NCCN Categories of Evidence and Consensus
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Overview
Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous tumor that combines the local recurrence rates of infiltrative nonmelanoma skin cancer along with the regional and distant metastatic rates of thick melanoma.1 Several large reviews document the development of local recurrence in 25% to 30% of all cases of MCC, 52% to 59% of all cases of regional disease, and 34% to 36% of all cases of distant metastatic disease.2-4 MCC has a high mortality rate that exceeds that of melanoma. The overall 5-year survival rates range from 30% to 64%.5-7
A history of extensive sun exposure is a major risk factor for MCC. Older whites (≥65 years of age) are at higher risk for MCC, which tends to occur on sun-exposed skin.8 MCC is disproportionally more common in individuals with immunosuppression, such as those with organ transplants, lymphoproliferative malignancies (eg, chronic lymphocytic leukemia), or HIV infections.1
In 2008, Feng et al9 identified a novel polyomavirus in MCC tumor tissues. This Merkel cell polyomavirus (MCV) is detected in 43% to 100% of patient samples.10 The role of MCV in the pathogenesis of MCC is under active investigation.11
The NCCN Non-Melanoma Skin Cancer Panel has developed guidelines outlining treatment of MCC to supplement the basal and squamous cell skin cancer guidelines (see NCCN Guidelines for Basal and Squamous Cell Skin Cancers, available online at NCCN. org).12 MCC is a rare tumor; therefore, prospective, statistically significant data are lacking to verify the validity of prognostic features or treatment outcomes. The panel relied on trends that are documented in smaller, individual studies, in meta-analyses, and in their own collective experiences.
Diagnosis and Workup
The diagnosis of MCC is rarely clinically suspected, because the primary tumor lacks distinguishing characteristic features. Initial workup of a suspicious lesion starts with a complete examination of the skin and lymph nodes followed by biopsy. The histologic diagnosis may also be challenging because MCC is similar to a variety of other widely recognized small, round, blue cell tumors. The most difficult differentiation is often between primary MCC and metastatic small cell lung cancer.
NCCN Clinical Practice Guidelines in Oncology: Merkel Cell Carcinoma, Version 1.2014
Version 1.2014, 12-20-13 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 3; 10.6004/jnccn.2014.0041
NCCN Clinical Practice Guidelines in Oncology: Merkel Cell Carcinoma, Version 1.2014
Version 1.2014, 12-20-13 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 3; 10.6004/jnccn.2014.0041
NCCN Clinical Practice Guidelines in Oncology: Merkel Cell Carcinoma, Version 1.2014
Version 1.2014, 12-20-13 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 3; 10.6004/jnccn.2014.0041
NCCN Clinical Practice Guidelines in Oncology: Merkel Cell Carcinoma, Version 1.2014
Version 1.2014, 12-20-13 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 3; 10.6004/jnccn.2014.0041
Pathology Report
The Principles of Pathology in the algorithm (see MCC-A, page 416) outlines elements that should be includes in a pathology report, preferably in synoptic format. The College of American Pathologists (CAP) provides a complete synoptic report protocol for cutaneous MCC.13 The goals are to (1) accurately diagnose the condition and distinguish it from cutaneous simulants and metastatic tumors; (2) provide complete pathologic tumor characteristics for staging according to recommended AJCC and CAP guidelines; and (3) standardize pathologic data collection to further understand the critical biologic features that influence MCC behavior and prognosis. At minimum, the report should include tumor size, peripheral and deep margin status, lymphovascular invasion, and extracutaneous extension to the bone, muscle fascia, or cartilage. The prognostic value of histopathologic features of the primary tumor remains uncertain. However, an emerging body of literature suggests that tumor thickness, mitotic rate, tumor growth pattern, tumor-infiltrating lymphocytes (particularly intratumoral CD8+ lymphocytes), and the presence of a second malignancy, such as concurrent squamous cell carcinoma, may provide relevant prognostic information regarding survival or sentinel lymph node positivity in MCC.14-18 Therefore, including these features in pathology report is recommended whenever possible.
Initial diagnosis of MCC in the primary lesion by hematoxylin-eosin (H&E) staining should be further confirmed with immunohistochemical (IHC) staining. An appropriate immunopanel should preferably include cytokeratin 20 (CK20) and thyroid transcription factor-1 (TTF-1), which often provide the greatest sensitivity and specificity for excluding small cell lung cancer.19-21 CK20 is a very sensitive marker for MCC, with positive results in 89% to 100% of cases. TTF-1 is expressed in 83% to 100% of small cell lung cancer cases, but it is consistently absent in MCC. Other IHC markers, including chromogranin A, synaptophysin, neurofilament protein, neuron-specific enolase, and CD56, may be used in addition to CK20 and TTF-1 to exclude other diagnostic considerations.22
Imaging
Additional workup of a patient with MCC may include imaging studies.23 In asymptomatic patients with primary MCC, sentinel lymph node biopsy (SLNB) is considered the most sensitive staging test for the detection of nodal metastases.15,16,18 Imaging may be useful for identifying distant metastases, as clinically indicated, because of the metastatic potential of this tumor. PET/CT scanning is gaining importance in diagnostic imaging of MCC and may be preferred in some instances. CT or MRI may be used if PET/CT is not available.
In a review of 102 patients, PET/CT changed the stage and primary treatment in 22% of cases.24 PET also altered the radiation technique or dose recommended in another 15% of cases. Similar results were reported in another review of 97 cases, 16% of which were upstaged after baseline PET/CT scans.25 In addition, PET/CT frequently identified bone metastases that were not detected with CT. According to a meta-analysis of 6 studies, the sensitivity and specificity of PET/CT are 90% and 98%, respectively.26
Imaging (CT, MRI, or PET/CT scan) may also be indicated to evaluate for the possibility of a skin metastasis from a noncutaneous carcinoma (eg, small cell lung cancer), especially when CK20 is negative.
Staging
In the biomedical literature, the most consistently reported adverse prognostic feature is tumor stage followed by tumor size.2,4,27-33 The staging of MCC in these guidelines parallels that of the AJCC guidelines and divides presentation into local, regional, and disseminated disease.34 The AJCC staging system is based on an analysis of 5823 cases from the National Cancer Data Base with a median follow-up of 64 months.7 An MCC Web site from Seattle Cancer Care Alliance also has a useful staging table (available at www.merkelcell.org).
Treatment
After workup, treatment primarily depends on accurate histopathologic interpretation and microstaging of the primary lesion. A multidisciplinary panel is recommended to ensure high-quality coordinated care for patients diagnosed with this rare and challenging disease.35
Surgery is the primary treatment modality for MCC. However, individual clinicians and NCCN Member Institutions show some variability regarding the management of patients with MCC because of the absence of prospective clinical trials. Therefore, these guidelines are suitably broad to reflect all of the approaches offered by participating NCCN Member Institutions.
Surgery
Surgery is the mainstay of primary treatment for clinically localized (N0, M0) MCC.36 Because of the historic high risk of local recurrence in MCC, the panel’s tenets for surgical excision emphasize complete extirpation of tumor at initial resection to achieve clear surgical margins when clinically feasible. However, this should not be pursued to the degree that it significantly delays any planned adjuvant radiation therapy (RT). An analysis of 3 pooled prospective trials in patients receiving adjuvant RT for high-risk MCC found that preradiation margin status had no impact on time to locoregional failure.37
Wide local excision with 1- to 2-cm margins to the investing fascial layer remains the standard surgical technique.36 Mohs surgery, modified Mohs surgery, or complete circumferential peripheral and deep-margin assessment (CCPDMA) may be considered if tissue sparing is critical, such as for facial MCC.38,39 Mohs micrographic surgery is superior to conventional surgical excision in high-risk basal and squamous cell carcinomas. In MCC, it may be used to ensure complete tumor removal and clear margins, while secondarily sparing surrounding healthy tissue.40 If Mohs is used, the panel emphasized that a specimen from the central portion of the tumor should be sent for permanent section microstaging.
In all cases, treatment should be coordinated so that SLNB is performed before definitive surgery, because surgery may alter lymphatic drainage. SLNB is usually performed intraoperatively during wide local excision.
Reconstruction: Reconstruction is usually performed immediately after surgery. Because histologic margins may be obscured by extensive undermining or tissue movement, verification of clear margins should precede any major reconstruction. Efforts should also be made to minimize delay to adjuvant radiation, such as through primary closure. If postoperative radiation is planned, significant tissue movement should be avoided because it may obscure the target area.
SLNB
SLNB is very important in the staging and treatment of MCC, although its reported effect on overall survival has been mixed in literature.41 One review of 161 patients with MCC found that SLNB allowed identification of micrometastases in one-third of patients with early-stage disease.42 Recurrence occurred in 56% of SLNB-positive and 39% of SLNB-negative patients.
Essentially all participating NCCN Member Institutions use the SLNB technique routinely for MCC, as they do for melanoma. The panel believes that identifying patients with positive microscopic nodal disease and then performing full lymph node dissections or RT maximizes the care of regional disease in this patient population. However, it should be noted that SLNB may be less reliable in the head and neck region than in the trunk and extremities. The complex and variable drainage pattern of the area can lead to false-negative results.43 Performing a wide local excision before SLNB may potentially interfere with the accuracy of subsequent SLNB.
IHC analysis has been shown to be effective in detecting more lymph node metastases in patients with MCC and should be included in the SLNB evaluation in addition to H&E sections.6,44 CK20 immunostaining in the pathologic assessment of sentinel lymph nodes removed from patients with MCC is a valuable diagnostic adjunct, because it allows accurate identification of micrometastases.45,46 Other elements to be detailed are the tumor burden of each node, location, and presence or absence of extracapsular extension.
Radiation Therapy
Although reports in the literature on the benefits of RT have been mixed, recent studies provide increasing support for the use of postoperative radiation in MCC to minimize locoregional recurrence.47 According to a meta-analysis comparing surgery alone with surgery plus adjuvant radiation, the use of local adjuvant radiation after complete excision lowered the risk of local and regional recurrences.48 Jouary et al49 conducted the only randomized trial to date in MCC. Patients with stage I disease treated with wide excision and RT to the tumor bed were randomized to undergo adjuvant regional RT or observation. The trial was closed prematurely because of a decline in recruitment attributed to the advent of sentinel node dissection. Analysis of 83 cases showed no overall survival improvement with adjuvant radiation, but a significant decrease in risk of regional recurrence was found compared with the observation group (0% vs 16.7%). A large retrospective analysis of 1187 cases from the SEER database showed longer overall survival in patients who received adjuvant RT after surgery compared with those who did not (median survival, 63 vs 45 months; P=.0002).50 Improvement was most pronounced for patients with tumors larger than 2 cm (median survival, 50 vs 21 months; P=.0003).
The panel included radiation as a treatment option for all stages of MCC. However, because of the lack of prospective trials with clearly defined patient cohorts and treatment protocols (eg, surgical margins before RT, location of radiation field), the recommendations are suitably broad to reflect all the approaches taken by participating NCCN Member Institutions. Adjuvant radiation is commonly performed within a few weeks after surgery, because delay may lead to negative outcomes. Radiation may also be useful in the palliative setting. Specifications on radiation dosing, and for different MCC sites (head and neck vs extremity and torso), are detailed in Principles of Radiation Therapy in the algorithm (see MCC-B, page 417).
Chemotherapy
Literature on chemotherapeutic options for MCC is sparse.51 Most NCCN Member Institutions only use chemotherapy with or without surgery and/or RT for stage IV distant metastatic disease (M1). A few institutions suggest considering adjuvant chemotherapy for select cases of clinical (macroscopic) regional (N1b or N2) disease. The most common regimen used for regional disease is cisplatin or carboplatin with or without etoposide. Available data from retrospective studies do not suggest a prolonged survival benefit for adjuvant chemotherapy.52,53 Data are insufficient to assess whether chemotherapeutic regimens improve either relapse-free or overall survival in patients with MCC with distant metastatic disease.5,54-58
If chemotherapy is used, the panel recommends cisplatin or carboplatin with or without etoposide.5,59 Topotecan has also been used in some instances (eg, older patients). Cyclophosphamide in combination with doxorubicin and vincristine (CAV) was a commonly administered regimen, but it is associated with significant toxicity.56 Clinicians should exercise independent medical judgment in choosing the chemotherapeutic regimen. Although the panel recognized that MCC is a rare disease that precludes robust randomized studies, enrollment in clinical trials is encouraged whenever available and appropriate.
NCCN Recommendations
Clinical Node-Negative Disease: Excisional biopsy of the entire lesion with narrow clear surgical margins is preferred, whenever possible, to obtain the most accurate diagnostic and microstaging information. SLNB is offered to patients with clinical N0 disease for accurate nodal staging. As in melanoma, performing the SLNB before definitive local excision to maximize accuracy in MCC is best. In clinical practice, SLNB is typically performed concurrent with definitive wide local excision.
After surgery, patients may consider observation of the primary site or undergo postoperative RT. Observation should be limited to patients with small primary lesions that have been widely excised and who present with no adverse risk factors, such as lymphovascular invasion or immunosuppression.60 Radiation is acceptable as primary therapy in select cases when complete excision is not feasible or refused by the patient.
A positive sentinel lymph node is preferably followed up with a multidisciplinary tumor board consultation. Clinical trial participation is preferred when available. Most patients undergo completion lymph node dissection and/or RT.
Clinical Node-Positive Disease: A clinical N+ diagnosis should be confirmed using fine-needle aspiration or core biopsy with an appropriate immunopanel. If initial biopsy results are positive, imaging studies (CT, MRI, or PET/CT) are recommended if not already performed at baseline. If distant metastasis is detected, management should follow the M1 pathway. If no distant metastasis is present, the panel recommends multidisciplinary tumor board consultation and lymph node dissection with or without RT. Adjuvant chemotherapy may be considered in select cases, although no survival benefit has been reported.
An open biopsy may be considered to confirm a negative initial biopsy result. If results remain negative, patients should be managed as clinical N0.
Metastatic Disease: The panel recommends multidisciplinary tumor board consultation for patients with metastatic disease to consider any or a combination of chemotherapy, radiation, and surgery. Full imaging workups are recommended for all patients with clinically proven regional or metastatic disease. In general, the management of patients with distant metastases must be individually tailored. Chemotherapy and RT will likely be the primary treatment options to consider. Surgery may be beneficial for select patients with oligometastasis. All patients should receive best supportive care. The panel encourages participation in clinical trials when available.
Follow-Up and Recurrence
The panel’s recommendations for close clinical follow-up of patients with MCC immediately after diagnosis and treatment parallel recommendations in the literature. The physical examination should include a complete skin and regional lymph node examination every 3 to 6 months for the first 2 years, then every 6 to 12 months thereafter. The recommended frequency of follow-up visits is purposely broad to allow for an individualized schedule based on the risk of recurrence, stage of disease, and other factors, such as patient anxiety and clinician preference. The panel’s recommendations also reflect the fact that the median time to recurrence in patients with MCC is approximately 8 months, with 90% of the recurrences occurring within 24 months.5,6,30 Self-examination of the skin is useful for patients with MCC, because these patients are likely at greater risk for other nonmelanoma skin cancers. Imaging studies should be performed as clinically indicated. For patients at high risk, routine imaging should be considered. PET/CT scans may be useful to identify and quantify metastases, especially bone involvement.25
Patients who present with local or regional recurrence should receive individualized treatment. For disseminated recurrence, the treatment pathway for metastatic disease should be followed.
Individual Disclosures for the NCCN Merkel Cell Carcinoma Panel
References
- 2.↑
Akhtar S, Oza KK, Wright J. Merkel cell carcinoma: report of 10 cases and review of the literature. J Am Acad Dermatol 2000;43:755–767.
- 3.
Gillenwater AM, Hessel AC, Morrison WH et al.. Merkel cell carcinoma of the head and neck: effect of surgical excision and radiation on recurrence and survival. Arch Otolaryngol Head Neck Surg 2001;127:149–154.
- 4.↑
Medina-Franco H, Urist MM, Fiveash J et al.. Multimodality treatment of Merkel cell carcinoma: case series and literature review of 1024 cases. Ann Surg Oncol 2001;8:204–208.
- 5.↑
Allen PJ, Bowne WB, Jaques DP et al.. Merkel cell carcinoma: prognosis and treatment of patients from a single institution. J Clin Oncol 2005;23:2300–2309.
- 6.↑
Bichakjian CK, Lowe L, Lao CD et al.. Merkel cell carcinoma: critical review with guidelines for multidisciplinary management. Cancer 2007;110:1–12.
- 7.↑
Lemos BD, Storer BE, Iyer JG et al.. Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the first consensus staging system. J Am Acad Dermatol 2010;63:751–761.
- 8.↑
Agelli M, Clegg LX. Epidemiology of primary Merkel cell carcinoma in the United States. J Am Acad Dermatol 2003;49:832–841.
- 9.↑
Feng H, Shuda M, Chang Y, Moore PS. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 2008;319:1096–1100.
- 10.↑
Rollison DE, Giuliano AR, Becker JC. New virus associated with merkel cell carcinoma development. J Natl Compr Canc Netw 2010;8:874–880.
- 11.↑
Amber K, McLeod MP, Nouri K. The Merkel cell polyomavirus and its involvement in Merkel cell carcinoma. Dermatol Surg 2013;39:232–238.
- 12.↑
Miller SJ, Alam M, Andersen J et al.. NCCN Clinical Practice Guidelines in Oncology for Merkel Cell Carcinoma. J Natl Compr Canc Netw 2006;4:704–712.
- 13.↑
Rao P, Balzer BL, Lemos BD et al.. Protocol for the examination of specimens from patients with merkel cell carcinoma of the skin. Arch Pathol Lab Med 2010;134:341–344.
- 14.↑
Andea AA, Coit DG, Amin B, Busam KJ. Merkel cell carcinoma: histologic features and prognosis. Cancer 2008;113:2549–2558.
- 15.↑
Fields RC, Busam KJ, Chou JF et al.. Recurrence and survival in patients undergoing sentinel lymph node biopsy for Merkel cell carcinoma: analysis of 153 patients from a single institution. Ann Surg Oncol 2011;18:2529–2537.
- 16.↑
Schwartz JL, Griffith KA, Lowe L et al.. Features predicting sentinel lymph node positivity in Merkel cell carcinoma. J Clin Oncol 2011;29:1036–1041.
- 17.
Paulson KG, Iyer JG, Tegeder AR et al.. Transcriptome-wide studies of merkel cell carcinoma and validation of intratumoral CD8+ lymphocyte invasion as an independent predictor of survival. J Clin Oncol 2011;29:1539–1546.
- 18.↑
Fields RC, Busam KJ, Chou JF et al.. Five hundred patients with merkel cell carcinoma evaluated at a single institution. Ann Surg 2011;254:465–475.
- 19.↑
Cheuk W, Kwan MY, Suster S, Chan JK. Immunostaining for thyroid transcription 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.
- 20.
Hanly AJ, Elgart GW, Jorda M et al.. Analysis of thyroid transcription factor-1 and cytokeratin 20 separates merkel cell carcinoma from small cell carcinoma of lung. J Cutan Pathol 2000;27:118–120.
- 21.↑
Scott MP, Helm KF. Cytokeratin 20: a marker for diagnosing Merkel cell carcinoma. Am J Dermatopathol 1999;21:16–20.
- 22.↑
Gruber SB, Wilson LD. Merkel cell carcinoma. In: Miller SJ, Maloney ME, eds.: Cutaneous Oncology: Pathophysiology, Diagnosis, and Management. Malden, MA: Blackwell Science; 1998:710–721.
- 23.↑
Enzenhofer E, Ubl P, Czerny C, Erovic BM. Imaging in patients with merkel cell carcinoma. J Skin Cancer 2013;2013:973123.
- 24.↑
Siva S, Byrne K, Seel M et al.. 18F-FDG PET provides high-impact and powerful prognostic stratification in the staging of Merkel cell carcinoma: a 15-year institutional experience. J Nucl Med 2013;54:1223–1229.
- 25.↑
Hawryluk EB, O’Regan KN, Sheehy N et al.. Positron emission tomography/computed tomography imaging in Merkel cell carcinoma: a study of 270 scans in 97 patients at the Dana-Farber/Brigham and Women’s Cancer Center. J Am Acad Dermatol 2013;68:592–599.
- 26.↑
Treglia G, Kakhki VR, Giovanella L, Sadeghi R. Diagnostic performance of fluorine-18-fluorodeoxyglucose positron emission tomography in patients with Merkel cell carcinoma: a systematic review and meta-analysis. Am J Clin Dermatol 2013;14:437–447.
- 27.↑
Allen PJ, Zhang ZF, Coit DG. Surgical management of Merkel cell carcinoma. Ann Surg 1999;229:97–105.
- 28.
Haag ML, Glass LF, Fenske NA. Merkel cell carcinoma: diagnosis and treatment. Dermatol Surg 1995;21:669–683.
- 29.
Kokoska ER, Kokoska MS, Collins BT et al.. Early aggressive treatment for Merkel cell carcinoma improves outcome. Am J Surg 1997;174:688–693.
- 30.↑
Ott MJ, Tanabe KK, Gadd MA et al.. Multimodality management of Merkel cell carcinoma. Arch Surg 1999;134:388–392; discussion 392-393.
- 31.
Pitale M, Sessions RB, Husain S. An analysis of prognostic factors in cutaneous neuroendocrine carcinoma. Laryngoscope 1992;102:244–249.
- 32.
Ratner D, Nelson BR, Brown MD, Johnson TM. Merkel cell carcinoma. J Am Acad Dermatol 1993;29:143–156.
- 33.↑
Skelton HG, Smith KJ, Hitchcock CL et al.. Merkel cell carcinoma: analysis of clinical, histologic, and immunohistologic features of 132 cases with relation to survival. J Am Acad Dermatol 1997;37:734–739.
- 34.↑
Edge SB, Byrd DR, Compton CC, eds. AJCC Cancer Staging Manual, 7th edition. New York, NY: Springer-Verlag, LLC; 2009.
- 35.↑
Schneider S, Thurnher D, Erovic BM. Merkel cell carcinoma: interdisciplinary management of a rare disease. J Skin Cancer 2013;2013:189342.
- 36.↑
Tai P. A practical update of surgical management of merkel cell carcinoma of the skin. ISRN Surg 2013;2013:850797.
- 37.↑
Finnigan R, Hruby G, Wratten C et al.. The impact of preradiation residual disease volume on time to locoregional failure in cutaneous Merkel cell carcinoma: a TROG substudy. Int J Radiat Oncol Biol Phys 2013;86:91–95.
- 38.↑
Boyer JD, Zitelli JA, Brodland DG, D’Angelo G. Local control of primary Merkel cell carcinoma: review of 45 cases treated with Mohs micrographic surgery with and without adjuvant radiation. J Am Acad Dermatol 2002;47:885–892.
- 39.↑
O’Connor WJ, Roenigk RK, Brodland DG. Merkel cell carcinoma: comparison of Mohs micrographic surgery and wide excision in eighty-six patients. Dermatol Surg 1997;23:929–933.
- 40.↑
Pennington BE, Leffell DJ. Mohs micrographic surgery: established uses and emerging trends. Oncology (Williston Park) 2005;19:1165–1171; discussion 1171-1172, 1175.
- 41.↑
Gupta SG, Wang LC, Penas PF et al.. Sentinel lymph node biopsy for evaluation and treatment of patients with Merkel cell carcinoma: the Dana-Farber experience and meta-analysis of the literature. Arch Dermatol 2006;142:685–690.
- 42.↑
Santamaria-Barria JA, Boland GM, Yeap BY et al.. Merkel cell carcinoma: 30-year experience from a single institution. Ann Surg Oncol 2013;20:1365–1373.
- 43.↑
Willis AI, Ridge JA. Discordant lymphatic drainage patterns revealed by serial lymphoscintigraphy in cutaneous head and neck malignancies. Head Neck 2007;29:979–985.
- 44.↑
Allen PJ, Busam K, Hill AD et al.. Immunohistochemical analysis of sentinel lymph nodes from patients with Merkel cell carcinoma. Cancer 2001;92:1650–1655.
- 45.↑
Su LD, Lowe L, Bradford CR et al.. Immunostaining for cytokeratin 20 improves detection of micrometastatic Merkel cell carcinoma in sentinel lymph nodes. J Am Acad Dermatol 2002;46:661–666.
- 46.↑
Schmalbach CE, Lowe L, Teknos TN et al.. Reliability of sentinel lymph node biopsy for regional staging of head and neck Merkel cell carcinoma. Arch Otolaryngol Head Neck Surg 2005;131:610–614.
- 47.↑
Rush Z, Fields RC, Lee N, Brownell I. Radiation therapy in the management of Merkel cell carcinoma: current perspectives. Expert Rev Dermatol 2011;6:395–404.
- 48.↑
Lewis KG, Weinstock MA, Weaver AL, Otley CC. Adjuvant local irradiation for Merkel cell carcinoma. Arch Dermatol 2006;142:693–700.
- 49.↑
Jouary T, Leyral C, Dreno B et al.. Adjuvant prophylactic regional radiotherapy versus observation in stage I Merkel cell carcinoma: a multicentric prospective randomized study. Ann Oncol 2012;23:1074–1080.
- 50.↑
Mojica P, Smith D, Ellenhorn JD. Adjuvant radiation therapy is associated with improved survival in Merkel cell carcinoma of the skin. J Clin Oncol 2007;25:1043–1047.
- 51.↑
Desch L, Kunstfeld R. Merkel cell carcinoma: chemotherapy and emerging new therapeutic options. J Skin Cancer 2013;2013:327150.
- 52.↑
Garneski KM, Nghiem P. Merkel cell carcinoma adjuvant therapy: current data support radiation but not chemotherapy. J Am Acad Dermatol 2007;57:166–169.
- 54.↑
Poulsen MG, Rischin D, Porter I et al.. Does chemotherapy improve survival in high-risk stage I and II Merkel cell carcinoma of the skin? Int J Radiat Oncol Biol Phys 2006;64:114–119.
- 55.
Poulsen M, Rischin D, Walpole E et al.. High-risk Merkel cell carcinoma of the skin treated with synchronous carboplatin/etoposide and radiation: a Trans-Tasman Radiation Oncology Group Study-TROG 96:07. J Clin Oncol 2003;21:4371–4376.
- 56.↑
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 2000;18:2493–2499.
- 57.
Voog E, Biron P, Martin JP, Blay JY. Chemotherapy for patients with locally advanced or metastatic Merkel cell carcinoma. Cancer 1999;85:2589–2595.
- 58.↑
McAfee WJ, Morris CG, Mendenhall CM et al.. Merkel cell carcinoma: treatment and outcomes. Cancer 2005;104:1761–1764.
- 59.↑
Pectasides D, Pectasides M, Psyrri A et al.. Cisplatin-based chemotherapy for merkel cell carcinoma of the skin. Cancer Invest 2006;24:780–785.
- 60.↑
Paulson KG, Iyer JG, Blom A et al.. Systemic immune suppression predicts diminished Merkel cell carcinoma-specific survival independent of stage. J Invest Dermatol 2013;133:642–646.
