Introduction

Merkel Cell Carcinoma (MCC) is designated as a highgrade primary cutaneous neuroendocrine carcinoma in the current iteration of the World Health Organization (WHO) classification of Endocrine and Neuroendocrine Tumors [1]. This rare entity was first described by Toker in 1972 as a trabecular carcinoma of the skin [2]. Though, the precise cell of origin of MCC remains contentious in the literature, Merkel cells are favored as the cellular progenitor of MCC as they bear histologic and phenotypic similarities as being the only neuroendocrine cells native to the epidermal stratum basale [3].

MCC has a predilection for occurring in the elderly or immunosuppressed, male patients, and classically presents as a painless, rapidly growing violaceous cutaneous lesion arising on the sun-exposed sites of the head and neck [4, 5]. MCC predominantly presents as a localized cutaneous disease (65%) or with regional lymph node metastases (26%), and in a minority of patients with distant metastases (8%) [4]. The Surveillance, Epidemiology, and End Results (SEER) database showed that the 10-year survival rate for MCC was 71%, 48%, and 20% for localized cutaneous disease, regional lymph node metastases, and distant metastases, respectively [6]. The commonest sites for MCC metastasis include distant lymph nodes (60.1%), distant skin (30.3%), lung (23.4%), brain (18.4%), and bone (15.2%) [7]. Metastatic MCC involving the GI tract is an uncommon event with limited evidence based publications [8].

We present a case of metastatic MCC to the colon that on clinical, radiological, and at colonoscopy was presumed to represent primary colonic carcinoma. The endoscopic biopsy however revealed the presence of an uncommon lesion which with additional immunohistochemistry was accurately recognized as metastatic MCC. A previous history of MCC from a presumed unknown cutaneous primary (MCCUP) was confirmed in a right axillary node dissection three years ago.  A comprehensive literature review is also performed to summarize the clinical and pathological insights into cases with metastatic MCC to the colon. The primary objective of our case report is to increase awareness of such uncommon metastases being diagnosed from endoscopic biopsies for a presumed primary colonic carcinoma. Accurate recognition of these uncommon lesions is vital for the discussion of relevant management options that need to be tailored on an individual basis.

Case Presentation

An 82-year-old gentleman presented to the emergency department with increasing confusion and melena over 5 days. This gentleman had complex comorbidities notable for Heyde syndrome, heart failure with reduced ejection fraction (EF= 39%), multivessel coronary artery disease, severe aortic stenosis, wellcontrolled type 2 diabetes mellitus, and atrial fibrillation managed on apixaban. He endorsed a 20-pounds unintentional weight loss over the past year. Physical examination was otherwise unremarkable. Laboratory tests revealed microcytic anemia and prerenal acute kidney injury, and other biochemical tests were all within normal ranges.

In the emergency department, to correct his hypovolemic and microcytic anemia, resuscitation with crystalloid fluid and blood transfusion with 4 units of packed red blood cell were given. Initial colonoscopy was terminated due to multiple unsuccessful attempts to reach the transverse colon related to significant left-sided diverticulosis and inadequate bowel prep. Computer Tomography (CT) enterography (Figure 1) was performed which showed an apple core-type lesion (5 x 3 cm) at the splenic flexure devoid of active bleeding. Repeat colonoscopy evaluation further characterized this lesion as a circumferential ulcerated large mass at 65 cm with an appearance highly suspicious for colonic cancer. Endoscopic mucosal biopsies were procured for pathological analysis, and the patient was transferred to medical oncology with the preliminary diagnosis of primary colon cancer.

Figure 1: Abdominal CT with triple phase enterography

Histopathological evaluation of the left-sided colon mucosal biopsy revealed fragments of ulcer and colonic mucosa with expansion of the lamina propria with sheets of malignant cells (Figure 2A). The basaloid neoplastic cells show a solid architecture, composed of small cells with elongated nuclei, scant cytoplasm, and increased mitotic figures (Figure 2B). Immunohistochemical (IHC) staining of these neoplastic cells showed them to be strongly positive for pan cytokeratin, (Figure 2C), synaptophysin and

chromogranin (Figure 2D). There was no expression of CK7 while Cytokeratin 20 (CK20) showed the classic dot like positivity of the neoplastic cells in contrast to the strong membrane staining of the adjacent colonic glands as seen in Figure 2E. The noncolonic origin of the neoplastic cells was also supported by no expression of CDX2 with strong internal control staining of the colonic glands as seen in Figure 2F. Additional IHC stains expressed in the neoplastic cells were CD117 and Ber-EP4. There was no expression of CD3, CD 20, CDX2, TTF1, NKX3.1, GATA3 and PAX8 immunostains in the neoplastic cells. The Ki-67 proliferating index was over 90%. The histological appearance and the pattern of IHC staining was consistent with Merkel cell carcinoma. Retrospective medical chart review yielded a pathology report from 3 years ago which showed that the patient had a right axillary lymph node dissection that reported MCC metastatic to the lymph nodes from an Unknown Cutaneous Primary [MCCUP]. He had refused adjuvant radiotherapy at that time. This confirmed the diagnosis of an uncommon mucosal metastatic lesion of Merkel cell carcinoma in these colonic biopsies in contrast to the expected primary colonic carcinoma.

Figure 2: Summary of key histopathological findings seen in the endoscopic mucosal biopsy

Laparoscopic resection and palliative chemotherapy were offered to the patient; however, due to his complex cardiac history and high cerebrovascular accident risk, non-operative supportive management was opted for. Our patient unfortunately passed away 25 days after the colonoscopy from acquired pneumonia and decompensated cardiac failure.

Discussion

Merkel Cell Carcinoma (MCC) is an aggressive, primary cutaneous endocrine neoplasm that predominantly presents as a localized cutaneous disease (65%) [4]. Up to 26% of MCC have regional lymph node metastases at presentation [4]. Distant metastases are rarely observed (8%) with common sites being lymph nodes (60.1%), distant skin (30.3%), lung (23.4%), brain (18.4%), and bone (15.2%) [7]. The literature review showed that colorectal metastasis from MCC is rare. Furthermore, such metastases from MCCUP like our case is exceedingly rare in the published English literature [9, 10]. This case report will be the third case of MCCUP metastasizing to the colon as seen in Table 1.

Table 1: Literature review summarizing the clinical and pathological parameters of MCC metastatic to the colon.

Our literature review, limited to the English language, yielded 9 cases with documented metastatic MCC to the colon (Table 1). The patients in our literature review cohort had an average age of 71.9 ± 7.5 years with a 1.5 fold male predilection (M:F = 6:4). The predominant presenting complaints in these patients were symptoms associated with bowel obstruction or per rectum bleeding. CT imaging results did not show any laterality. MCC metastasis to the colon was uniformly distributed across from the cecum to the descending colon. The prominent endoscopic findings for MCC were stricture formation, edema, and/or ulceration subjacent to a circumferential mass. The predominant goal of management was palliative intent in these patients. Even with this smaller sample size (n=10) it can be gleaned that the mortality rate for MCC metastasizing to the colon remains abysmally high at 70% by 7.9 ± 10 months. With a larger dataset the extrapolated overall survival at 10 years for this cohort might even approach less than 10%. This highlights the aggressive nature of MCC metastasizing to the colon.

The histopathological diagnosis of MCC can be particularly challenging as they are often not considered in the differential diagnosis when they occur in rare distant metastatic sites such as the colon. In a recent review of 55,154 consecutive endoscopic colorectal biopsies from our laboratory only 52 (0.4%) were identified as cases representing the presence of non-colonic mucosal metastases [8]. A biopsy diagnosis of primary MCC by light microscopy alone is extremely challenging due to the overlapping histopathologic features between MCC and other poorly differentiated small round blue cell tumors such as small cell carcinoma, lymphoma, neuroblastoma, Ewing’s sarcoma, and melanoma [18]. The cytology of MCC is described as round to oval nuclei, hyperchromatic nuclei with finely stippled (salt-andpepper) chromatin, inconspicuous nucleoli, with scant cytoplasm and neuroendocrine granules [18]. These neoplastic cells are arranged in trabeculae, sheets, or cords and show high mitotic rate, vascular invasion, as well as interspersed lymphoplasmacytic infiltrates. Therefore, though MCC’s neuroendocrine features maybe suspected from its characteristic cytology, the overall histological appearance is not distinct enough to rule out other small blue round cell tumors entities such as poorly differentiated adenocarcinomas, and small cell variant of malignant melanoma [18]. Definitive diagnosis relies on the immunohistochemical profiling of the neoplastic cells. MCC expresses neuroendocrine markers such as synaptophysin (92%), chromogranin-A (84%), neuron specific enolase (80%), and CD56 (88%). Cytokeratin 20 (CK20) is the most specific marker and shows the characteristic perinuclear punctate or dot-like positivity [19]. The IHC specificity (94%) and sensitivity (88%) for MCPyV’s large T-antigen shows potential for optimized detection of the MCPyV subset of MCC [20]. In this case report, our patient’s metastatic MCC showed positivity for BerEP4. BerEP4 positivity is a common feature of all Neuroendocrine Carcinomas (NEC), basaloid epithelial tumor of the skin, and does not aid in distinguishing MCC from other NEC. Interestingly, though BerEP4 could be utilized as a surrogate marker for the detection of MCPyV; as higher BerEP4 expression levels are seen in MCPyV-positive cases 57% (n= 46 out of 81) compared to MCPyV-negative cases (p<0.0003) [21]. MCPyV detection would also facilitate consideration of immune checkpoint inhibitor therapy. Supplementary table S1 summarizes the IHC panels performed, and results reported as available for each patient in our Literature review.

Supplementary Table S1: Literature review – This table summarizes the comorbidities, laboratory findings and the key histopathological findings reported with their Immunohistochemical profile.