HIV-related Merkel cell carcinoma: A report of three cases from the UK

Merkel cell carcinoma (MCC) of the skin is a rare, aggressive and often fatal neuroendocrine skin cancer.^1–8 The most significant features of MCC can be summarized in the acronym: AEIOU (asymptomatic/lack of tenderness, expanding rapidly, immune suppression, older than 50 years, and ultraviolet-exposed site on a person with fair skin). ¹

The incidence of MCC has significantly increased in the last decades. ² Factors that have been associated with the development of MCC include infection with Merkel Cell polyomavirus (MCPyV), ultraviolet exposure, hematologic malignancies and immunosuppression e.g. organ transplant recipients, HIV or therapeutic immunosuppression such as azathioprine.^3–8

We present three cases of patients living with HIV who were diagnosed with MCC. The first is a 60-year-old, HIV positive MSM (man having sex with men) who attended the HIV Dermatology clinic for regular follow up. He reported a rapidly growing, otherwise asymptomatic lesion on his right shoulder, present for the previous two to three months. The Fitzpatrick skin type was 1. On examination, there was a 1 cm² flesh coloured, firm, subcutaneous lesion with a visible punctum in the centre. Clinically the lesion was in keeping with an epidermoid cyst. However, an urgent excision was done to rule out the possible atypical presentation of a malignant tumour. The histology showed MCC.

He underwent a wide local excision (2 cm) to achieve histologically ascertained local clearance. The MDT discussion recommended CT (computed tomography) scan staging and referral to oncology for radiotherapy. The CT staging showed right axilla nodal involvement. The MDT (multidisciplinary team) decided on axillary node dissection followed by radiotherapy to the tumour site and axillary nodal basin.

The patient had a significant medical history. In 1993 he was diagnosed with HIV. He had been on and off antiretroviral treatment (ART) throughout the years mainly due to non-compliance. For the last 2 years, however, he had been compliant with treatment (dolutegravir/rilpivirine/tenofovir). His latest viral load (VL) was < 50 copies and his CD4+: 230/mm³ (500–1500/mm³).

In 1995 he developed Kaposi’s sarcoma that was treated with radiotherapy. In 2017 he was diagnosed with poorly differentiated squamous cell carcinoma (SCC) of the right cheek involving the parotid and facial nerve. He had surgery and postoperative radiotherapy. In the same year he was also diagnosed with SCC of the anus following longstanding anal intraepithelial neoplasia (AIN) with human Papillomavirus (HPV) related changes that had been resistant to treatments including: photodynamic therapy, imiquimod, multiple excisions and laser ablative surgery.

The second case is a 53-years-old female patient originally from the Ivory Coast who presented with a 3-month history of right calf pain with a rapidly growing lesion. Initially the lesion was thought to be an arterio-venous malformation following ultrasound and she was referred to the vascular team. An excisional biopsy was performed. The histological appearances were of a dermal tumour disposed in sheets showing neuroendocrine morphology with stippled ‘salt-pepper’ chromatin and numerous mitoses; features in keeping with MCC.

A subsequent PET (Positron emission tomography)-CT scan showed no evidence of metastatic disease but some tracer uptake to corresponding lymph nodes. A sentinel lymph node biopsy was performed and was negative for further disease. She had been diagnosed with HIV in 2007 with a nadir CD4 of 64/mm³, however the CD4 at time of diagnosis of MCC was 2109, with VL of 53. Regarding her past medical history, she had been treated for MAI/TB (Mycobacterium avium-intracellulare/tuberculosis) in 2016.

The final case is of a 60-year-old male who presented with a new lesion of the left thigh on a background of well controlled HIV (CD4 440/mm³, UDVL). Biopsy confirmed this to be MCC and he had a wide local excision performed. A year later he developed a similar lesion on his left buttock and left groin that were both biopsied and found to be further MCCs. Following this, he underwent radiotherapy with further excision and lymph node dissection. There has been no further recurrence, although he has had a lymph node biopsy that showed reactive follicular hyperplasia only.

Given the paucity of cases of MCC described in the UK in people living with HIV, it is informative to tabulate pertinent details (Table 1):

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Table 1.

Patients’ characteristics.

Patient	A	B	C
Age at diagnosis	60	52	60
Gender	M	F	M
Sexual orientation	MSM	WSM	MSM
Year of HIV dx	1993	2007	1989
Nadir CD4	<100	64	<250
VL At time of MCC dx	<50	53	<50
CD4 at onset of MCC dx	230	2109 (Oct 2019)	440
ARVs	DTG/RPV/TDF	ABC/3 TC + ATZ	FTC/TDF/RPV
Year of MCC dx	2018	2021	2013
PMH	SCC right cheek, anal SCC, KS	MAI/MTB	AIN-3

A low nadir CD4 appears to be common between all three but with all patients having well controlled HIV at the time of presentation.

It was in 2008 that MCPyV was found to be the main etiological agent of this skin cancer and it is detected in approximately 80% of all MCCs. The role of MCPyV in the pathogenesis of MCC may be exacerbated by immunodysfunction.^3,4,5,8

The mechanism by which immunosuppression interacts with MCPyV and UV radiation exposure in the pathogenesis of MCC is unknown. Possible mechanisms include: (1) immunosuppression which may facilitate the replication of MCPyV and increase the chance of virus integration in the MCC progenitor cells (2) reduced immune surveillance which may contribute to the survival and proliferation of atypical cells (3) immunosuppressive agents, such as azathioprine have been shown to act synergistically with UV radiation in inducing mutagenesis and promoting skin carcinogenesis.^3,4,5,7,8.

Specifically, in HIV, MCPyV prevalence is increased compared with healthy controls. ⁹ HIV also increases the risk of developing UV-induced skin cancers such as SCC and basal cell carcinoma (BCC) and therefore may also increase the risk for virus-negative MCC. However, MCC occurs frequently on sites not exposed to sunlight. The age of onset of MCC in HIV is lower and the mortality is higher.^3,4

Clinically, MCC may closely mimic many benign and malignant lesions occurring on sun-exposed skin. ¹

Diagnosis is made by histologic examination and usually requires immunohistochemistry to distinguish MCC from other blue-cell tumours such as metastatic non-cutaneous neuroendocrine neoplasms (especially metastatic small cell carcinoma of lung), lymphoma, melanoma, round cells sarcomas. Merkel cell carcinoma express epithelial markers such as CK20, EMA, AE1/AE3 as well as neuroendocrine markers (chromogranin, synaptophysin, CD56). Merkel cell carcinoma cells are also positive for neurofilament (NF). The staining for CK20 and NF has characteristic dot or cup-like pattern. Merkel cell carcinoma is negative for TTF1, S100, leukocyte common antigen. ⁸

Histology in our cases showed a dermal malignant blue-cell tumour composed of cell with scanty cytoplasm and highly atypical nuclei. Focal nuclear moulding was seen and numerous mitotic figures were present. (Figure 1). Immunohistochemically the tumour cells were CK20, (NF) and synaptophysin positive. TTF1 staining was negative. The staining for CK20 and NF had cup-like pattern. (Figure 2).OPEN IN VIEWER

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Figure 2.

Tumour cells display cup and dot-like pattern of CK20 expression.

Merkel cell carcinoma should be included in the differential diagnosis of skin neoplasms in HIV and especially in patients who have a history of UV exposure, prolonged intercurrent immunocompomise and other virally induced skin cancers (as in case A).

HIV cases associated with MCC have been rarely reported and to our knowledge, not yet before in the UK. We present these cases to highlight an important differential for skin lesions in the context of people living with HIV.