A Rapidly Developing Nodule in a Patient With Hairy Cell Leukemia in Remission: Merkel Cell Carcinoma: A Case Report

Discussion

MCC is a rare cutaneous neuroendocrine neoplasm and one of the most aggressive skin cancers (8). It usually presents in the 7^th decade of life, most commonly affects white males, and is often identified in sun-exposed sites such as the head and neck region, particularly the peri-orbital region, neck and extremities while unusual sites of involvement such as a case of MCC arising in nasal vestibule with clinical features mimicking suture scar post trauma have also been reported (4, 9, 10).

The diagnosis is histological and is established by positive staining for chromogranin, synaptophysin, neuron-specific enolase and the neural cell adhesion molecule (11). The most important risk factors for MCC are chronic sun exposure and immunosuppression (12). Immunocompromised patients, such as organ transplant recipients, human-immunodeficiency virus (HIV) infected patients and patients with lymphoproliferative malignancies, mainly chronic lymphocytic leukemia (CLL) are more prone to MCC (7, 13).

Recently, Merkel cell polyomavirus (MCPyV), detected in 43% to 100% of MCCs, has been implicated in the pathogenesis of the tumor (14). MCC generally develops rapidly over a period of weeks to months and usually presents as a firm red-violet, dome-shaped cutaneous nodule, as in our case (9). A question arises whether MCC has distinct features in hematologic patients. In contrast with the usual presentation of MCC in sun-exposed areas, mainly head and neck, in patients with hematological malignancies unusual sites may be involved. In a small series of patients with CLL/SLL reported by Katerji et al., three of nine patients developed MCC in the buttocks (6). The presentation of MCC in our patient in a non-sun exposed area, such as the shin, is in line with unusual site predilection of MCC in patients with hematological malignancies. On the other hand, HCL is an uncommon indolent B-cell lymphoproliferative disorder. It is more common in men with a median age at diagnosis of 55 years while it appears that HCL is less frequently encountered in the Arab population, where it occurs at a younger age. Skin lesions have been reported in about 10-12% of HCL patients mostly related to autoimmune or infectious processes (1, 2, 5).

Among hematologic disorders, CLL is mostly associated with MCC (15). Profound immunological dysregulation in CLL, with defects in both B- and T-lymphocytic functions may explain the higher incidence of MCC (15). Sporadically, MCC has also been reported in the setting of multiple myeloma and NHL, particularly after chemoimmunotherapy with a regimen combining fludarabine and rituximab (16).

Concurrent metastatic MCC and HCL have also been observed at initial presentation in a patient with a markedly swollen leg, with several small skin nodules and similar lesions on the right upper back. In this case, MCC was confirmed with a skin biopsy and bone marrow proved to be invaded by both HCL and MCC (17).

To our knowledge our case is the first of MCC following diagnosis and treatment of HCL. Standard treatment of HCL with purine analogs, cladribine and pentostatin can achieve long-term remission and excellent response that may last for several years, however at the cost of profound and long-lasting immunosuppression (2, 18).

Our patient received pentostatin as a first line treatment, achieving a nine-year remission, and at the relapse setting experienced again an excellent response. Pentostatin is a purine analog that inhibits adenosine deaminase with the most consistent side effect a decrease in CD4 count (19). CD4+ T cells are key players in the immune response as they orchestrate CD8 cytotoxic T-cell responses, which play a central role in mediating the elimination of malignant cells (20). Our patient displayed a profound decrease of CD4 (+) T- cells at the value of 69/μl, caused by pentostatin, predisposing him to develop a tumor like MCC.

MCC commonly spreads locally, to regional lymph nodes and hematogenously to more distant sites (9). Adverse prognostic factors include larger primary tumor size (>1 cm), chronic T-cell immunosuppression, HIV, CLL, solid organ transplantation, head/neck primary site, and lymphovascular invasion (12).

Regarding MCC therapy, typical management of localized disease includes wide surgical excision and sentinel lymph node biopsy with or without post-operative radiation, whereas metastatic disease is usually treated with an immune checkpoint inhibitor or systemic chemotherapy (21). Post-operative radiotherapy is controversial, however in the case of positive surgical margins and the presence of adverse prognostic factors, its use is advocated (22).

Our patient presented only with loco-regional disease, however given his immunosuppression, predicted to be long-lasting, he was offered adjuvant radiotherapy.

Our case highlights the association of two rare entities, HCL and MCC, and further supports the strong relationship between immunosuppression and MCC. Moreover, it underlies the need for a prompt and early diagnosis of any suspicious skin lesion in patients with disease or treatment related impaired immune function, as any delay in diagnosis is related with an extremely poor outcome.