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Histological Characteristics of Metastasizing Thin Melanomas
A Case-Control Study of 43 Cases
Joan Guitart, MD;
Lori Lowe, MD;
Michael Piepkorn, MD, PhD;
Victor G. Prieto, MD, PhD;
Michael S. Rabkin, MD, PhD;
Salve G. Ronan, MD;
Christopher R. Shea, MD;
Victor A. Tron, MD;
Wain White, MD;
Raymond L. Barnhill, MD
Arch Dermatol. 2002;138:603-608.
ABSTRACT
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Objective To study clinical and histological features associated with metastasizing
thin melanomas (MTMs).
Design Case-control study of clinicopathological features of patients with
MTMs by a panel of 10 dermatopathologists.
Setting Members of the North American Melanoma Pathology Study Group selected
the cases from the melanoma databases at 8 academic institutions.
Patients Forty-three patients with MTMs (<1 mm thick) and 42 control subjects
without metastasis matched for age, sex, tumor site, and Breslow thickness.
Intervention None.
Main Outcome Measures Clinical (age, sex, site of lesion, stage at diagnosis, metastasis site,
disease-free survival, and outcome) and histological (Breslow thickness, Clark
level, growth phase, regression, and inflammatory response) features of patients
with MTMs vs controls.
Results There was an overrepresentation of axial tumors among patients with
MTMs. Extensive regression was present in 18 patients (42%) with MTM vs 2
matched control subjects (5%) (95% confidence interval, 21%-53%; P = .001). Other histological variables were not significantly different.
Two patients had melanomas in situ with subsequent metastasis.
Conclusions Thin melanomas with extensive regression represent a group at higher
risk for the development of metastasis. Furthermore, the risk of metastasis
cannot be dismissed in cases of melanoma in situ.
INTRODUCTION
MICROSCOPIC assessment of Breslow thickness is the most accurate prognostic
indicator in malignant melanoma.1 There is
ample evidence that tumor thickness is directly proportional to the development
of metastasis and to the overall patient survival.2
In general, melanomas with a Breslow thickness of less than 1 mm have a good
prognosis, with a low incidence of metastasis. However, thin melanomas may
develop metastasis.3-12
We have reviewed our experience with metastasizing melanomas with a Breslow
thickness of less than 1 mm. Our goal was to identify those clinical and histological
factors that may predict a subset of thin melanomas more likely to metastasize.
MATERIALS AND METHODS
Electronic records were searched from the melanoma databases and pathology
departments at University of Michigan, Ann Arbor; University of Illinois,
Chicago; Duke University, Durham, NC; Vancouver University, Vancouver, British
Columbia; the Connecticut Tumor Registry, Hartford; The Johns Hopkins University,
Baltimore, Md; Wake Forest University, Winston-Salem, NC; and Northwestern
University, Chicago. Histopathological material from patients with primary
melanoma with a Breslow thickness of less than 1 mm and a known history of
metastasis were selected. All metastases were confirmed by histological examination.
All biopsy specimens from patients were reviewed, and it was found that they
had negative surgical margins, or if the margins were involved, a complete
reexcision specimen had been performed. Each case was evaluated by the contributing
pathologists before submission to the study. The slides selected for panel
evaluation were the most representative sections of the lesion. The slides
were reviewed independently by a panel of 10 dermatopathologists with experience
in pigmented lesions. The control group included 42 patients with thin melanomas
with no evidence of metastasis after a minimum follow-up of 6 years. The control
patients were matched for age (within a 10-year range), sex, site (extremities,
truncal, or head and neck), and Breslow thickness. The diagnosis was confirmed
in all lesions. The following factors were assessed: thickness, Clark level,
and growth phase (tumorigenic vs nontumorigenic). Tumorigenic growth phase
was defined by the presence of dermal mitosis or dermal aggregates of tumor
cells larger than the nests in the epidermal component (Figure 1).13 Presence, extent (<50%
or  50%), and evolutionary stage of regression were also assessed. The
percentage of regression was not related to the overall surface area of the
lesion, but was based on the percentage of linear regression on the most representative
slide of the lesion. Regression was defined as dermal fibroplasia with an
absence of epidermal and dermal involvement by melanoma cells, but allowing
for lentiginous single-cell proliferation of atypical melanocytes along the
dermal epidermal junction (Figure 2).
Host response was defined as the presence of tumor-infiltrating lymphocytes
intermingled among tumor cells or a lymphoid infiltrate at the base of the
lesion. Other notable histological findings (coexisting lesion and angiolymphatic
spread) were recorded. If agreement by all panelists was not achieved, a simple
majority was considered sufficient for tabulation purposes. Follow-up information,
including patients' current status, stage at the time of diagnosis, disease-free
survival, and sites of metastasis, was obtained from tumor registries and
from patients' medical records. t Tests and  2 assays were used for statistical analysis. P<.05 was considered significant.
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Figure 1. The tumorigenic phase is established
by the presence of dermal aggregates of melanoma cells larger than the junctional
malignant nests (hematoxylin-eosin, original magnification x200).
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Figure 2. Lentiginous single-cell proliferation
of atypical melanocytes overlying an area of fibroplasias and regression (hematoxylin-eosin,
original magnification x200).
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RESULTS
CLINICAL
The study group consisted of 43 patients (23 men and 20 women), with
a mean age of 50.0 years (range, 27-79 years) (Table 1). The back and shoulder were the most common locations for
lesions, affected in 21 (49%) patients. The second most common location was
the lower extremity (10 patients), followed by the upper extremity and chest,
occurring in 4 patients in each location. Two had lesions on the ears and
1 patient each had lesions on the scalp and abdomen. Staging performed at
the time of diagnosis revealed 27 (63%) patients without clinical evidence
of metastasis (stage I). Lymph node metastases (stage III) were detected in
12 (28%) patients. Four patients (9%) had distant metastasis (stage IV) at
the time of presentation. Eventually, metastases were detected in every patient.
The most common site for metastasis was the regional lymph nodes, affected
in 23 patients. Nine patients had metastasis to more than 1 lymphatic region
or had lymphatic metastasis associated with systemic metastases. Six patients
had metastasis involving soft tissue or skin. Lung or pleura was the site
of metastasis in 4 patients and liver in 3. Two patients had metastasis reported
in the stomach and bone. In addition, other sites of metastasis included the
brain (2 patients) and parotid gland (1 patient). One case with in-transit
metastasis also occurred. The mean follow-up was 52 months. The time to detection
of metastasis was not available in most cases. Five patients reported as having
developed metastasis had unspecified sites. When the study was closed, 26
patients had died with melanoma, and 12 patients were alive with disease.
Five patients were alive without clinical evidence of melanoma.
The matched control cases included 42 patients (23 men and 19 women),
with a mean age at presentation of 48.5 years (range, 23-72 years) and a mean
follow-up of 13 years (range, 6-27 years) without evidence of metastasis.
The lesions were located on the torso in 25 patients, extremities in 14, and
head or neck in 3.
HISTOPATHOLOGICAL
The panel agreed on the diagnosis of melanoma in all the cases. The
mean ± SD thickness for the metastasizing lesions was 0.59 ±
0.20 mm (range, 0 [melanoma in situ] to 0.95 mm). There was some discordance
in the assessment of Clark level. Consensus, defined as agreement with no
more than 1 dissension within the panel, was reached in 15 (35%) of the 43
patients . In 3 of the cases, the panelists' assessments were evenly divided
and a simple majority could not be reached. Patients with metastasizing thin
melanoma (MTM) were classified as follows: level I, 2 patients; I or II, 1
patient; II, 10 patients; III, 22 patients; III or IV, 2 patients; and IV,
6 patients. The distribution was not significantly different from that of
the control cases (P = .81). Consensus for the assessment
of growth phase was reached in 39 patients (91%). Ten cases (23%) were determined
to be in the nontumorigenic (radial growth) phase and 33 (77%) in the tumorigenic
(vertical growth) phase. Consensus regarding growth phase could not be reached
in 5 patients (12%). Dermal mitotic figures were noted in 8 cases, while large
dermal aggregates of tumor cells were seen in all the tumorigenic cases. Regression
was identified in 21 patients (49%) vs 8 control cases (19%) (P = .001) (Figure 3, Figure 4, and Figure 5). Extensive regression involving 50% or more of the lesion
surface was noted in 18 patients (42%) and less than 50% involvement in 3
(7%). Regression was not identified in 22 patients. In the control group,
2 patients (5%) had extensive regression. The occurrence of extensive regression
was significantly different between patients and controls (95% confidence
interval, 21%-53%; P = .001). A mononuclear cell
inflammatory infiltrate was prominent in 36 cases. The infiltrate was predominantly
at the base of the melanocytic lesion in 9 cases and was mostly intermingled
with the melanocytes (tumor-infiltrating lymphocytes) in 13. A combined infiltrate
at the base with tumor-infiltrating lymphocytes was noted in 14 cases. Five
cases had no significant inflammatory infiltrate. A coexisting melanocytic
nevus was identified in 7 cases, including 2 congenital nevi and 2 dysplastic
nevi. In 4 cases, dermal nevomelanocytic nests were noted, but extensive regression
prevented further assessment of the nevi.
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Figure 3. Low-power view of a metastasizing
thin melanoma showing extensive areas of regression and melanoderma (hematoxylin-eosin,
original magnification x50).
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Figure 4. Aggregates of melanin-laden macrophages
(nodular melanosis) are noted within an area of regression (hematoxylin-eosin,
original magnification x100).
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Figure 5. Expansion of the papillary dermis
in an area of extensive regression and fibrosis with scattered lymphocytes
and melanophages (hematoxylin-eosin, original magnification x50).
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The mean thickness for the control specimens was 0.56 mm (range, 0-0.94
mm) (P = .70). Clark level distribution was II in
16 cases; III, 20; III or IV, 3; and IV, 3. Thirty cases (71%) were determined
to be in the tumorigenic phase and 12 (29%) in the nontumorigenic phase (P = .62). Regression was absent in 34 control cases (81%)
and was present in 8 (19%), with 6 showing limited regression (<50%) and
2 showing extensive regression (50%). A host response was absent in 5
cases, a lymphoid infiltrate at the base was noted in 26, and tumor-infiltrating
lymphocytes were seen in 25. The inflammatory host response of the metastasizing
cases vs the control group was not significantly different (P = .52). Seven control cases had a coexisting lesion, including 6
dysplastic nevi and 1 congenital nevus. None of the MTM or control cases were
ulcerated.
COMMENT
In recent decades, a steady increase in the incidence of thin melanomas
has been reported.14-15 This disturbing
trend may, however, reflect the detection and removal of melanomas at early
stages, when there is less risk for metastasis. Regrettably, thin melanomas
have metastatic potential, with an estimated risk of 3% to 8%, depending on
the length of follow-up.7, 9, 16-18
Despite numerous studies on the subject, the clinical and pathological risk
factors for these MTMs are largely unclear. This problem is partly because
of variations in the defining criteria for thin melanomas used in prior studies,7, 19 with Breslow thickness varying from
0.76 mm to 1.69 mm. Furthermore, some investigations combined recurring lesions
with MTMs, further confounding the results.20
The histological criteria associated with high metastatic risk in thin melanomas
have not been clearly elucidated. There is some evidence that the metastatic
potential of thin melanomas, compared with that of thick melanomas, is significantly
more affected by factors other than thickness. The size of the lesion as measured
by surface area, the presence of regressive changes, and location may be important
variables in the prognosis of thin melanomas.3, 21-24
Thin melanomas show regression more frequently than do thick melanomas.3, 25 The presence of regression has been
reported in 7% to 61% of all thin melanomas and in 40% to 100% of MTMs.3, 18, 26-28
The variability in the reported incidence of regression in thin melanomas
is probably again because of the lack of uniformity in defining criteria and
the minimal area of involvement required for inclusion. In our study, tumor
regression was the most conspicuous histological finding, encountered in 21
MTM cases (49%) vs 8 (19%) of the control cases. Furthermore, extensive regression
involving 50% or more of the lesion was seen mostly in the metastasizing group
(P = .001). Slingluff and colleagues7, 26
found a similar rate (40%) of severe regression in MTMs, compared with 17%
of nonmetastasizing thin melanomas. Other studies10, 29
have identified a higher rate of metastasis in thin melanomas with regression
(8%) compared with cases without regression (5%). Moreover, the 10-year survival
for patients with thin melanomas with regression was 79% vs more than 95%
in patients without regression.17, 30
All patients from the Sydney Melanoma Unit cohort27
and University of Illinois database28 with
thin melanomas and lymph node metastasis at presentation had extensive regression
involving more than 75% of the tumor area. The poorer prognosis of MTM with
extensive regression has been corroborated by other reports.21, 23
However, less extensive regression was also noted in 61% of thin melanomas
that never metastasized or recurred.27 Other
investigators could not demonstrate an effect of regression on disease-free
interval or survival.11, 25, 31-34
Severe regression has been reported more frequently in back lesions
and in men.3, 7, 31
Our findings concur with the overrepresentation of lesions from the back.
However, we could not confirm the male predominance among patients with MTM.
Sondergaard and Hou-Jensen30 found that
metastasis was correlated not only with the extent of regression but also
with the thickness of it. Patients with regression but without thick scar
formation had a better prognosis. The implication is that the regressed tumor
was preceded by an originally thicker tumor.
We identified 2 cases of apparent melanoma in situ that subsequently
developed metastasis. One of the cases had extensive regression involving
more than 50% of the surface area. This observation suggests a preceding invasive
tumor with metastatic potential, before regression of the dermal component.
However, regression was not identified in the other melanoma in situ with
metastasis. This perplexing case is difficult to reconcile with the notion
that theoretical nontumorigenic lesions have metastatic potential. Although
a thorough examination did not reveal a second primary lesion, a primary occult
visceral melanoma cannot be excluded. Nonetheless, our results show that it
cannot be assumed that an apparent level I melanoma will not metastasize.
Furthermore, 10 of the MTM cases studied were histologically classified by
the panel as nontumorigenic. Although consensus in the panel regarding growth
phase was reached in 91% of the cases, there were cases in which growth phase
status was difficult to determine. The overall high reproducibility of growth
phase assessment has been corroborated by other recent studies.35-36
However, the clinical relevance of such determination is less clear, as shown
by the 10 "nontumorigenic," yet metastasizing, cases in our series. Perhaps,
we should resist from providing such categorical predictions that, in some
instances, may not be more than an educated guess, yet with profound prognostic
implications to the patient.
Contrary to prior reports, we did not find a high incidence of MTM lesions
from the head and neck area, but did find a high number of axial tumors, primarily
from the back. A higher incidence of axial lesions among MTM cases has also
been observed by other authors.3, 7, 19, 26
Two other studies37-38 also showed
that patients with thin melanomas involving extremities had a lower metastatic
rate and better prognosis.
In some studies,39-42
thin melanomas from the head and neck have shown a higher rate of recurrence
and metastasis. The higher rate of recurrence reported in head and neck melanomas
may be associated with narrower surgical margins in anatomical sites cosmetically
compromised and with difficult surgical repair. Another possible explanation
is that the skin from the head and neck also has a thinner reticular dermis,
which is often damaged by actinic changes. Hence, a thin Breslow level could
be associated with a deep anatomical level of invasion (Clark level). Because
there were only 3 head and neck cases in our cohort, we could not draw any
definite conclusions about this subset of patients.
There is no reliable marker for the metastatic potential of thin melanomas.
Studies of proliferation markers (MIB-1)43
and p53 expression44 of thin melanomas found
no association between the proportion of positive cells and risk of metastasis.
Bjornhagen et al45 showed statistically significant
differences between MTM and nonmetastasizing thin melanoma in regard to the
nuclear correlation coefficient, indicating that thin melanomas with pleomorphic
and, possibly, densely packed nuclei were more likely to recur. A significant
difference of mean nuclear volume between MTMs and nonmetastasizing thin melanomas
has also been reported.17 Angiogenesis of thin
melanomas has been investigated, with conflicting results. Although Guffey
et al46 found no predictive value in measuring
vascularity in thin melanomas, Barnhill and Levy47
suggested that the onset of angiogenesis is related to inflammatory regression
and progression to the vertical growth phase.
Our study confirms that thin melanomas with extensive spontaneous regression
represent a group at higher risk for the development of metastasis. Such patients
should be carefully followed up, especially when the primary lesion involves
the torso. However, in about half of our patients, we were unable to identify
regression or any other histological or clinical distinguishing features.
This should encourage further research to identify reliable molecular or serological
prognostic indicators for patients with thin melanomas.
AUTHOR INFORMATION
Accepted for publication June 20, 2001.
We appreciate the comments and contributions of Lynn From, MD; David
Elder, MD; and Alfred W. Rademaker, PhD.
Corresponding author: Joan Guitart, MD, Department of Dermatology,
Northwestern University Medical School, 675 N St Clair, Suite 19-150, Chicago,
IL 60611 (e-mail: j-guitart{at}nwu.edu).
From the Department of Dermatology, Northwestern University Medical
School, Chicago, Ill (Dr Guitart); Department of Pathology, University of
Michigan, Ann Arbor (Dr Lowe); Department of Dermatology, University of Washington,
Seattle (Dr Piepkorn); Department of Pathology, M. D. Anderson Cancer Center,
Houston, Tex (Dr Prieto); Rabkin Dermatopathology Laboratory, Pittsburgh,
Pa (Dr Rabkin); Department of Pathology, University of Illinois, Chicago (Dr
Ronan); Department of Dermatology, Duke University, Durham, NC (Dr Shea);
Department of Pathology, University of Alberta, Edmonton (Dr Tron); Department
of Pathology, Bowman-Gray School of Medicine, Winston-Salem, NC (Dr White);
and Department of Dermatology, Georgetown University Medical Center, Washington,
DC (Dr Barnhill). Dr Shea is now affiliated with the Department of Medicine,
The University of Chicago.
Dr Ronan is deceased.
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