Keywords melanoma - oral cavity - pathology - immunohistochemistry - palliative care
Introduction
Melanoma is a malignant neoplasm comprising abnormal melanocytes, which originates
from neural crest cells. Oral melanoma is a rare neoplasm that represents ~2% of all
melanomas and 0.5% of all oral malignancies, occurring much less frequently than its
cutaneous relatives.[1 ]
[2 ]
[3 ] Most oral melanoma studies report a wide range of ages and are more common in males
than females.[4 ]
[5 ] The most regular site of occurrence is the palate, followed by the upper alveolar
ridge. Other oral sites are the lower alveolar ridge, tongue, buccal mucosa, upper
and lower lip.[2 ]
[5 ]
[6 ]
Varied clinical features of oral melanoma have been reported. The most common presentation
is an asymptomatic brown, dark blue, or black macule, sometimes with erythema or ulceration.[1 ] Histologically, melanomas comprise medium-to-large cells that may be polyhedral,
fusiform, round, spindle, pleomorphic, epithelioid, microcytic, or various shapes.[7 ] Immunohistochemically, melanomas variously express S-100 protein and melanocytic
markers, including HMB-45, melanoma antigen recognized by T-cells 1, or melanoma antigen
A (MART-1/Melan-A), tyrosinase, and microphthalmia-associated transcription factor
(MITF).[3 ]
[7 ] The prognosis for patients with oral melanoma is poor. These patients’ poor outcomes
may be partly a result of a delay in diagnosis.[8 ]
This article presented a case of large oral melanoma at the right buccal mucosa involving
the right lower alveolar ridge and lip commissure in a 69-year-old female who preferred
to obtain palliative care rather than surgery or other alternative treatments, including
radiotherapy, chemotherapy, and immunotherapy.
Case Report
A 69-year-old Thai female patient presented to the oral and maxillofacial clinic to
evaluate an asymptomatic black lesion at her right buccal mucosa. The patient reported
that the lesion had been present for 4 months with a gradual increase in size. Extraoral
examination revealed no cervical lymphadenopathy and no facial paresthesia. Intraoral
examination showed asymptomatic scattered black patches, exhibiting flat, irregular,
nodular, and ulcerative surfaces, at the right buccal mucosa extending posteriorly
to the right alveolar ridge and anteriorly to the lip commissure. The size of the
lesion was ~5 × 3 cm ([Fig. 1 ]). An incisional biopsy was performed at the buccal mucosal lesion, which showed
a prominent nodular surface, and a computed tomography (CT) scan was taken.
Fig. 1 Clinical appearance. Asymptomatic scattered black patches exhibiting flat, irregular,
nodular, and ulcerative surfaces, at the right buccal mucosa extending posteriorly
to the right alveolar ridge and anteriorly to the lip commissure. The size of the
lesion was ~5 × 3 cm.
The CT scan revealed a heterogeneous, enhancing mass with central hypodensity involving
the right lower alveolar ridge with the destruction of the right mandible and bulging
in a subcutaneous, right buccal region. The lesion’s total size was ~4.7 × 2.4 × 1.9
cm ([Fig. 2 ]). Histopathological findings demonstrated several atypical, pleomorphic melanocytes
with melanin pigments in basal and some suprabasal cell layers of the epithelium.
These pleomorphic cells are strongly positive for S-100, HMB-45, and Melan-A. An early
invasion of atypical melanocytes containing melanin pigments into the superficial
lamina propria was seen. The pathological diagnosis of oral melanoma with a superficial
invasion was confirmed ([Fig. 3 ]). Another panel of immunohistochemical staining further demonstrated the expression
of BRAF (V600E) and CD117 (c-kit) of atypical cells at the superficially invasive
and in situ components ([Fig. 4 ]).
Fig. 2 Computed tomography scan revealed a heterogeneous, enhancing mass with central hypodensity
involving the right lower alveolar ridge with the destruction of the right mandible
and bulging in a subcutaneous, right buccal region. The total size of the lesion was
~4.7 × 2.4 × 1.9 cm.
Fig. 3 Histopathologic features. (A , B ) Hematoxylin and eosin stained section demonstrated several atypical, pleomorphic
melanocytes with melanin pigments in basal and some suprabasal cell layers of the
epithelium. A pagetoid spread of some melanocytes to the superficial layer of epithelium
is observed (A : ×100, B : ×200). (C , D ) S-100 (C : ×100, D : ×200). (E , F ) HMB-45 (E : ×100, F : ×200). (G , H ) Melan-A (G : ×100, H : ×200).
Fig. 4 The hematoxylin and eosin-stained section and immunohistochemical study of BRAF (V600E)
and CD117 (c-kit) at the superficially invasive area (A –C ) and in situ component of an incisional biopsy specimen (D –F ). (A , D ) Hematoxylin and eosin (×400). (B , E ) BRAF (V600E) (×400). (C , F ) CD117 (c-kit) (×400).
Although the pathological diagnosis of an incisional biopsy from the right buccal
mucosa showed a superficial invasion of oral melanoma, the bone invasion of the lesion
at the right mandible demonstrated by a CT scan indicated an advanced stage of oral
melanoma. On the follow-up day, we informed the patient about the diagnosis and treatment
options, including surgical treatment and/or chemoradiotherapy. She denied radical
surgery and preferred alternative medical treatment. Therefore, she was referred to
be treated by the oncologist for radiation therapy and/or systemic chemotherapy. Later,
with the pandemic of coronavirus disease 2019 (COVID-19), the patient subsequently
chose palliative care, in which some of the appointments were delivered by telemedicine
instead of previously planned radiation therapy with chemotherapy. She received morphine
for analgesia, metoclopramide for antiemetic, and diazepam or lorazepam for adjuvant
therapy. After 4 months of follow-up, she continued to refuse radiotherapy and systemic
chemotherapy. Her caregiver informed us that the patient was satisfied with this mode
of treatment.
Discussion
Oral melanoma is a rare neoplasm and very aggressive tumor of melanocytic origin,
accounting for only 0.5% of all oral malignancies. It frequently involves the hard
palate and upper alveolar ridge but rarely occurs in the buccal mucosa, lower alveolar
ridge, and lip.[2 ]
[6 ] The pathogenesis of oral mucosal melanomas has not yet confirmed whether mucosal
melanocytes’ dysfunction is the main cause. Most studies have reported that the lesion
occurs more frequently in males than females, with an average age of 53.[4 ]
[6 ] The exact etiology of oral melanoma is unknown. However, smoking and chronic irritation
caused by ill-fitting dentures, as well as swallowing and inhaling environmental carcinogens
at elevated internal body temperature, have been proposed to play a role in the development
of malignant lesions.[3 ]
[9 ]
Clinically, oral melanoma demonstrates as a slow-growing, asymptomatic, brown, purple,
or black pigmentation with irregular borders and may appear as a rapidly expanding
mass with or without ulceration.[1 ]
[10 ] The clinical differential diagnosis should exclude oral melanoma from normal variations[11 ]and other benign, harmless black lesions such as melanotic macule, smoker’s melanosis,
amalgam and graphite tattoos, and pigmented nevus.[12 ] In this case report, we encountered a large oral melanoma at the buccal mucosa,
involving the lower alveolar ridge and lip commissure. A CT scan highlighted an invasion
of a lesion into the right mandible. According to previous studies, oral melanomas
of the buccal mucosa, lower alveolar ridge, and lip, which are infrequent locations,
have been found in only 4 to 7% of all oral melanomas.[2 ]
[4 ] Another learning point of this case was that an incisional biopsy’s pathological
result revealed only a superficial invasion of oral melanoma. Even though we carefully
selected the darkest and the most raised region of the lesion at the buccal mucosa
for the incisional biopsy, this area was not representative of the true infiltrative
and destructive nature of this lesion as represented by a CT scan that showed a large
destructive area in the right mandible. However, clinical features consisting of the
“ABCD” warning signs (A: asymmetry; B: border irregularities; C: color variegation;
D: diameter >6 mm)[3 ] and radiographic presentations of this case, in conjunction with histopathological
features, offered a diagnosis of oral melanoma.
The histopathology of oral malignant melanoma is similar to cutaneous melanoma, with
an initial phase characterized by a “radial growth phase” followed by an invasion
of the underlying tissues known as the “vertical growth phase.” The malignant tumor
cells of oral malignant melanoma exhibit a wide variety of forms, including spindle
cells, plasmacytoid cells, clear cells, small round blue cells, and epithelioid cells,
organized into sheets, organoid/alveolar, or desmoplastic formation.[13 ] The general histopathologic appearance of this case demonstrated atypical melanocytes
with melanin pigments, horizontally spreading in the basal and suprabasal cell layers,
along with a superficial invasion of these atypical cells into the superficial lamina
propria.
Immunohistochemical study, positive staining for S-100 protein, MART-1 or Melan-A,
tyrosinase, and HMB-45 strongly confirm the diagnosis of melanoma.[2 ]
[3 ] In this case, the pathological diagnosis was confirmed by the expression of S-100
protein, Melan-A, and HMB-45 by tumor cells, as shown in [Fig. 3 ]. Besides, it has been suggested that MITF serves as a useful immunohistochemical
marker in diagnosing melanoma. Furthermore, studies show that MITF has high sensitivity
and specificity for metastatic melanoma, and positivity has been reported in S-100
negative melanoma,[14 ]
[15 ] indicating that MITF may be another optional immunohistochemical marker to confirm
the diagnosis of oral melanoma. The mutational analysis for BRAF and KIT mutations, which are primarily found in an advanced stage of melanoma, is another
beneficial molecular test for therapeutic decision making for the most appropriate
targeted therapy in treating melanoma to improve patient survival rate.[16 ] In this case, we did not perform the mutational analysis of BRAF and KIT but found that BRAF (V600E) and CD117 (c-kit) protein aberrantly expressed in our
case by an immunohistochemical study ([Fig. 4 ]).
The 5-year survival rate for patients with oral melanoma remains poor and has been
reported to be 13 to 38%.[17 ]
[18 ] The poor outcome of these patients may be, in part, the result of a delay in diagnosis.
Widespread metastases are the leading cause of death in patients with oral melanoma.
Oral melanoma metastases develop in regional lymph nodes or distant organs such as
the brain and breast.[19 ]
[20 ]
[21 ] Since the mucosal surfaces of the oral cavity are not regularly self-examined, and
these surfaces are not visible to others, the lesion may remain asymptomatic and continue
to grow overlooked for some period of time.
The treatment of oral melanoma is currently controversial, and there is no consensus
on the best therapeutic approach. However, surgery remains the main modality of treatment,
with additional radiotherapy and/or chemotherapy to prevent recurrence and metastasis.
Although patients have received aggressive resection and multimodal treatments, the
prognosis of oral melanoma is still inferior.[18 ]
[22 ] Palliative treatment, including symptomatic management with painkillers such as
morphine and other adjuvant medicines such as metoclopramide or benzodiazepine, is
also an alternative option for cancer management.[23 ]
In this case, the patient finally chose symptomatic palliative treatment, requiring
a regular stay at or travel to the hospital. Unfortunately, there was an outbreak
of COVID-19, a fatal disease, especially for cancer patients.[24 ] Therefore, some of the present case’s appointments were provided via telemedicine.
As an alternative option to hospitalization, telemedicine has played an essential
role in oral cancer palliative care in the COVID-19 era. Symptomatic medication adjustments
and palliative care counseling can be provided to the caregivers and patients to prevent
the spread of COVID-19 infection.[25 ]
Based on our experience in managing patients with large oral melanoma, there are some
key issues to consider. Clinicians should be aware of the dreadfulness of oral melanoma
and rule it out from other benign black pigmented lesions with similar clinical findings,
as the behavior and survival rate of these two types of tumors are different. Also,
clinicians should provide sufficient information on how harmful this lesion is to
patients, direct patients to get prompt diagnosis and appropriate early treatment,
and avoid a delay in diagnosis, which can significantly reduce patients’ survival
rates.
Conclusion
This case report highlighted the rare occurrence of an extensive oral melanoma at
the buccal mucosa, involving the lower alveolar ridge and lip commissure. Biologically,
this type of malignancy shows aggressive behavior and poor survival. Like this case,
most previously reported cases reveal a delay in diagnosis, leading to widespread
lesions and swelling. Due to the poor prognosis of this disease, precise early diagnosis
of these tumors can help clinicians plan appropriate treatment to prevent tumor extension
and reduce the risk of metastasis, leading to the improved prognosis of patients.
