A meta analysis of the prognostic signif

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; 3 of 4 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 2 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 1 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


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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 1.
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 1.

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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-


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28:2:February 2002

115

Table 1. 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
1
2–6
1
2
3
4
5
6
7
1–2
3–16
1
2
1
2
1
1
2

3
1
2
3
4
5
1
2
3
4
5
6

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
4
6
8
11
4
6
6.5b
6.5b
NR
NR
16
13
6
14
12
8
21
38
—c
3
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-


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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.

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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.

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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