60 y. o. Female. Tumour on the right upper arm 60 y.o. Female. Tumour on the right upper arm. Non-melanoma skin cancer? CASE 27

Merkel 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.

No consensus on management Rare Aggressive No consensus on management It 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

Keratin 20 Synapsin CD 56 Ki67 As 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

British 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 2007 10

Immunolabelling Profiles Tumour CK20 CK7 NSE NFP S100 LCA CD99 TTF1 Merkel-cell carcinoma + - Rare Small-cell carcinoma of lung +/- Lymphoma Peripheral primitive neuro-ectodermal tumour Small-cell melanoma Histology 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 20 CK7: cytokeratin 7 NSE: neurone-specific enolase NFP: neurofilament protein S100: S100 protein LCA: leucocyte common antigen CD99: cluster-of-differentiation antigen 99 TTF1: thyroid transcription factor 1 +: positive stain –: negative stain British Association of Dermatology July 2007 11

Immunohistochemistry 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

Merkel Cell Carcinoma Merkel Cell Carcinoma Rare highly malignant neuroendocrine skin tumour USA - 0.23 / 100 000 Male predominance Average age at presentation – 69y MCC 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 0.23/100 000 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.

Associations Associations UV light most commonly seen on the head and neck region and the lower leg Immunosuppression Post organ transplant (0.13 / 1000 patient yrs) HIV Haematological malignancies Sunlight 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.

Clinical Diagnosis Clinical diagnosis is difficult Red / violaceous nodule May resemble an SCC / BCC or amelanotic melanoma Clinical diagnosis is difficult as MCC often resembles other skin cancers such as an SCC/ BCC or amelanotic melanoma.

Poor Prognostic Markers Good Prognostic Markers Advanced stage at presentation Immunosupression CD+ Lymphocyte invasion of the tumour Prescence of Polyomavirus To 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

MCPyV 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 MCC 17

The 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

Retrospective Analysis of MCC over 10years 14 cases identified SSMDT Barts Health NHS Trust We have analysed our cohort of merkel cell carcinoma patients over the past 10years 19

Results: Demographics 9 female, 5 male Mean age of presentation: 73years (range 54 to 87years) 21% presented with metastatic disease

Results: Treatment INTERVENTION Frequency WLE with 1-3cm margins ALL Adjunctive Radiotherapy Majority (57%) Sentinel Lymph Node Biopsy Few (14%) Adjunctive Chemotherapy Enrolled onto MCC-1 Trial 1 All 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.

Polyomavirus 10/14 tested 80% had positive polyomavirus Positive virus did not correlate with outcome

Results: Survival Rates All patients who presented with metastases died within a year (3/14) Of the remaining 11/14 patients, 1 died within a year Other comorbidities 10/14 patients are still alive to date Date range from 2005- 2012

Radiotherapy induced skin cancers BCC - 3.6% SCC - 0.003% Angiosarcoma Fibrosarcoma Melanoma Merkel cell carcinoma It 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 2007 24

Guidelines Germany France USA UK WLE margin 3cm 2-3cm Not specified Radiotherapy to surgical bed Yes SLND Not obligatory Adjunct Chemotherapy No Yes- enrol in Clinical trials Chemotherapy in Metastases Follow-up 5-years 5years Minimum 3years Compared to USA, Europe has given MCC some attention

Suggestions for UK pathway Histopathological criteria and Staging J Diaz- Perez et al. “Merkel cell carcinoma: a clinicopathological study of 11 cases.” JEADV, 2005 WLE with 2-3cm or Mohs S. 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 Radiotherapy L. 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, 2003 Sentinel lymph node biopsy L. 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 chemotherapy Based on our analysis, our suggestions for a pathway would include 26