7Merkel Cells, initially described by German Histopathologist Friedrich Merkel, are localised to the epidermal basal layer and are thought to be touch receptors of ectodermal origin. As you know, the malignant tumour Merkel cell carcinoma arises from these cells.
8No consensus on management RareAggressiveNo consensus on managementIt is rare with an incidence of 2.2 cases per million in Europe and North America. It is very aggressive; at time of presentation a third of people with MCC will have distant metastatic disease. The mortality rate far worse than SCC or malignant melanoma, which both have existing UK guidelines. To date, there is no consensus in the UK on management. These are 2 cases from our series.8
9Keratin 20SynapsinCD 56Ki67As you know, Merkel cell carcinoma histologically is a small oat cell tumour. Therefore a series of stains and labels are involved in differentiating it from other small cell tumours such as small cell lung cancer. With low molecular staining, there is a characteristic perinuclear staining pattern. (CK20 is highly specific for MCC and helps distinguish MCC from small cell lung tumours providing a characteristic perinuclear staining pattern. Labelling with synapsin, a neuroendocrine marker. CD56 is the strongest staining neuroendocrine marker for MCC. Ki67 the nuclear marker is normally visible only in the basal layer, but in MCC it is abundant throughout the dermis.9
10British Association of Dermatology July 2007 Merkel cell carcinoma was confirmed by immunohistochemistry with epithelial stains, including keratin 20, a low molecular keratin which showed a typical paranuclear dot and streaming pattern and is highly sensitive for merkel cell carcinoma. Neuroendocrine stains, such as synapsin and neurone specific enolase are less sensitive.British Association of Dermatology July 200710
11Immunolabelling Profiles TumourCK20CK7NSENFPS100LCACD99TTF1Merkel-cell carcinoma+-RareSmall-cell carcinoma of lung+/-LymphomaPeripheral primitive neuro-ectodermal tumourSmall-cell melanomaHistology is typical of several blue cell tumours, differentiation is confirmed by immunoexpression. This table shows the characteristic labelling patterns for the main differentials. Positive epithelial and neuroendocrine stains, higlighted in yellow indicate merkel cell carcinoma.CK20: cytokeratin 20CK7: cytokeratin 7NSE: neurone-specific enolaseNFP: neurofilament proteinS100: S100 proteinLCA: leucocyte common antigenCD99: cluster-of-differentiation antigen 99TTF1: thyroid transcription factor 1+: positive stain–: negative stainBritish Association of Dermatology July 200711
12Immunohistochemistry Ck 20. We were also able to demonstrate a few normal Merkel cells in the distal hair follicle. Collectively, these features were all consistent with a MCC.Cytokeratin 20
13Merkel Cell Carcinoma Merkel Cell Carcinoma Rare highly malignant neuroendocrineskin tumourUSA /Male predominanceAverage age at presentation – 69yMCC is a rare skin tumour of neuroendocrine origin. It is highly malignant and spreads via the dermal lymphatics and blood. In America the estimated incidence is 0.23/ in white populations. This figure is lower in other racial groups. It is predominatly a tumour of the elderlyand the average age of presentation is 69 years.
14Associations Associations UV lightmost commonly seen on the head and neck region and the lower legImmunosuppressionPost organ transplant (0.13 / 1000 patient yrs)HIVHaematological malignanciesSunlight has been implicated as a cause for MCC and accordingly, lesions are commonly seen on sun-exposed sites such as the head and neck region and the lower leg. However as it can occur on non-sun exposed sites, other factors must be involved in the aetiology. Immunosuppression has also been associated and there have been several cases in patients following solid organ transplantation and also in patients with HIV and haem malignancies such as chronic lymphocytic leukaemia. The risk of MCC in renal transplant recepients has been estimated at 0.13/1000 person years.
15Clinical Diagnosis Clinical diagnosis is difficult Red / violaceous noduleMay resemble an SCC / BCC or amelanotic melanomaClinical diagnosis is difficult as MCC often resembles other skin cancers such as an SCC/ BCC or amelanotic melanoma.
16Poor Prognostic Markers Good Prognostic Markers Advanced stage at presentationImmunosupressionCD+ Lymphocyte invasion of the tumourPrescence of PolyomavirusTo date, Merkel cell carcinoma lacks robust prognostic markers. What is known is that an advanced clinical stage at presentation and immunosuppression leads to a poorer outcome. Tumour size does not affect outcome.16
17MCPyV MCV Clonally integrated in 80% of MCC In 2008 Merkel cell polyomavirus (MCPyV), was identified in MCC. Its prevalence has been reported as up to 80% of MCC. It Inactivates tumour suppressor proteins and is not associated with aggression. It has been suggested that two groups of MCC may exist; MCPyV driven, which tends to be less aggressive, and a more aggressive non-MCPyV driven group.Clonally integrated in 80% of MCC17
18The virus can be identified by PCR or Antibody detection The virus can be identified by PCR or Antibody detection. Merkel cell polyomavirus has also been indentified in other skin neoplasms.18
19Retrospective Analysis of MCC over 10years 14 cases identifiedSSMDTBarts Health NHS TrustWe have analysed our cohort of merkel cell carcinoma patients over the past 10years19
20Results: Demographics 9 female, 5 maleMean age of presentation: 73years (range 54 to 87years)21% presented with metastatic disease
21Results: Treatment INTERVENTION Frequency WLE with 1-3cm margins ALL Adjunctive RadiotherapyMajority(57%)Sentinel Lymph Node BiopsyFew (14%)Adjunctive ChemotherapyEnrolled onto MCC-1 Trial1All of our patients underwent WLE and the majority had adjunctive radiotherapy to the surgical bed. 2/14 had sentinel lymph node biopsy- these have been the 2 most recent cases that did not present with metastases. The benefits of adjunctive chemotherapy are unknown; due to the rarity of the condition prospective trials are lacking. In the UK, the Phase II MCC-1 trial is in progress using the Tyrosine Kinase inhibitor Pazopanib.
22Polyomavirus 10/14 tested 80% had positive polyomavirus Positive virus did not correlate with outcome
23Results: Survival Rates All patients who presented with metastases died within a year (3/14)Of the remaining 11/14 patients, 1 died within a yearOther comorbidities10/14 patients are still alive to dateDate range from
24Radiotherapy induced skin cancers BCC - 3.6%SCC %AngiosarcomaFibrosarcomaMelanomaMerkel cell carcinomaIt is well known that radiotherapy can induce skin cancer. BCCs are most common, seen in upto 3.6% of individuals treated with radiotherapy and SCC. The other skin cancers seen rarely are angiosarcoma as illustrated here, fibrosarcoma, melanoma and merkel cell carcinoma.British Association of Dermatology July 200724
25Guidelines Germany France USA UK WLE margin 3cm 2-3cm Not specified Radiotherapy to surgical bedYesSLNDNot obligatoryAdjunct ChemotherapyNoYes- enrol in Clinical trialsChemotherapy in MetastasesFollow-up5-years5yearsMinimum 3yearsCompared to USA, Europe has given MCC some attention
26Suggestions for UK pathway Histopathological criteria and StagingJ Diaz- Perez et al. “Merkel cell carcinoma: a clinicopathological study of 11 cases.” JEADV, 2005WLE with 2-3cm or MohsS. J. Miller, M. Alam, J. Andersen, et al., “Merkel cell carcinoma,” Journal of the National Comprehensive Cancer Network, vol. 7, no. 3, pp. 322–332, 2009.Adjunctive RadiotherapyL. Mortier, X. Mirabel, C. Fournier, F. Piette, and E. Lartigau, “Radiotherapy alone for primary Merkel cell carcinoma,” Archives of Dermatology, vol. 139, pp. 1587–1590, 2003Sentinel lymph node biopsyL. K. E. Rodrigues, S. P. L. Leong, M. Kashani-Sabet, and J. H. Wong, “Early experience with sentinel lymph node mapping for Merkel cell carcinoma,” Journal of the American Academy of Dermatology, vol. 45, no. 2, pp. 303–308, 2001.?Role of Adjunctive chemotherapyBased on our analysis, our suggestions for a pathway would include26