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Amelanotic Anorectal Malignant Melanoma: Case Report with

Immunohistochemical Study and Literature Review

Article in Case Reports in Oncology · February 2009

DOI: 10.1159/000204788 · Source: PubMed

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 Case Rep Oncol 2009;2:30–37 Published online: February 28, 2009 © 2009 S. Karger AG, Basel 30
DOI: 10.1159/000204788 ISSN 1662–6575
www.karger.com/cro

Amelanotic Anorectal
Malignant Melanoma: Case
Report with
Immunohistochemical Study
and Literature Review
Juan B. Laforga Canalesa Joan M. Gasent Blesab
Departments of a Pathology and b Oncology, Hospital de Dénia, Denia, Spain

Key Words
Malignant melanoma · Rectum · Anus · Immunohistochemistry · Gastrointestinal stromal
tumor

Abstract
Epithelioid cell tumors presenting in the gastrointestinal tract are uncommon, but when
they arise, arriving at a correct diagnosis is important. We report a case of anal malignant
melanoma in an 82-year-old man who microscopically showed an epithelioid malignant
tumor simulating a gastrointestinal stromal tumor. C-kit stain and Melan-A were diffusely
and strongly positive, while HMB-45 was focally positive. This case illustrates the
potential pitfall of relying on a single antibody or inadequate panel of
immunohistochemical stains to confirm the diagnosis. We recommend to apply an
adequate immunohistochemical panel which includes S-100 protein, HMB-45 and
Melan-A in order to make an accurate diagnosis, and discuss the differential diagnosis
and surgical treatment modalities.

Introduction

Anorectal melanomas (ARM) are uncommon neoplasias, and most of them are
metastases from a cutaneous primary [1]. Primary ARM represents 0.4 to 1.6% of all
melanoma manifestations [2, 3]. Nevertheless, the anorectum is the most common site of
primary melanoma in the alimentary tract [4].
Malignant melanoma (MM) occurs in up to 15% of primary malignant tumors of the
anus. The tumor originates from melanocytes that are normally found in the transitional
zone above the dentate line. In early stages, it can mimic clinically thrombosed

Dr. Juan Laforga Servicio de Patología, Hospital de Dénia

Ptda. Beniadéa, s/n
ES–03700 Denia (Spain)
Tel. +34 966 429 077, E-Mail [email protected]
 Case Rep Oncol 2009;2:30–37 Published online: February 28, 2009 © 2009 S. Karger AG, Basel 31
DOI: 10.1159/000204788 ISSN 1662–6575
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hemorrhoids [5]. Grossly ARM may display a polypoid mass covered by a smooth surface
which may eventually be ulcerated and usually extends into the lower rectum. The
epidemiology of ARM has not been studied, although its putative relevance and
prognostic studies have been based on referred cases [6]. Some epidemiologic data
suggest that immunodeficiency virus infection increases the risk of ARM [3, 7]. Due to its
low incidence, treatment of ARM is not well standardized since it was implemented based
on retrospective studies referring to a short series of cases from data collected for up to 64
years [7].
The most frequent presentation is rectal bleeding, followed by palpable mass and pain
[8]. ARM presents as a large protuberant or ulcerating mass which usually extends into
the lower rectum. The mass is pigmented in only one third of cases. Most patients present
with lesions >2 mm thick. At the time of diagnosis about 30% of cases present distant
metastases, and metastases eventually develop in 60% [6, 7, 9, 10].

Case Report

An 82-year-old man complained of rectal bleeding. Physical examination showed a polypoid and
firm tumor mass which was thought to be clinically malignant. No endoscopic study was performed.
Chest X-ray and whole-body computed tomography failed to show any tumor mass. The patient
underwent a local transrectal resection of the anorectal mass.

Pathologic Findings

The gross specimen was a segmental anorectal resection measuring 2.6 × 1.7 × 0.7 cm. In the center,
a polypoid well-delimitated lesion, measuring 1.7 cm in diameter, which was whitish and elastic, was
observed. Microscopically, the tumor was located in the submucosa and muscularis mucosae and
extended to rectal mucosa infiltrating lamina propria. Extensive areas of ulceration were present. No
junctional activity or connection was observed with the lining squamous upper mucosa. The tumor cells
were epithelioid with abundant cytoplasms and paranuclear clear spaces. The nuclei were round and
showed prominent nucleoli. Mitotic figures were frequent and atypical, averaged 16 per 10 high-power
fields. Vascular or perineural invasion was not observed. The surgical margins were free of tumor. The
tumor cells showed strong positivity for vimentin (V9), CD117 (C-kit), S-100 protein, and MART-1
(Melan-A). HMB-45 stain was focally positive at the inner portion of the tumor (20% of the cells). Stains
for cytokeratins, smooth muscle actin, desmin, h-caldesmon, chromogranin, synaptophysin and CD34
(QBEN-10) were negative. With ki67 the proliferative activity was 60%. A diagnosis of submucosal
amelanotic malignant melanoma, ulcerated of the anus, Breslow 2.8 mm thick, was made. After the
diagnosis, the patient was examined by a dermatologist and no skin lesion suggestive of cutaneous
melanoma was observed. The patient denied any complementary surgical treatment. Currently, 5
months after the diagnosis, the patient is well and free of tumor.

Discussion

Anal melanomas exhibit the same immunohistochemical and ultrastructural features

as their cutaneous counterparts [11]. However, similar to melanomas arising in other
mucous membranes, they are typical of the acrolentiginous type. Invasive melanomas in
this region are commonly epithelioid, although spindle cell and desmoplastic variants
have been described.
Differentiation of anal malignant amelanotic epithelioid melanoma from Paget’s
disease, lymphoma, undifferentiated carcinoma and gastrointestinal stromal tumor
(GIST) can be difficult on the basis of histologic criteria alone. Immunostains are of
invaluable help to make the diagnosis accurately. In Paget’s disease, the tumor cells
should stain with cytokeratins. Lymphoma should stain for CD45 and CDs.
 Case Rep Oncol 2009;2:30–37 Published online: February 28, 2009 © 2009 S. Karger AG, Basel 32
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Undifferentiated carcinoma may stain with chromogranin and synaptophysin. The most
challenging diagnosis in this particular case were GIST and epithelioid leiomyosarcomas.
The microscopic appearance should indicate a malignant epithelioid GIST, with high risk
of metastasis because of the presence of nuclear atypia and large number of mitosis/HPF.
Although it is infrequent to find a high-grade GIST measuring less than 2 cm, it could be
possible. Rectal GISTs are nearly always positive for CD34 [12]. Unlike leiomyomas and
leiomyosarcomas, colorectal GISTs rarely present as mucosal polyps because they arise
within the muscularis propria [12, 13]. Besides, those muscular tumors stain positively
with smooth muscle antigens (desmin and caldesmon), all of which were negative in our
case. It should be kept in mind that c-kit positivity is not specific of GIST. In fact it is
well-known that leukemias, some lymphomas, germinal cell tumors, and melanomas
show positive results with this antibody, and awareness of this is important in order to
prevent a diagnostic error with treatment and outcome consequences [14–16]. Further, its
application should be interpreted in an appropriate context. Chute el al. studied a series of
17 cases of ARM and reported that c-kit is frequently expressed (75%), although specific
melanoma markers HMB-45 and Melan-A are not always expressed in this tumor [17].
On the other hand, melanomas may not always uniformly stain for HMB-45. It should be
realized that MART-1 (Melan-A) may be positive in cases of melanomas which
completely lack reactivity or show a heterogeneous pattern of reactivity with HMB-45
stain, as in the case discussed here. Recently, Seya et al. [18] reported a rectal malignant
melanoma that was misdiagnosed in the endoscopic biopsy as neuroendocrine carcinoma
or GIST because of the reactivity with CD56, S100 and CD117, and a malignant
melanoma was ruled out because HMB-45 was negative. However, the study of the
surgical specimen showed HMB-45 and Mart-1 reactivity in both biopsy and surgical
specimen [18]. The phenotypic variability is most likely due to tumor heterogeneity or
suboptimal fixation. Similarly, if our case had been endoscopically biopsied and if a
limited immunohistochemical panel of antibodies would have been employed, such as
cytokeratins–, CD34–/+, Ckit+ and HMB-45– (in the main part of the tumor mass, nearly
80%), a misdiagnosis of GIST would have been more likely. Therefore, we favor the
application of an adequate immunohistochemical panel in epithelioid tumors of the
anorectal region in order to rule out leiomyosarcoma, GIST or MM, which pursue
different biological behaviors. In the case of suspected malignant melanoma, this panel
should include S-100, vimentin and both specific antibodies HMB-45 and Mart-1. Once a
diagnosis of malignant melanoma has been established, it must be determined whether
the tumor is primary or metastatic. The presence of junctional activity beneath the
squamous epithelium favors a primary malignant melanoma, although it may be
obscured by ulceration. In fact, our case showed large areas of ulceration which could
miss this important key feature. However, the absence of the obviously helpful history of
primary melanoma elsewhere should it exist; we assumed confidently that the tumor was
primarily from the anorectal region.
The prognosis of anal melanoma is poor, regardless of the type of treatment [7, 10, 19],
with a mean 5-year survival of approximately 15% [3, 20], ranging from 6 to 31% [21, 22].
Thus, ARM may represent a systemic disease at the time of diagnosis in most cases, and
the choice of surgical or other local procedures to amend the primary tumor may not
have great influence on the systemic course of the disease. Most recurrences occur within
the first 30 months, and common sites are the inguinal lymph nodes, lung, liver and
bones. Local recurrence is almost always associated with or followed by regional or
disseminated disease. The thickness of the tumor measured from the top of the overlying
intact mucosa or ulcerated tumor correlates with the outcome. Anal melanomas of less
than 2.0 mm in thickness have better prognosis than those greater than 2.0 mm in
thickness.
 Case Rep Oncol 2009;2:30–37 Published online: February 28, 2009 © 2009 S. Karger AG, Basel 33
DOI: 10.1159/000204788 ISSN 1662–6575
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Regarding the surgical treatment of ARM, it is a matter of debate between wide local
excision (WLE) and abdominoperineal resection (APR). A meta-analysis which included
compiled data of 426 patients failed to show the advantage of either approach with respect
to the overall survival [19]. It should be noted, however, that in most studies it was
difficult to compare patients’ prognostic factors due to the fact that the information
provided was insufficient. Nevertheless, there was a trend for local disease to be more
effectively controlled by APR than WLE [4, 10, 19, 23]. Ballo et al. [22] reported that
adjuvant radiation of the pelvis and inguinal lymph nodes after WLE showed similar rates
of local tumor control as APR. WLE should be the procedure of choice for other
investigators, because the alternative of APR may have a high mortality rate and lack of
survival advantages [24].
In ARM treatment, therapeutic strategies should be adjusted to the prognosis of the
disease. Prognostic parameters still remain to be defined. Only a few studies have
addressed this question. Goldman et al. [9] reported a correlation between overall survival
and the size of the tumor. Among 33 patients, only 2 were long-term survivors and the
tumor was less than 2 cm in diameter. The tumor thickness was below 2.5 mm.
Unfortunately, the histopathologic data were not provided for all patients. On the other
hand, Slingluff et al. [21] suggested that the only significant value for survival was the
stage of disease at the time of diagnosis, whereas Ballo et al. reported a favorable disease-
free survival with less than 4 mm of tumor thickness [22]. More recently, a series of 19
patients with ARM were studied [25]. The median tumor thickness was 10 mm (range
0.6–40 mm). 9 out of 19 patients presented either regional or distant metastases at the
time of diagnosis. The remaining 13 patients were treated with curative intent (APR or
WLE). There were no significant differences in overall survival. The incidence of local
recurrences was lower following APR even for patients with less favorable tumors. The
authors concluded that WLE alone is not sufficient for local tumor control in thick ARM.
 Case Rep Oncol 2009;2:30–37 Published online: February 28, 2009 © 2009 S. Karger AG, Basel 34
DOI: 10.1159/000204788 ISSN 1662–6575
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Fig. 1. a Anal malignant melanoma lined by epithelial mucinous cells. HE. ×400. b Rectal malignant
melanoma lined by squamous rectal epithelium. Note the large ulcerated areas (arrows). HE. ×400.
 Case Rep Oncol 2009;2:30–37 Published online: February 28, 2009 © 2009 S. Karger AG, Basel 35
DOI: 10.1159/000204788 ISSN 1662–6575
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Fig. 2. a Tumor cells showed strong and diffuse reactivity with C-kit. CD117 stain ×400. b Only 20% of
tumor cells showed positivity with HMB-45, in the deeper portion (arrows). HMB-45 stain ×100. c The
tumor showed diffuse and strong positivity with Melan-A. Note the absence of junctional features.
Mart-1 ×100. d Epithelioid atypical cells infiltrating rectal glands. Mart-1 ×400.
 Case Rep Oncol 2009;2:30–37 Published online: February 28, 2009 © 2009 S. Karger AG, Basel 36
DOI: 10.1159/000204788 ISSN 1662–6575
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