1. 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

7. 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.

8. 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

9. 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

10. 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

11. 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

12. 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

13. Merkel Cell Carcinoma Merkel Cell Carcinoma
Rare highly malignant neuroendocrine
skin tumour
USA /
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/ 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.

14. 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.

15. 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.

16. 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

17. 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

18. 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

19. 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

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

21. 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.

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

23. 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

24. Radiotherapy induced skin cancers
BCC - 3.6%
SCC %
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

25. 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

26. 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