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July 2007, Volume 57, Issue 7

Review Articles

Clinical features and management of Merkel Cell Carcinoma

Ahmed Nadeem Abbasi  ( Dept. of Radiation Oncology, Faculty of Health Sciences, Aga Khan University, Karachi. )

Abstract

 Merkel cell carcinoma (MCC) is an aggressive dermal tumour of neuroendocrine origin. MCC is a raretumour and all information pertaining to its behaviour,therapy and prognosis is based on retrospective reports. The two potentially curative treatment modalities are surgeryand radiotherapy. It is a rare, highly malignant primary skintumour, originally called "trabecular carcinoma" of the skin.MCC poses a challenge to the clinician because of its rarityand poor prognosis. The optimal therapy is customised and tailored for each individual patient with the appropriate useof operative resection and radiation therapy. This reviewcovers reports from several authors regarding the rationale of using postoperative radio therapy to the primary tumour and regional lymphatics. Although MCC is classified as atype of neuroendocrine carcinoma, it is less likely to be controlled by systemic chemotherapy. Management of primary lesion with clinically localised disease is wide excision with margin of at least 2 cm whenever possible.MCC is a radio sensitive tumour, adjuvant radiotherapy has been advocated in order to control local as well as regional disease Radiation induced toxicity should be considered and discussed with the patient. Adjuvant radiation to the nodalbed after complete lymphadenectomy in patients with metastatic disease is generally not recommended.

Introduction

 Merkel cell carcinoma (MCC) is an aggressive dermal tumour of neuroendocrine origin. It is a rare, highly malignant primary skin tumour, originally called "trabecularcarcinoma" of the skin. MCC poses a challenge to the clinician because of its rarity and poor prognosis.1It was first described by Toker in 1972.2He had observed that the tumour originates from the neuroendocrine cells of the basalepidermis of the skin. Merkel described the cell of the originas epidermal, non-dendritic, non-kerotinocytic cell that he referred to as a tactile cell.3Electron microscopy andimmunocyto chemical studies are often required for accurate diagnosis.Clinical Features:Although this carcinoma isusually found in elderly individuals, it can occur in young patients as well. Median age at presentation is approximately 67 years. The vast majority of patientsaffected by MCC are white. It has strong male predominance. Mostly MCC, occur on areas of the bodyexposed to sunlight.4Common sites of the tumour are headand neck (47-50%), extremities (40%) and trunk (8%).The aetiology of MCC is not known. Sun exposureis considered as one of the risk factors as ultra violet exposure induced C to Tmutation was found in some MMCcell lines.5 The occurrence of MCC has also been reportedin HIVinfected patients together with other malignancies.Recent reports have shown an increased incidence in immunosuppressed transplant patients, in rheumatoidarthritis and in B cell malignancies. The natural history of MCC shares many commonfeatures with melanoma like melanoma MCC is also acutaneous malignancy of same embryonic origin. These two malignancies also show similar clinical features and behaviour e.g an early spread to nodal sites, high local recurrence rate and early metastasis.6Yom et al7 suggested that the differential diagnosis of Merkel cell carcinoma should be included in patients presenting with mucosal lesions of head and neck,especially if the tumor is sub-mucosal. MCC can also involve the tongue. Mucosal MCC is aggressive, and there is a high risk for local recurrence and regional and distantmetastasis.7Diagnostic evaluation:Histologically the tumourconsists of sheets of small round blue cells, an appearance that is similar to melanoma and metastatic small cellcarcinoma. Immunohisto chemical stains may be used todetermine whether the primary tumour is indeed a primary MCC of the skin or cutaneous metastases from a visceralsmall cell carcinoma. MCC has immunohisto chemical features of both neuroendocrine and epithelial cells. It is usually positive for cytokeratin, CK20 (unlike melanomaand metastatic squamous cell carcinoma) and is usually negative for S100 and thyroid transcription factor 1(TTF-1),a newly described nuclear protein that appears to be specific for small cell carcinoma of pulmonary origin.8Are port published in Anticancer Research in June2006 has evaluated the role of cell cycle-regulatoryproteins(p53/p21/p27) in Merkel Cell Carcinoma'spathogenesis and prognosis. Twenty-four primary MCCspecimens with corresponding clinical data were analysed by immunohistochemistry for p21, p27 and p53 antibodies.

The staining was evaluated semi-quantitatively and the results were analysed. p53 was negative in 80% and p21 in71% of the samples. Positive staining for p27 was evident in92% of the samples. However, the expression of these antibodies did not correlate with the outcome of the patient. The proportion of p53- and p21-negative samples seems to indicate that correction processes after DNA damage are not activated during MCC pathogenesis, asupposition that is supported by the aggressive nature of this tumour. It was concluded that the above mentioned three cell cycle regulators cannot serve as prognostic markers for survival.9Under the microscope most of the MCC specimens show a clear Grenz zone separating the epidermis from thetumour.The immunohistochemistry of MCC exhibits positive staining to neurofilament,cytokeratin,neuronspecific enolase and epithelial membrane antigen.10Staging:Patient with MCC can be staged accordingto the American Joint Committee on Cancer (AJCC) stagingsystem for skin cancer. Alternatively, a relatively simplesystem was proposed by Yiengpruksawan et al.11which can be used for stage grouping :StageI : patients with localized disease; those with tumour of less than 2 cm are considered stage 1A, whereas those with tumour of 2 cm or more are considered as stage1B.Stage II, with regional lymph node metastasis Stage III; with distant metastasis.Yiengpruksawan and colleagues have reported that at the time of first consultation 70% to 80% of patients with MCC have stage I, 10% to30%have stage II and 15 to 4%have stage III disease.11Treatment:MCC is a rare tumour and all information pertaining to its behaviour, therapy and prognosis is based on retrospective reports. The two potentially curative treatment modalities are surgery and radiotherapy. The optimal therapy is individualised in any given patient with the appropriate use of operative resectionand radiation therapy. Several authors reported that postoperative radiotherapy to the primary tumour and regional lymphatic significantly improves local control anddisease free survival,12The mainstay of treatment is widelocal excision of tumour with reconstructive surgery.13Management of primary lesion with clinically localised disease is wide excision with a margin of at least2 cm whenever possible. The excision should include the skin and subcutaneous tissue. Resection of the underlying fascia is also performed when the tumour is close to it.Excision margins of less than 3cm are associated with high incidence of local failures.11Due to high incidence of nodalmetastasis, prophylactic lymphadenectomy is also suggested in some reports, alternatively sentinel nodebiopsy can be considered as an appropriate procedure inclinically node negative patient. Approximately 25% of patients are found to have metastatic disease in the sentinel node biopsy. Early removal of microscopic disease detected by this diagnostic approach may offer the patient a greater opportunity for cure.14It is often difficult or impossible to excise MCC of the head and neck or distal extremity with awide margin. Adjuvant radiotherapy can be considered in these cases. If the primary cancer is to be treated with radiotherapy alone, the regional lymphatics may be electively irradiated. Patient who present with fixed,unresectable nodal metastasis are treated with preoperative radiotherapy followed by salvage surgery of the primary site with a possible nodal dissection.MCC is a radiosensitive tumour, adjuvant radiotherapy has been advocated in order to control local aswell as regional disease.12Radiation induced toxicity should be considered and discussed with the patient.Adjuvant radiation to the nodal bed after completely mphadenectomy in patients with metastatic disease isgenerally not recommented.  Regional recurrence is uncommon after a complete lymphadenectomy is performed in patients who had positive sentinel nodebiopsy.14On the other hand in patients with clinically proven regional disease adjuvant radiation treatment improves regional control.There is no established dose response curve for theMCC. It is quite likely that its response to radiation is similar to that observed in squamous cell carcinoma.Therefore, the dose fractionation schedule for patients with negative surgical margin is of the order of 60 Gray in 30fractions over 6 weeks or equivalent.15Systemic chemotherapy is recommended in patients with regional or systemic metastasis as a palliative measure.It gives 50% to 60% palliative response rate which is found to be more evident in patients with regional disease and less for visceral metastases. The use of various chemotherapeutic agents, both single and in combination,are reported in the literature. Agents likecyclophosphamide, doxorubicine, vincristine, etoposide,cisplatin, carboplatin, octreotide and dacarbazine have shown some palliative benefits.16The option of systemic chemotherapy should be offered to patients who present with nodal or metastatic disease.17Ametanalysis concluded that surgery plus adjuvantir radiation was associated with significantly lower rates oflocal and regional recurrence of MCC than surgery alone.Prospective investigation is needed to clarify the presence of a survival benefit from combination therapy.1Swann and Yoon have done a review of MCC which is published in the Seminars of Oncology in February 2007.They have drawn some pertinent conclusions on theprognosis and management of MCC. The prognosis ofMCC is variable. Natural history of localized disease is indolent and these tumours are well controlled with localexcision alone. On the other side of spectrum , majority oftumours behave aggressively and have a tendency for locoregional recurrence and distant metastases. In locally advanced and metastatic disease the option of systemic chemotherapy with regimens similar to those which are used in the treatment of  small cell carcinoma of the lung,may be considered in adjuvant setting following surgery.18MCC is characterized by a high incidence of localand regional recurrence. Long term survival with low incidence of recurrence is reported in patients with early stage of tumour. Most recurrences occur in the first 24months and frequent follow up during this period is recommended. Patients who develop a local recurrence after primary excision (regardless of site) should undergo re-excision, if possible, and adjuvant radiotherapy should be considered if not previously given. The long survival can be achieved after the treatment of loco regional recurrence.Voog and colleagues have reported that patients with loco-regional relapse and distant metastasis had 2 year survivalrate of 35% and 17% respectively, versus 86% and 100%respectively for those who do not have these two forms of recurrences. The median overall survival after starting chemotherapy was 9 months for patients with distant metastasis and 24 months for patients with loco regional disease.16The role of immunotherapy is not fully defined.Immunotherapeutic agents such as alpha- interferon orintralesional application of tumour necrosis factor-alpha were shown to have some effects in some patients.19,20 Sandel HD et al21compared the clinical and histopathological criteria including tumour size and depthof invasion with clinical outcomes in MCC patients.Disease-free survival rates were found to be 52%, 39%, and9% at 1, 2, and 5 years, respectively. The average disease-free interval was 18.4 months (range, 1-80 months). Overallrecurrence was found in 60.7% of patients with local recurrence occurring in 18.1%, regional recurrence 40.9%,and distant recurrence 47.8%. However, there was a trendtoward increased local and regional recurrence rates when comparing size and depth and in specimens with positivetumor margins.21 These outcomes are consistent with those reported inrecent literature and further characterize the unpredictable nature of this disease. An aggressive approach should be taken, including wide local excision with negative tumor margins and lymph node dissection.Ortin Parez et al22have reported eight cases of MCCwho under went sentinel node biopsy. All  sentinel nodeswere successfully harvested. Three patients (37.5%)showed metastatic involvement and they were subjected toregional lymphadenectomy.This report published in theEuropean Journal of Surgical Oncology  in February 2007suggested that sentinel node biopsy appears to be a reliable staging technique which can be considered in the surgicalmanagement of MCC.22Aretrospective review was published in the Journal of Surgical Oncology in March 2007. The review of 38consecutive patients with surgically treated extremity MCC was presented. Surgical techniques of Wide local excisionand  Mohs' surgery was compared. No difference in local recurrence was found between the two procedures. A reduced local recurrence rate was observed in patients who were treated by adjuvant radiotherapy with a hazard ratio of0.29 (95% Confidence Interval [0.10, 0.85]).It has noimpact on overall survival.This retrospective review further supports the rationale of using adjuvant radiation therapy inimproving locoregional tumour control in MCC patients.23

References

 

1. Lewis KG, Weinstock MA, Weaver AL, Otley CC.Adjuvant local irradiation for Merkel cell carcinoma. Arch Dermatology. 2006 142:693700.

2.   Toker C. Trabecular carcinoma of skin. Arch Dermatol 1972. 105; 107-10.

3.   Goessfng W, McKee PH, Mayor RJ. Merkel cell carcinoma. J Clin Oncol 2002; 20: 588-98.

4.   Akhtar S, Oza KK, Wright J: Merkel cell carcinoma ; report of 10 cases and review of the literature. J Am Acad Dermotol 2000;43: 755-67.

5.   Van Gele M,Kaghad M,Leonard JH,Van Roy N,Naeyaert JM,Geerts ML,et al.Mutation analysis of P73 and TP53 in Merkel cell carcinoma. Br J Cancer 2000;82: 823-6.

6.   Price P, Sikora K. Treatment of Cancer,4th Edition. Arnold Publishers London 2002; pp 1213-9.

7.   Yom SS, Rosenthal DI, El-Naggar AK, Kies MS, Hessel AC. Merkel cell carcinoma of the tongue and head and neck oral mucosal sites. Oral Surg Oral Mod Oral Pathol Oral Radiol Ended 2006;101:761-8.

8.   Leech SN, Kolar AJ, Barrett PD,Sinclair SA,Leonard N. Merkel cell carcinoma can be distinguished from metastatic small cell carcinoma using antibodies to cytokeratin 20 and TTF-1. J Clin Pathol 2001;54;727-9.

9.   Koljonen V, Tukiainen E, Haglund C, Bohling T. Cell cycle control by p21, p27 and p53 in Merkel cell carcinoma.Anticancer Res 2006;26:2209-12.

10.   Tope WD, Sangueza OP. Merkel cell carcinoma. Histopathology, immunocyto chemistry and cytogenetic analysis. J Dermatol Surg Oncol 1994;20:653-4.

11.   Yiengpruksawan A, Coit DG Thaler HT, Urmacher C, Knapper WK. Merkel cell carcinoma. Prognosis and management. Arch Surg 1991; 126: 1514-9.

12.   Meeuwissen JA, Boume RG, Kearsley JH. The importance of postoperative radiation therapy in the treatment of Merkel cell carcinoma. Int J Radiat Oncol Biol Phys 1995;31: 325-31.

13. Clifford KS, Parez CA,Brady LW.Radiation Oncology,management decisions.2nd Edition 2001,Lippincot Williams & Wilkins Publishers, Philadelphia, Chapter 13 pp 116.

14.   Mehrany K, Otley CC, Weenig RH, Phillips PK, Roenigk RK, Nguyen TH. A metanalysis of the prognostic significance of SLN status in Merkel cell carcinoma. Dermatol Surg 2002;28;113-7.

15.   Nathu RM, Mendenhall WM, Persons JT. Merkel cell carcinoma of the skin. Radiat Oncol Investig 1998;6:233-9.

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