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Merkel cell carcinoma of the upper extremity: Case report and an update

Abstract

Background

Merkel cell carcinoma is a rare but aggressive cutaneous primary small cell carcinoma. It is commonly seen in elderly affecting the head, neck, and extremities. Macroscopically may be difficult to distinguish MCC from other small cells neoplasms especially oat cell carcinoma of the lung.

Case presentation

It is presented a case report concerning a 72 years old male with a MMC on the dorsal aspect of the right wrist. The patient underwent a diagnostic excisional biopsy and after the histological confirmation of the diagnosis a second excision was performed to achieve free margins. No postoperative radiation or adjuvant chemotherapy was given and within 9 years follow up no recurrence was reported.

Conclusion

Although most cases present as localized disease treatment should be definitive due to high rates of local or systemic recurrence. Treatment includes excision of the lesion, lymphadenectomy, postoperative radiotherapy and chemotherapy depending on the stage of the disease. Even when locoregional control is achieved close surveillance is required due to high rates of relapse.

Background

Merkel cell carcinoma (MCC) is a rare cutaneous malignancy that was first described by Toker in 1972 [1]. This rare aggressive neoplasm is thought to originate from the neurocrest derivatives round shaped Merkel cells located in the basal layer of the epidermis and containing neurosecretory granules [2–5].

Although aetiology is not fully illuminated, there are several risk factors that contribute to its pathogenesis. Those include UV light, sun-related skin malignancies (Squamous Cell Carcinoma, Basal Cell Carcinoma), psoriasis treatment with methoxsalen and arsenic exposure. Patients on immunosuppressive agents or patients with diagnosis of AIDS, chronic lymphocytic leukemia, congenital dysplasia syndrome and organ recipients carry a higher risk as well [6–11].

Clinically, MCC appears as a painless, firm, non tender, ulcerated skin lesion commonly less than 2 cm in size at the time of presentation [4, 8]. Most cases present as localized disease (70%–80%) followed by regional lymph node involvement (9%–26%) and distant metastasis (1%–4%) [8]. These characteristics often raise the suspicion of a skin malignancy but confirmation of diagnosis is made by excisional biopsy. The differential diagnosis of MCC from other small cells neoplasms can be difficult, even on histological examination [10]. For definitive diagnosis in these cases, electron microscopy is necessary [5].

Case presentation

A 72-year-old male presented in December 1998 with a painless nodular, red and firm 2 cm plaque located on the dorsal aspect of the right wrist (Figure 1) noticed 1–2 months before. No history of previous skin lesions elsewhere was reported.

Figure 1
figure 1

Macroscopic view of the lesion

An excisional biopsy was performed. Microscopical examination of the lesion revealed the invasion of dermis and subcutaneous tissue by a small cell solid tumor with diffuse pattern of infiltration (Figure 2). The excisional margins were positive although dermal lymphatics were intact and no exceeding to the adjacent structures such us, veins, tendons or nerves was discovered. The tumor cells were small, with scanty acidophilic cytoplasm, round vescicular nuclei and multiple nucleoli (Figure 3). Mitotic figures were numerous. In immunohistochemical examination, the tumor cells showed diffuse positivity for Epithelial Membrane Antigen (EMA, Figure 4) and Neuron Specific Antigen (NSE, Figure 5). Lymphatic Common Antigen (LCA), Thyroid Transcription Factor – 1 (TTF-1) and CD99 were negative. Based on to these histological and immunohistochemical features, diagnosis of Merkel Cell Tumor was established.

Figure 2
figure 2

H-E x 100

Figure 3
figure 3

H-E x 400

Figure 4
figure 4

EMA x 400

Figure 5
figure 5

NSE x 400

The patient underwent an imaging evaluation with a CT scan for staging. The CT did not reveal any masses, lymphadenopathy or distant metastases. An additional excision was performed in order to achieve approximately margins 2–3 cm wide and 1–2 cm deep. The patient expressed the willing not to receive postoperative radiation or adjuvant chemotherapy which was justified based on the stage of the disease and the cardiovascular and pulmonary co-morbidities. We scheduled CT imaging follow up every 6 months for the first 3 years and then annually for the upcoming years. No recurrence was reported until April 2007. (Figure 6).

Figure 6
figure 6

9 years post-op

Discussion

MMC is an aggressive neoplasm with an overall unfavourable prognosis [12], therefore it requires definite treatment. It usually occurs in older patients with less than 5% cases seen before the age of 50 years and it has an annual incidence of 0.42 per 100.000. Both sexes are affected with a male predominance, although in some series higher incidence in women is reported [4, 8, 9]. Higher likelihood is reported in whites and it affects sun exposed areas such as head and neck (50%), upper and lower limbs (35%–40%) and less than 10% in the trunk [8]. It has also been reported that MMC rarely can occur on anatomic sites such as vulva, penis, pharynx and oral or nasal mucosa. [7].

Macroscopically, MCC appears as a nodular, sometimes ulcerated skin lesion with a reddish or violaceous hue [12]. Microscopically, the tumor is centered in the dermis or sometimes in the subcutaneous tissue, with the overlying epidermis being usually not involved [13]. The tumor cells are small and round, disposed in a diffuse or, rarely, trabecular architectural pattern [14, 15]. The cytoplasm is scanty, visible as a thin eosinophilic rim. The nuclei are round and vescicular, with a typically fine granular chromatin, multiple nucleoli and numerous mitotic figures. The tumour stroma contains abundant vessels with hypertrophic endothelial cells. [15, 16]

Immunohistochemically, the tumor cells are usually positive for low-molecular-weight cytokeratin (CK AE1), predominantly cytokeratin 20 (CK20) [17], neurofilaments and NSE [18]. Additionally to these markers, some cases of MCC have shown focal reactivity for chromogranin, synaptophysin, vasoactive intestinal peptid, pancreatic polypeptide, calcitonin, substance P, somatostatin, ACTH, other peptide hormones and CD117. [19–24]

Differential diagnosis has to be made between MCC and other small cell neoplasms (small cell neuroendocrine lung carcinoma, malignant lymphoma, Ewing's sarcoma/PNET category). Sometimes, tumors with an appearance identical to pulmonary small cell neuroendocrine carcinoma are found in the skin. [12] The consistent positivity of the MCC for CD20 and the negativity for TTF-1 are important in the differential diagnosis from small cell neuroendocrine lung carcinoma [25–27]. The monotonous nature of the dermal round cell infiltrate and the diffuse pattern of infiltration are responsible for MCC's misdiagnosis as malignant lymphoma [28]. Differential diagnosis in this case is made using the immunohistochemical lymphatic marker LCA. Finally, differential diagnosis of MCC from PNET is base on the negativity of the neoplastic Merkel cells for CD99, positive in Ewing's sarcoma/PNET [29].

The fact that MCC can be seen in association with in situ or invasive SCC, with duct-like structures of eccrine type, and with basal call carcinoma-like areas suggests that it originates from a potential stem cell of ectodermal derivation. [30–33]

Chromosomal abnormalities localized on the short arm of chromosome 1, associated with Merkel cell tumor are common in melanoma and neuroblastoma. Chromosomal abnormalities (loss of heterozygosis in chromosome 3p21) associated with small cell lung neuroendocrine carcinoma is related to Merkel cell carcinoma as well. [8].

Due to its rarity and the lack of cases for a randomized prospective trial no consensus of the appropriate treatment protocol for MCC is made so far [6–8]. Therapeutic options depend on the stage of the disease at the time of presentation whereas the most important prognostic factor is the absence of nodal involvement [34].

Surgery remains the gold standard for localized disease and is considered to be successful when margins 3 cm wide and 2 cm deep are achieved [8, 34]. Some controversy exists showing that when the tumour size is less than 1.5–2 cm, obtaining margins less than 2–3 cm did not lead to higher recurrences rates. [11] Mohs micrographic surgery is an alternative method of wide clearance, especially on sites required excellent cosmetic results [6] and some studies report better rates of locoregional control [8, 10, 35, 36]. A benefit of this method is the better inspection of all major borders of the lesion. [7, 36]

Postoperative radiotherapy in node free patients either discovered clinically, with imaging techniques, with a negative sentinel node biopsy, or after routine nodal dissection still remains controversial. Due to the high rates of local relapse, routine use of 45–60 Gy [8, 10] to the area of the lesion has been found to decrease local recurrence [36]. Other series showed no significant difference compared with surgery only [11] and distant metastasis and overall survival seem to be similar compared to those who did not receive radiation [10, 37]. Postoperative radiotherapy could be beneficial in cases of large primary tumours or unattainable free surgical margins due to cosmetic or functional difficulties [4, 8] but radiating permanent margins did not yield satisfactory results [34].

Many authors advocate that lymph node recurrence often represents the delayed manifestation of pre-existing occult micrometastases rather than inadequate local control of primary tumour [11]. Based on this, sentinel node biopsy should be strongly considered. [11]. Involvement of the regional lymph nodes decreases dramatically the survival rates (88% to 50%) and it appears in 50%–70% of all patients within 2 years by the time of diagnosis [38]. Other poor prognostic factors are tumour size >2 cm, male sex, age >60 years, immunosuppression and location on lower extremities [7–9, 36]. Due to this high rate of spreading, prophylactic nodal clearance of free disease nodes is advocated in order to improve outcome. In some studies sentinel node status was evaluated and a sentinel node biopsy was performed in order to identify occult micrometastases, showing low relapsing rates [6, 11, 38]. However, sentinel node biopsy is not attempted if additional therapy is not tolerated by the patient [11]. Based on an another study it has been recommended prophylactic lymphadenectomy only in patients with lesions present for longer than 6 weeks prior seeking medical advise or when tumour exceeds 1.5 cm in size. [10] Many authors advocate the routine lymph node dissection, including or not sentinel node biopsy [7, 34] but others conclude that routine lymph node dissection improves locoregional control but has no effect on survival [39].

When nodal infiltration is established, definite management includes complete lymphadenectomy and postoperative radiotherapy. As a result of increased rate of recurrence, even when lymph nodes have been removed, strict follow-up is required. [8, 10, 38].

Disseminated disease whether primary or recurrent has a very poor prognosis with an average expected survival of 8 months by the time of diagnosis. Imaging techniques such as CT, MRI, PET scan and ocrteotide schintigraphy have all been used to detect regional or distant metastases. [7, 11] Regional metastases are common, and distant metastases can also occur, particularly in liver, bone, lung, brain and skin. Rare cases of distant metastases of MCC in bone marrow, pleura, testis, small bowel and stomach have been reported [5, 8, 37]. Treatment in case of MCC with distal metastases consists of palliative radiotherapy and chemotherapy. Multiple agents have been used with different response rates [38]. Those include cyclophosphamide, doxorubicin, etoposide, cis-platinum, vincristine, methotrexate, 5-fluorouracile, carboplatinum [8, 34]. Biologic agents such as interferon, tumour necrosis factor (TNF) and imatinib mesylate promise better results on local (TNF) or systemic control of MCC. [7] Radiotherapy can be used as palliative therapy of cutaneous deposits or bone and brain metastases [8]. Patients developing recurrence within the radiotherapy field are not candidates for further high dose radiotherapy (>50 Gy) [9].

Conclusion

The overall 5-year survival rate for patients with Merkel cell carcinoma is 50% to 68% [38]. Considering the high incidence of local recurrence (27%–60%) regional node involvement (45%–91%) or distant metastases (18%–52%) [8], treatment should be definite with close follow up. Despite the aggressiveness of MCC, early diagnosis, optimal resection with clear margins and postoperative radiotherapy achieve loco regional control of the tumor and long term survival, although radiotherapy still remains controversial [40]. In the cases of lymph node involvement, prognosis is less favourable considering that despite nodal dissection and adjuvant radiotherapy the majority of patients will ultimately develop distant metastases.

References

  1. Toker C: Trabecular carcinoma of the skin. Arch Dermatol. 1972, 105: 107-110. 10.1001/archderm.105.1.107.

    Article  CAS  PubMed  Google Scholar 

  2. Youker SR, Billingsley EM: Combined Merkel cell carcinoma and atypical fibroxanthoma. J Cutan Med Surg. 2005, 9: 6-9. 10.1007/s10227-005-0024-4.

    Article  PubMed  Google Scholar 

  3. Schwartz RA, Lambert WC: The Merkel cell carcinoma: a 50-year retrospect. J Surg Oncol. 2005, 89: 1-4. 10.1002/jso.20165.

    Article  Google Scholar 

  4. McAfee WJ, Morris CG, Mendenhall CM, Werning JW, Mendenhall NP, Mendenhall WM: Merkel cell carcinoma: treatment and outcomes. Cancer. 2005, 15; 104: 1761-1764. 10.1002/cncr.21355.

    Article  Google Scholar 

  5. Payne MM, Rader AE, McCarthy DM, Rodgers WH: Merkel cell carcinoma in a malignant pleural effusion: case report. Cytojournal. 2004, 18; 1: 5-10.1186/1742-6413-1-5.

    Article  Google Scholar 

  6. Koljonen V: Merkel cell carcinoma. World J Surg Oncol. 2006, 4: 7-10.1186/1477-7819-4-7.

    Article  PubMed Central  PubMed  Google Scholar 

  7. Dinh V, Feun L, Elgart G, Savaraj N: Merkel cell carcinomas. Hematol Oncol Clin North Am. 2007, 21: 527-544. 10.1016/j.hoc.2007.04.008.

    Article  PubMed  Google Scholar 

  8. Pectasides D, Pectasides M, Economopoulos T: Merkel cell cancer of the skin. Ann Oncol. 2006, 24: 1489-1495. 10.1093/annonc/mdl050.

    Article  Google Scholar 

  9. Veness MJ: Merkel cell carcinoma (primary cutaneous neuroendocrine carcinoma): an overview on management. Australas J Dermatol. 2006, 47: 160-165. 10.1111/j.1440-0960.2006.00263.x.

    Article  PubMed  Google Scholar 

  10. Boyse K, Foley EH, Bradley V, Scarborough D: Merkel cell carcinoma: a case report with treatment summary and updates. Cutis. 2004, 74: 350-356.

    PubMed  Google Scholar 

  11. Bichakjian CK, Lowe L, Lao CD, Sandler HM, Bradford CR, Johnson TM, Wong SL: Merkel cell carcinoma: critical review with guidelines for multidisciplinary management. Cancer. 2007, 110: 1-12. 10.1002/cncr.22765.

    Article  PubMed  Google Scholar 

  12. Rosai J: Rosai and Ackerman's Surgical Pathology. Mosby. 2004, 1: 177-179. 9

    Google Scholar 

  13. Bayrou O, Avril MF, Charpentier P, Caillou B, Guillaume JC, Prade M: Primary neuroendocrine carcinoma of the skin. Clinicopathologic study of 18 cases. J Am Acad Dermatol. 1991, 24: 198-207.

    Article  CAS  PubMed  Google Scholar 

  14. Sidhu GS, Feiner TJ, Mullins JD, Schaefler K, Schultenhover SJ: Merkel cell Neoplasms. Histology, electron microscopy, biology and histogenesis. Am J Dermatopathol. 1980, 2: 101-119. 10.1097/00000372-198000220-00001.

    Article  CAS  PubMed  Google Scholar 

  15. Walsh NM: Primary neuroendocrine (Merkel cell) carcinoma of the skin. Morphologic diversity and implications thereof. Hum Pathol. 2001, 32: 680-689. 10.1053/hupa.2001.25904.

    Article  CAS  PubMed  Google Scholar 

  16. Gaudin PB, Rosai J: Florid vascular proliferation associated with neural and neuroendocrine neoplasms: a diagnostic clue and potential pitfall. Am J Surg Pathol. 1995, 19: 642-652.

    Article  CAS  PubMed  Google Scholar 

  17. Scott MP, Helm KF: Cytokeratin 20: a marker for diagnosing Merkel cell carcinoma. Am J Dermatopathol. 1999, 21: 16-20. 10.1097/00000372-199902000-00003.

    Article  CAS  PubMed  Google Scholar 

  18. Wick MR, Scheithauer BW, Kovacs K: Neuron-specific enolase in neuroendocrine tumours of the thymus bronchus and skin. Am J Clin Pathol. 1983, 79: 703-707.

    CAS  PubMed  Google Scholar 

  19. Brinkschmidt C, Stolze P, Fahrenkamp AG, Hundeiker M, Fisher-Colbrie R, Zelger B, Bocker W, Schmid KW: Immunohistochemical demonstration of cromogranin A, chromogranin B, and secretoneurin in Merkel cell carcinoma of the skin. An immunohistochemical study on 18 cases suggesting two types of Merkel cell carcinoma. Appl Immunohistochem. 1995, 3: 37-44.

    Google Scholar 

  20. Haneke E, Schulze HJ, Mahrle G: Immunohistochemical and immunoelectron microscopic demonstration of chromogranin A in formalin-fixed tissue of Merkel cell carcinoma. J Am Acad Dermatol. 1993, 28: 222-226.

    Article  CAS  PubMed  Google Scholar 

  21. Layfield L, Ulich T, Liao S, Barr R, Cheng L, Lewin KL: Neuroendocrine carcinoma of the skin. An immunohistochemical study of tumour markers and neuroendocrine products. J Cutan Pathol. 1986, 13: 268-273. 10.1111/j.1600-0560.1986.tb01522.x.

    Article  CAS  PubMed  Google Scholar 

  22. Sibley RK, Dahl D: Primary neuroendocrine (Merkel cell?) carcinoma of the skin. II. An immunohistochemical study of 21 cases. Am J Surg Pathol. 1985, 9: 109-116. 10.1097/00000478-198502000-00005.

    Article  CAS  PubMed  Google Scholar 

  23. Silva EG, Ordóòez NG, Lechago J: Immunohistochemical studies in neuroendocrine carcinoma of the skin. Am J Clin Pathol. 1984, 81: 558-562.

    CAS  PubMed  Google Scholar 

  24. Su LD, Fullen DR, Lowe L, Uherova P, Schnitzer B, Valder R: CD117 (KIT receptor) expression in Merkel cell carcinoma. Am J Dermatopathol. 2002, 24: 289-293. 10.1097/00000372-200208000-00001.

    Article  PubMed  Google Scholar 

  25. Byrd-Gloster AL, Khoor A, Glass LF, Messina JL, Whitsett JA, Livingstone SK, Cagle PT: Differential expression of Thyroid Trascription Factor – 1 in small cell lung carcinoma and Merkel cell tumor. Hum Pathol. 2000, 31: 58-62. 10.1016/S0046-8177(00)80199-9.

    Article  CAS  PubMed  Google Scholar 

  26. Chan JK, Suster S, Wenig BM, Tsang WY, Chan JB, Lau AL: Cytokeratin 20 immunohistochemistry distinguishes Merkel cell (primary cutaneous neuroendocrine) carcinomas and salivary gland small cell carcinomas from small cell carcinomas of various sites. Am J Surg Pathol. 1997, 21: 226-234. 10.1097/00000478-199702000-00014.

    Article  CAS  PubMed  Google Scholar 

  27. Cheuk W, Kwan MY, Suster S, Chan JK: Immunostaining for Thyroid Trascription Factor – 1 and cytokeratin 20 aids the distinction of small cell carcinoma from Merkel cell carcinoma, but not pulmonary from extrapulmonary small cell carcinomas. Arch Pathol Lab Med. 2001, 125: 228-231.

    CAS  PubMed  Google Scholar 

  28. Wick MR, Kaye VN, Sibley RK, Tyler R, Frizzera G: Primary neuroendocrine carcinoma and small cell malignant lymphoma of the skin. A discriminant immunohistochemical comparison. J Cutan Pathol. 1986, 13: 347-358. 10.1111/j.1600-0560.1986.tb00469.x.

    Article  CAS  PubMed  Google Scholar 

  29. Rosai J: Rosai and Ackerman's Surgical Pathology. Mosby. 2004, 1: 50-9

    Google Scholar 

  30. Cerroni L, Kerl H: Primary cutaneous neuroendocrine (Merkel cell) carcinoma in association with squamous- and basal-cell carcinoma. Am J Dermatopathol. 1998, 19: 610-613. 10.1097/00000372-199712000-00011.

    Article  Google Scholar 

  31. Gomez LG, DiMaio S, Silva EG, Mackay B: Association between neuroendocrine (Merkel cell) carcinoma and squamous carcinoma of the skin. Am J Surg Pathol. 1983, 7: 171-177.

    Article  CAS  PubMed  Google Scholar 

  32. Gould E, Albores-Saavedra J, Dubner N, Smith W, Payne CM: Eccrine and squamous differentiation in Merkel cell carcinoma. An immunohistochemical study. Am J Surg Pathol. 1988, 12: 768-772.

    Article  CAS  PubMed  Google Scholar 

  33. Heenan PJ, Cole JM, Spagnolo DV: Primary cutaneous neuroendocrine carcinoma (Merkel cell tumour). Immunohistochemical and biochemical analyses. Virchows Arch [A]. 1985, 406: 339-350.

    Article  Google Scholar 

  34. Eng TY, Boersma MG, Fuller CD, Cavanaugh SX, Valenzuela F, Herman TS: Treatment of merkel cell carcinoma. Am J Clin Oncol. 2004, 27 (5): 510-515. 10.1097/01.coc.0000135567.62750.f4.

    Article  PubMed  Google Scholar 

  35. Eng TY, Naguib M, Fuller CD, Jones WE, Herman TS: Treatment of recurrent Merkel cell carcinoma: an analysis of 46 cases. Am J Clin Oncol. 2004, 27 (6): 576-583. 10.1097/01.coc.0000135926.93116.c7.

    Article  PubMed  Google Scholar 

  36. Senchenkov A, Barnes SA, Moran SL: Predictors of survival and recurrence in the surgical treatment of merkel cell carcinoma of the extremities. J Surg Oncol. 2007, 1;95 (3): 229-234. 10.1002/jso.20647.

    Article  Google Scholar 

  37. Yamana N, Sueyama H, Hamada M: Cardiac metastasis from Merkel cell skin carcinoma. Int J Clin Oncol. 2004, 9 (3): 210-212. 10.1007/s10147-004-0396-2.

    Article  PubMed  Google Scholar 

  38. Mehrany K, Otley CC, Weenig RH, Phillips PK, Roenigk RK, Nguyen TH: A meta-analysis of the prognostic significance of sentinel lymph node status in Merkel cell carcinoma. Dermatol Surg. 2002, 28 (2): 113-117. 10.1046/j.1524-4725.2002.02901.x.

    PubMed  Google Scholar 

  39. Dancey AL, Rayatt SS, Soon C, Ilchshyn A, Brown I, Srivastava S: Merkel cell carcinoma: a report of 34 cases and literature review. J Plast Reconstr Aesthet Surg. 2006, 59 (12): 1294-1299. 10.1016/j.bjps.2006.03.044.

    Article  CAS  PubMed  Google Scholar 

  40. Allen PJ, Bowne WB, Jaques DP, Brennan MF, Busam K, Coit DG: Merkel cell carcinoma: prognosis and treatment of patients from a single institution. J Clin Oncol. 2005, 23 (10): 2300-2309. 10.1200/JCO.2005.02.329.

    Article  PubMed  Google Scholar 

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Correspondence to Michail Papamichail.

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Authors' contributions

MP: drafted the article; LN: helped in drafting the article; NN helped in drafting the draft CG carried out the immunoassays; LL: participated in the design of the study and performed the statistical analysis; MK: conceived of the study, and participated in its design and coordination and helped to draft the manuscript. KK: conceived of the study, and participated in its design and coordination and helped to draft the manuscript. MD: Supervised the preparation of the article and helped in preparation of final manuscript.

All authors read and approved the final manuscript.

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Papamichail, M., Nikolaidis, I., Nikolaidis, N. et al. Merkel cell carcinoma of the upper extremity: Case report and an update. World J Surg Onc 6, 32 (2008). https://doi.org/10.1186/1477-7819-6-32

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