendocrine tumor. Arch Ophthalmol Ophthalmol. 2000;118:841845. 4. Brannan SO, Lessan NG, Hiscott P, et al. A choroidal amyloid-rich neuroendocrine tumor: initial manifestation of Cushing syndrome. Arch Ophthalmol Ophthalmol. 1999;117:1081-1083. 5. Moertel CG, Kvols KK, O’Connell MJ, et al. Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Cancer. 1991;68:227-232. 6. Mitry E, Rougier P. The treatment of undifferentiated neuroendocrine tumors. Crit Rev Oncol-Hematol Oncol-Hematol. 2001;37:47-51.

Review Daniel Farray, MD Joseph I. Clark, MD Loyola University, Chicago, Ill.

Poorly differentiated neuroendocrine carcinoma of unknown primary site was first described as a new pathologic entity in 1988.1 These carcinomas are part of the neuroendocrine family of tumors, which includes small-cell lung cancer, carcinoid tumors, islet cell tumors, and other less frequent neoplasms. The clinical scenario for the diagnosis is usually one of metastatic poorly differentiated carcinoma of unknown primary in which immunoperoxidase stains for either synaptophysin or chromogranin are positive or electron microscopy shows the presence of neurosecretory granules. It is important to make a specific diagnosis since these neoplasms are extremely sensitive to platinum-based chemotherapy, with complete remissions reported and median survivals averaging approximately 11 months.2 The case described by Midathada et al shows an unusual clinical presentation of a rare disease. Nevertheless, it is not uncommon for a choroidal metastasis to be the first symptomatic site of metastatic carcinomas. In the study by Ferry et al,3 roughly half of the patients presented with eye symptoms prior to the detection of a primary tumor. Uveal metastases are the most common form of intraocular malignant tumors. Of these, due to its rich vascularity, the choroid is involved in approximately 80%.4 The most common tumor type to metastasize to the choroids are carcinomas, with breast and lung cancers being the most frequent.3 However, metastasis to the choroids has been described for almost all carcinomas. The main differential diagnosis when evaluating a choroidal mass is metastases versus a primary choroidal melanoma. In general, choroidal metastases can be distinguished from a primary choroidal melanoma by its typical ophthalmoscopic features (presence or absence of pigment, multifocality, shape, growth pattern); ancillary tests such as ultrasound, MRI, and fluorescein angiography, which may aid in the characterization of the lesion; and, finally, an intraocular biopsy, which can be performed if previous tests are inconclusive. However, since a choroidal metastasis is unlikely to be the only metastatic site and primary choroidal melanomas have the tendency to metastasize, a

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systemic workup should always be done whenever there is a choroidal tumor to help further elucidate the diagnosis. Choroidal melanoma is usually localized to the eye at diagnosis.5,6 Once metastatic, the median survival ranges from 2 to 9 months.7-9 In a series of 679 patients,10 the most common metastatic sites were the liver (91%), followed by the lungs (28%), bone (18%), subcutaneous tissue (12%), and brain (5%), regardless of the size of the primary tumor. In this same study, the 5- and 10-year cumulative metastatic rates were 24% and 32%, respectively, and the rates of metastasis increased with the size of the primary tumor. In the case presented, the pattern of metastasis was consistent with either a metastatic choroidal melanoma or a metastatic carcinoma. Nevertheless, metastases at presentation are unusual for choroidal melanoma, which tends to spread after the diagnosis is made. In a retrospective review of 99 patients with metastatic choroidal melanoma, the time from primary to metastasis diagnosis ranged widely, from 3 months to 9 years 8 months.11 This case report shows the significance of making a pathological diagnosis in oncology. Although they are both lethal diseases, the treatment, response to therapy, and prognosis are different in these 2 neoplasms. These are important variables to be discussed with patients in

order to make informed decisions and before administering potentially harmful cytotoxic therapies.

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