Final Diagnosis -- Merkel cell carcinoma

DIAGNOSIS:

MERKEL CELL CARCINOMA WITH METASTASES TO LIVER, SKIN, BONE MARROW OF RIB, MESENTERIC LYMPH NODES, DIAPHRAGM, PANCREAS, AND ADRENAL GLAND.

DISCUSSION: Merkel cell carcinoma is also known as trabecular cell carcinoma, cutaneous small cell carcinoma, and neuroendocrine carcinoma of the skin. The neoplasm usually occurs in older adults and the elderly on the face, neck, and extremities. Clinically, Merkel cell carcinoma presents as an enlarging red, pink, or violaceous dermal nodule, sometimes with ulceration.

The neoplasm was first described by Toker in 1972 and called trabecular carcinoma.(1) In 1978, the link between this neoplasm and normal neuroendocrine (Merkel) cells in the skin was suggested (2), but to this day, remains controversial. Merkel cells are most abundant in the skin of the digits, lips, outer root sheath of hair follicles, and tactile hair disks, and are thought to be mechanoreceptors.(3) They contain neurosecretory granules and are reactive for neuron specific enolase, neurofilaments, chromogranin, synaptophysin, cytokeratins (including CK20), and peptide hormones, (4, 5)

Microscopically, Merkel cell carcinoma usually presents as a dermal nodule composed of sheets or trabeculae of small round blue cells. Cytoplasm is scanty and the nuclei are vesicular with finely granular chromatin (usually referred to as "pepper-salt" chromatin). Mitotic figures and nuclear fragments are easily identifiable. (6) The immunohistochemical profile is nearly identical to that of normal Merkel cells, with neoplasm cells exhibiting positivity for CK20, neurofilaments, and neuron-specific enolase. (7) A single punctate zone of immunoreactivity for CK20 or neurofilaments is characteristic, although not always present (especially in recurrences and metastases) (8). The differential diagnosis includes cutaneous metastases from small cell carcinoma of the lung, atypical carcinoid tumor, lymphoma, and melanoma.

Merkel cell carcinoma has a predilection for lymph node metastases, with approximately one fourth of patients in the general population having positive lymph nodes at diagnosis. Recurrence is common, and usually within the first two years, with >50% of patients having a recurrence in a large single-center study of 102 patients. (9) Current treatment modalities for Merkel cell carcinoma include resection of primary neoplasm with negative histological margins, sentinel lymph node biopsy (with utilization of keratins and neuroendocrine markers), chemotherapy for node-positive patients and patients with distant metastases, and radiotherapy for local control.

Merkel cell carcinoma has been shown to occur in association with other cutaneous malignancies, particularly squamous cell carcinoma. This has been shown in solid-organ transplant patients on long-term immunosuppression, as was the case with this patient. Skin cancers are the most common neoplasms in the transplant population, with 80% involving head and neck sites, and basal cell carcinoma and squamous cell carcinoma accounting for more than 90% of these malignancies. (10) Skin cancers behave more aggressively in transplant recipients, and are multiple in 50%, with local recurrence in 13% and metastases in 8%. (11) Risk factors for the development of skin cancer include older age at transplantation, duration and intensity of immunosuppression, prior actinic keratoses, and smoking. (10)

Fifty-five cases of Merkel cell carcinoma in transplant patients have been reported in the literature. These patients were younger than average for patients diagnosed with Merkel cell carcinoma, and 49% had other malignancies, mostly cutaneous malignancies. The clinical course of Merkel cell carcinoma in transplant recipients is more aggressive, with increased (56%) mortality at 2 years and lymphatic metastases in 68% of the patients at diagnosis. (12)

SUMMARY:

This was a man in his seventies with polycystic kidney disease who developed renal failure and underwent cadaveric renal transplant. He was eight years post-transplant when his first cutaneous malignancy was diagnosed. Following this diagnosis, multiple squamous cell carcinomas and basal cell carcinomas occurred, mostly in areas with extensive solar damage. This patient's Merkel cell carcinoma developed 10 years post-transplant, and widely metastasized. Unfortunately, the patient's metastatic disease could not be controlled; the patient died within three years of initial diagnosis of Merkel cell carcinoma.

REFERENCES:

1. Toker, C. Trabecular carcinoma of the skin. Arch Dermatol 105: 107-110, 1972.
2. Tang C, Toker C. Trabecular carcinoma of the skin: An ultrastructural study. Mount Sinai J Med 46:516-523, 1979.
3. Kidd RL, Krawczyk WS, Wilgram GF. The Merkel cell in human epidermis: Its differentiation from other dendritic cells. Arch Dermatol Forsch 1971;241:374.
4. Gould VE, Moll R, Moll I, Lee I, Franke WW. Neuroendocrine (Merkel) Cells of the skin. Hyperplasias, dysplasias and neoplasias. Lab Invest 1985, 52: 334-353.
5. Moll R, Moll I, Franke WW. Identification of Merkel cells in human Skin by specific cytokeratin antibodies. Changes of cell density and distribution in fetal and adult plantar epidermis. Differentiation 1984, 28: 136-154.
6. Walsh NMG, Primary Neuroendocrine (Merkel Cell) Carcinoma of the Skin: Morphologic Diversity and Implications Thereof. Hum Path 2001;32(7):680-689.
7. Leff EL, Brooks JSJ, Trojanowski JQ. Expression of neurofilament and neuron specific enolase in small cell neoplasms of skin using immunohistochemistry. Cancer 1985, 56:625-631.
8. Chan JK, Suster S, Wenig BM, Tsang WY, Chan JB, Lau AL. Cytokeratin 20 immunoreactivity distinguishes Merkel cell (primary Cutaneous neuroendocrine) carcinomas and salivary gland small cell Carcinomas from small cell carcinomas of various sites. Am J Surg Pathol 1997, 21:226-134.
9. Allen PJ, Zhang ZF, Coit DG. Surgical management of Merkel cell carcinoma. Ann Surg 1999; 229:97-105.
10. Euvrard S, Kanitakis J, Claudy A: Skin cancers after organ transplantation. N Engl J Med 2003, 348:1681-1691.
11. EPBG Expert Group on Renal Transplantation: European best practice guidelines for renal transplantation. Section IV: long-term management of the transplant recipient. IV.6.2. Cancer risk after renal transplantation. Nephrol Dial Transplant 2002, 17(suppl 4):31-36.
12. Penn I, First MR. Merkel's cell carcinoma in organ recipients: report of 41 cases. Transplantation 1999, 68: 1717-1721.