A rare presentation of Merkel cell carcinoma in a young immunocompetent woman

Introduction

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin tumor that has quadrupled in incidence during the past 20 years. Between 2000 and 2013, there was a 95% increase in reported cases of MCC, compared to 56% and 15% increases in melanoma and all solid tumors, respectively.¹ Since 2016, US Food and Drug Administration approved immune checkpoint inhibitors have become first-line therapy for metastatic MCC, transforming the therapeutic landscape and improving survival in advanced cases. Classically, MCC tumor heterogeneity has been attributed to 2 disease etiologies, mediated by either ultraviolet exposure or Merkel cell polyomavirus (MCPyV).¹

MCC predominantly affects White males aged more than 65 years, with only ∼4% of cases in patients aged less than 50 years, which are considered early onset MCC.^1,2 However, early onset MCCs are more likely to be diagnosed at an advanced stage and are associated with MCPyV as well as inherited mutations in cancer-predisposing genes like ATM, BRCA1, and TP53 are frequently detected.² Survival rates in early onset MCC are similar to older patients with the same disease stage.

Definitive MCC diagnosis requires immunohistochemistry confirmation of expression of epithelial markers, for example, cytokeratin 20 or pancytokeratin, as well as neuroendocrine markers, for example, synaptophysin, chromogranin, and neuron-specific enolase. To further differentiate MCC from small cell neuroendocrine carcinomas (SmCC) originating from other sites, additional MCC markers including negative thyroid transcription factor-1 and neurofilament and special AT-rich sequence-binding protein 2 (SATB2) are used in diagnostic evaluation.^3,4

At initial diagnosis, ∼30% of patients may have loco-regional metastases, while 6% to 12% may present with distant metastases.⁵ Common metastatic sites include nonregional lymph nodes (41%), skin/body wall (25%), liver (23%), bone (21%), pancreas (8%), lung (7%), and brain (5%).⁶ MCC involving the ovary is exceptionally uncommon, with only 4 cases reported in the literature (Table I).⁷ Due to its rarity, epidemiological data are limited. Notably, ∼5% of cases arise with unknown primary origin. Several studies have consistently found that patients with ‘‘unknown” primaries have a better prognosis and survival benefit may be associated with improved cell-mediated immunity which clears the primary tumor.⁷

Table I.

Reported MCC cases with ovarian metastases

Author (y)	Sex	Age (y)	Primary lesion	Sites of metastasis	Outcome
George et al (1985)7	F	62	Left inguinal skin	Regional lymph nodes, local recurrences/skin lesions, pelvis/abdominal mass, and right ovary	Dead 32 months after diagnosis, 14 months after chemotherapy
Eichhorn et al (1993) (Case 6)7	F	34	Right inguinal skin	Right inguinal lymph node, pelvic mass, and left ovary	Dead 8 months after presentation
Açıkalın et al (2014)7	F	34	Right lower auricular	Left ovary	Alive 12 months status post salpingo-oopherectomy.
Keller et al (2019)7	F	80	Cheek	Left ovary, left suprarenal gland, left musculus piriformis, right distal femur, thorax, supraclavicular node, and heart	Palliative supportive care

F, Female; MCC, Merkel cell carcinoma.

Here, we report a rare case of a young immunocompetent Caucasian woman who presented with MCC involving the axillary lymph node and the ovary in the absence of a cutaneous primary.

Case report

A 44-year-old Caucasian woman initially presented with a 3-month subcutaneous nodule in the right axilla with cytology consistent with MCC. There was no primary MCC identified on full body examination and a fluorodeoxyglucose-avid multiseptated cystic mass in the left ovary was also detected on the positron emission tomography/computed tomography during staging (Fig 1). The patient underwent right axillary lymph node dissection and left salpingo-oophorectomy. Since MCPyV is an accepted etiology for MCC, and the small T antigen (sTAg) (the MCPyV viral oncoprotein) is considered the causative factor, we used well-established primer sets to detect sTAg by quantitative polymerase chain reaction.⁸ As shown in Fig 2, sTAg was detectable in both tumors, suggestive of MCC origin; the lower viral load in the ovarian metastasis is possibly due to cellular dilution. To further confirm the presence of the viral genome, we performed direct DNA sequencing using primers described in the landmark discovery of MCPyV in MCC. Genomic DNA from both tumors was subjected to Sanger sequencing and probed using the Basic Local Alignment Search Tool, which confirmed sequence alignment with the MCPyV genome (data not shown). Neurofilament and SATB2, a transcription factor which has been suggested to play a role in assigning sites of origin in well-differentiated SmCC, and detection of neurofilament and SATB2 expression is indicative of a likely skin neuroendocrine carcinoma—MCC. Consistently, both neurofilament and SATB2 were expressed in these lymph node and ovarian metastases (Fig 3). The patient received a total of 3 cycles of pembrolizumab (200 mg every 3 weeks) but her disease progressed rapidly, and at the time of this report, the patient is deceased.

Fig 1.

Positron emission tomography-computed tomography (PET-CT) demonstrates fluorodeoxyglucose (FDG) uptakes in the (A) right axillary lymph node and (B) left ovary in the coronal, sagittal, and axial planes, respectively (arrows).

Fig 2.

Higher MCPyV viral load in lymph node tumor compared to ovary tumor, by quantitative real-time PCR. Both ‘Set9’ and ‘small T’ are published sequences detecting the presence of small T antigen region of the MCPyV genome. MCPyV, Merkel cell polyomavirus; PCR, polymerase chain reaction.

Fig 3.

Immunohistochemical staining of lymph node and ovary tumors. Positive for CK20 (cytokeratin 20), CHG (chromogranin), NF (neurofilament), and SATB2 (special AT-rich sequencing-binding protein 2) and negative for TTF1 (thyroid transcription factor). Images are shown at 100× magnification with 100 μm scale bar; inset images are shown at 400× magnification with 50 μm scale bar.

Discussion

Early onset MCC is extremely rare, especially in women. Unlike melanoma, in which incidence is higher in women aged less than 50 years,⁹ MCC incidence below the age of 50 is too low to evaluate a potential trend of increased risk in younger women.² Although early onset MCC is associated with inherited genetic mutation, a low mutation burden with only SMARCA4 mutation was detected by Altera (Natera, Inc) in our patient’s MCC. Consistent with previous reports, our patient’s lymph node and ovarian metastases harbor MCPyV as detected by quantitative polymerase chain reaction and direct DNA sequencing (Fig 2).

To date, there are only 4 reported cases of metastatic MCC with ovary involvement, all of which had definitive diagnosis of primary skin MCC (Table I).⁷ As primary skin MCC was absent in our patient, it is crucial to exclude small cell neuroendocrine carcinoma of the ovary (pulmonary-type), which shares similar neuroepithelial marker expression patterns.³ Since MCPyV is a known MCC etiology, detection of a higher viral load in the lymph node tumor supports cutaneous origin (Fig 2). Moreover, a study by Stanoszek et al suggests that neurofilament is superior to cytokeratin 20 in differentiating MCC, from SmCC in lung, bladder, prostate, and ovary, etc.³ They found that neurofilament was expressed in 42 of 55 MCC examined including 7 of 9 MCPyV-negative MCC with 96.7% specificity. In particular, neurofilament expression was absent in all 3 SmCC from the ovary, implying that the ovary tumor in our patient most likely presented as the distant metastasis from MCC. Furthermore, in line with previous reports, SATB2 expression was also observed in metastatic tumors involving both the lymph node and ovary in our patient.⁴

Established MCC risk factors include age, male sex, fair skin, and immunosuppressed individuals constitute approximately 10% of the MCC patient population. About half of MCC cases in immunosuppressed patients occur before the age of 50, a much younger demographic than the general MCC population.^2,10 Competent immune status in our patient might contribute to regressed primary skin MCC.⁵ Thus, in future studies, it is important to delineate the underpinning mechanisms and identify effective therapeutics for early onset MCC in immunocompetent patients without apparent genetic predisposition.

Conflicts of interest

None disclosed.