2023, Volume 39, Number 1, Page(s) 023-030
BRAF, NRAS, KIT, TERT, GNAQ/GNA11 Mutation Profile and Histomorphological Analysis of Anorectal Melanomas: A Clinicopathologic Study
Orhun Cig TASKIN1, Sule OZTURK SARI1, Ismail YILMAZ2, Ozge HURDOGAN1, Metin KESKIN3, Nesimi BUYUKBABANI1, Mine GULLUOGLU1
1Department of Pathology, Istanbul University, Istanbul Faculty of Medicine, ISTANBUL, TURKEY
2Sultan II. Abdulhamid Han Training and Research Hospital, University of Health Sciences, ISTANBUL, TURKEY
3Department of Surgery, Istanbul University, Istanbul Faculty of Medicine, ISTANBUL, TURKEY
Keywords: Anorectal melanoma, BRAF, NRAS, KIT, TERT, GNA
Primary anorectal melanomas (AMs) are uncommon neoplasms with aggressive behavior. Molecular profile and clinicopathologic
features of AMs are still not well established. In this study, we aimed to investigate BRAF, NRAS, KIT, TERT, and GNAQ/GNA11 mutation status
and clinicopathologic features of AMs.
Material and Method: All diagnostic slides of 15 AMs were reviewed. Histopathological and follow-up information were documented. Mutations
in exon 15 of the BRAF gene; exons 2 and 3 of the NRAS gene; exons 9, 11, 13, 17, and 18 of the KIT gene; and exons 4 and 5 of the GNAQ/GNA11
genes and mutations in the promoter region of the TERT gene (chr.5, 1,295,228C>T and 1,295,250C>T) were analyzed.
Results: BRAF(V600E) and KIT(V555I and K642E) mutations were observed in one (7%) and two cases (14%), respectively. NRAS, TERT and
GNAQ/GNA11 mutations were not detected. The mean age was 65. Patients presented with rectal mass, rectal bleeding, pain, and weight loss.
73% of the lesions were macroscopically polypoid. The most common tumor cell type was epithelioid. Mean tumor thickness was 10.4 mm.
One third of the cases lacked pigmentation. In situ melanoma was present in one third of the cases. Among 14 patients with follow-up data, 12
succumbed to disease. The mean overall survival was 36 months.
Conclusion: AMs are uncommon tumors with dismal survival, usually occurring in the elderly in various gross and microscopic appearances. In
terms of molecular profile, BRAF and KIT mutations are rarely detected. Profiling of larger cohorts is required to elucidate the pathogenesis and
to identify potential molecular indicators that may contribute to the development of individualized targeted therapies.
Primary anorectal melanomas (AMs) are uncommon
neoplasms that account for about 1% of anal canal tumors
. Among mucosal melanomas, which constitute around
1% of all malignant melanomas 2,
the anal canal is the
second most common site of origin, following the head and
. AMs are believed to arise from the melanocytes
of the anal squamous epithelium and extend towards the
anal canal 4,5
; however, cases that originated from the
rectal mucosa -without the involvement of the squamous
epithelium- have also been reported 6,7
Patients with AM usually present with rectal bleeding and
pain. Tumors often mimic hemorrhoids, anal polyps or
rectal carcinoma, forming large, dark-colored masses with
expansile and nodular borders, with or without ulceration8,9. Microscopically, tumors are often composed of
sheets/fascicles of epithelioid or spindled malignant cells
with vesicular chromatin and prominent nucleoli, with
variable amounts of pigmentation 10. However, unusual
presentations and rare histologic/cytologic patterns often
challenge pathologists in the differential diagnosis of AMs,
which includes carcinomas, sarcomas and even lymphomas
11,12. In challenging cases, a panel of immunohistochemical
stains, including markers of melanocytic lineage
is required to render the accurate diagnosis 13.
Similar to mucosal melanomas of other sites, AMs behave
much worse than their cutaneous counterparts. Despite
the use of various treatment regimens including extensive
surgery, radiotherapy, chemotherapy, and targeted therapies,
AMs have an aggressive clinical course with an overall 5-year survival rate of less than 25% 3,14. Additionally,
AMs were associated with the poorest prognosis among
mucosal melanomas in a large European cohort 15.
The recent progress in the molecular profiling of cutaneous
melanomas has greatly contributed in our understanding
of their pathogenesis, as well as their management with
the use of targeted therapies and immunotherapy 16.
However, mucosal melanomas tend to differ from their
cutaneous counterparts in terms of molecular profiling;
albeit showing a heterogeneous molecular profile, they
have lower BRAF and TERT, and relatively higher NRAS
and KIT mutation frequencies 17-27. Additionally,
GNAQ/GNA11 mutations, which have been reported
in uveal melanomas and subjected to targeted therapies
28,29, also occur rarely in AMs 30, but not in other
mucosal melanomas 31. However, molecular profiles of
mucosal melanomas are still not well established due to
their rareness. In addition to their molecular background,
data concerning their clinicopathologic features are highly
limited. Accordingly, widely accepted treatment protocols
do not exist. In this study, as an extension to our previous
work on head and neck mucosal melanomas 31, we
aimed to investigate the BRAF, NRAS, KIT, TERT and
GNAQ/GNA11 mutation status of 15 AMs, as well as their
|Case Selection, Clinical and Pathological Data Collection
The digital database of the pathology department (Istanbul
Faculty of Medicine, Istanbul University, Istanbul, Turkey)
was searched for cases diagnosed as AM between the years
2000 and 2019, including both in-house material and
outside consultations. Data on clinical history and physical/
radiologic examination were reviewed for all retrieved
cases in order to exclude previous history of cutaneous
melanoma and/or the possibility of metastasis. Cases with
a suspicion of secondary melanoma were not included.
Diagnostic slides and paraffin blocks were retrieved from
the archives. All slides (hematoxylin and eosin and/or
immunohistochemically stained) were reviewed. Tumor
cell types were classified under four categories (epithelioid,
spindle, pleomorphic, and lymphoma-like), as mentioned
in the literature 9,12,32,33, and combined morphology
was assessed when appropriate. Histopathological information
regarding tumor thickness (Breslow), presence of
perineural and lymphovascular invasion, pigmentation,
ulceration, necrosis, tumor infiltrating lymphocytes, mitotic
count (per high power field), and margin status (when
applicable) were also documented. Follow-up information
was obtained from the clinical files or national database.
Tumor targets (>90% viable tumor) were manually microdissected
from 10-mm thick unstained histologic sections
for enrichment of tumor cellularity. Deparaffinization of
tissue sections was performed. Then, DNA was isolated
by using the QIAamp DNA FFPE Tissue Kit (50) (catalog
#: 56404) (QIAGEN, Hilden, Germany). DNA concentrations
of the samples were assessed spectrophotometrically
using a Nanodrop 1000 spectrophotometer (ThermoScientific,
Mutations in exon 15 of BRAF gene; exons 2 and 3 of the
NRAS gene; exons 9, 11, 13, 17, and 18 of the KIT gene; and
exons 4 and 5 of the GNAQ and GNA11 genes (well-known
hotspot regions for oncogenic mutations) and mutations in
the promoter region of the TERT gene (chr5, 1,295,228C>T
and 1,295,250C>T) were analyzed by validated previously
described polymerase chain reaction (PCR)-based direct
Sanger sequencing (analytical sensitivity 25%) by using 200
ng of each tumor DNA 31.
The Helsinki principles were respected in this study and
patients’ data confidentiality was ensured according to their
guidelines. This study was approved by the institutional
The study was conducted with 15 cases of 15 patients (8
males and 7 females) with a mean age of 65 years (range:
30 - 86 years). The specimens consisted of 8 local excisions,
3 abdominoperineal resections, 1 polypectomy and 3 incisional
biopsies. By definition, all tumors originated from
the anal canal. Among patients with available information
(n=9), presenting symptoms were described as rectal mass,
rectal bleeding, pain and weight loss.
Diagnostic slides of the fifteen cases were systematically
reviewed. Tumors were polypoid in 73%. The cell type was
epithelioid and spindle in 33%, epithelioid and lymphomalike
in 27%, spindle in 13%, epithelioid and pleomorphic in
13%, spindle and lymphoma-like in 7%, and lymphoma-like
in 7% of cases (Figure 1). Mean tumor thickness in 12 cases
was 10.4 mm (range: 1.1-22 mm). Tumor thickness could
not be measured in 2 incisional biopsies and 1 polypectomy
due to poor orientation. Majority of cases (67%) showed
pigmentation, whereas 33% were amelanotic (Figure 2).
Ulceration was seen in 80% of cases. Mean mitotic count was 4.9 per 10 high power fields (range 0-10). In situ melanoma
was detected in 33% of the cases (Figure 2). Intratumoral
lymphocytes were prominent in 53%. Metastasis in lymph
nodes was observed in 3 abdominoperineal resections.
Click Here to Zoom
|Figure 1: Neoplastic cells in anorectal melanoma demonstrate various morphologic appearances: A) Epithelioid melanoma cells with
roundish nuclei and wide eosinophilic cytoplasm, B) Lymphoma-like small neoplastic cells, admixed in a fibrous stroma, showing crush
artifact, C) Pleomorphic melanoma cells with huge, bizarre nuclei and prominent cytoplasm, D) Spindle cells showing elongated nuclei
and sparse cytoplasm (A-D: Hematoxylin&Eosin, x400).
Click Here to Zoom
|Figure 2: A) Anorectal melanoma cells, which lack melanin pigment (Hematoxylin&Eosin, x200), B) Melanoma in situ, atypical
melanocytes showing continuous growth at the basal layer (Hematoxylin&Eosin, x400).
Among 15 cases, 10 were subjected to immunohistochemical
analysis. Five cases that did not require immunohistochemical
analysis harbored in situ melanoma component
and/or prominent pigmentation.
Among melanocytic markers, S-100 and HMB-45 were
positive in all cases (100%; n=9 and 7; respectively).
Melan-A was positive in 6/7 (86%) cases. Epithelial
markers (Pan-cytokeratin, epithelial membrane antigen,
and carcinoembryonic antigen), neuroendocrine markers
(chromogranin, synaptophysin), muscle markers (desmin,
smooth muscle actin) were all negative when performed,
along with leukocyte common antigen, CD30 and CD34.
CD117 was positive in 2 of 3 cases performed.
A total of 3 cases (20%) were found to harbor mutations.
BRAF (V600E) and KIT (V555I and K642E) mutations were
observed in one (7%) and two cases (14%), respectively.
NRAS, TERT, and GNAQ/GNA11 mutations were not
Follow-Up and Survival Information
Among 14 patients with available information, 12 died.
The mean overall survival was 36 months (range: 0-112
months). The histopathological, clinical, and mutational
findings and follow-up information are summarized in
Mutational profile of mucosal melanomas is known to differ
from their cutaneous counterparts, suggesting a different
pathway in the pathogenesis: They harbor lower BRAF
and TERT, and relatively higher NRAS and KIT mutation
. The absence of UV damage is often
mentioned to be associated with this disparity. Furthermore,
regarding the site of origin, differences also exist in the same
subgroup: in an earlier study, we concluded that NRAS and
TERT promoter mutation rates were significantly higher
in sinonasal than in oral mucosal melanomas of the head
and neck 31
. In the current literature, data on AMs’
molecular profile is mostly merged with cutaneous and/or
mucosal melanomas, primarily due to their rareness 34-39
. In studies with relatively large cohorts of AMs, KIT
mutations were most commonly encountered, followed by mutations in NRAS. The newly introduced NF1 gene also
has an important role in the oncogenesis. BRAF mutations
were also observed with different frequencies, most likely
due to small sample sizes or populational differences of the
. In addition, one study showed around 2%
GNAQ and 6% GNA11 mutations 39
. In our study group,
BRAF and KIT mutations were found in 7% and 14%,
respectively. NRAS, TERT, and GNAQ/GNA11 mutations
were absent. Together, these supported the low mutation
burden of AMs, as stated in the literature 45
. In a large
cohort of mucosal melanomas, 3% of AMs showed BRAF,
10% showed NRAS, and 19% showed KIT mutations. This
study analyzed a subset of cases by Sanger sequencing,
and others by next-generation sequencing (NGS); and
proposed NRAS mutation as a predictor of worse survival,
independent of stage in all mucosal melanomas 46
Those being mentioned, as a limitation of this study, we
had a limited number of cases, impeding a correlation
analysis between mutational status and prognostic data.
We also did not have access to NGS techniques. Therefore
we were unable to perform a comprehensive genomic
analysis including NF1, which was recently integrated in
the molecular classification of AMs.
Our findings verified that AMs are highly rare and
aggressive neoplasms that generally occur in elder patients,
with a mean age of 65 years in the present study. In one
study, older age (>70 years) was found to be an independent
poor prognostic factor 10. Although our data did not
reveal any significant sex predilection, geographic and
populational differences in the relative frequency between
two genders have been reported 10,47.
Clinically, recognizing AMs can be challenging for
physicians. The symptomatology may include nonspecific
rectal bleeding and pain, as well as weight loss in
metastatic disease 48. Endoscopically, tumors can present
with various appearances. Polypoid masses are frequently
encountered, similar to 73% of our cases. Anal prolapse, and
luminal or submucosal masses with or without ulceration
or pigmentation can also be seen 48. This may cause
misdiagnosis of AM as hemorrhoids, perianal abscess, anal
polyps or other malignancies 49.
The presence of melanin pigmentation can help render the
accurate diagnosis. However, it is not always present, with
some studies reporting 37% of their cases as amelanotic
12,32. In addition, in situ melanoma component, or
junctional melanocytic activity, which are characteristic in
cutaneous melanomas, have been reported in up to 75% of
AMs 12,32,49. However, this feature may be missing due
to the absence of adjacent mucosa in incisional biopsies that consist entirely of tumor, and also due to ulceration
and fragmentation in excisional biopsies. In our study, a
third of the tumors were amelanotic and a third had an in
Microscopically, epithelioid, spindled, pleomorphic, and
lymphoma-like tumor cells may co-exist, with epithelioid
being the most frequent with combination of the others
32,40, similar to the present study. Therefore, AMs can
mimic a large spectrum of malignancies, making the use
of immunohistochemistry crucial in differential diagnosis.
Additionally, lack of in situ component and/or lack of
pigmentation, also complicate the diagnostic puzzle. At this
point, an immunohistochemical panel of commonly used
melanocytic markers, S-100 protein/SOX10, Melan-A,
HMB-45, can be helpful. Moreover, additional markers
may be required to rule out other entities including
primary or metastatic carcinomas, neuroendocrine
neoplasms, sarcomas, lymphomas, and gastrointestinal
stromal tumors. Among those, the use of CD117 requires
careful interpretation due to its frequent positivity in
AMs (up to 75% in the literature), which can lead to a
misdiagnosis of rectal gastrointestinal stromal tumor, if not
performed along with other melanocytic markers 12,33.
Additionally, CD117 immunohistochemistry is known not
to correlate with KIT status and therefore should not be
used with mutation screening purposes 44.
In terms of pathological staging and prognosis, specific
guidelines for reporting AMs do not exist. They are usually
reported according to the American Joint Commission on
Cancer (AJCC) guidelines for cutaneous melanoma 50,
which depends mostly on tumor thickness, causing several
issues in the daily practice. In the vast majority of cases on
reported series 10,40,45,51-53 including ours (10.4 mm),
the average tumor thickness was much thicker than the 4
mm threshold used for staging T4 cutaneous melanomas.
This threshold inevitably categorizes the bulk of cases
as T4, thus diminishing the prognostic stratification of
the T classification. Several attempts have been made
in order to sharpen the prognostic accuracy, including
the implementation of different thickness cut-offs 51,
subclassification depending on the localization 52 and
metastatic status 40. Among other histopathologic
prognostic factors, presence of metastasis, lymphovascular
and perineural invasion, invasion of muscularis propria/
anal sphincter were also reported 10,40,51. Mitotic rate
is a very strong prognostic factor in cutaneous melanomas
54. Although high mitotic rates are frequently
encountered similar to our study, their correlation
with the clinical outcome is not well established in AMs 12,33. Nevertheless, studies on larger cohorts are needed
in order to define the relationship between the distinct
histopathologic parameters and prognosis.
In terms of treatment, optimal algorithms are lacking and
satisfactory results are yet to be achieved 55. The primary
choice of treatment is complete surgical removal of the tumor
8. Advantages of local approaches (mucosal resection or
local excision) over extensive surgery (abdominoperineal
resection) have long been discussed; however, literature
data lack proof to recommend one modality over the other
56-58. Moreover, adjuvant or neoadjuvant therapies do
not seem to make significant difference on the clinical
outcome 55. The results of recently implemented
immunotherapy is yet to be proven 59. Since our data
involved limited information on adjuvant treatment, we
were unable to draw any conclusions on this subject.
In conclusion, AMs are uncommon tumors with aggressive
behavior and poor survival. They usually occur in the
elderly and present in various gross and microscopic
appearances, thus involving a wide spectrum of differential
diagnoses. For accurate diagnosis, the melanocytic lineage
should be demonstrated with immunohistochemistry,
especially in the absence of conventional morphological
clues such as pigmentation and/or in situ component. In
terms of molecular profile, BRAF and KIT mutations rarely
occur. Profiling of larger cohorts is required to elucidate the
pathogenesis and to identify potential molecular indicators
that may contribute in the development of individualized
Conflict of Interest and Funding Statement
Authors have no conflicts of interest to declare. All authors have
read and contributed to the final manuscript and confirm that this
is an original work that has not been previously published, nor
has it been submitted to another journal for simultaneous review.
This study is supported by the Scientific Research Project Fund of
Istanbul University (Project number: 51524). This study was partially
presented in 28th Congress of the European Society of Pathology, 25-
29 September 2016, Cologne, Germany.
Concept: SOS, OT, Design: SOS, OT, Data collection or processing:
OS, OT, IY, OH, Analysis or Interpretation: SOS, OT, IY, OH,
Literature search: OT, OH, Writing: SOS, OT, OH, Approval: NB,
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