Regional lymph nodes are the most common site of metastasis in Merkel cell carci-noma, and metastatic disease is highly predictive of poor outcome.2,3 Regional node involvement develops
Trang 1© 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
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
cutane-ous 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
Mer-kel 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
bi-opsy-positive sentinel lymph node; 33% of this group
experi-enced local, regional, or systemic recurrence at 12 months me-dian follow-up Risk of recurrence or metastasis was 19-fold greater in biopsy-positive patients (odds ratio, 18.9; p
0.005) None of 15 biopsy-positive patients who underwent therapeutic lymph node dissection experienced a regional recur-rence; 3 of 4 who did not receive therapeutic lymphadenectomy experienced regional recurrence.
conclusion. Sentinel lymph node positivity is strongly predic-tive of a high short-term risk of recurrence or metastasis in pa-tients with Merkel cell carcinoma Therapeutic lymph node dis-section appears effective in preventing short-term regional nodal recurrence Aggressive adjuvant treatment should be con-sidered for patients with positive sentinel lymph nodes.
MERKEL CELL CARCINOMA is an extremely
ag-gressive cutaneous neoplasm first described by Toker1
in 1972 The clinical course of Merkel cell carcinoma
is notable for a significant tendency for local
recur-rence and metastasis Regional lymph nodes are the
most common site of metastasis in Merkel cell
carci-noma, and metastatic disease is highly predictive of
poor outcome.2,3 Regional node involvement develops
in 50% to 70% of patients within 2 years and is
ap-parent at initial presentation in 12% to 31% of
pa-tients.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
in-volve 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 carci-noma to metastasize to the lymph nodes, recent atten-tion 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 mela-noma, 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 hypo-thetical 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 positive and biopsy-negative sentinel lymph nodes
Methods
The English-language literature from January 1976 to Au-gust 2001 was searched in AuAu-gust 2001 with the PubMed
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 1 month were used to calculate rates of recurrence and metastasis Case details re-corded included number of patients, success in identifying
Presented at the 2001 Annual Meeting of the American Society for
Dermatologic Surgery, American College of Mohs Micrographic
Sur-gery, and Cutaneous Oncology Meeting, Dallas, TX, October 27,
2001.
Address correspondence and reprint requests to: Clark Otley, MD,
De-partment of Dermatology, Mayo Clinic, 200 First Street SW,
Roches-ter, MN 55905.
Trang 2114 mehrany et al.: sentinel lymph node status Dermatol Surg 28:2:February 2002
and removing a sentinel lymph node, histologic status of the
sentinel lymph nodes, primary and adjuvant treatment
mo-dalities, recurrence or metastasis, and duration of follow-up
A meta-analysis of all case series was performed
compar-ing the outcome of patients with Merkel cell carcinoma
ac-cording to sentinel lymph node status Case details were
tab-ulated 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
senti-nel lymph node status; Fisher exact test was used to
considered statistically significant
Results
In the literature searched, 60 patients with Merkel cell
carcinoma were reported as having undergone
suc-cessful 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
fol-low-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
follow-up duration was not specified, also were free of
dis-ease 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
bi-opsy-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
chemo-therapy Details are presented in Table 1
The biopsy result was positive in 20 of the 60
pa-tients (33%) with successful sentinel lymph node
bi-opsy 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
re-currence, or systemic metastatic Merkel cell
carci-noma Follow-up duration was not reported for one of
these six patients; in the other five patients, the
me-dian 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
exci-sion or Mohs micrographic surgery Adjuvant therapy
was administered to all but one patient and included
therapeutic lymph node dissection, postoperative
radi-ation therapy, or chemotherapy Details are presented
in Table 1
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 0.005) Fif-teen patients with a positive biopsy result underwent therapeutic lymph node dissection; none of the 10 pa-tients for whom follow-up status was reported experi-enced 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 ther-apeutic 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 neu-roendocrine 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 nod-ules and are most commonly located on the head or neck.21 Median age at presentation is 66 years.22 Al-though 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 carci-noma have a similar natural history The clinical behav-ior 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 as-sociated 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 con-fined in lymph nodes before hematogenous dissemina-tion remains controversial
In patients with high-risk melanoma, the histologic features of the primary tumor, specifically Breslow
Trang 3thick-Dermatol Surg 28:2:February 2002 mehrany et al.: sentinel lymph node status 115
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
pa-tients are at increased risk of nodal or systemic
me-tastases Therefore, sentinel lymph node biopsy has
been proposed as a method to permit pathologic
mi-crostaging 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
carci-noma or to determine whether the status of the
senti-nel lymph node carries any prognostic significance
On the basis of the meta-analysis presented here,
sentinel lymph node biopsy appears to be a reliable
tech-nique 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 senti-nel 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 pa-tients because they received a variety of adjuvant ther-apies to both the primary site and regional nodes Two patients underwent complete lymph node dissec-tion despite negative results on sentinel lymph node biopsy, and two others had adjuvant radiation
Study authors (year)
Patient no.
Sentinel lymph node status
Adjuvant treatment
Recurrence
or metastasis
Duration of follow-up (mo.)
Wasserberg et al 17 (2000) 1 Positive WLE, TLND, XRT, CTX None 14
Rodrigues et al 19 (2001) 1 Positive WLE, TLND,d XRT, CTX None 15
a CTX, chemotherapy; Mohs, Mohs micrographic surgery; NR, not reported; TLND, therapeutic lymph node dissection; WLE, wide local excision; XRT, radiation therapy.
b 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.
Trang 4116 mehrany et al.: sentinel lymph node status Dermatol Surg 28:2:February 2002
apy One biopsy-negative patient received adjuvant
chemotherapy It is important to note that 35 of 40
bi-opsy-negative patients (88%) underwent only wide
lo-cal excision and had no adjuvant therapy Therefore,
most patients with a negative result on sentinel lymph
node biopsy experienced no short-term recurrence
af-ter 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
re-currence, 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%)
under-going therapeutic lymph node dissection died of
com-plications 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
radia-tion therapy to the regional nodal basin that was
in-volved with a biopsy-positive sentinel lymph node rather
than complete lymphadenectomy The other two
pa-tients refused therapeutic lymph node dissection after
wide local excision and sentinel lymph node biopsy
Al-though 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
asso-ciated with sentinel lymph node biopsy-guided
thera-peutic lymph node dissection, the risk of local
recur-rence or systemic metastasis in patients with a positive
biopsy result remains high The prognosis is poor
de-spite the use of multimodality therapy in all but one
case Of 18 biopsy-positive patients for whom
follow-up data were reported, six (33%) experienced local
re-currence, regional rere-currence, or systemic metastasis,
with a median reported follow-up time of 12 months
This very high and rapid rate of recurrence or
me-tastasis demonstrates that a positive result on sentinel
lymph node biopsy in patients with Merkel cell
carci-noma 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
ag-gressive adjuvant therapy, including complete
thera-peutic lymph node dissection as well as adjuvant
radi-ation 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
contigu-ity to the lymphatic basin remains uncertain, as does
the role of adjuvant chemotherapy
In conclusion, this study of data reported in the med-ical literature found that one-third of patients with Merkel cell carcinoma who had clinically unaffected lymph nodes harbored occult metastatic disease Senti-nel lymph node biopsy appears to provide prognosti-cally 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 in-creased short-term recurrence and thus can be used to identify patients for whom adjuvant therapy should be considered There are no highly effective and well-defined strategies for managing patients with high-risk Merkel cell carcinoma; however, when confronted with
a biopsy-positive sentinel lymph node, strong consid-eration should be given to multimodality adjuvant therapy, including therapeutic lymph node dissection, radiation therapy, or chemotherapy Prospective, ran-domized, multicenter trials are needed to define the optimal adjuvant treatment modalities in patients with Merkel cell carcinoma who have positive results on bi-opsy of the sentinel lymph node
It would be equally advantageous to reduce expo-sure 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 meta-analysis, Merkel cell carcinoma patients with a nega-tive 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 pa-tients 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 ex-perience are needed for a more accurate assessment of the long-term significance of sentinel lymph node status
in patients with Merkel cell carcinoma
References
1 Toker C Trabecular carcinoma of the skin Arch Dermatol 1972; 105:107–10.
2 Gruber SB, Wilson L Merkel cell carcinoma In: Miller SJ, Mal-oney ME, eds Cutaneous Oncology: Pathophysiology, Diagnosis, and Management Malden, MA: Blackwell Science, 1998: 710–21.
3 Pitale M, Sessions RB, Husain S An analysis of prognostic factors
in cutaneous neuroendocrine carcinoma Laryngoscope 1992;102: 244–9.
4 Ratner D, Nelson BR, Brown MD, Johnson TM Merkel cell carci-noma J Am Acad Dermatol 1993;29:143–56.
5 Goepfert H, Remmler D, Silva E, Wheeler B Merkel cell carcinoma (endocrine carcinoma of the skin) of the head and neck Arch Oto-laryngol 1984;110:707–12.
6 Hitchcock CL, Bland KI, Laney RG III, Franzini D, Harris B, Cope-land EM III Neuroendocrine (Merkel cell) carcinoma of the skin Its natural history, diagnosis, and treatment Ann Surg 1988;207: 201–7.
Trang 5Dermatol Surg 28:2:February 2002 mehrany et al.: sentinel lymph node status 117
7 O’Connor WJ, Brodland DG Merkel cell carcinoma Dermatol
Surg 1996;22:262–7.
8 Harrington AC, Freitag DS Uncommon cutaneous neoplasms Md
Med J 1997;46:255–62.
9 Gershenwald JE, Thompson W, Mansfield PF, et al
Multi-institu-tional 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
lymphadenec-tomy in patients with Merkel cell (cutaneous neuroendocrine)
car-cinoma Ann Surg Oncol 1997;4:389–95.
11 Bilchik AJ, Giuliano A, Essner R, et al Universal application of
in-traoperative 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.
17 Wasserberg N, Schachter J, Fenig E, Feinmesser M, Gutman H Ap-plicability 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 expe-rience with sentinel lymph node mapping for Merkel cell carci-noma J Am Acad Dermatol 2001;45:303–8.
20 Reed RJ, Argenyi Z Tumors of neural tissue In: Elder D, ed Le-ver’s Histopathology of the Skin, 8th edn Philadelphia: Lippincott-Raven, 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 prognos-tic 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 out-come 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
recommen-dations This publication illustrates not only what a powerful
tool the meta-analysis can be, but also the strengths and
weak-nesses 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 ag-gregating the results of case reports and case series As such, while indicating strong trends, this is essentially reformatted an-ecdotal data As the authors correctly point out, prospective, ran-domized trials are needed to prove the validity of their findings.
Stuart J Salasche, MD
Co-Editor Tucson, Arizona