MCC is a rare, aggressive, neuroendocrine cutaneous malignancy with a propensity for both lymphatic and haematogenous spread.1,2 The pathogenesis of MCC, whilst still under investigation, has been attributed to two independent pathways.3,4 Firstly, the presence of Merkel Cell polyomavirus [MCPyV] inducing gene mutations, particularly in immunosuppressed individuals.5 Secondly, cumulative UV damage in chronically sun-exposed skin.1
The worldwide incidence of MCC has been reported to be highest in Queensland, 1.6 per 100,000 population.6 This high incidence has been attributed to the predominant Caucasian population with high UVB exposure and year-round outdoor lifestyle.6 This incidence is rapidly increasing, 2.6% per year, due to the aging population, increasing cumulative sun exposure and better diagnostic tools.6
We report a case of Merkel cell carcinoma found incidentally in an otherwise healthy 77-Year-old female. Due to its rarity, optimal treatment pathways are still not well established. No current therapeutic guidelines exist within Australia to guide diagnosis and management of this highly aggressive malignancy.
Case Report
A 77-year-old Caucasian female presented in May 2018 for a routine appointment when her GP noticed a lesion on her right anterior-medial lower leg. The patient first noticed the lesion approximately 2 years ago, she reported recognisable change in appearance within the last 4 months. The patient reported no localising symptoms, such as pain or pruritis, and was unconcerned by the lesion.
Our patient reported a strong history of UV exposure, growing up on a farm with limited sunscreen use and numerous burns throughout her lifetime. She had a past history of widespread disseminated superficial actinic porokeratosis and numerous Basal Cell Carcinomas. She had no history of immunosuppressive conditions or medications. There was no reportable family history of MCC or other cutaneous malignancies.
Physical examination revealed a pink/brown 20 x 12 mm nodular lesion, suspected at this time to be a pyogenic granuloma or a Squamous cell carcinoma.
The lesion was excised with 4mm margins. The histopathology revealed an exophytic polypoid basaloid malignant tumour composed of nests of cells and central cystic degeneration. The cells featured large irregular nuclei with granular chromatin, numerous mitoses and apoptotic cells. The adjacent epidermis demonstrated changes consistent with Bowens disease. Immunohistochemistry showed strong positive staining for neuroendocrine markers CD56 and Synaptophysin. Stains for CGA, CK5/6 and p40 were negative. This histopathology was consistent with MCC and the lesion was completely excised.
The high risk of regional and distant metastases warranted urgent referral for further investigations, including staging CT and PET scan, and multidisciplinary management. Following these investigations our patient was found to have Lymph node involvement and subsequently staged T1 N1 M0. Management of this patient was guided with the use of melanoma clinical guidelines and expert opinion from a multidisciplinary team consisting of a plastic surgeon, medical oncology and radiation oncology. Management consisted of wide local excision, Chemotherapy (Carboplatin and Etoposide) and adjuvant Radiotherapy.
Discussion
MCC is an aggressive malignancy with high recurrence and mortality rate.4 Whilst the pathogenesis of MCC is still not completely understood several risk factors are well defined.4 UV exposure has been implicated as a major risk factor, particularly in Australia, with 81% of MCC occurring on UV exposed sites.1,2,7 Merkel Cell Polyomavirus [MCPyV] has been identified as a causal oncogenic virus.8 The role of MCPyV in the southern hemisphere, where UV exposure predominates, is much more controversial than that of the Northern Hemisphere where up to 80% of MCC are MCPyV positive.8 More research is needed into the role of MCPyV, particularly in Australia, to determine the relationship between viral status, clinical course of the disease and prognostic implications. Further knowledge on the impact of the virus may help to guide recommendations for serological testing of patients diagnosed with MCC. Other risk factors which have been associated with MCC include states of immunosuppression, such as Post organ transplantation, HIV infection, Chronic Lymphocytic leukaemia or drug induced.1 The only identifiable risk factor in our patient was her history of chronic UV exposure which had also manifested itself as other UV induced skin damage throughout her life. This strong risk profile, locality of the primary lesion and lack of any other risk factors make this the most likely origin of our patients’ malignancy.
MCC is rarely suspected from its clinical presentation prior to biopsy, which can contribute to a delayed diagnosis and have drastic prognostic implications.2,3 MCC most commonly presents as a painless, non-descript, rapidly expanding indurated nodule.8 An acronym ‘AEIOU’ has been developed to help summarise five classical features to help guide clinical suspicion.7 The features include; Asymptomatic/Non-tender, Expanding rapidly, immunosuppression, Older than 50 years old, UV exposed skin.7 A prospective study conducted identified that 89% of all patients met three or more criteria.7 Our patient presented for an unrelated matter and unconcerned by her ‘warty’ lesion, however, she met 4 of the AEIOU criteria which significantly raises the suspicion for MCC. This aspect of our case raises the need to increase both public and clinician awareness of MCC and its clinical characteristics to improve early diagnosis and thus prognosis.
MCC is associated with a high incidence of loco-regional and metastatic spread. Up to a third of patients present with nodal involvement and 6-12% with metastatic disease.4 This propensity to spread warrants a thorough examination and investigations to adequately assess the stage of disease. The aggressive nature of MCC is reflected in poor prognostic figures, with a median 3-year mortality rate of 36-43%.4 However, intervention with early referral and treatment have the potential to positively influence a patient’s outcomes.4 The diagnostic and treatment process could be streamlined, and patient outcomes improved, if evidence based clinical guidelines were available. However, to date, no such guidelines exist within Australia and treatment is largely based on melanoma guidelines and expert opinion. Whilst the greater emphasis which is placed on melanoma may be warranted given its higher incidence, MCC is associated with significantly reduced survival expectations comparatively and therefore should be addressed on its own merit.6
At diagnosis, patients should undergo a thorough work up to assess disease burden as this has important management and prognostic implications.1 This may include a clinical examination for satellite lesions or lymph node involvement, staging imaging including CT and PET scan to determine burden of disease and a sentinel lymph node biopsy (SLNB).1,2,8 SLNB is growing in use to identify patients with subclinical nodal disease who may benefit from early definitive treatment.8 It has been found to identify up to a third of patients with micrometastases who would have otherwise been under staged.8 As no Australian guidelines exist and its role from various studies is controversial, SLNB is not routinely performed in patients diagnosed with MCC. International guidelines recommend its routine use to optimally stage patients, particularly those with local disease.8 However, growing interest in the use of prophylactic nodal irradiation in high risk patients, if implemented, would challenge the role of SLNB.8 Staging imaging in our patient had important diagnostic implications as nodal involvement was discovered on PET scanning. As a result of this nodal involvement she was ineligible for consideration for SLNB and thus proceeded direct to nodal US and biopsy.
Diagnosis of MCC is reliant on histopathology and immunohistochemical studies. Microscopically MCC appears as a non-descript small cell neuroendocrine carcinoma with densely staining blue cells centred in the epidermis.1,5 Actinic keratosis or Bowens disease are commonly identified in the overlying skin, such as seen in our case, further emphasising the role of UV exposure as a common causal risk factor.5 Immunohistochemical staining is required to differentiate MCC from other small cell tumours through the expression of different neuroendocrine markers such as Synaptophysin, chromogranin and CD56.1
Due to the rarity of MCC and the lack of controlled therapeutic trials, no consensus currently exists on the optimal management of MCC.1,7 Although the optimal treatment pathways are still under scrutiny, it is well established that prompt referral for aggressive treatment and avoidance of treatment delays have important implications on patient outcomes.2 Treatment options vary according to the stage of disease however mostly include a combination of wide local excision, adjuvant radiotherapy and chemotherapy.7
Wide local excision and adjuvant radiotherapy is the primary treatment for localised disease.5 Appropriate margins for excision are controversial, however, due to the propensity for spread, wide margins 2-3cm are commonly advocated.1,2 Smaller lesions, in cosmetically challenging sites may be suitable for 1cm margins, particularly if adjuvant radiotherapy is being offered.1,2 In limited cases, due to cosmetically challenging areas or patient comorbidities, radiotherapy alone to the primary site may be appropriate.2 Adjuvant radiotherapy should be offered at all stages of disease as it has been shown to increase local and regional control and improve long term survival of patients.1
Management of patients with lymph node involvement becomes more indeterminate. Treatment options include lymphadenectomy or radiotherapy, alone or in combination.5,8 The significant morbidity associated with nodal dissection and scarcity of evidence to prove combined modality treatment improves patient outcomes has challenged its role in management.8 Our patient who was diagnosed with radiological node positive disease is due to commence 5 weeks of radiotherapy to both the primary site and the involved lymph nodes.
Although MCC is chemosensitive, the role of chemotherapy and the overall survival benefit is not well established.2,8 Palliative chemotherapy, usually with a platinum-based agent and Etoposide, in the case of metastatic disease is commonly recommended.1,2 Adjuvant chemotherapy may be administered in some patients to sensitise the tumour to radiotherapy and eliminate subclinical micrometastatic disease.2 However; significant toxicities and morbidity associated with systemic chemotherapy often limit the tolerability in these patients.8 Our patient was prescribed neoadjuvant chemotherapy consisting of Carboplatin and Etoposide to sensitise her tumour to the radiotherapy. However; this regime was ceased prematurely as a consequence of adverse effects.
Conclusion
Our case, of an incidental diagnosis of MCC, helps to support the current literature relating to the risk profile and clinical presentation of this aggressive malignancy. Improving public and clinician awareness about clinical features and lethality of MCC is central to improving patient outcomes. The lack of Australian clinical guidelines and paucity of evidence-based research on optimal diagnostic and management principles remain a major hurdle to optimal management of these patients. However; urgent diagnosis and referral for multimodal management, including surgery and radiotherapy, remain central to achieve favourable outcomes.