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Journal of Clinical Oncology, Vol 24, No 6 (February 20), 2006: pp. 1008-1009 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.01.7103
CASE 1. Testis: A Sanctuary Site in Merkel Cell Carcinoma
University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD A 54-year-old white man presented with a 4-month history of a "boil" on his left forearm. The boil's increase in size over a period of 2 weeks prompted an incisional biopsy, which revealed Merkel cell cancer (MCC). An immunocytochemical profile showed tumor cells positive for neuron-specific enolase and negative for leukocyte common antigen (CD 45) and chromogranin. Clinical examination revealed a 5 x 5 cm nodular mass with ulceration at the apex of the proximal left forearm. The rest of the physical examination was negative. Further staging work-up included computed tomography scans of the head, chest, and abdomen and a positron emission tomography scan of the body, all of which were negative for cancer. The patient underwent excision of the tumor on the left forearm, along with a left axillary node dissection (Fig 1). The primary skin tumor was poorly circumscribed (Fig 1A) and was composed of small hyperchromatic cells, typical of small-cell carcinoma (Fig 1B). The margins of the surgical specimen were negative for tumor but two of five lymph nodes were positive for the tumor. The patient was treated with adjuvant radiotherapy to the tumor site and the left axilla with a total of 50.4 Gy in 28 fractions over a period of 40 days followed by six cycles of adjuvant chemotherapy with carboplatin and etoposide. Two months after completion of the chemotherapy, the patient noticed a hard mass on his right testicle. He underwent a right inguinal orchiectomy and pathology revealed a metastatic neuroendocrine tumor consistent with the patient's prior diagnosis of MCC (Fig 1C). The testis showed seminiferous tubules surrounded by tumor cells (Fig 1C). The tumor cells stained with antibodies to neuroendocrine markers, including chromogranin (Fig 1D). The patient received no additional treatment as it was felt that testicular metastasis occurred in a sanctuary site and was treated appropriately with orchiectomy. He remained well with no evidence of metastatic disease at the time of his last follow-up 3 years later.
Merkel cell cancer is a rare cutaneous neoplasm, mainly of the elderly. Patients' mean age at diagnosis is 68 to 70 years, with only 5% of all reported cases occurring in patients ages younger than 50 years. MCC originates in sun-exposed areas of the skin with approximately 50% of the tumors occurring in the face and neck, 40% on the extremities, and 10% on the trunk and genitals. Most patients with MCC present with localized disease (76% to 89% of patients), 10% to 18% of patients have regional lymph node involvement, and 1% to 2% of patients have distant metastases at the time of initial presentation. MCC is an aggressive tumor and although it is a very chemo- and radiosensitive tumor, complete remissions are usually brief. Median overall survival after chemotherapy is 22 months. Local relapses are found in 20% to 40% of patients, regional metastases in 22% to 55% of patients, and distant metastases in 36% to 50% of patients.1-4 Common secondary sites include the skin (28%), lymph nodes (27%), liver (10%), bones (10%), and brain (6%).3,5 Only three cases of testicular metastases from MCC have been reported in the literature.6,7 It behaves like metastatic small-cell carcinoma of the lung, amelanotic melanoma, and aggressive lymphoma. It is distinguished by histologic and immunocytochemical criteria. MCC usually expresses cytokeratin (CK) 5.2 and more specifically CK 20, often as a paranuclear dot.8,9 It often stains for neuron-specific enolase (60% to 100% of tumors), synaptophysin (50% of tumors), and chromogranin A (33% to 80% of tumors), as well as for epithelial membrane antigen.10-12 The tumor cells are usually negative for the S-100 protein and leukocyte common antigen (CD45), delineating MCC from melanoma and cutaneous lymphomatous deposits. CK 7 and thyroid transcription factor (TTF-1) is positive in small-cell lung cancer but negative in MCC. Certain differences exist among highly aggressive tumors like melanoma, small-cell carcinoma, and MCC. In case reports of small- cell lung cancer metastasizing to the testes, treatment failure was reported to occur after completion of adjuvant chemotherapy.13-15 Cutaneous melanoma tends to metastasize to several organs simultaneously including the testes in up to 20% of patients with metastatic disease. Isolated testicular recurrences occur in 1.7% to 13% of patients with acute lymphoblastic leukemia after complete remission, with a mean time to testicular recurrence of 36 months. The testes are the most common site of disease recurrence in acute lymphoblastic leukemia; 40% to 45% of all relapses after complete remission occur in the testes or the CNS.16,17 Relapse of disease in the testis during chemotherapy is associated with a poor prognosis. Testicular relapse in MCC is a rarely reported event. This patient developed tumor recurrence in the testis within 2 months of completion of local and systemic adjuvant therapy, similar to a patient reported recently.7 The finding of the tumor in one testis soon after completion of adjuvant chemotherapy could suggest that the testes act as a sanctuary site for the cancer cells, with chemotherapy effectively eradicating the tumor everywhere else. This would suggest that a blood-testes barrier prevented the chemotherapy from entering the testes and eradicating metastatic foci there. The presence of a blood-testes barrier has been described to have three components.18 First, a physiochemical barrier consisting of continuous capillaries, Sertoli cells in the tubular wall, which are connected together with narrow tight junctions and a myoid cell layer around the seminiferous tubules. Second, an efflux-pump barrier that contains P-glycoprotein in the luminal capillary endothelium and on the myoid cell layer and multidrug-resistance–associated protein 1 (MRP-1) located basolaterally on the Sertoli cells. And third, an immunologic barrier, consisting of Fas ligand on Sertoli cells which bind to Fas on activated T lymphocytes to help protect germ cells against effector mechanisms of the cellular immune system. This along with efflux pumps such as P-glycoprotein and MRP-1 play a part in maintaining low concentrations of lipophilic cytotoxic molecules in the testicular tissue. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES
1. Tai PT, Yu E, Winquist E, et al: Chemotherapy in neuroendocrine/Merkel cell carcinoma of the skin: Case series and review of 204 cases. J Clin Oncol 18:2493-2499, 2000 2. Shaw JH, Rumball E: Merkel cell tumour: Clinical behaviour and treatment. Br J Surg 78:138-142, 1991[Medline] 3. Hitchcock CL, Bland KI, Laney RG 3rd, et al: Neuroendocrine (Merkel cell) carcinoma of the skin: Its natural history, diagnosis, and treatment. Ann Surg 207:201-207, 1988[Medline] 4. Cotlar AM, Gates JO, Gibbs FA Jr: Merkel cell carcinoma: Combined surgery and radiation therapy. Am Surg 52:159-164, 1986[Medline] 5. Voog E, Biron P, Martin JP, et al: Chemotherapy for patients with locally advanced or metastatic Merkel cell carcinoma. Cancer 85:2589-2595, 1999[CrossRef][Medline] 6. Ro JY, Ayala AG, Tetu B, et al: Merkel cell carcinoma metastatic to the testis. Am J Clin Pathol 94:384-389, 1990[Medline] 7. Rufini V, Perotti G, Brunetti M, et al: Unsuspected testicular metastases from Merkel cell carcinoma: A case report with therapeutic implications. Am J Clin Oncol 27:636-637, 2004[Medline] 8. Leech SN, Kolar AJ, Barrett PD, et al: Merkel cell carcinoma can be distinguished from metastatic small cell carcinoma using antibodies to cytokeratin 20 and thyroid transcription factor 1. J Clin Pathol 54:727-729, 2001 9. Ratner D, Nelson BR, Brown MD, et al: Merkel cell carcinoma. J Am Acad Dermatol 29:143-156, 1993[Medline] 10. Kontochristopoulos GJ, Stavropoulos PG, Krasagakis K, et al: Differentiation between merkel cell carcinoma and malignant melanoma: An immunohistochemical study. Dermatology 201:123-126, 2000[CrossRef][Medline] 11. Warner TF, Uno H, Hafez GR, et al: Merkel cells and Merkel cell tumors: Ultrastructure, immunocytochemistry and review of the literature. Cancer 52:238-245, 1983[CrossRef][Medline] 12. Sibley RK, Dehner LP, Rosai J: Primary neuroendocrine (Merkel cell?) carcinoma of the skin, I: A clinicopathologic and ultrastructural study of 43 cases. Am J Surg Pathol 9:95-108, 1985[CrossRef][Medline] 13. Meares EM Jr, Ho TL: Metastatic carcinomas involving the testis: A review. J Urol 109:653-655, 1973[Medline] 14. Stein A, Sova Y, Lurie M, et al: Bilateral testicular metastases of pulmonary small cell carcinoma: A rare incidental finding following orchiectomy for prostatic carcinoma. Br J Urol 63:552, 1989 15. Rosser CJ, Gerrard E: Metastatic small cell carcinoma to the testis. South Med J 93:72-73, 2000[Medline] 16. Touroutoglou N, Dimopoulos MA, Younes A, et al: Testicular lymphoma: Late relapses and poor outcome despite doxorubicin-based therapy. J Clin Oncol 13:1361-1367, 1995[Abstract] 17. Tondini C, Ferreri AJ, Siracusano L, et al: Diffuse large-cell lymphoma of the testis. J Clin Oncol 17:2854-2858, 1999 18. Bart J, Groen HJ, van der Graaf WT, et al: An oncological view on the blood-testis barrier. Lancet Oncol 3:357-363, 2002[CrossRef][Medline]
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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