Purpose of This PDQ Summary
General Information
Cellular Classification
Stage Information
Stage I Merkel Cell Carcinoma

Current Clinical Trials

Stage II Merkel Cell Carcinoma

Current Clinical Trials

Stage III Merkel Cell Carcinoma

Current Clinical Trials

Recurrent Merkel Cell Carcinoma

Current Clinical Trials

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Changes to This Summary (12/13/2007)
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Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of Merkel cell carcinoma. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.

Information about the following is included in this summary:

• Epidemiology and clinical presentation.
• Cellular classification.
• Staging.
• Treatment options by cancer stage.

This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version, written in less technical language, and in Spanish.

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General Information

Merkel cell carcinoma (MCC), or neuroendocrine carcinoma of the skin, is an uncommon and often aggressive malignancy that has a poor prognosis. More than 400 new cases of MCC occur in the United States each year, and the mortality rate is approximately 25%.[1] MCC is predominantly a tumor of the elderly, and most reported cases have occurred in white subjects.[2-6] It occurs most frequently in the head and neck region and the extremities and has a predilection for the periocular region.[2,3,5,6] People treated with methoxsalen and ultraviolet A for psoriasis and people who are immunocompromised have an increased incidence of developing MCC.[7]

The Merkel cell is located in or near the basal layer of the epidermis and is closely associated with terminal axons.[2,3,8] While MCC may be difficult to diagnose, it usually presents as a painless, indurated, solitary dermal nodule with a slightly erythematous to deeply violaceous color. MCC frequently involves regional lymph nodes (10%–45% at initial presentation),[2-5,9] and between 50% and 75% of patients will develop regional lymph node metastases at some time during the course of their disease.[2-4] Distant metastases eventually occur in as many as 50% of patients, with lymph nodes, the liver, bone, brain, lung, and skin the most common sites of distant involvement.[2,3,5,6,10] MCC may progress rapidly and similarly to aggressive melanoma. After primary tumor excision, local recurrence develops in 25% to 44% of patients; this has been attributed to inadequate surgical margins.[2,4,5]

References

1. Nghiem P, McKee PH, Haynes HA: Merkel cell (cutaneous neuroendocrine) carcinoma. In: Sober AJ, Haluska FG, eds.: Skin Cancer. Hamilton, Ontario: BC Decker Inc., 2001., pp 127-141. 
   
   
2. Haag ML, Glass LF, Fenske NA: Merkel cell carcinoma. Diagnosis and treatment. Dermatol Surg 21 (8): 669-83, 1995.  [PUBMED Abstract]
   
   
3. Ratner D, Nelson BR, Brown MD, et al.: Merkel cell carcinoma. J Am Acad Dermatol 29 (2 Pt 1): 143-56, 1993.  [PUBMED Abstract]
   
   
4. Yiengpruksawan A, Coit DG, Thaler HT, et al.: Merkel cell carcinoma. Prognosis and management. Arch Surg 126 (12): 1514-9, 1991.  [PUBMED Abstract]
   
   
5. Goepfert H, Remmler D, Silva E, et al.: Merkel cell carcinoma (endocrine carcinoma of the skin) of the head and neck. Arch Otolaryngol 110 (11): 707-12, 1984.  [PUBMED Abstract]
   
   
6. Gollard R, Weber R, Kosty MP, et al.: Merkel cell carcinoma: review of 22 cases with surgical, pathologic, and therapeutic considerations. Cancer 88 (8): 1842-51, 2000.  [PUBMED Abstract]
   
   
7. Lunder EJ, Stern RS: Merkel-cell carcinomas in patients treated with methoxsalen and ultraviolet A radiation. N Engl J Med 339 (17): 1247-8, 1998.  [PUBMED Abstract]
   
   
8. Gould VE, Moll R, Moll I, et al.: Neuroendocrine (Merkel) cells of the skin: hyperplasias, dysplasias, and neoplasms. Lab Invest 52 (4): 334-53, 1985.  [PUBMED Abstract]
   
   
9. Tai PT, Yu E, Winquist E, et al.: Chemotherapy in neuroendocrine/Merkel cell carcinoma of the skin: case series and review of 204 cases. J Clin Oncol 18 (12): 2493-9, 2000.  [PUBMED Abstract]
   
   
10. Marks ME, Kim RY, Salter MM: Radiotherapy as an adjunct in the management of Merkel cell carcinoma. Cancer 65 (1): 60-4, 1990.  [PUBMED Abstract]
    
    

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Cellular Classification

Merkel cell carcinoma (MCC) is usually found within the dermis but may extend into the subcutaneous tissue. The combination of vesicular nuclei with small nucleoli, abundant mitoses, and apoptosis is characteristic of this tumor when evaluated within the context of certain architectural features. Histologically, MCC has been classified into three distinct subtypes:[1-3]

Trabecular

• Cells are arranged in distinctly organoid clusters and trabeculae with occasional ribbons.
• Individual cells are round to polygonal in shape and are compactly arranged.
• Cell cytoplasm is comparatively abundant and often well defined.
• Mitoses are few to moderate in number.
• The tumor is usually found adjacent to adnexal structures, particularly hair follicles.
• Trabecular is the least frequent histologic pattern identified.

Intermediate

• The tumor exhibits a solid and diffuse growth pattern.
• Cells are less compactly arranged, and the cytoplasm is less abundant than in the trabecular type.
• Mitoses and focal areas of necrosis are frequently seen.
• Intermediate tumors arise adjacent to adnexa but may also invade the epidermis.
• Intermediate tumors may behave in a clinically more aggressive manner than trabecular tumors.
• Intermediate is the most frequent histologic subtype identified.

Small cell

• The tumor closely mimics small cell tumors of other sites.
• The tumors arise in the dermis and appear as solid sheets and clusters of cells.
• Areas of necrosis and crushing artifact are frequently seen.
• The clinical behavior of small cell tumors appears to be as aggressive as that of intermediate tumors.

References

1. Haag ML, Glass LF, Fenske NA: Merkel cell carcinoma. Diagnosis and treatment. Dermatol Surg 21 (8): 669-83, 1995.  [PUBMED Abstract]
   
   
2. Ratner D, Nelson BR, Brown MD, et al.: Merkel cell carcinoma. J Am Acad Dermatol 29 (2 Pt 1): 143-56, 1993.  [PUBMED Abstract]
   
   
3. Gould VE, Moll R, Moll I, et al.: Neuroendocrine (Merkel) cells of the skin: hyperplasias, dysplasias, and neoplasms. Lab Invest 52 (4): 334-53, 1985.  [PUBMED Abstract]
   
   

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Stage Information

No widely accepted or standardized staging classification based upon prognosis is available. A commonly used staging system is based upon clinical presentation:[1]

• Stage IA: Primary tumor smaller than 2 cm with no evidence of spread to lymph nodes or distant sites.
• Stage IB: Primary tumor 2 cm or larger with no evidence of spread to lymph nodes or distant sites.
• Stage II: Regional node involvement but no evidence of distant metastases.
• Stage III: Presence of systemic metastases beyond the regional lymph nodes.

References

1. Aasi SZ, Leffell DJ: Cancer of the skin. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 1717-44. 
   
   

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Stage I Merkel Cell Carcinoma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Wide local excision has been recommended whenever possible for patients with stage I Merkel cell carcinoma (MCC).[1-3][Level of evidence: 3iiiDiii] Frozen section control has also been recommended, especially when the tumor is in an anatomical site that is not amenable to wide margins. Some authors have advocated the use of Mohs micrographic surgery as a tissue-sparing technique. The reported relapse rate is similar to or better than that of wide excision, but comparatively few cases have been treated in this manner and definitive clinical studies have yet to be conducted.[2,4,5]

The role of elective lymph node dissection (ELND) in the absence of clinically positive nodes is unclear. ELND has been recommended for larger tumors, tumors with more than 10 mitoses per high-power field, lymphatic or vascular invasion, and the small-cell histologic subtypes.[1-3] Sentinel lymph node (SLN) biopsy has been suggested as an alternative to complete ELND for the proper staging of MCC. SLN biopsy has lower morbidity than complete nodal dissection. Furthermore, for MCC sites with indeterminate lymphatic drainage, such as those on the back, SLN biopsy techniques can be used to identify the pertinent lymph node bed(s). Several reports have found the use of SLN biopsy techniques in patients with MCC to be reliable and reproducible.[6-9] A meta-analysis found that SLN positivity is strongly predictive of a high short-term risk of recurrence and that subsequent therapeutic lymph node dissection was effective in preventing short-term regional nodal recurrence.[10]

Because of the aggressive nature of MCC and the high incidence of locoregional recurrence after surgery alone, many authors advocate adjuvant radiation therapy to the primary site and to the regional lymph node basin.[1,2,4,11] Convincing data from prospective trials are not available; based on retrospective reviews, however, radiation therapy has been used in patients with larger tumors, tumors with lymphatic invasion, tumors approaching the surgical margins of resection, and locally unresectable tumors. Improved locoregional control has been achieved with resection followed by radiation therapy as compared to surgery alone in some retrospective nonrandomized reports.[12] Studies suggest that the appropriate total dose is about 50 Gy to the surgical bed and the draining regional lymphatics, delivered in 2 Gy fractions.[1,2,11-13] For patients with unresected tumors or tumors with microscopic evidence of spread beyond resected margins, higher doses of 56 Gy to 65 Gy have been recommended.[1][Level of evidence: 3iiiDiii]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage I neuroendocrine carcinoma of the skin. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

1. Haag ML, Glass LF, Fenske NA: Merkel cell carcinoma. Diagnosis and treatment. Dermatol Surg 21 (8): 669-83, 1995.  [PUBMED Abstract]
   
   
2. Ratner D, Nelson BR, Brown MD, et al.: Merkel cell carcinoma. J Am Acad Dermatol 29 (2 Pt 1): 143-56, 1993.  [PUBMED Abstract]
   
   
3. Yiengpruksawan A, Coit DG, Thaler HT, et al.: Merkel cell carcinoma. Prognosis and management. Arch Surg 126 (12): 1514-9, 1991.  [PUBMED Abstract]
   
   
4. Goepfert H, Remmler D, Silva E, et al.: Merkel cell carcinoma (endocrine carcinoma of the skin) of the head and neck. Arch Otolaryngol 110 (11): 707-12, 1984.  [PUBMED Abstract]
   
   
5. Nghiem P, McKee PH, Haynes HA: Merkel cell (cutaneous neuroendocrine) carcinoma. In: Sober AJ, Haluska FG, eds.: Skin Cancer. Hamilton, Ontario: BC Decker Inc., 2001., pp 127-141. 
   
   
6. Messina JL, Reintgen DS, Cruse CW, et al.: Selective lymphadenectomy in patients with Merkel cell (cutaneous neuroendocrine) carcinoma. Ann Surg Oncol 4 (5): 389-95, 1997 Jul-Aug.  [PUBMED Abstract]
   
   
7. Hill AD, Brady MS, Coit DG: Intraoperative lymphatic mapping and sentinel lymph node biopsy for Merkel cell carcinoma. Br J Surg 86 (4): 518-21, 1999.  [PUBMED Abstract]
   
   
8. Wasserberg N, Schachter J, Fenig E, et al.: Applicability of the sentinel node technique to Merkel cell carcinoma. Dermatol Surg 26 (2): 138-41, 2000.  [PUBMED Abstract]
   
   
9. Rodrigues LK, Leong SP, Kashani-Sabet M, et al.: Early experience with sentinel lymph node mapping for Merkel cell carcinoma. J Am Acad Dermatol 45 (2): 303-8, 2001.  [PUBMED Abstract]
   
   
10. Mehrany K, Otley CC, Weenig RH, et al.: A meta-analysis of the prognostic significance of sentinel lymph node status in Merkel cell carcinoma. Dermatol Surg 28 (2): 113-7; discussion 117, 2002.  [PUBMED Abstract]
    
    
11. Gollard R, Weber R, Kosty MP, et al.: Merkel cell carcinoma: review of 22 cases with surgical, pathologic, and therapeutic considerations. Cancer 88 (8): 1842-51, 2000.  [PUBMED Abstract]
    
    
12. Goessling W, McKee PH, Mayer RJ: Merkel cell carcinoma. J Clin Oncol 20 (2): 588-98, 2002.  [PUBMED Abstract]
    
    
13. Marks ME, Kim RY, Salter MM: Radiotherapy as an adjunct in the management of Merkel cell carcinoma. Cancer 65 (1): 60-4, 1990.  [PUBMED Abstract]
    
    

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Stage II Merkel Cell Carcinoma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Wide local excision of the primary tumor, whenever possible, and regional lymph node dissection have been recommended for patients with stage II Merkel cell carcinoma (MCC).[1,2][Level of evidence: 3iiiDiii] Because of the aggressive nature of MCC and the high incidence of locoregional recurrence after surgery alone, many authors advocate adjuvant radiation therapy to the primary site and to the regional lymph node basin.[1-4] Convincing data from prospective trials are not available; based on retrospective reviews, however, radiation therapy has been used in patients with larger tumors, tumors with lymphatic invasion, tumors approaching the surgical margins of resection, and locally unresectable tumors. Improved locoregional control has been achieved with resection followed by radiation therapy as compared with surgery alone in some retrospective nonrandomized reports.[5] Studies suggest that the appropriate total dose is about 50 Gy to the surgical bed and the draining regional lymphatics, delivered in 2 Gy fractions.[1,2,4-6] For patients with unresected tumors or tumors with microscopic evidence of spread beyond resected margins, higher doses of 56 Gy to 65 Gy have been recommended.[1][Level of evidence: 3iiiDiii]

The role of adjuvant chemotherapy remains unproven but is advocated by some authors.[1,6,7] Studies have shown response rates in the range of 60% in the setting of locally advanced or metastatic disease using chemotherapy regimens similar to those used for patients with small cell lung cancer.[5] (See the PDQ summary on Small Cell Lung Cancer Treatment for chemotherapeutic options.) The benefit of chemotherapy as adjuvant therapy is yet to be determined.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage II neuroendocrine carcinoma of the skin. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

1. Haag ML, Glass LF, Fenske NA: Merkel cell carcinoma. Diagnosis and treatment. Dermatol Surg 21 (8): 669-83, 1995.  [PUBMED Abstract]
   
   
2. Yiengpruksawan A, Coit DG, Thaler HT, et al.: Merkel cell carcinoma. Prognosis and management. Arch Surg 126 (12): 1514-9, 1991.  [PUBMED Abstract]
   
   
3. Goepfert H, Remmler D, Silva E, et al.: Merkel cell carcinoma (endocrine carcinoma of the skin) of the head and neck. Arch Otolaryngol 110 (11): 707-12, 1984.  [PUBMED Abstract]
   
   
4. Marks ME, Kim RY, Salter MM: Radiotherapy as an adjunct in the management of Merkel cell carcinoma. Cancer 65 (1): 60-4, 1990.  [PUBMED Abstract]
   
   
5. Goessling W, McKee PH, Mayer RJ: Merkel cell carcinoma. J Clin Oncol 20 (2): 588-98, 2002.  [PUBMED Abstract]
   
   
6. Tai PT, Yu E, Winquist E, et al.: Chemotherapy in neuroendocrine/Merkel cell carcinoma of the skin: case series and review of 204 cases. J Clin Oncol 18 (12): 2493-9, 2000.  [PUBMED Abstract]
   
   
7. Feun LG, Savaraj N, Legha SS, et al.: Chemotherapy for metastatic Merkel cell carcinoma. Review of the M.D. Anderson Hospital's experience. Cancer 62 (4): 683-5, 1988.  [PUBMED Abstract]
   
   

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Stage III Merkel Cell Carcinoma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Chemotherapy is the treatment most often used for patients with stage III Merkel cell carcinoma (MCC).[1-5][Level of evidence: 3iiiDiv] Because of morphologic and immunohistochemical similarities, the regimens employed are similar to those used for patients with small cell lung cancer. (See the PDQ summary on Small Cell Lung Cancer Treatment for chemotherapeutic options.) Cyclophosphamide, doxorubicin, and vincristine and etoposide plus cisplatin are the most commonly used regimens. MCC often responds to chemotherapy initially, but the response is usually short-lived and the impact of chemotherapy on survival is uncertain.[1-5]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage III neuroendocrine carcinoma of the skin. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

1. Haag ML, Glass LF, Fenske NA: Merkel cell carcinoma. Diagnosis and treatment. Dermatol Surg 21 (8): 669-83, 1995.  [PUBMED Abstract]
   
   
2. Ratner D, Nelson BR, Brown MD, et al.: Merkel cell carcinoma. J Am Acad Dermatol 29 (2 Pt 1): 143-56, 1993.  [PUBMED Abstract]
   
   
3. Tai PT, Yu E, Winquist E, et al.: Chemotherapy in neuroendocrine/Merkel cell carcinoma of the skin: case series and review of 204 cases. J Clin Oncol 18 (12): 2493-9, 2000.  [PUBMED Abstract]
   
   
4. Feun LG, Savaraj N, Legha SS, et al.: Chemotherapy for metastatic Merkel cell carcinoma. Review of the M.D. Anderson Hospital's experience. Cancer 62 (4): 683-5, 1988.  [PUBMED Abstract]
   
   
5. Voog E, Biron P, Martin JP, et al.: Chemotherapy for patients with locally advanced or metastatic Merkel cell carcinoma. Cancer 85 (12): 2589-95, 1999.  [PUBMED Abstract]
   
   

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Recurrent Merkel Cell Carcinoma

Treatment options for patients with local recurrence include regional lymph node dissection and adjuvant radiation therapy if the regional draining nodes have not been previously treated.[1,2] An alternative approach for patients who have not had a complete regional lymph node dissection would be a sentinel lymph node biopsy and complete nodal dissection if positive nodes are identified.[3]

When possible, adjuvant radiation therapy of the site of recurrence as well as of the regional lymph node beds is recommended after surgery.[4,5] Chemotherapy may be an option for patients with unresectable recurrent tumors or for patients who have received their maximum tolerated radiation dose.[1]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent neuroendocrine carcinoma of the skin. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

1. Haag ML, Glass LF, Fenske NA: Merkel cell carcinoma. Diagnosis and treatment. Dermatol Surg 21 (8): 669-83, 1995.  [PUBMED Abstract]
   
   
2. Ratner D, Nelson BR, Brown MD, et al.: Merkel cell carcinoma. J Am Acad Dermatol 29 (2 Pt 1): 143-56, 1993.  [PUBMED Abstract]
   
   
3. Allen PJ, Zhang ZF, Coit DG: Surgical management of Merkel cell carcinoma. Ann Surg 229 (1): 97-105, 1999.  [PUBMED Abstract]
   
   
4. Nghiem P, McKee PH, Haynes HA: Merkel cell (cutaneous neuroendocrine) carcinoma. In: Sober AJ, Haluska FG, eds.: Skin Cancer. Hamilton, Ontario: BC Decker Inc., 2001., pp 127-141. 
   
   
5. Herbst A, Haynes HA, Nghiem P: The standard of care for Merkel cell carcinoma should include adjuvant radiation and lymph node surgery. J Am Acad Dermatol 46 (4): 640-2, 2002.  [PUBMED Abstract]
   
   

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Changes to This Summary (12/13/2007)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Added Purpose of This PDQ Summary as a new section.

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