Interesting case of an abdominal wall Merkel cell carcinoma highlighting the importance of developing an Australian clinical practice guideline

Abstract

A 66-year-old Australian male farmer was referred for management of an asymptomatic, rapidly expanding, anterior abdominal wall mass. It was firm and well circumscribed. There were no overlying skin changes, constitutional symptoms or weight loss. His medical history included small bowel obstruction and resection from a Meckel’s diverticulitis and a 40-pack-year smoking history. Core biopsy was suggestive of a neuroendocrine tumour and Gallium-68-Dodecane-Tetraacetic-Acid (68GaTate) positron emission tomography revealed an avid solitary lesion confined to the subcutaneous space in the left anterior abdominal wall. Wide local excision was performed, and histopathology revealed Merkel cell carcinoma (MCC). Although classically regarded as a primary cutaneous neuroendocrine tumour, MCC may originate from the subcutaneous fat without obvious skin involvement. Older patients with asymptomatic, rapidly enlarging lesions, particularly if immunosuppressed, with significant ultraviolet sunlight exposure, should raise a high index of suspicion for MCC. Like melanoma, non-metastatic MCC should be treated aggressively for best prognosis.

Background

Merkel cell carcinoma (MCC) remains a rare but aggressive cutaneous neuroendocrine tumour that affects older, fair-skinned individuals.¹ MCC is twice as lethal as malignant melanoma with a reported mortality of 30%–35%.^{2 3} It is associated with high rates of locoregional recurrence and poor prognosis. In the USA, Paulson et al found a 95% increase in the number of reported MCC cases between 2000 and 2013 with an incidence of 0.7 cases per 100 000 persons/year.⁴ Paulson et al also found that the incidence of MCC increased exponentially with age from 0.1, 1.0 and 9.8 per 100 000 between age groups 40–44, 60–64 and ≥85 years, respectively.⁴ Incidence rates for MCC in Australia and New Zealand are at least double those reported in the USA with Queensland, Australia boasting the highest incidence of 1.6 per 100 000 persons/year.⁵ With an ageing population across the globe, we can expect an increase in the incidence of MCC and therefore awareness of MCC diagnosis and management is paramount in achieving better patient outcomes.

Case presentation

A 66-year-old man from rural Queensland, Australia presented with an 8-week history of a rapidly enlarging, asymptomatic left anterior abdominal mass measuring approximately 3 cm in diameter. It was firm, well circumscribed and tethered to skin. There were no overlying skin changes, constitutional symptoms or weight loss. Significant medical history included a midline laparotomy with small bowel resection for a Meckel’s diverticulum causing small bowl obstruction 4 years prior and an ongoing 40 pack-year smoking history. He was fair-skinned and worked as a farmer for over 50 years. He rarely used sunscreen; however, he had no history of melanotic or non-melanotic lesions diagnosed or excised.

Investigations

The rate of growth and concerning examination features of this subcutaneous left anterior abdominal wall mass, prompted an early ultrasound-guided core biopsy. Histology was consistent with neuroendocrine carcinoma staining positive for CD5/6, CK8/18, synaptophysin and chromogranin on immunohistochemistry. Histological subtype was unable to be determined.

His previous Meckel’s diverticulum was re-examined considering his biopsy result and the tumours location on the abdominal wall. However, no evidence of a previously missed neuroendocrine tumour was evident on the re-examined specimen.

Serum chromogranin A, platelet serotonin and routine blood tests were normal. Staging 68GaTate positron emission tomography-CT (PET-CT) demonstrated an intensely 68GaTate avid subcutaneous soft tissue lesion measuring 29×20×19 mm in the left anterior abdominal wall without nodal or distal metastasis (figure 1).

Figure 1.

Top left image—sagittal slice of CT scan demonstrating subcutaneous soft tissue mass in abdominal wall. Top right image—axial slice of CT scan demonstrating subcutaneous soft tissue mass in left abdominal wall. Bottom left image—sagittal slice of 68GaTate positron emission tomography/CT (PET/CT) demonstrating an intensely 68GaTate avid subcutaneous soft tissue lesion in anterior abdominal wall. Bottom right image—axial slice of 68GaTate PET/CT demonstrating an intensely 68GaTate avid subcutaneous soft tissue lesion in left anterior abdominal wall.

Differential diagnosis

Soft tissue subcutaneous masses have a broad differential list. Given it was solitary neuroendocrine tumour with a history of previous small bowel resection, the provisional working diagnosis was a secondary deposit from a missed primary gastrointestinal neuroendocrine tumour.

Treatment

The case was discussed at a weekly oncology multidisciplinary team (MDT) meeting. Given indeterminate histological subtype and negative nodal status on PET, the recommendation was for surgical wide local excision (WLE) only. The tumour resected off underlying fascia and a wide 2 cm macroscopic margins were taken. There was no evidence of posterior deposition of tumour.

Outcome and follow-up

Anatomical histopathology revealed a 29×25×20 mm tumour consistent with MCC in the dermis and subcutis. Immunohistochemistry stained negative for TTF-1 and MCPyC but positive for CAM5.1 and CK20 classically suggestive of MCC. The tumour invaded 20 mm deep but had clear circumferential margins of at least 10 mm.

Formal diagnosis of stage IIB, R0 MCC prompted a rediscussion at the next MDT meeting given the aggressive nature of this tumour. Given alteration of the postoperative lymphatic drainage, a subsequent sentinel lymph node biopsy (SLNB) was not recommended. The patient received adjuvant radiotherapy to the surgical bed. Surveillance is ongoing with 6 monthly CT scans. The patient remains healthy and disease free 3 years later.

Discussion

MCC is a rare but aggressive malignancy that requires judicious and timely diagnosis for effective management to achieve the best possible prognosis. Harms et al demonstrated that 65% of patients present with local disease, 26% present with nodal disease and 8% present with distal disease.⁶ Harms et al also demonstrated that the overall 5-year survival rates for local, nodal and distal MCC were 55.8%, 41.1% and 31.8%, respectively.⁶

Only 10% of MCC exhibit epidermal change thereby limiting data on dermoscopic findings and no specific diagnostic features have been identified.⁷ It is almost impossible to diagnose MCC on the basis of physical examination alone with the correct diagnosis made in only 1% of cases.^8–10 Discordance remains in the literature regarding the histological origin of MCC. Traditionally thought to arise from Merkel cell mechanoreceptors in the basal layer of the epidermis and dermal papillae, recent cancer genomic studies suggest these tumours may originate from immature totipotential stem cells with an oncoviral origin.¹¹ A meta-analysis of 22 studies (n=699) by Santos-Juanes et al found an overall Merkel cell polyomavirus (MCPyV) prevalence of 79% in Merkel cell tumour compared with 12% in control skin samples.¹² MCPyV exerts oncogenesis through DNA integration which was demonstrated to precede clonal expansion of the tumour.^{13 14} Viral oncogenesis as the primary cause of MCC is not universal but geographical. Ultraviolet (UV) mediated mutation is by far the most common cause of MCC in Australia and New Zealand.⁵ Viral MCPyV DNA integration was only observed in 30% of MCC cases in Australia compared with 80% of MCC cases in the northern hemisphere.^{14 15} Interestingly, MCC in the head, neck and sun-exposed regions were more prevalent in high UV index regions such as Queensland and western Australia but a larger percentage of truncal MCC was noted in low UV index regions such as Scandinavia.^{5 16 17} Heath et al summarised the most significant clinical features that raise suspicion of MCC with the acronym AEIOU.¹⁰ Asymptomatic (88%), expanding rapidly (63%), immune suppression (8%), older than 50 (90%) and UV-exposed are in fair-skinned individuals (81%). They found that 89% of their case series with primary MCC had three or more of these features.

Medline, PubMed, Google Scholar and Cochrane were interrogated for systematic reviews, clinical trials and practice guidelines. Non-English publications were excluded. Seven major clinical guidelines were identified, and all consistently recommended SLNB. However, there was little consistency on resection margins ranging between 10 mm and 30 mm. Vazquez et al used the guidelines that scored highest on the AGREE II, a quality assessment tool for practice guidelines, to address nine clinical questions and provide recommendations accordingly.⁸ The clinical practice guidelines included in the study were National Comprehensive Cancer Network guidelines in oncology,¹⁸ the European consensus-based interdisciplinary guideline,¹⁹ the Alberta Health Services Clinical Practice Guideline,²⁰ the guidelines of the American Cancer Society²¹ and the Cutaneous Oncology Group of the French Society of Dermatology.²² They concluded that:

1. Diagnosis using classical clinical ‘AEIOU’ features is insufficient and that definitive diagnosis should be made in combination with histologically with confirmatory immunohistochemistry (Grade C).

2. Contrary to melanoma, SLNB should be performed whenever possible regardless of patients without clinically evident nodal disease, regardless of primary tumour size, location or pathological predictors (Grade C).

3. PET-CT should be used for initial staging (Grade B).

4. Radiation therapy for all lesions regardless of size with risk factors such as lymphovascular invasion or immunosuppression and lesions with diameter of 2 cm or more (Grade B).

5. Sentinel lymph node dissection is recommended if positive SLNB (Grade C).

6. Regional radiotherapy recommended for patients who did not undergo SLNB or patients with positive SLNB who did not undergo lymph node dissection or patients with a negative SLNB that is likely to be false negative (Grade B).

7. Close follow-up recommended for 2–3 years at intervals of 1–6 months and then at intervals of 6–12 months thereafter. Monitor for at least 5 years (Grade D).

8. Lack of consensus on which tests to order at different clinical stages. If concern for recurrence, PET-CT has greater sensitivity for restaging compared with CT (Grade C).

Our case highlights the diagnostic challenge and management dilemma for MCC. Given its rarity, it is often forgotten when considering cutaneous skin lesions. It is vital to exclude MCC from the pool of poorly differentiated neuroendocrine tumours as this diagnosis greatly impacts management.

In hindsight, with the recommendations put forth by Vazquez et al, confirmatory core biopsy would have proved vital as SLNB should have been performed in conjunction with WLE. MCC remains rare and as a result, there is a paucity in strong evidence to guide clinical practice. Despite having the highest incidence of MCC globally, Australia has yet to establish its own clinical guidelines and this is certainly an area that should be developed and improved to achieve best patient outcome.

Learning points.

• Merkel cell carcinoma (MCC) is an aggressive under-recognised and often misdiagnosed cutaneous lesion.

• Confirmatory immunohistopathology in addition to clinical ‘AEIOU’ features should be used to confidently diagnose MCC.

• It is vital to exclude MCC from the pool of poorly differentiated neuroendocrine tumours as this diagnosis greatly impacts management.

• sentinel lymph node biopsy is recommended regardless of tumour size, location or pathological predictors.

• An Australian clinical practice guideline aiding the diagnosis management of MCC is lacking.