Mucosal melanoma – diagnostic challenge

INTRODUCTION

Mucosal melanoma malignum (mMM) is defined as a malignant tumor originating from melanocytes, with a primary site on the mucous membranes [1]. The tumor was first described by Weber in 1859 [2]. It is most typically found in the oral and nasopharyngeal cavities, on the conjunctiva, and in the genital region. Less common sites include the mucous membranes of the digestive, respiratory, and urinary tracts [3, 4]. Mucosal melanoma requires differentiation from a metastasis of a primary cutaneous melanoma [5].
Mucosal melanoma malignum is an uncommon malignancy, accounting less than 0.8–3.7% (on average approximately 1%) [3] of all diagnosed melanomas [4, 6, 7]. While being rare, mucosal melanomas have a far worse prognosis compared to cutaneous melanomas [4]. This is attributed to their aggressive growth and the often asymptomatic nature of the lesions leading to the diagnosis being made at the advanced disease stage [3]. Moreover, the oral and genital regions are difficult to self-examine due to their specific location, and they are frequently overlooked by physicians during dermatological examinations. However, early diagnosis is crucial for prognosis [3].
The article reviews the current medical knowledge of mucosal melanoma with the aim of presenting key information on the molecular characteristics, diagnosis and treatment of mMM. A particular emphasis is placed on melanoma developing in the oral cavity and genital mucosa (figs. 1 A–D).

EPIDEMIOLOGY

Contrary to the increasing incidence of cutaneous melanomas, the occurrence of mucosal melanoma malignum is believed to be stable [4, 8]. Mucosal melanoma malignum accounts for 1.3% to 6.8% of all diagnosed melanoma types. However, there are significant discrepancies in the data reported in the literature [8–10]. Mucosal melanoma usually develops between the fourth and seventh decades of life [8]. The mean age at diagnosis is approximately 70 years [4, 7], and the disease is diagnosed on average 13 years later than in patients with cutaneous melanoma [11].
The risk of the disease is known to increase with age [12]. Based on available reports, women are more frequently affected by mMM compared to men, which may be attributed to the higher incidence of melanoma developing in the vulva and vagina, as opposed to the male genital mucosa which are more readily accessible during routine examinations [13]. However, men are slightly more prone to developing primary melanoma of the oral mucosa compared to women [8]. No correlation has been found between the prevalence of mMM and race [1, 4], unlike in cutaneous melanoma, which is more prevalent among the Caucasian population [4]. Mucosal melanomas are usually diagnosed at a late disease stage. Lymph node involvement at diagnosis is found in 21% of head and neck mMM cases, 23% of vulvar and vaginal mMM cases, and 61% of anorectal mMM cases [14]. By comparison, in patients with cutaneous melanoma, lymph node involvement is observed in only 9% of cases. Distant metastases are present in 23% of patients at the time of mMM diagnosis [7].
Melanoma can occur on the mucous membrane in any location [6]. The most common primary sites of mMM are the head and neck region (55.4%), female genital organs (18%), and the rectal and anal area (23.8% of cases) [10]. Rare cases of melanoma arising in the mucous membranes of the gastrointestinal tract, respiratory system, and urinary tract have also been documented [4].

PATHOGENESIS

The risk factors associated with the development of mMM remain poorly understood [12]. No links have been found between mucosal melanoma development and HSV (herpes simplex virus), HHV (human herpes virus), and pylomavirus infections [1]. Some literature reports suggest that mechanical tissue irritation and smoking may be implicated as risk factors, but this hypothesis has not been definitively confirmed [4, 8]. In contrast to primary cutaneous melanoma, exposure to sunlight does not increase the risk of developing mMM [1].
The biological progression of mucosal melanoma differs significantly from that of cutaneous melanoma [14]. Rich blood and lymphatic vascularization of the mucosa expedites tumor progression within the affected tissue [4, 10, 15].
The exact pathogenesis of mMM still remains incompletely understood [4]. Studies have shown that structural gene mutations in tumor cells play a more significant role in the pathogenesis of mMM, while point mutations are comparatively less important than in cutaneous melanoma [16, 17].
It needs to be stressed that mmM because of its pathogenesis unrelated to UV radiation is characterized by a lower tumor mutational burden (TMB) compared to cutaneous melanoma [16]. Also, mucosal melanoma is distinguished by lower rates of BRAF and NRAS mutations, which are significantly more prevalent in cutaneous melanoma. In contrast, SF3B1 and KIT mutations are reported considerably more frequently in mMM compared to cutaneous melanoma [9, 14, 16, 18–20]. Such substantial differences in genetic factors underlying mucosal and cutaneous melanomas may result in varied response to standard treatment [21]. It is important to highlight that specific mutation variants differ between mMM located in the lower and upper body [14, 17], while the expression of vascular endothelial growth factor (VEGF) plays a significant role in the progression of oral mucosal melanoma [22].
The WHO histopathological classification of melanocytic lesions distinguishes the following mucosal melanoma types: a. lentiginous mucosal melanoma and b. nodular mucosal melanoma [23].

CLINICAL CHARACTERISTICS

Mucosal melanoma usually develops on previously normal mucosa. In a proportion of patients (30–37%) [8], mMM arises from a pigmented nevus that is initially considered benign [3, 24]. Most cases of mMM are either asymptomatic or mildly symptomatic in the early stage of progression [15, 25], and 20% of all mucosal melanomas are amelanotic melanomas [15].

Oral mucosal melanoma

Oral mucosal melanoma accounts for 0.5–0.7% of all oral malignancies [8]. The available data indicates that mMM does not occur with equal frequency in all oral mucosal sites [26]. Most commonly, it is located on the mucosa of the hard palate and on the maxillary gingiva (approximately 70% of cases) [8, 12, 24, 26–29]. Less frequently, mMM may be found on the mandibular gingiva, floor of the mouth, mucosa of the lips, cheeks, tongue, and tonsils [26].
The appearance of the primary lesion can vary significantly. Usually, mMM presents as a plaque or nodule located on the mucosal surface, varying in color from brown to black. Areas of red or violaceous pigmentation along with depigmented patches may be visible [30]. Skin lesions typically exhibit asymmetry and irregular margins [27]. Usually, they are over 6 mm in diameter and characterized by continuous growth [24]. Lymph node involvement is present in one-third of patients at the time of diagnosis, while ulceration of the primary lesion is found in less than one-third of cases [8].
Bleeding and ulceration typically manifest in the later stages of the disease [31]. In the advanced stage of mMM, patients may also experience tooth mobility, a sensation of ill-fitting dentures, and paresthesias [28]. Occasionally, satellite foci around the primary lesion are found [8]. Cases of amelanotic melanoma in the oral cavity have also been reported in the literature [8, 32, 33].

Mucosal melanoma of the female genital tract

Up to 76% of melanomas affecting the female genital area develop in the vulva [34]. The most prevalent sites of mMM in this body location are the labia majora (approximately 50%), labia minora (less than 20%), and Bartholin glands (less than 5% of cases) [13]. Cases of melanoma with the primary site on the clitoris have also been reported [35, 36]. Only 19% of lesions have their primary site in the vagina [34].
In the early stages of the disease, mMM manifests as a flat or elevated nevus [25], whereas in later stages, the cancer may take on the appearance of a polypoid tumor [37]. Vulvar melanoma may be accompanied by symptoms such as bleeding, pain, pruritus, and abnormal vaginal discharge [7, 37, 38]. In 40% of cases, involvement of regional lymph nodes or distant metastases are observed at the time of diagnosis [34].
Melanomas affecting the mucous membranes of the oral cavity and female genital organs are typically diagnosed in the phase of radial growth. In contrast, lesions located in difficult-to-visualize regions – like the nasal sinuses and internal organs – are frequently identified when the cancer manifests as a sizable tumor infiltrating surrounding tissues [1].

STAGING

The foundation for the diagnosis of mMM is histopathological examination of the whole surgically removed lesion [39]. Determining the stage of mucosal MM can be difficult due to the absence of a standardized classification system. The staging of mucosal melanomas of the head and neck region relies on The American Joint Committee Cancer (AJCC) [40] tumor/node/metastasis (TNM) classification. The TNM staging is only suitable for evaluating mMM in the head and neck area [4, 41].
Local tumor progression is determined through a comprehensive assessment of the entire skin surface for any other unusual-looking pigmented or satellite lesions, palpation of cervical lymph nodes, and imaging studies such as computed tomography (CT) or magnetic resonance imaging (MRI). An orthopantomogram of the mandible and maxilla can also be performed as an optional procedure [39, 41]. Routine imaging is not advised in patients with stage pT1a melanoma. In higher T stages (pT1b-pT4b), ultrasound evaluation of regional lymph nodes is recommended prior to scar removal, in conjunction with sentinel node biopsy [39]. The overall tumor stage is determined by contrast-enhanced CT of the chest, abdomen, and pelvis, and MRI or CT of the head with contrast [41]. Positron emission tomography (PET-CT) and MRI of the brain should be performed to systematically assess the advancement of the disease [42]. According to Polish guidelines for the diagnostic and therapeutic management of melanoma, in the absence of clinical symptoms, imaging studies such as CT of the chest, abdomen, and pelvis, PET-CT, and MRI of the brain are not recommended [39].
Breslow thickness measuring the depth of tissue infiltration by melanoma cells from the granular layer of the epidermis, expressed in millimeters, is the most crucial prognostic factor for patients diagnosed with cutaneous melanoma [43]. However, this method is unsuitable for predicting the prognosis of patients with mMM since no differences in patient prognosis are observed based on the depth of infiltration [3]. Melanoma affecting the mucous membranes of the genitals, irrespective of the depth of invasion, carries a poorer prognosis compared to cutaneous melanoma [43].
Laboratory tests are not routinely performed in patients with mMM, but in stage IV disease, lactate dehydrogenase (LDH) measurement is recommended [39].

DERMOSCOPY

Dermoscopy plays an important role in the differential diagnosis of melanoma with benign pigmented lesions. A significant challenge associated with using this method for the evaluation of mucous membranes lies in their uneven surface and anatomical constraints, particularly within the oral cavity and in the genital regions [7, 15]. Furthermore, the dermoscopic picture may be influenced by the stretching of the mucosa during the examination, which is a common maneuver in the dermoscopic examination of areas with the resticted access [15].
The most common changes associated with melanoma of the vulvar and vaginal mucosa seen on dermoscopy include asymmetry in structure and color (91.7%), blue-white veil or white-gray areas (68.4%), areas of regression (47.4%), irregular dots and globules (42.1%), atypical and irregular pigment network (34.2%) [24].
Since oral mucosal melanoma is rare, there are only limited reports of the dermoscopic features of this condition in the available literature. Matsushita et al. [44] reported a case of mucosal melanoma located on the lip, which on dermoscopy showed features including irregular pigmentation, pseudoreticular pattern, blue-white veil, and areas of regression [44]. These features were recognized as characteristic not only for melanomas arising at the mucocutaneous border but also for those involving the oral mucosa [45].
Based on a retrospective study, Blum et al. [46] found that the combination of blue, gray, or white colors with structureless areas was the key factor distinguishing malignant from benign mucosal lesions. Kamińska-Winciorek et al. [47] described the evolution of dermoscopic findings in melanoma located on the upper lip. Initially, a multi-element pattern was observed, comprising both homogeneous and partially annular patterns. Over a course of several months, a blue veil with areas of regression appeared. One year later, pseudoreticular, homogenous, and non-specific patterns were reported. On the periphery of the lesion, annular-granular structures were identified.
Lin et al. summarized the most common dermoscopic features of melanoma of the mucous membranes and the mucocutaneous junction, which include structural asymmetry, blue-white veil, irregular dots or globules, areas of regression, spots, irregular vessels, and an irregular pigment network [48].
The role of dermoscopy in the early detection of mucosal melanoma is limited by the absence of standardized diagnostic criteria [15], Throughout the years, many schemes and algorithms have been developed to aid in the assessment of suspected malignant lesions on the skin. To date, dermoscopic features of many benign lesions located within the mucous membranes (mucoscopy) have been described. However, because of the limited number of mucosal melanoma cases, the understanding of typical dermoscopic changes associated with this tumor is limited [25, 49].

DIFFERENTIAL DIAGNOSIS AND WORKUP OF mMM

The differential diagnosis of mucosal melanoma is presented in table 1 [7–9, 29].
An excisional biopsy of a focal lesion in the oral cavity is recommended for lesions larger than 5 mm in diameter or if there are changes in appearance during the follow-up. In addition, excisional biopsy should be performed independently in patients with concerning clinicodermoscopic findings and medical history. For diffuse lesions, a targeted biopsy is recommended if morphological evolution is observed during the follow-up period or there is suspicion of melanoma [8].

TREATMENT

Treatment of mMM poses a major challenge. No clear recommendations for the therapy of this type of neoplasm have been developed yet. According to the most recent guidelines, complete excision of the primary lesion is the preferred treatment for mucosal melanoma [4] and the sole option for achieving complete cure [50]. Given their anatomical location, these lesions pose challenges in surgical removal with sufficient margins. This applies in particular to cases of mucosal lentiginous melanoma, where it can be difficult to ascertain tumor cell-free margins [51]. Recommended surgical margins have not yet been established [39].
Sentinel node involvement is not considered to be a prognostic factor for mucosal melanoma. Opinions on whether resection of local lymph nodes is a recommended approach after sentinel node involvement is identified are divided because of the high rate of distant metastases [52].
It is important to highlight that patients with mucosal melanoma exhibit considerably poorer response to immunotherapy and systemic treatments compared to patients with cutaneous melanoma [53].
According to current guidelines, patients with metastatic mucosal melanoma should be treated with combination immunotherapy comprising an anti-PD-1 immune checkpoint inhibitor (ICI), i.e. an anti-programmed cell death 1 antibody, along with an anti-CTLA-4 agent, i.e. antibody targeting the cytotoxic T-lymphocyte-associated antigen 4 (recommendation level: B) [54].
In their study, Yan et al. [55] found that the addition of bevacizumab to carboplatine and paclitaxel resulted in a significant increase in progression-free time and expected survival of mMM patients with distant metastases. The study showed the importance of anti-angiogenic therapies for the effective management of mMM. Furthermore, a study by Li et al. [21] provided evidence supporting the anticancer activity of toripalimab combined with axitinib in patients with advanced mMM along with extension of patient survival following treatment with this combination. Combination therapies are more effective in treating mMM compared to monotherapy. Anti-angiogenic drugs in conjunction with immunotherapy using immune checkpoint inhibitors represent the most promising approach to improve the prognosis of patients [53].
In addition, postoperative radiation therapy is recommended to reduce the rate of local recurrence following excision of the primary lesion in the head and neck region [52]. Radiation therapy should be considered when surgical resection is incomplete or primary tumor resection is not possible [7]. However, it does not contribute to improving long-term survival rates [20].
New therapeutic options are continuously being sought for the treatment of patients with mucosal melanoma and distant metastases [47].

PROGNOSIS

The overall five-year survival rate for mucosal melanoma ranges from 0% to 45% [3, 4], with an average survival of 2 years [15]. The five-year survival rates for vulvar, vaginal and oral melanoma are 58%, 27%, and 15–38%, respectively [27, 34], while the five-year survival rate for primarily cutaneous melanoma may be as high as 92% [25].
Key factors known to improve patient prognosis include early diagnosis [15] and complete excision of the lesion [51]. Other factors impacting patient prognosis include age, stage at diagnosis, distant metastases, tumor size, lymph node involvement, histological type, number of mitotic figures, and the presence of ulceration, lymphatic involvement, perineural invasion, and satellite metastases [25].

CONCLUSIONS

Considering the aggressive nature, poor prognosis, and frequent delays in the diagnosis of mucosal melanoma, dermatologists and clinicians of other specialties should conduct regular examinations of the oral cavity and genital mucosa as part of routine patient check-ups. Moreover, educating patients about the possibility of melanoma developing not only on the skin but also on the mucosa might expedite the diagnosis of malignant lesions in these body areas.
Patients should be encouraged to regularly self-examine their mucous membranes, and informed that in case of any concerning changes, they should promptly seek medical attention. It is important to bear in mind that the most significant prognostic factor for patients with mMM is tumor stage at a time of diagnosis, which determines the possibility of radical resection of the lesion.

FUNDING

The study has been conducted as part of statutory activity of the Medical University of Lodz (project No. 503/1-152-01/503-11-002).

ETHICAL APPROVAL

Not applicable.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

References