Unusual Presentation of Rare Aggressive Cancer

An 80-year-old Afro-Panamanian man presents to a surgery clinic in New York City with an isolated, hard, discolored nodule on his right buttock. He says the bump, although not painful, has been growing in size since it appeared about 2 months previously. His medical history is otherwise unremarkable.

The surgeon suspects that the hyperpigmented nodule is a simple fibrolipoma, and does not order any imaging. The patient undergoes surgery and surgeons excise a nodule of pink-tan dense tissue measuring 6.5 × 5.5 × 4 cm; the specimen is preserved in formalin and sent to pathology.

Surgeons note that the tissue at the surgical site is fresh and necrotic, and histological examination shows nests of monotonous round tumor cells with infiltration of the subcutis.

Tumor cells have a scant eosinophilic cytoplasmic rim and round, vesicular nuclei with numerous mitotic figures, and staining reveals that the cells are positive for neuroendocrine features, CD56, and synaptophysin.

Immunohistochemical stain CK20 shows paranuclear dot-like staining that is consistent with Merkel call carcinoma (MCC). Based on the negative staining for CD45, clinicians rule out lymphoma. The margins of the tumor are positive, with evidence of vascular invasion.

The patient returns a month after the initial surgery for wide re-excision, and the margins are deemed to be clear.

A follow-up examination about 2 months later reveals an enlarged right local inguinal node, and the patient undergoes another surgery. The lymph node is biopsied and found to be positive.

A positron emission tomography scan is performed, but there is no evidence of any further distant malignancies. Clinicians refer the patient for adjuvant radiotherapy to the tumor bed and nodal basin, at a dose of 50 Gy over 5 weeks, and at the time the case is reported, the patient has received the first dose a week earlier.

Discussion

Clinicians presenting this case of a patient with MCC note that the disease is unique in its primary presentation (1) in a site that does not receive sun exposure, and (2) in a patient who is Afro-Panamanian and (3) is not immunosuppressed. The authors note that the aim of writing about the case is to raise awareness of the possibility of a rare presentation of the notably aggressive neuroendocrine cancer of the skin, and show the importance of prompt diagnosis and treatment.

The annual incidence of MCC worldwide is about 0.13 to 1.6 cases per 100,000 population, with at least 1,500 new cases diagnosed each year in the U.S. -- which is an almost fourfold increase in the last 20 years.

Risk factors for MCC in general include advancing age, light skin, immunosuppression, sun exposure, and having another malignancy such as multiple myeloma or chronic lymphocytic leukemia (CLL). Immunosuppression in particular increases the relative risk approximately 13-fold in patients with HIV and 10-fold in solid-organ transplant patients.

With a mortality rate of 30% at 2-years and 50% at 5-years post-diagnosis, MCC is about twice as deadly as malignant melanoma. MCC typically occurs in elderly, fair-skinned individuals, presenting as a rapidly growing, painless, firm, red or flesh-colored nodule with a smooth surface, and usually develops in sun-exposed areas such as the head and neck (43% of cases) and upper limbs and shoulder (24%), the case authors explain.

Although in approximately 65% of patients, the disease has not metastasized at the time of diagnosis, an estimated 26% have regional lymph node involvement and 8% have distant metastases.

MCC is thought to develop from the Merkel cells in the basal layer of the epidermis and hair follicles, the authors note, also citing research suggesting that the cancer originates from totipotential stem cells in the dermis or precursor B cells.

Most cases are associated with monoclonal integration of Merkel cell polyomavirus (MCPyV), a non-enveloped, double-stranded DNA virus, into the host genome. Approximately 80% of individuals over age 50 have MCPyV antibodies, and the majority of the remaining viral-negative cases of MCC are associated with UV-related DNA mutations.

Diagnosis

The case authors note that MCC may be mistaken for a benign lesion, such as a lipoma or epidermoid cyst, and may also resemble more common malignant lesions like basal cell carcinoma and amelanotic melanoma.

The acronym AEIOU has been used to remember the risk factors for MCC, particularly when at least three are present:

• Asymptomatic

• Expanding rapidly (i.e., weeks to months)

• Immunosuppression (due to, for example, CLL, HIV, or organ transplant)

• Age over 50

• UV-exposed area in a light-skinned individual

Still, given the vagueness of these features, biopsy and histological analysis are key to confirming the diagnosis, the case authors emphasize.

The tumor -- which can expand from the dermis to the epidermis -- comprises strands or nests of monotonous small round blue cells with prominent nuclei and little cytoplasm, and the cells have frequent mitoses with "salt and pepper" chromatin.

Definitive diagnosis is based on immunohistochemistry findings, with 80-90% of MCC cases marked by CK20 stains in a paranuclear dot-like pattern, due to clumping of intermediate filaments.

Furthermore, the cells frequently stain positive for neuroendocrine markers such as chromogranin, synaptophysin, and CD56. MCC may also be distinguished from small-cell lung cancer and by negative staining for TTF-1 and CD45, respectively.

The authors note that this case reflects typical histopathologic characteristics of MCC, but is among the less than 9% of cases occurring in a non-sun exposed area and is also believed to be the first case reported in a Panamanian patient.

Treatment and Future Research

Surgery is the mainstay of treatment, along with adjuvant radiation therapy, which has been shown to reduce recurrence 3.7-fold, the case authors write, advising vigilance through imaging and physical examination for recurrence.

Lymphovascular invasion as occurred in this case is associated with a poor prognosis, and this patient may require additional therapy if disseminated disease is discovered.

The role of chemotherapy in MCC has yet to be determined, the authors note, citing updated efficacy findings from a phase II clinical trial of avelumab, a monoclonal antibody that binds to PD-1 and was given FDA approval in 2017 for first-line treatment of metastatic disease.

Additionally, immunotherapies targeting PD-1, PD-L1, and CTLA-4 are currently in clinical trials. which will have important implications for patients with advanced MCC, the case authors predict.

Comment