YOUNG INVESTIGATOR’S AWARD WINNER A Meta-analysis of the Prognostic Significance of Sentinel Lymph Node Status in Merkel Cell Carcinoma Khosrow Mehrany, MD, Clark C Otley, MD, Roger H Weenig, MD, P Kim Phillips, MD, Randall K Roenigk, MD, and Tri H Nguyen, MD Department of Dermatology, Mayo Clinic, Rochester, Minnesota background Merkel cell carcinoma is an aggressive cutaneous neoplasm with a high propensity to metastasize to lymph nodes objective The objective of this study was to determine the prognostic significance of sentinel lymph node status in patients with Merkel cell carcinoma methods A meta-analysis of case series of patients with Merkel cell carcinoma managed with sentinel lymph node biopsy was performed results Forty of 60 patients (67%) had a biopsy-negative sentinel lymph node; 97% of this group had no recurrence at 7.3 months median follow-up Twenty patients (33%) had a biopsy-positive sentinel lymph node; 33% of this group experi- enced local, regional, or systemic recurrence at 12 months median follow-up Risk of recurrence or metastasis was 19-fold greater in biopsy-positive patients (odds ratio, 18.9; p ϭ 0.005) None of 15 biopsy-positive patients who underwent therapeutic lymph node dissection experienced a regional recurrence; of who did not receive therapeutic lymphadenectomy experienced regional recurrence conclusion Sentinel lymph node positivity is strongly predictive of a high short-term risk of recurrence or metastasis in patients with Merkel cell carcinoma Therapeutic lymph node dissection appears effective in preventing short-term regional nodal recurrence Aggressive adjuvant treatment should be considered for patients with positive sentinel lymph nodes MERKEL CELL CARCINOMA is an extremely aggressive cutaneous neoplasm first described by Toker1 in 1972 The clinical course of Merkel cell carcinoma is notable for a significant tendency for local recurrence and metastasis Regional lymph nodes are the most common site of metastasis in Merkel cell carcinoma, and metastatic disease is highly predictive of poor outcome.2,3 Regional node involvement develops in 50% to 70% of patients within years and is apparent at initial presentation in 12% to 31% of patients.2,4–6 The median time to clinically detectable nodal metastases is approximately 7–8 months.2,4,7 The 5-year survival rate for patients with positive nodes is less than 50%, compared with approximately 88% for patients with negative nodes.3 Disseminated metastases occur in more than 30% of patients and most commonly involve lung, bone, and brain.8 The overall 5-year survival rate for patients with Merkel cell carcinoma is 50% to 68%.6,8 Because of the high propensity of Merkel cell carcinoma to metastasize to the lymph nodes, recent attention has been focused on the use of sentinel lymph node biopsy as a means of staging clinically negative regional nodes This strategy is based on the successful use of sentinel lymph node biopsy in staging melanoma, in which the status of the sentinel lymph node is the most accurate prognostic factor for survival.9 Therapeutic effects of sentinel lymph node biopsy in melanoma and Merkel cell carcinoma remain hypothetical Several case reports and case series of patients with Merkel cell carcinoma managed with sentinel lymph node biopsy have appeared recently Because Merkel cell carcinoma is a rare tumor, a meta-analysis of all reported cases was conducted to determine the prognostic significance of biopsy-positive and biopsynegative sentinel lymph nodes Methods Presented at the 2001 Annual Meeting of the American Society for Dermatologic Surgery, American College of Mohs Micrographic Surgery, and Cutaneous Oncology Meeting, Dallas, TX, October 27, 2001 Address correspondence and reprint requests to: Clark Otley, MD, Department of Dermatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 The English-language literature from January 1976 to August 2001 was searched in August 2001 with the PubMed interface and using the key words sentinel and Merkel All case reports and case series involving Merkel cell carcinoma managed with sentinel lymph node biopsy were examined for case details and outcome Only cases reporting status of survival with a follow-up of at least month were used to calculate rates of recurrence and metastasis Case details recorded included number of patients, success in identifying © 2002 by the American Society for Dermatologic Surgery, Inc • Published by Blackwell Publishing, Inc ISSN: 1076-0512/02/$15.00/0 • Dermatol Surg 2002;28:113–117 114 mehrany et al.: sentinel lymph node status and removing a sentinel lymph node, histologic status of the sentinel lymph nodes, primary and adjuvant treatment modalities, recurrence or metastasis, and duration of follow-up A meta-analysis of all case series was performed comparing the outcome of patients with Merkel cell carcinoma according to sentinel lymph node status Case details were tabulated and analyzed according to sentinel lymph node status and outcome The odds of disease recurrence or metastasis were calculated for biopsy-positive vs biopsy-negative sentinel lymph node status; Fisher exact test was used to determine statistical significance A p-value less than 0.05 was considered statistically significant Results In the literature searched, 60 patients with Merkel cell carcinoma were reported as having undergone successful sentinel lymph node biopsy The biopsy result was negative in 40 of the 60 patients (67%) For 35 of these 40 patients, survival status after a specified follow-up period was reported; 34 patients (97%) had no evidence of disease at a median follow-up of 7.3 months The other five patients, for whom the followup duration was not specified, also were free of disease at the time of reporting One patient died of widespread metastatic disease at 46-month follow-up Treatment of the primary site in patients with a biopsy-negative sentinel lymph node included wide local excision or Mohs micrographic surgery No adjuvant therapy was administered to 35 of the 40 patients (88%) with a biopsy-negative sentinel lymph node Adjuvant therapy was administered to the other five patients; this included complete regional lymph node dissection, postoperative radiation therapy, or chemotherapy Details are presented in Table The biopsy result was positive in 20 of the 60 patients (33%) with successful sentinel lymph node biopsy In the 14 patients for whom follow-up duration was reported, the median follow-up duration was 12 months Survival status was reported for 18 patients; six (33%) experienced local recurrence, regional recurrence, or systemic metastatic Merkel cell carcinoma Follow-up duration was not reported for one of these six patients; in the other five patients, the median follow-up duration was 12 months Statistical analysis excluded one patient with no disease status reported and one patient who died of complications from a therapeutic lymph node dissection Treatment of the primary site in patients with a positive result on sentinel lymph node biopsy included wide local excision or Mohs micrographic surgery Adjuvant therapy was administered to all but one patient and included therapeutic lymph node dissection, postoperative radiation therapy, or chemotherapy Details are presented in Table Dermatol Surg 28:2:February 2002 Over a median follow-up period of 10.5 months, the odds of recurrence or metastasis were 19-fold greater in patients with a positive biopsy result than in patients with a negative result (odds ratio, 18.9; p ϭ 0.005) Fifteen patients with a positive biopsy result underwent therapeutic lymph node dissection; none of the 10 patients for whom follow-up status was reported experienced regional nodal recurrence at a median follow-up of 8.8 months In contrast, three of four patients (75%) with a positive biopsy result who did not undergo therapeutic lymph node dissection experienced regional recurrence An odds ratio comparing regional lymph node recurrence in biopsy-positive patients who had therapeutic lymph node dissection vs biopsy-positive patients who did not would yield infinity and thus was not quantifiable Discussion Merkel cell carcinoma is an uncommon cutaneous neoplasm associated with a high rate of recurrence and metastasis Although initially described as a sweat gland carcinoma, in 1978 it was reclassified as a neuroendocrine tumor on the basis of the appearance of cellular granules identified by electron microscopy.2,20 The lesions typically present as pink, red, or gray nodules and are most commonly located on the head or neck.21 Median age at presentation is 66 years.22 Although Merkel cell carcinoma has been reported in African Americans, it usually occurs in whites, with an equal incidence in men and women.4,7,8 In several ways, melanoma and Merkel cell carcinoma have a similar natural history The clinical behavior of Merkel cell carcinoma is considered comparable to an intermediate-thickness or thick melanoma.2,6,23 Both malignancies have a high propensity for regional and systemic metastasis In Merkel cell carcinoma, lymph node involvement and distant metastases are associated with 5-year survival rates of 50% or less and 35%, respectively, figures that are comparable to those reported for melanoma.2,6,7,23 In addition to having high rates of metastasis, both melanoma and Merkel cell carcinoma respond poorly to systemic therapy.6 Furthermore, in malignant melanoma and in Merkel cell carcinoma an orderly progression of metastasis has been proposed in which metastases occur first at the sentinel lymph node and next at downstream lymph nodes; ultimately, systemic, hematogenous metastases occur.2,24–26 Although the sentinel lymph node status reliably reflects the status of more proximal nodes, the concept that viable metastatic disease remains confined in lymph nodes before hematogenous dissemination remains controversial In patients with high-risk melanoma, the histologic features of the primary tumor, specifically Breslow thick- Dermatol Surg mehrany et al.: sentinel lymph node status 28:2:February 2002 115 Table Summary of Reported Patients With Merkel Cell Carcinoma and Successful Sentinel Lymph Node Biopsy a Study authors (year) Messina et al.10 (1997) Bilchik et al.11 (1998) Ames et al.12 (1998) Hill et al.13 (1999) Sian et al.14 (1999) Zeitouni et al.15 (2000) Kurul et al.16 (2000) Wasserberg et al.17 (2000) Duker et al.18 (2001) Rodrigues et al.19 (2001) Patient no Sentinel lymph node status 1–2 3–12 2–6 1–2 3–16 2 1 3 5 Positive Negative Positive Negative Negative Positive Positive Negative Positive Negative Negative Positive Negative Positive Positive Negative Positive Negative Positive Positive Negative Negative Positive Positive Positive Positive Positive Positive Negative Negative Positive Negative Adjuvant treatment WLE, TLND WLE WLE, TLND WLE WLE, TLND, XRT WLE, TLND WLE, TLND, XRT WLE, TLND WLE, TLND WLE WLE WLE, TLND WLE WLE, TLND, XRT WLE, TLND Mohs, XRT Mohs, XRT WLE WLE, TLND, XRT, CTX WLE, TLND, XRT, CTX WLE, TLND WLE WLE, TLND WLE, TLND WLE, TLND WLE WLE, TLND,d XRT, CTX WLE, CTX WLE, CTX WLE WLE, XRT, CTX WLE Recurrence or metastasis Duration of follow-up (mo.) None None None None None Local Systemic None None None None None None Local NR None Regional lymph node None None None None None None NR None Widespread None Widespread Widespread None None None NR 10.5b NR NR 16 11 6.5b 6.5b NR NR 16 13 14 12 21 38 —c 12 15 35 46 13 18 19 a CTX, chemotherapy; Mohs, Mohs micrographic surgery; NR, not reported; TLND, therapeutic lymph node dissection; WLE, wide local excision; XRT, radiation therapy Median c TLND lethal complication d Patient had complete therapeutic removal of positive epitrochlear node but not axillary dissection, as the axillary basin had been completely excised previously for breast cancer b ness and ulceration, are correlated with prognosis and can be used as a guide to select patients for sentinel lymph node biopsy In contrast to melanoma, Merkel cell carcinoma has no clinical or histologic features of the primary tumor that reliably indicate which patients are at increased risk of nodal or systemic metastases Therefore, sentinel lymph node biopsy has been proposed as a method to permit pathologic microstaging in patients with Merkel cell carcinoma and clinically negative regional nodes There has been no reported analysis to determine the accuracy of sentinel lymph node biopsy in patients with Merkel cell carcinoma or to determine whether the status of the sentinel lymph node carries any prognostic significance On the basis of the meta-analysis presented here, sentinel lymph node biopsy appears to be a reliable technique for clinically staging unaffected regional nodes in patients with Merkel cell carcinoma, given that the sentinel lymph node was identified in all reported cases Only one patient with a negative result on sentinel lymph node biopsy experienced disease recurrence The other 34 biopsy-negative patients with disease and reported survival status had no local recurrence, regional metastasis, or systemic metastasis at a median follow-up of 7.3 months Therefore, a negative result on biopsy of the sentinel lymph node in patients with Merkel cell carcinoma appears associated with a good prognosis, at least in the short term It is impossible to deduce the optimal therapy from this group of patients because they received a variety of adjuvant therapies to both the primary site and regional nodes Two patients underwent complete lymph node dissection despite negative results on sentinel lymph node biopsy, and two others had adjuvant radiation ther- 116 mehrany et al.: sentinel lymph node status apy One biopsy-negative patient received adjuvant chemotherapy It is important to note that 35 of 40 biopsy-negative patients (88%) underwent only wide local excision and had no adjuvant therapy Therefore, most patients with a negative result on sentinel lymph node biopsy experienced no short-term recurrence after only wide local excision In patients with a positive result on sentinel lymph node biopsy, biopsy-guided therapeutic lymph node dissection appears effective at minimizing regional recurrence, with none of 15 patients experiencing nodal relapse at a median follow-up of 8.8 months Further experience and longer follow-up are needed to assess the significance of this finding Potential complications must be considered for all therapeutic interventions, as shown by the fact that one of 19 patients (5%) undergoing therapeutic lymph node dissection died of complications from this procedure In biopsy-positive patients who did not undergo therapeutic lymph node dissection, the risk of regional nodal recurrence is high, as occurred in three of four patients One of the three patients had received radiation therapy to the regional nodal basin that was involved with a biopsy-positive sentinel lymph node rather than complete lymphadenectomy The other two patients refused therapeutic lymph node dissection after wide local excision and sentinel lymph node biopsy Although larger studies would be needed for definitive conclusions to be drawn, it seems prudent to consider strongly therapeutic lymph node dissection in a patient with a positive result on sentinel lymph node biopsy Despite the good regional nodal control rates associated with sentinel lymph node biopsy-guided therapeutic lymph node dissection, the risk of local recurrence or systemic metastasis in patients with a positive biopsy result remains high The prognosis is poor despite the use of multimodality therapy in all but one case Of 18 biopsy-positive patients for whom followup data were reported, six (33%) experienced local recurrence, regional recurrence, or systemic metastasis, with a median reported follow-up time of 12 months This very high and rapid rate of recurrence or metastasis demonstrates that a positive result on sentinel lymph node biopsy in patients with Merkel cell carcinoma is a harbinger of poor outcome The presence of a biopsy-positive sentinel lymph node in a patient with Merkel cell carcinoma warrants consideration of aggressive adjuvant therapy, including complete therapeutic lymph node dissection as well as adjuvant radiation therapy to the primary site and lymphatic basin Whether to target the radiation at a small area around the primary site or a larger area extending in contiguity to the lymphatic basin remains uncertain, as does the role of adjuvant chemotherapy Dermatol Surg 28:2:February 2002 In conclusion, this study of data reported in the medical literature found that one-third of patients with Merkel cell carcinoma who had clinically unaffected lymph nodes harbored occult metastatic disease Sentinel lymph node biopsy appears to provide prognostically significant information for patients with Merkel cell carcinoma and should be strongly considered as a staging technique A positive result on sentinel lymph node biopsy is predictive of statistically significant increased short-term recurrence and thus can be used to identify patients for whom adjuvant therapy should be considered There are no highly effective and welldefined strategies for managing patients with high-risk Merkel cell carcinoma; however, when confronted with a biopsy-positive sentinel lymph node, strong consideration should be given to multimodality adjuvant therapy, including therapeutic lymph node dissection, radiation therapy, or chemotherapy Prospective, randomized, multicenter trials are needed to define the optimal adjuvant treatment modalities in patients with Merkel cell carcinoma who have positive results on biopsy of the sentinel lymph node It would be equally advantageous to reduce exposure to adjuvant therapy for the 67% of patients with Merkel cell carcinoma who have a negative sentinel lymph node biopsy result On the basis of this metaanalysis, Merkel cell carcinoma patients with a negative sentinel lymph node biopsy result have an extremely low short-term risk for recurrence and metastasis The decision to use adjuvant therapy in biopsy-negative patients remains complex, but the findings of this study are reassuring, particularly in light of the fact that only one patient (3%) experienced recurrence in a group in which 88% of patients underwent wide local excision without adjuvant treatment Extended follow-up and further experience are needed for a more accurate assessment of the long-term significance of sentinel lymph node status in patients with Merkel cell carcinoma References Toker C Trabecular carcinoma of the skin Arch Dermatol 1972; 105:107–10 Gruber SB, Wilson L Merkel cell carcinoma In: Miller SJ, Maloney ME, eds Cutaneous Oncology: Pathophysiology, Diagnosis, and Management Malden, MA: Blackwell Science, 1998: 710–21 Pitale M, Sessions RB, Husain S An analysis of prognostic factors in cutaneous neuroendocrine carcinoma Laryngoscope 1992;102: 244–9 Ratner D, Nelson BR, Brown MD, Johnson TM Merkel cell carcinoma J Am Acad Dermatol 1993;29:143–56 Goepfert H, Remmler D, Silva E, Wheeler B Merkel cell carcinoma (endocrine carcinoma of the skin) of the head and neck Arch Otolaryngol 1984;110:707–12 Hitchcock CL, Bland KI, Laney RG III, Franzini D, Harris B, Copeland EM III Neuroendocrine (Merkel cell) carcinoma of the skin Its natural history, diagnosis, and treatment Ann Surg 1988;207: 201–7 Dermatol Surg 28:2:February 2002 O’Connor WJ, Brodland DG Merkel cell carcinoma Dermatol Surg 1996;22:262–7 Harrington AC, Freitag DS Uncommon cutaneous neoplasms Md Med J 1997;46:255–62 Gershenwald JE, Thompson W, Mansfield PF, et al Multi-institutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients J Clin Oncol 1999;17:976–83 10 Messina JL, Reintgen DS, Cruse CW, et al Selective lymphadenectomy in patients with Merkel cell (cutaneous neuroendocrine) carcinoma Ann Surg Oncol 1997;4:389–95 11 Bilchik AJ, Giuliano A, Essner R, et al Universal application of intraoperative lymphatic mapping and sentinel lymphadenectomy in solid neoplasms Cancer J Sci Am 1998;4:351–8 12 Ames SE, Krag DN, Brady MS Radiolocalization of the sentinel lymph node in Merkel cell carcinoma: a clinical analysis of seven cases J Surg Oncol 1998;67:251–4 13 Hill AD, Brady MS, Coit DG Intraoperative lymphatic mapping and sentinel lymph node biopsy for Merkel cell carcinoma Br J Surg 1999;86:518–21 14 Sian KU, Wagner JD, Sood R, Park HM, Havlik R, Coleman JJ Lymphoscintigraphy with sentinel lymph node biopsy in cutaneous Merkel cell carcinoma Ann Plast Surg 1999;42:679–82 15 Zeitouni NC, Cheney RT, Delacure MD Lymphoscintigraphy, sentinel lymph node biopsy, and Mohs micrographic surgery in the treatment of Merkel cell carcinoma Dermatol Surg 2000;26: 12–8 16 Kurul S, Mudun A, Aksakal N, Aygen M Lymphatic mapping for Merkel cell carcinoma Plast Reconstr Surg 2000;105:680–3 mehrany et al.: sentinel lymph node status 117 17 Wasserberg N, Schachter J, Fenig E, Feinmesser M, Gutman H Applicability of the sentinel node technique to Merkel cell carcinoma Dermatol Surg 2000;26:138–41 18 Duker I, Starz H, Bachter D, Balda BR Prognostic and therapeutic implications of sentinel lymphonodectomy and S.-staging in Merkel cell carcinoma Dermatology 2001;202:225–9 19 Rodrigues LK, Leong SP, Kashani-Sabet M, Wong JH Early experience with sentinel lymph node mapping for Merkel cell carcinoma J Am Acad Dermatol 2001;45:303–8 20 Reed RJ, Argenyi Z Tumors of neural tissue In: Elder D, ed Lever’s Histopathology of the Skin, 8th edn Philadelphia: LippincottRaven, 1997: 977–1010 21 Shaw JH, Rumball E Merkel cell tumour: clinical behaviour and treatment Br J Surg 1991;78:138–42 22 Yiengpruksawan A, Coit DG, Thaler HT, Urmacher C, Knapper WK Merkel cell carcinoma: prognosis management Arch Surg 1991; 126:1514–9 23 Balch CM, Soong SJ, Milton GW, et al A comparison of prognostic factors and surgical results in 1,786 patients with localized (stage I) melanoma treated in Alabama, USA, and New South Wales, Australia Ann Surg 1982;196:677–84 24 Smith DE, Bielamowicz S, Kagan AR, Anderson PJ, Peddada AV Cutaneous neuroendocrine (Merkel cell) carcinoma A report of 35 cases Am J Clin Oncol 1995;18:199–203 25 Pfeifer T, Weinberg H, Brady MS Lymphatic mapping for Merkel cell carcinoma J Am Acad Dermatol 1997;37:650–1 26 Kokoska ER, Kokoska MS, Collins BT, Stapleton DR, Wade TP Early aggressive treatment for Merkel cell carcinoma improves outcome Am J Surg 1997;174:688–93 Commentary This is certainly an important article and we should be grateful to the authors for formulating a coherent management scheme for patients with Merkel cell carcinoma But a note of caution about the level of reliance one should place on these recommendations This publication illustrates not only what a powerful tool the meta-analysis can be, but also the strengths and weaknesses of case series While the authors lend confidence to their assertions with numerous statistics, it must be borne in mind that these numbers are derived not from a compilation of clini- cal studies, as is usually the case in meta-analyses, but from aggregating the results of case reports and case series As such, while indicating strong trends, this is essentially reformatted anecdotal data As the authors correctly point out, prospective, randomized trials are needed to prove the validity of their findings Stuart J Salasche, MD Co-Editor Tucson, Arizona ... well as adjuvant radiation therapy to the primary site and lymphatic basin Whether to target the radiation at a small area around the primary site or a larger area extending in contiguity to the. .. rates of metastasis, both melanoma and Merkel cell carcinoma respond poorly to systemic therapy.6 Furthermore, in malignant melanoma and in Merkel cell carcinoma an orderly progression of metastasis... quantifiable Discussion Merkel cell carcinoma is an uncommon cutaneous neoplasm associated with a high rate of recurrence and metastasis Although initially described as a sweat gland carcinoma,