1.Department of Radiation Oncology, Royal Prince Alfred Hospital, Camperdown, Sydney, NSW, Australia.
2.Discipline of Medicine, The University of Sydney, Sydney, NSW, Australia.
Merkel cell carcinoma is a rare, aggressive, cutaneous neuroendocrine tumour which has a propensity for both loco-regional and distant spread. This review considers its epidemiology, diagnosis, staging and management, including the roles of surgery, radiation therapy and chemotherapy, and guidelines for patient management are presented. Patients should be referred promptly to an experienced specialist centre for definitive management, because treatment delays are associated with a worse outcome. Given the rarity of this tumour, patients should be enrolled on prospective databases and managed in a multidisciplinary setting, ideally in the context of a clinical trial.
Merkel cell carcinoma is an aggressive cutaneous tumour that tends to occur in the sun-exposed skin of the elderly. It was first described by Toker in 1972.1 Merkel cell carcinoma is also called primary cutaneous neuroendocrine carcinoma, based on the ultrastructural finding of dense core granules within the tumour cells and immunohistochemical evidence of neuroendocrine differentiation.2,3 Merkel cells were first described by Friedrich Sigmund Merkel as Tastzellen or ‘touch cells’, but details of their function and origin remained elusive. Merkel cells appear to be essential for the specialised coding by which afferent nerves resolve fine spatial details.4 Skin graft experiments in birds initially implied that Merkel cells were neural crest derived, but more recent studies in mammals indicate an epidermal origin.5
Merkel cell carcinoma has a non-specific clinical appearance and is often diagnosed belatedly, or misdiagnosed. It may present as a painless, indurated, solitary dermal nodule with a slightly erythematous to deeply violaceous colour, and rarely, an ulcer (figure 1). Merkel cell carcinoma may infiltrate locally via dermal lymphatics, resulting in multiple satellite lesions.6 Regional lymph nodes are involved at presentation in approximately one third of cases. In 10-20% of cases, Merkel cell carcinoma presents solely as a lymph node metastasis, or the primary may have been cryo-ablated.7 Investigators have used the acronym ‘AEIOU’ to summarise this tumour entity as possibly being Asymptomatic, Expanding rapidly, and more likely to occur in Immunosuppressed patients Older than 50 years in UV exposed skin.8 To this previously described acronym we would add the letter ‘R’ for both Rare and Remember.
Ultraviolet irradiation is the major risk factor for developing Merkel cell carcinoma. Merkel cell carcinoma incidence increases progressively with age. The median age at diagnosis is around 65 years.9 There is an increased incidence of this disease in immunosuppressed patients. Recently, it was discovered that a polyomavirus (termed Merkel cell virus, MCPyV) was clonally integrated into the genome of Merkel cell carcinoma in the majority of patients.10 However, the role of the virus in the pathogenesis of Merkel cell carcinoma remains controversial, particularly since the prevalence of MCPyV appears to differ between Merkel cell carcinoma patients in the United States and Europe compared with Australia. Thus, there may be two independent pathways for the development of Merkel cell carcinoma – one driven by the presence of MCPyV, and the other driven primarily by sun damage.11
Merkel cell carcinoma consists of small round cells with hyperchromatic nuclei and scant cytoplasm. Typically, nuclei have evenly dispersed, peppered chromatin and inconspicuous nucleoli. Immunohistochemistry is useful to differentiate Merkel cell carcinoma from metastatic visceral neuroendocrine carcinomas, particularly from small cell lung carcinoma. CK-20, a low-molecular-weight intermediate filament, is a highly sensitive marker for Merkel cell carcinoma. Other helpful markers include CD117 neuron-specific enolase, chromogranin A, synaptophysin, and neurofilament protein. Conversely, Merkel cell carcinoma is typically negative for CK-7 and thyroid transcription factor-1 (both positive in small cell lung carcinoma), and for S-100 and leukocyte-common antigen, distinguishing it from melanoma and cutaneous lymphoma, respectively.12
Because loco-regional spread is common, newly diagnosed Merkel cell carcinoma patients require a thorough clinical examination for satellite lesions and regional node involvement. Imaging may include a computed tomography (CT) scan of the chest and abdomen to rule out primary small cell lung cancer, as well as distant and regional metastases. Fluorodeoxyglucose-positron emission tomography (PET- see Emmett and Ho, pp 134 ) results have been reported only in selected cases, but Merkel cell carcinomas generally show high avidity. PET can detect metastatic deposits in sub-centimetre lymph nodes that may not have been appreciated on initial CT assessment.13 In a recent review of 18 patients with Merkel cell carcinoma, PET-CT contributed to altered staging in seven patients (33%) and a change in management in nine patients (43%).14
The American Joint Committee on Cancer (AJCC) staging system, modified in 2009, is based on the size of the primary lesion (<2cm or >2cm) and the presence or absence of lymph node involvement (table 1).
The role of sentinel lymph node biopsy is not well elucidated. Some have suggested that sentinel lymph node biopsy may have a role in selecting patients with clinical stage I disease who may then avoid elective nodal treatment.15 Others argue that sentinel lymph node biopsy is not an accurate predictor of loco-regional recurrence in Merkel cell carcinoma, with a higher false negative rate (range 5-33%) than is seen in melanoma or breast cancer.16,17 For example, in a series from Melanoma Institute Australia, five of six patients with pathologically negative sentinel lymph node recurred within the node field.17 In contrast, the failure rate for melanoma detection after a negative sentinel lymph node biopsy was only 2.7% in over 1000 patients treated at the same centre.18 Despite this uncertainty, pre-operative lymphoscintigraphy to identify the location of sentinel lymph nodes and draining node fields may be of value in radiotherapy field planning in certain situations.17
The extent of disease at presentation provides the most useful estimate of prognosis. For stage I disease, a tumour diameter <2cm is associated with an improved outlook.19 Other clinicopathological factors that influence prognosis remain poorly defined. It has been reported that p63 expression in primary Merkel cell carcinoma is strongly associated with clinical outcome.20 However, a recent analysis of 95 patients with Merkel cell carcinoma found p63 expression was infrequent (9% of primary Merkel cell carcinoma) and showed no significant association with disease outcome. Tumour thickness was nevertheless significantly associated with disease-free survival in Merkel cell carcinoma.21 The most relevant prognostic levels (akin to Breslow thickness in melanoma) remain to be elucidated, but it is strongly recommended that thickness be routinely measured in pathology reports.22
Early referral to a specialist centre experienced in managing Merkel cell carcinoma is important, as delays between diagnosis and treatment lead to poorer outcomes.23 The exact integration of surgery, radiotherapy and possibly chemotherapy needs to be tailored to the patient, location of the tumour and stage of disease, from definitive treatment employing surgery or radiotherapy, through to the palliation of incurable disease.
Surgery is the initial treatment modality in most patients, even if only to establish the diagnosis. The extent of excision margins that are required remains a subject of controversy. Historically, wide local excision with a 2-3cm margin has been recommended, but no formal trial has ever been carried out to confirm this. Extensive surgery – given that Merkel cell carcinoma occurs predominantly in cosmetically challenging areas – becomes less critical if adjuvant radiation treatment is to be delivered to the primary site.
Occasionally, primary tumour excision is not possible, especially in elderly patients or in cosmetically sensitive areas. Several reported series document the use of radiation or chemoradiation alone to treat Merkel cell carcinoma, achieving durable local control (figure 2). Doses used in this setting have ranged from 45 to 60Gy in varying fractionation schedules.24-28
Elective irradiation of regional lymph nodes should be considered in patients with stage I Merkel cell carcinoma. It may be particularly valuable in the head and neck region where the draining node field is usually in close proximity to the primary tumour. Furthermore, elective radiotherapy obviates the need for sentinel lymph node biopsy. A recently published French randomised control trial (which has the distinction of being the only one in this disease),29 demonstrated that regional irradiation reduced the probability of regional node recurrence (16.7% v 0%) but had no impact on progression-free or overall survival.
Adjuvant radiotherapy may follow surgery, either to the primary alone, or to both the primary and a directed regional node field. Multiple series have demonstrated benefits from adjuvant radiotherapy in improving both loco-regional control and disease-free survival when compared to series managed with surgery alone.6,30-34 An analysis of over 1600 patients in the US Surveillance, Epidemiology and End Results database demonstrated statistically significant improvements in survival with the use of postoperative (adjuvant) radiation treatment.35 The use of adjuvant radiation was associated with improved survival in all age groups, and for all tumour sizes. Therefore, surgical and radiation oncologists should manage these patients together using a team approach.36
It appears important that radiation treatment be delivered promptly. A higher risk of progression (41%) was seen in patients who waited more than a median of 24 days for radiation treatment.23
Merkel cell carcinomas are generally sensitive to chemotherapy, with high initial response rates. However, relapse inevitably occurs. Chemotherapy may sensitise Merkel cell carcinoma to the effects of radiation treatment and thereby enhance the local cell kill from radiation treatment. It may also act further afield to eliminate subclinical micrometastatic disease. The most widely used chemotherapy agents for Merkel cell carcinoma are either cisplatin or carboplatin plus etoposide.
The Trans-Tasman Radiation Oncology Group (TROG) has investigated the use of adjuvant chemo-radiotherapy in patients with high-risk Merkel cell carcinoma. Trial 96.07 included 53 patients with high-risk Merkel cell carcinoma.37 Patients had disease localised to the primary site and nodes, with at least one of the following high risk features: recurrence after initial therapy; involved nodes; primary tumour size > 1 cm; gross residual disease after surgery; or occult primary with nodes. Treatment consisted of radiation to the primary site and nodes and synchronous carboplatin and etoposide. This study demonstrated excellent overall survival and loco-regional control, with three-year overall and relapse-free survival rates of 76% and 65%, respectively, despite high-risk disease. However, grade 3 or more neutropenia occurred in 57% of the patients, with febrile neutropenia in 35%.
Given the advanced age of most patients with Merkel cell carcinoma, and in order to reduce the toxicity seen in trial 96.07, TROG investigators have piloted the use of weekly carboplatin synchronous with the radiation treatment, with three cycles of adjuvant carboplatin and etoposide.38 This regimen forms the basis for a phase II efficacy study of chemo-radiotherapy in high risk Merkel cell carcinoma (primary greater than 2cm in diameter and/or involved regional lymph nodes), TROG trial 09.03.39 Here, radiation treatment doses are tailored to disease burden and PET scans are performed to assess the proportion of patients in whom PET imaging results in a change in management, and also to assess metabolic response in those with macroscopic disease.
The presence of distant disease carries a grave outlook, with the most commonly-affected organs being the liver, bone, lung, brain and skin. Responses to chemotherapy (either cisplatin, doxorubicin and vincristine, or etoposide and cisplatin) are generally short-lived and most patients die from the disease.40,41 Furthermore, many patients are elderly and the chemotherapy regimens are especially toxic in this group.12 Radiotherapy may also be employed for palliation of symptomatic disease, particularly bone or brain metastases.
Patients with Merkel cell carcinoma should be referred urgently to a multidisciplinary specialist centre with experience in the disease, and managed on a case by case basis. If a patient presents with positive margins after initial biopsy or resection, definitive radiation treatment or chemo-radiotherapy is an alternative to further surgery and, importantly, results in less delay to (adjuvant) radiation treatment. Such a patient may also undergo elective radiation treatment of the draining lymph node field, obviating the need for sentinel lymph node biopsy or full node dissection. Entering patients with Merkel cell carcinoma into prospective trials and recording information about them on national databases is essential if we are to better understand the behaviour of this rare disease and determine its optimal management.
Merkel cell carcinoma is a rare disease where treatment by definitive radiation treatment or chemo-radiotherapy has an expanding role in addition to surgery. It is important that recruitment to prospective trials (such as TROG 09.03) continues in order to validate and improve our approach to this enigmatic disease entity.
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