Open Access

An updated review of mucosal melanoma: Survival meta‑analysis

  • Authors:
    • Hyung Min Hahn
    • Kyoung Geun Lee
    • Won Choi
    • Seung Hyun Cheong
    • Ki Bum Myung
    • Hyung Jin Hahn
  • View Affiliations

  • Published online on: May 29, 2019     https://doi.org/10.3892/mco.2019.1870
  • Pages: 116-126
  • Copyright: © Hahn et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Mucosal melanoma (MM) is a highly lethal variant of melanoma that carries a poor prognosis. Extremely low incidence and survival rates have led to few clinical trials, and a lack of protocols and guidelines. The present study performed a survival meta‑analysis for the quantitative synthesis of available evidence to search for key patterns that would help clinicians tailor optimal therapeutic strategies in MM. PubMed, EMBASE, Cochrane, MEDLINE, Google Scholar and other databases were searched. Hazard ratios, in disease‑specific and overall survival, were calculated for each of the survival‑determining variables. MM was 2.25 times more lethal than cutaneous melanoma (CM). The most significant threats to survival were advanced Tumor‑Node‑Metastasis stage, sino‑nasal location, and old age. Chemotherapy was the most effective form of adjuvant therapy. Disease‑specific survival, the primary measure of the effect sizes, can fluctuate depending on the accuracy of the reported cause of mortality. In conclusion, MM is a peculiar type of melanoma, with clinical and molecular profile vastly different from the much‑familiar CM. In the wake of the era of precision oncology, further studies on driver mutations and oncogenic pathways would likely lead to improved patient survival.

Introduction

Mucosal melanoma (MM) represents a highly aggressive variant of malignant melanoma that arises within the resident melanocytes of mucous linings. Comprising barely one-hundredth fraction of all melanomas, it is an entity that is notorious for the infinitesimal 5-year survival rate (<25%) (1). Although MM is often understood as a blanket term for any extracutaneous melanoma, it nevertheless comes with somewhat hazy disease definition; some authors regard uveal or conjunctival melanomas as bona fide MM, while others are less inclined to label the ocular tumours as such. The head and neck (H&N) is cited as the region most heavily represented (~50%), followed by the ano-rectum, and the female genital tract (FGT) (2). The insidious nature of the disease compounds accurate diagnosis, depriving the affected of any remaining chance for an early detection. Failure to intervene early often boomerangs with the amplified lethality, which is the hallmark of the mucosal disease.

Given the miniscule incidence and patient survival rate, randomised clinical trials (RCT) have been understandably difficult to come by. The resulting paucity of evidence have long clouded our understanding of tumour behaviour. Field clinicians facing therapeutic decisions inevitably suffer from general lack of consensus over virtually all aspects of the disease, from staging to management. While it is tempting to extrapolate from CM-derived data, the notion, that MM is fundamentally a distinctive entity, is now considered canonical (3). Such discrepancies include female preponderance, limited role of UV (ultraviolet) light, and mutation status (4). The different makeup of mutation landscape is thought to be the impetus that drives the divergence between the two (57).

In the present meta-analysis and systematic review, the authors present a comprehensive assessment of available evidence to elaborate crucial factors that determine clinical outcome in MM.

Materials and methods

Data collection and inclusion criteria

Literature search was conducted using multiple engines, most notably but not limited to, PubMed, EMBASE, Cochrane, MEDLINE, and Google Scholar, up to March of 2018. The query employed various keywords, such as ‘mucosal malignant melanom’, ‘anorectal melanoma’, ‘sino-nasal melanoma’ and ‘survival’; the search was intended to include any abstract proceedings or graduate theses [www.thesis.de], so as not to discount ‘grey’ literature from the study. No restriction was applied in terms of the language of publication. The following criteria were considered for selection: i) primary mucosal melanomas, ii) reporting of Kaplan-Meier survival analysis results, or iii) Cox regression analysis with time-to-event information. Where HR were not explicitly given, they were imputed using the method described by Tierney et al (8). Excluded were studies i) on leptomeningeal melanomatosis, ii) based on cell lines iii) performed on canine, murine or other non-human subjects. The present study was conducted in accordance to the Meta-analysis of Observational Studies in Epidemiology guidelines for the reporting of meta-analyses of observational studies (MOOSE) (9).

Statistical analysis

The principal parameter of effect size (ES) reporting used in the study was hazard ratio (HR), in terms of melanoma-specific survival (=disease-specific survival, DSS) and overall survival (=all-cause survival, OS). The main surrogate for detecting between-study heterogeneity was the I2 statistic. The assumption of homogeneity was considered valid if I2 was <50%, in which cases the fixed effect model was used; for all other cases, the random effect model was used. Before incorporating a study into analysis, sensitivity testing was performed to decide if there was a pulling effect by single studies with substantial weight. Publication bias was assessed with funnel plots and Egger test. Statistical analyses were carried out with Comprehensive Meta-Analysis Software (v3.0; Biostat, Englewood, NJ, USA). P<0.05 were considered to indicate a statistically significant difference.

Results

PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) (10) flow diagram of the search strategy, and characteristics of the included studies are given in Fig. 1 and Table I, respectively. Search query using the aforementioned keywords initially returned 1,459 articles from 8 different databases, of which 52 were deemed to suit our agenda. All the studies originated from three continent regions: North/Central America (18, 34.6%), Asia/Indian subcontinent/Oceania (21, 40.4%), and the European Union (13, 25.0%). Topographically, 27 studies (51.9%) were on head and neck region (MMHN), 4 (7.7%) on gastrointestinal tract, 3 (5.8%) on urinary/female genital tract, and 18 (34.6%) on all mucosal sites. Potential survival variables were arbitrarily categorised into three groups: i) host factors, which is demographic characteristics of the affected individual, ii) tumour factors, relating to various aspects of tumour histology, behaviour, and staging, and iii) treatment factors, which are parameters that assess the impact of differing treatment modalities on survival.

Table I.

Characteristics of included studies.

Table I.

Characteristics of included studies.

Author, year CountrybLocationNo. of patientsFollow-upRef.
Abugideiri et al, 2016USAH&N39 (SRT=27; S=12)Median 8.1 years17
Ahn et al, 2010KoreaH&N32 (SRT=16; S=16)Median 25.3 months18
Aiempanakit et al, 2018ThailandAll mucosal17 (S=14, UN=3)Median 18.2 months19
Ajmani et al, 2017USASN704 (SRT=399; S=305)NR20
Amit et al, 2018USASN198 (SRT=81; S=79; SCRT=24; C or CRT=14)Median 26 months21
D'Angelo et al, 2016USAAll mucosal889 (ipilimumab and nivolumab)6.2 months22
Benlyazid et al, 2010FranceH&N160 (SRT=78; S=82)Median 65.2 months23
Bishop and Olszewski 2014USAAll, including CMa229,976 (NR)NR24
Chiu and Weinstock, 1996USAOC40,320 (NR)NR25
Ciarrocchi et al, 2017ItalyAnorectum208 (SRT=32; S=167)Median 14 months26
Ercelep et al, 2016TurkeyAll mucosal229,976 (NR)Median 27 months27
Harada et al, 2016JapanOesophagus10 (S=10)NR28
Hasebe et al, 2017JapanH&N85 (RT=85)Median 42.5 months29
Heinzelmann-AustraliaVulva33 (NR)NR30
Schwarz et al, 2014
Heppt et al, 2017GermanyAll mucosal444 (NR)NR31
Hughes et al, 2013AustraliaAll, including CMa485 (Lymphadenectomy)Median 17.4 months32
Jang et al, 2014KoreaAll, including CMa206 (S=197; C=46; RT=31)NR33
Kang et al, 2018ChinaAll mucosal60 (NR)Median 36 months34
Khan et al, 2014USASN567 (NR)NR35
Kirchoff et al, 2016USAAll mucosal227 (S=53; S + other=174)NR36
Kirschner et al, 2013USAVagina201 (SRT=53; S=87; RT=30)Median 14 months37
Kong et al, 2016ChinaAll, including CMa412 (NR)Median 31 months38
Konuthula et al, 2017USASN695 (SRT=271; S=206; SC=29; SCRT=49; C=21; RT=42)NR39
Koto et al, 2017JapanH&N260 (RT=105; CRT=155)Median 22 months40
Kuk et al, 2016KoreaOC39 (S=22; S + C or RT=17)NR41
Lansu et al, 2018NetherlandsSN63 (SRT=63)Median 23 months42
Lawaetz et al, 2016DenmarkH&N98 (SRT=26; S=49; SC=2; SCRT=2; RT=8; None=8)Median 24.5 months43
Lee et al, 2017KoreaH&N31 (SRT=13; S=9; SC=7; SCRT=2)Mean 9 months44
Lee et al, 2017USAOC232 (NR)NR45
Lombardi et al, 2016ItalySN58 (SRT=13; S=42; SCRT=3)Median 30 months46
Mücke et al, 2009GermanyOC10 (NR)NR47
Nakamura et al, 2018JapanAll mucosal45 (checkpoint inhibitors)NR48
Oba et al, 2011JapanAll, including CMa78 (NR)Median 40 months49
Pandey et al, 2002IndiaH&N60 (SRT=6; S=17; SC=3; SCRT=1; C=8; RT=7)NR50
Pfeil et al, 2011GermanyAll mucosal172 (NR)Median 24 months51
Plavc et al, 2016SloveniaH&N61 (SRT=14; S=17; C=1; RT=15)Median 16.5 months52
Roh et al, 2016KoreaAll mucosal392 (NR)Mean 55.4 months53
Samstein et al, 2016USASN78 (SRT=64; S=14)Median 21 months54
Sanchez et al, 2016USAGenitourinary tract1,586 (NR)NR55
Schaefer et al, 2017GermanyAll mucosal75 (checkpoint inhibitors)NR56
Schmidt et al, 2017USAH&N1,368 (SRT=704; S=566; RT=98)Median 55.2 months57
Shoushtari et al, 2017USAAll mucosal81 (NR)NR58
Shuman et al, 2011USAH&N52 (SRT=15; S=13; SC=18; NR=6)Median 97 months59
Song et al, 2016ChinaOC62 (NR)Median 32.5 months60
Sun et al, 2014ChinaSN65 (SRT=13; S=18; SC=9; C=6; RT=4; CRT= 2)NR61
Tchelebi et al, 2016USARectum63 (SRT=18; S=45)Median 17 months62
Thariat et al, 2011FranceSN155 (NR)Median 37 months63
Wang et al, 2013ChinaOC81 (NR)NR64
Wen et al, 2017ChinaAll mucosal52 (checkpoint and PD-1 inhibitors)NR65
Won et al, 2015KoreaSN155 (NR)NR66
Yeh et al, 2006USAAnorectum46 (S=23; C=23)Median 29 months67
Yi et al, 2011KoreaAll, including CMa95 (NR)Median 41 months68

a Included for purpose of comparison with mucosal melanoma

b For multi-national groups, only the nationality of 1st author was listed. H&N, head and neck; SN, sino-nasal; CM, cutaneous melanoma; OC, oral cavity; S, surgery only; C, chemotherapy only; RT, radiotherapy only; SRT, surgery plus radiotherapy; SC, surgery plus chemotherapy; CRT, chemotherapy plus radiotherapy; SCRT, surgery plus chemotherapy plus radiotherapy; NR, not reported.

Host factors
Age

With respect to younger individuals (<50 years), the HR for those in the seventh decade of life was 1.3 (HR=1.31; 95% CI, 1.19–1.45; P=0.00). The disease-specific hazards for patients in their 70's were 1.7 (HR=1.69; 95% CI, 1.62–1.77; P=0.00). A similar pattern was seen with overall survival. There was no evidence of heterogeneity in any of the subgroups (Fig. 2).

Sex

The HR for males was calculated to be 1.1 (HR=1.11; 95% CI, 0.93–1.31; P=0.26). The value was similar for OS (HR=1.12; 95% CI, 1.03–1.23; P=0.01). No statistical heterogeneity was found (I2=32.14).

Ethnicity

Pooled HR, with non-Hispanic white Caucasians as reference, was computed for patients with African, Asian/Pacific Island, and other (including white Hispanic, Native American and Mestizos) ancestries. Compared to Caucasian individuals, the hazard to overall survival for non-Caucasians as a whole was ~1.4 (HR=1.39, 95% CI, 1.06–1.82; P=0.02). Apart from the overall death risk, ethnicity of the affected per se did not have seem to be a major influence on survival (Table II).

Table II.

Hazard ratios for non-Caucasian ethnicities.

Table II.

Hazard ratios for non-Caucasian ethnicities.

Ethnicity comparisonSurvivalNo. of studiesPooled HR95% CIZ-valueP-valueI2
Non-Caucasian vs. CaucasianDSS51.121.05–1.203.3540.0010.0001
Non-Caucasian vs. CaucasianOS31.391.06–1.822.3580.0180.0001
Afro-American vs. CaucasianDSS61.130.95–1.341.4210.1554.451
API vs. CaucasianDSS21.090.80–1.490.5630.57491.47

[i] HR, hazard ratio; CI, confidence interval; DSS, disease-specific survival; OS, overall survival; API, Asian and Pacific Islander.

Comorbidities and ‘High-risk’ lifestyle

Having one or more major comorbidities showed a weak correlation to increased risk in all-cause mortality (HR=1.43, 95% CI, 1.01–2.04; P=0.04). On the other hand, the mode of life traditionally considered ‘high-risk’-e.g., sedentariness, obesity, smoking-was found to be a significant threat to neither disease-specific (HR=1.41, 95% CI, 0.98–2.03; P=0.07) nor overall (HR=1.24, 95% CI, 0.98–1.56; P=0.14) survival.

Tumour factors
Cutaneous melanoma

The relative lethality of MM vs. CM was 2.25 (HR=2.27, 95% CI, 1.96–2.62; P=0.00). No significant heterogeneity was detected across the studies (I2=26.41; Fig. 3).

Location

A primary lesion originating within the sino-nasal (SN) cavity was found to be 1.4 times more deadly compared to other locations (HR=1.44; 95% CI, 1.28–1.63; P=0.00). The HR for OS was nearly 2.0 (HR=1.93; 95% CI, 1.59–2.33; P=0.00). Head and neck lesions (MMHN) as a whole showed an HR of 1.4 (HR=1.35; 95% CI, 1.02–1.79; P=0.00) for overall survival.

Multifocal disease

MM is a devastating cancer partly because of its tendency to arise from multiple foci. The associated disease-specific death risk was nearly 3.0 (HR=2.95; 95% CI, 2.72–3.19; P=0.00).

Clinical staging (MMHN)

The TNM staging system, developed by the American Joint Committee on Cancer (AJCC), is one of the most widely accepted standards for MMHN staging and conventionally the most accurate predictor of survival. T4 disease (T4a and T4b) was 2.4 times more fatal than T3 tumours (95% CI, 1.75–2.98; P=0.00). Meanwhile, N1 disease had an HR of 2.0 compared to N0 (HR=1.90; 95% CI, 1.62–2.23; P=0.00). For metastatic diseases (M1), the HR was 3.2 (HR=3.17; 95% CI, 2.72–3.70; P=0.00; Fig. 4).

Clinical features/Macro-morphology

Elevated lactate dehydrogenase (LDH) level was associated with the greatest HR for disease-specific survival (HR=2.06; 95% CI, 1.56–2.72; P=0.00). Higher performance score (PS) was correlated with increased risk for OS (HR=1.71; 95% CI, 1.32–2.21; P=0.00). Ulceration of primary lesions was also linked to unfavourable OS. The verdict on pigmentation (HR=0.87; 95% CI, 0.66–1.15; P=0.34), necrosis, and nodularity of primary tumours was inconclusive (Table III).

Table III.

Hazard ratios for clinical/macro-morphological features.

Table III.

Hazard ratios for clinical/macro-morphological features.

Feature comparisonSurvivalNo. of studiesPooled HR95% CIZ-valueP-valueI2
Elevated LDH vs. WNLDSS42.061.56–2.725.1040.0010.001
PS>1 vs. PS<0OS41.711.32–2.214.1120.0010.001
Ulceration vs. no ulcerationDSS31.320.91–1.901.4650.1436.401
Ulceration vs. no ulcerationOS41.441.04–2.012.1910.21532.95
Pigmentation vs. no pigmentationOS30.930.70–1.250.4640.6420.001
Necrosis vs. no necrosisDSS21.290.96–1.731.7080.0880.001
Necrosis vs. no necrosisOS20.960.55–1.680.0130.98972.12

[i] LDH, lactate dehydrogenase; PS, performance score HR, hazard ratio; CI, confidence interval; DSS, disease-specific survival; OS, overall survival.

Microscopic features

Margin status was the most important micro-morphological determinant of survival. The HR attributed to margin positivity was nearly 2.0 (HR=1.85; 95% CI, 1.34–2.54; P=0.00). The effect of perineural invasion (PNI) and lympho-vascular invasion (LVI) was not statistically significant. Meanwhile, Breslow thickness, depth of invasion, and mitotic count did not seem to play a significant role in either terms of survival (Table IV).

Table IV.

Hazard ratios for microscopic features.

Table IV.

Hazard ratios for microscopic features.

Feature comparisonSurvivalNo. of studiesPooled HR95% CIZ-valueP-valueI2
(+) Margin vs. (−) marginDSS101.851.34–2.543.7590.00123.84
(+) Margin vs. (−) marginOS101.591.21–2.083.3650.00144.22
Breslow >1 mm vs. Breslow <1 mmDSS61.070.99–1.191.7550.07929.63
Breslow >1 mm vs. Breslow <1 mmOS31.070.99–1.171.6210.10511.23
Invasion >2 mm vs. invasion <2 mmDSS32.020.68–6.031.2590.20881.02
Invasion >2 mm vs. invasion <2 mmOS42.021.26–0.232.9130.0040.001
Mitosis (+) vs. mitosis (−)DSS41.091.03–1.152.8750.0040.001
Mitosis (+) vs. mitosis (−)OS41.061.01–1.122.4050.0160.001
PNI vs. PNI (−)DSS22.080.97–4.41.8840.0642.65
Lymphovascular invasion vs. no invasionDSS31.240.94–1.641.5370.1240.001
Epithelioid type vs. non-epithelioidDSS31.290.94–1.781.5610.1180.001

[i] PNI, perineural invasion; HR, hazard ratio; CI, confidence interval; DSS, disease-specific survival; OS, overall survival.

Treatment factors
Extent of treatment

Radical operation was found to amplify overall death risk by 2.5 (HR=2.61; 95% CI, 2.04–3.34; P=0.00); When surgery was the sole modality of treatment, it was associated with a significant risk elevation in both terms of survival (HR of 1.72 and 2.21, respectively). Conversely, when any modality but surgery was used, similar increase in mortality was observed. For therapeutic regimen consisted entirely of chemotherapy, the attributed risk in mortality was around 1.5. Meanwhile, radiotherapy (RT) apparently carried the least detriment to patient survival as monotherapy.

The value of lymphadenectomy for primary tumours in the cephalo-cervical subsite was dubious (HR=0.86; 95% CI, 0.73–1.02; P=0.07). Likewise, endoscopic resection showed neither inferior nor superior results compared to the more traditional approach in terms of survival benefit (P=0.83 and 0.68, respectively; Table V).

Table V.

Hazard ratios for different modalities of treatment.

Table V.

Hazard ratios for different modalities of treatment.

Modality comparisonSurvivalNo. of studiesPooled HR95% CIZ-valueP-valueI2
Radical op. vs. Conservative TxOS52.612.04–3.3415.0790.00155.35
Op. alone vs. SC/SRTDSS111.781.55–2.058.1920.00130.85
RT alone vs. SRTDSS51.291.08–1.542.8310.00519.37
RT alone vs. SRTOS41.521.35–1.707.0870.00126.97

[i] Op., operation; RT, radiotherapy; SC, surgery plus chemotherapy; SRT, surgery plus radiotherapy; HR, hazard ratio; CI, confidence interval; DSS, disease-specific survival; OS, overall survival.

Adjuvant therapy

Adjuvant chemotherapy was found to reduce both disease-specific and overall death by some 30 percent. The therapeutic regimen included cisplatin/tamoxifen, dacarbazine (DTIC), and interferon-γ (INF-γ). RT, while also significantly effective, tended to be somewhat less efficacious (HR=0.84; 95% CI, 0.82–0.86; P=0.01; Fig. 5).

Immunotherapy

Immunotherapy, usually involving PD-1 (programmed death protein-1), immune checkpoint inhibitors (e.g., CTLA-4), or a combination of the two, was shown to more effective for MM than CM. The pooled HR was 0.49 (95% CI, 0.37–0.65; P=0.00; Fig. 6) for overall survival. No inter-study heterogeneity was found across the studies (I2=0.00).

Discussion

The present meta-analysis had aimed to provide an updated review on various aspects of MM, with data from the most recent studies. The genetic and molecular underpinning behind the distinctive biologic behaviour is believed to stem from amplification of c-Kit (11), a receptor tyrosine kinase (RTK). In contrast, b-Raf and n-Ras mutations are infrequent in MM. This oncogenic mutation profile is reminiscent of the acral lentiginous subtype of CM (ALM). Quite fittingly, ALM shares several characteristics with MM in common, namely i) infrequency (1–2% of all CM), ii) delayed detection and hence worse prognosis, and iii) relative preponderance in non-Caucasian ethnic groups.

Although what is known about MM pales in comparison to the cutaneous disease, a few generalities can be drawn from our analysis: in the authors' estimation, MM was two-and-a-quarter times more life-threatening than CM. As a whole, the influence of the ‘host factors’ was not imposing; one pattern that stood out was advanced age. The median age of onset for MM is higher than CM, at 67 years (vs. 55 years for CM). The death risk in this age group was more than 1.5, compared to the younger cohort (<50 years), which might partially account for the higher mortality. While the incidence tends to be higher and the prognosis grimmer for male melanoma patients in general, MM is an exception; it is reasonably well established that MM shows predilection for females (12). Moreover, there seemed to be no respect of sexes with MM when it comes to mortality, although male individuals may be at a slight disadvantage as far as overall survival is concerned. MM is also peculiar from ethnic perspectives because the higher proportion of non-Caucasian patients (especially African and Asian races) (13) is higher. This point is underlined by the fact that 40% of the referenced studies came from regions where the indigenous population is not of white Caucasian ancestry. Nevertheless, racial disparities did not appear to be a major deciding factor in MM-specific mortality. The higher all-cause mortality for non-white cohorts may point to either supposedly superior overall quality of care in Western facilities, or a legitimate, ethno-genetic differences in the ability of the body system to cope with the cancer or mount anti-tumour immune defence against. The fact that undesirable health-related behaviours played negligible role in survival may be one indication that the intrinsic cancer behaviour wields an overriding influence above other variables.

Mucosal melanoma of the head and neck (MMHN), cited as the most common location of MM occurrence overall, also carried the worst prognosis. Tumours in the paranasal sinuses (PNS)-maxillary and ethmoid, etc.-predisposed the individuals to significantly higher disease-specific and overall mortality, with the latter perhaps reflecting the inaccessibility of the subsite, rendering it all the more unfeasible to carry out effective surgical manoeuvres. Tumour thickness would normally be one of objective prognosticators for solid organ cancers. That said, the usefulness of the AJCC clinical stageing system in CM cannot be readily engrafted into mucosal patients, the reason for which is questionable validity of tumour thickness as a prognostic index (14). This notion has been backed by the authors' findings, that neither thickness nor depth of invasion is a significant determinant of survival (Table IV).

Although surgery constitutes the backbone of management strategy in many cases, radical excision seems to be a poor choice of treatment for the considerable morbidity and added mortality associated. Any mono-modality therapy was shown to increase death risk by at least 1.5. For inoperable cases, immunotherapeutic regimen, usually consisting of combination of CTLA-4 and PD-1 inhibitors (e.g., nivolumab and ipilimumab), may be the most rational option. Also, both chemotherapy and radiotherapy were found to be survival-benefitting adjuvant modalities. However, as of now, there is no clearly established formula for specific combination of for chemotherapeutic agents and anti-tumour biologics (‘cocktails’).

The current study was hampered by a few limitations. The validity of disease-specific survival (DSS), the primary measure of effect sizes, is grounded on the premise of the reported cause of death being accurate. This inherent risk can potentially be a limiting factor with cancers such as MM, in which the high lethality can often obscure the true cause of death. In addition, all but two of the included studies came out after the year 2010. This is mainly due to the rarity of the disease, with many studies taking several decades to complete.

In summing up, mucosal melanoma is a highly malignant entity that is difficult to detect, treat, and even study. It is accentuated by an oncogenic profile that is at odds with the more prevalent cutaneous disease. Microscopic frequency, coupled with air of pessimism surrounding the gross ineffectuality of conventional arsenal, may have pushed it into relative obscurity and disinterest. Nonetheless, a body of recent evidence indicates its incidence is on the rise (15,16), and may well be on its way to becoming a force to be reckoned with. Further studies, elaborating on the oncogenic pathways and driver mutations, are needed to improve the overall outlook of this fearsome cancer, especially now that the era of three P's-precision, personalized, and preventive oncology-is looming over the horizon.

Acknowledgements

Not applicable.

Funding

This work was supported by Konyang University Myunggok Research Fund of 16.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Authors' contributions

HMH and KGL designed and conducted the study. HJH and KGL produced the manuscript. WC, KGL, HJH, HMH, SHC and KBM performed the statistical analysis. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Glossary

Abbreviations

Abbreviations:

AJCC

American Joint Committee on Cancer

ALM

acral lentiginous melanoma

CI

confidence interval

CM

cutaneous melanoma

DSS

disease-specific survival

ES

effect sizes

H&N

head and neck

HR

hazard ratio

I2

degree of inconsistency

LDH

lactate dehydrogenase

LVI

lympho-vascular invasion

LRC

loco-regional control

MM

mucosal melanoma

MMHN

mucosal melanoma of head and neck

MSS

melanoma-specific survival

NR

not reported

OC

oral cavity

OS

overall survival

PNI

perineural invasion

PNS

paranasal sinuses

PS

performance score

RCT

randomised controlled trials

RT

radiotherapy

RTK

receptor tyrosine kinase

SN

sino-nasal

UV

ultraviolet

References

1 

Patrick RJ, Fenske NA and Messina JL: Primary mucosal melanoma. J Am Acad Dermatol. 56:828–834. 2007. View Article : Google Scholar : PubMed/NCBI

2 

Tacastacas JD, Bray J, Cohen YK, Arbesman J, Kim J, Koon HB, Honda K, Cooper KD and Gerstenblith MR: Update on primary mucosal melanoma. J Am Acad Dermatol. 71:366–375. 2014. View Article : Google Scholar : PubMed/NCBI

3 

Gru AA, Becker N, Dehner LP and Pfeifer JD: Mucosal melanoma: Correlation of clinicopathologic, prognostic, and molecular features. Melanoma Res. 24:360–370. 2014. View Article : Google Scholar : PubMed/NCBI

4 

Thierauf J, Veit JA, Affolter A, Bergmann C, Grünow J, Laban S, Lennerz JK, Grünmüller L, Mauch C, Plinkert PK, et al: Identification and clinical relevance of PD-L1 expression in primary mucosal malignant melanoma of the head and neck. Melanoma Res. 25:503–509. 2015. View Article : Google Scholar : PubMed/NCBI

5 

Ragnarsson-Olding BK, Karsberg S, Platz A and Ringborg UK: Mutations in the TP53 gene in human malignant melanomas derived from sun-exposed skin and unexposed mucosal membranes. Melanoma Res. 12:453–463. 2002. View Article : Google Scholar : PubMed/NCBI

6 

Zhu W, Li S, Zou B, Liu H and Wang S: Expressions and clinical significance of HER4 and CD44 in sinonasal mucosal malignant melanoma. Melanoma Res. 28:105–110. 2018. View Article : Google Scholar : PubMed/NCBI

7 

Kim SY, Kim SN, Hahn HJ, Lee YW, Choe YB and Ahn KJ: Metaanalysis of BRAF mutations and clinicopathologic characteristics in primary melanoma. J Am Acad Dermatol. 72:1036–46.e2. 2015. View Article : Google Scholar : PubMed/NCBI

8 

Tierney JF, Stewart LA, Ghersi D, Burdett S and Sydes MR: Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 8:162007. View Article : Google Scholar : PubMed/NCBI

9 

Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, Moher D, Becker BJ, Sipe TA and Thacker SB: Meta-analysis of observational studies in epidemiology: A proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 283:2008–2012. 2000. View Article : Google Scholar : PubMed/NCBI

10 

Moher D, Liberati A, Tetzlaff J and Altman DG; PRISMA Group, : Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med. 6:e10000972009. View Article : Google Scholar : PubMed/NCBI

11 

Ohashi A, Funasaka Y, Ueda M and Ichihashi M: c-KIT receptor expression in cutaneous malignant melanoma and benign melanotic naevi. Melanoma Res. 6:25–30. 1996. View Article : Google Scholar : PubMed/NCBI

12 

Postow MA, Hamid O and Carvajal RD: Mucosal melanoma: Pathogenesis, clinical behavior, and management. Curr Oncol Rep. 14:441–448. 2012. View Article : Google Scholar : PubMed/NCBI

13 

Altieri L, Wong MK, Peng DH and Cockburn M: Mucosal melanomas in the racially diverse population of California. J Am Acad Dermatol. 76:250–257. 2017. View Article : Google Scholar : PubMed/NCBI

14 

Luna-Ortiz K, Aguilar-Romero M, Villavicencio-Valencia V, Zepeda-Castilla E, Vidrio-Morgado H, Peteuil N and Mosqueda-Taylor A: Comparative study between two different staging systems for mucosal melanomas of the Head and Neck. Med Oral Patol Oral Cir Bucal. 21:e425–e430. 2016.PubMed/NCBI

15 

Youssef D, Vasani S, Marquess J and Cervin A: Rising incidence of head and neck mucosal melanoma in Australia. J Laryngol Otol. 131:S25–S28. 2017. View Article : Google Scholar : PubMed/NCBI

16 

Marcus DM, Marcus RP, Prabhu RS, Owonikoko TK, Lawson DH, Switchenko J and Beitler JJ: Rising incidence of mucosal melanoma of the head and neck in the United States. J Skin Cancer. 2012:2316932012. View Article : Google Scholar : PubMed/NCBI

17 

Abugideiri M, Patel K, Switchenko JM, Magliocca K, Buchwald ZS, Delgaudio J, Beitler JJ and Khan MK: Adjuvant radiation therapy improved local control for primary mucosal melanoma of the head and neck. Int J Radiation Oncol. 96:E384–E385. 2016. View Article : Google Scholar

18 

Ahn HJ, Na II, Park YH, Cho SY, Lee BC, Lee GH, Koh JS, Lee YS, Shim YS, Kim YK, et al: Role of adjuvant chemotherapy in malignant mucosal melanoma of the head and neck. Oral Oncol. 46:607–611. 2010. View Article : Google Scholar : PubMed/NCBI

19 

Aiempanakit K, Chiratikarnwong K, Auepemkiate S and Sriplung H: Clinicopathologic characteristics and survival outcomes of primary mucosal melanomas: A 10-year retrospective analysis from a single tertiary medical center in Thailand. Zhonghua Pifuke Yixue Zazhi xxx. 1–3. 2018.

20 

Ajmani GS, Liederbach E, Kyrillos A, Wang CH, Pinto JM and Bhayani MK: Adjuvant radiation and survival following surgical resection of sinonasal melanoma. Am J Otolaryngol. 38:663–667. 2017. View Article : Google Scholar : PubMed/NCBI

21 

Amit M, Tam S, Abdelmeguid AS, Roberts DB, Raza SM, Su SY, Kupferman ME, DeMonte F and Hanna EY: Approaches to regional lymph node metastasis in patients with head and neck mucosal melanoma. Cancer. 124:514–520. 2018. View Article : Google Scholar : PubMed/NCBI

22 

D'Angelo SP, Larkin J, Sosman JA, Lebbé C, Brady B, Neyns B, Schmidt H, Hassel JC, Hodi FS, Lorigan P, et al: Efficacy and safety of nivolumab alone or in combination with ipilimumab in patients with mucosal melanoma: A pooled analysis. J Clin Oncol. 35:226–235. 2017. View Article : Google Scholar : PubMed/NCBI

23 

Benlyazid A, Thariat J, Temam S, Malard O, Florescu C, Choussy O, Makeieff M, Poissonnet G, Penel N, Righini C, et al: Postoperative radiotherapy in head and neck mucosal melanoma: A GETTEC study. Arch Otolaryngol Head Neck Surg. 136:1219–1225. 2010. View Article : Google Scholar : PubMed/NCBI

24 

Bishop KD and Olszewski AJ: Epidemiology and survival outcomes of ocular and mucosal melanomas: A population-based analysis. Int J Cancer. 134:2961–2971. 2014. View Article : Google Scholar : PubMed/NCBI

25 

Chiu NT and Weinstock MA: Melanoma of oronasal mucosa. Population-based analysis of occurrence and mortality. Arch Otolaryngol Head Neck Surg. 122:985–988. 1996. View Article : Google Scholar : PubMed/NCBI

26 

Ciarrocchi A, Pietroletti R, Carlei F and Amicucci G: Extensive surgery and lymphadenectomy do not improve survival in primary melanoma of the anorectum: Results from analysis of a large database (SEER). Colorectal Dis. 19:158–164. 2017. View Article : Google Scholar : PubMed/NCBI

27 

Ercelep O, Topcu TO, Bayoglu IV, Ekinci AS, Koca S, Kavgaci H, Ozcelik M, Alacacioglu A, Uzunoglu S, Bozkurt O, et al: Retrospective multicenter evaluation of patients diagnosed with mucosal melanoma: A study of Anatolian Society of Medical Oncology. Tumour Biol. 37:12033–12038. 2016. View Article : Google Scholar : PubMed/NCBI

28 

Harada K, Mine S, Yamada K, Shigaki H, Oya S, Baba H and Watanabe M: Long-term outcome of esophagectomy for primary malignant melanoma of the esophagus: A single-institute retrospective analysis. Dis Esophagus. 29:314–319. 2016. View Article : Google Scholar : PubMed/NCBI

29 

Hasebe M, Yoshikawa K, Nishii R, Kawaguchi K, Kamada T and Hamada Y: Usefulness of 11C-methionine-PET for predicting the efficacy of carbon ion radiation therapy for head and neck mucosal malignant melanoma. Int J Oral Maxillofac Surg. 46:1220–1228. 2017. View Article : Google Scholar : PubMed/NCBI

30 

Heinzelmann-Schwarz VA, Nixdorf S, Valadan M, Diczbalis M, Olivier J, Otton G, Fedier A, Hacker NF and Scurry JP: A clinicopathological review of 33 patients with vulvar melanoma identifies c-KIT as a prognostic marker. Int J Mol Med. 33:784–794. 2014. View Article : Google Scholar : PubMed/NCBI

31 

Heppt MV, Roesch A, Weide B, Gutzmer R, Meier F, Loquai C, Kähler KC, Gesierich A, Meissner M, von Bubnoff D, et al: Prognostic factors and treatment outcomes in 444 patients with mucosal melanoma. Eur J Cancer. 81:36–44. 2017. View Article : Google Scholar : PubMed/NCBI

32 

Hughes MC, Wright A, Barbour A, Thomas J, Smithers BM, Green AC and Khosrotehrani K: Patients undergoing lymphadenectomy for stage III melanomas of known or unknown primary site do not differ in outcome. Int J Cancer. 133:3000–3007. 2013.PubMed/NCBI

33 

Jang HS, Kim JH, Park KH, Lee JS, Bae JM, Oh BH, Rha SY, Roh MR and Chung KY: Comparison of melanoma subtypes among Korean patients by morphologic features and ultraviolet exposure. Ann Dermatol. 26:485–490. 2014. View Article : Google Scholar : PubMed/NCBI

34 

Kang X, Zeng Y, Liang J, Li J, Ren D, Chai L, Sun Z, Yu S, Wu X, Han W, et al: Aberrations and clinical significance of BRAF in malignant melanoma: A series of 60 cases in Chinese Uyghur. Medicine (Baltimore). 97:e95092018. View Article : Google Scholar : PubMed/NCBI

35 

Khan MN, Kanumuri VV, Raikundalia MD, Vazquez A, Govindaraj S, Baredes S and Eloy JA: Sinonasal melanoma: Survival and prognostic implications based on site of involvement. Int Forum Allergy Rhinol. 4:151–155. 2014. View Article : Google Scholar : PubMed/NCBI

36 

Kirchoff DD, Deutsch GB, Foshag LJ, Lee JH, Sim MS and Faries MB: Evolving Therapeutic Strategies in Mucosal Melanoma Have Not Improved Survival Over Five Decades. Am Surg. 82:1–5. 2016.PubMed/NCBI

37 

Kirschner AN, Kidd EA, Dewees T and Perkins SM: Treatment approach and outcomes of vaginal melanoma. Int J Gynecol Cancer. 23:1484–1489. 2013. View Article : Google Scholar : PubMed/NCBI

38 

Kong Y, Si L, Li Y, Wu X, Xu X, Dai J, Tang H, Ma M, Chi Z, Sheng X, et al: Analysis of mTOR Gene Aberrations in Melanoma Patients and Evaluation of Their Sensitivity to PI3K-AKT-mTOR Pathway Inhibitors. Clin Cancer Res. 22:1018–1027. 2016. View Article : Google Scholar : PubMed/NCBI

39 

Konuthula N, Khan MN, Parasher A, Del Signore A, Genden EM, Govindaraj S and Iloreta AM: The presentation and outcomes of mucosal melanoma in 695 patients. Int Forum Allergy Rhinol. 7:99–105. 2017. View Article : Google Scholar : PubMed/NCBI

40 

Koto M, Demizu Y, Saitoh JI, Suefuji H, Tsuji H, Okimoto T, Ohno T, Shioyama Y, Takagi R, Nemoto K, et al Japan Carbon-Ion Radiation Oncology Study Group, : Multicenter study of carbon-ion radiation therapy for mucosal melanoma of the head and neck: Subanalysis of the Japan Carbon-Ion Radiation Oncology Study Group (J-CROS) Study (1402 HN). Int J Radiat Oncol Biol Phys. 97:1054–1060. 2017. View Article : Google Scholar : PubMed/NCBI

41 

Kuk SK, Won CH, Lee WJ, Shin WJ, Yoon HJ, Hong SD, Hong SP and Lee J: Prognostic significance of nestin in primary malignant melanoma of the oral cavity. Melanoma Res. 26:457–463. 2016. View Article : Google Scholar : PubMed/NCBI

42 

Lansu J, Klop WM, Heemsbergen W, Navran A, Al-Mamgani A, Langendijk JA, Kaanders JH, Terhaard C, Karakullukcu B and Hamming-Vrieze O: Local control in sinonasal malignant melanoma: Comparing conventional to hypofractionated radiotherapy. Head Neck. 40:86–93. 2018. View Article : Google Scholar : PubMed/NCBI

43 

Lawaetz M, Birch-Johansen F, Friis S, Eriksen JG, Kiss K, Gade S, Møller-Madsen M, Pourbordbari N and von Buchwald C: Primary mucosal melanoma of the head and neck in Denmark, 1982–2012: Demographic and clinical aspects. A retrospective DAHANCA study. Acta Oncol. 55:1001–1008. 2016. View Article : Google Scholar : PubMed/NCBI

44 

Lee G, Baek CH, Choi NY and Chung MK: The prognostic role of the surgical approach and adjuvant therapy in operable mucosal melanoma of the head and neck. Clin Exp Otorhinolaryngol. 10:97–103. 2017. View Article : Google Scholar : PubMed/NCBI

45 

Lee RJ, Lee SA, Lin T, Lee KK and Christensen RE: Determining the epidemiologic, outcome, and prognostic factors of oral malignant melanoma by using the Surveillance, Epidemiology, and End Results database. J Am Dent Assoc. 148:288–297. 2017. View Article : Google Scholar : PubMed/NCBI

46 

Lombardi D, Bottazzoli M, Turri-Zanoni M, Raffetti E, Villaret AB, Morassi ML, Ungari M, Vermi W, Battaglia P, Castelnuovo P, et al: Sinonasal mucosal melanoma: A 12-year experience of 58 cases. Head Neck. 38 (Suppl 1):E1737–E1745. 2016. View Article : Google Scholar : PubMed/NCBI

47 

Mücke T, Hölzle F, Kesting MR, Loeffelbein DJ, Robitzky LK, Hohlweg-Majert B, Tannapfel A and Wolff KD: Tumor size and depth in primary malignant melanoma in the oral cavity influences survival. J Oral Maxillofac Surg. 67:1409–1415. 2009. View Article : Google Scholar : PubMed/NCBI

48 

Nakamura Y, Fujisawa Y, Tanaka R, Maruyama H, Ishitsuka Y, Okiyama N, Watanabe R and Fujimoto M: Use of immune checkpoint inhibitors prolonged overall survival in a Japanese population of advanced malignant melanoma patients: Retrospective single institutional study. J Dermatol. 45:1337–1339. 2018. View Article : Google Scholar : PubMed/NCBI

49 

Oba J, Nakahara T, Abe T, Hagihara A, Moroi Y and Furue M: Expression of c-Kit, p-ERK and cyclin D1 in malignant melanoma: An immunohistochemical study and analysis of prognostic value. J Dermatol Sci. 62:116–123. 2011. View Article : Google Scholar : PubMed/NCBI

50 

Pandey M, Mathew A, Iype EM, Sebastian P, Abraham EK and Nair KM: Primary malignant mucosal melanoma of the head and neck region: Pooled analysis of 60 published cases from India and review of literature. Eur J Cancer Prev. 11:3–10. 2002. View Article : Google Scholar : PubMed/NCBI

51 

Pfeil AF, Leiter U, Buettner PG, Eigentler TK, Weide B, Meier F and Garbe C: Melanoma of unknown primary is correctly classified by the AJCC melanoma classification from 2009. Melanoma Res. 21:228–234. 2011. View Article : Google Scholar : PubMed/NCBI

52 

Plavc G, But-Hadžić J, Aničin A, Lanišnik B, Didanović V and Strojan P: Mucosal melanoma of the head and neck: A population-based study from Slovenia, 1985–2013. Radiat Oncol. 11:1372016. View Article : Google Scholar : PubMed/NCBI

53 

Roh MR, Gupta S, Park KH, Chung KY, Lauss M, Flaherty KT, Jönsson G, Rha SY and Tsao H: Promoter Methylation of PTEN Is a Significant Prognostic Factor in Melanoma Survival. J Invest Dermatol. 136:1002–1011. 2016. View Article : Google Scholar : PubMed/NCBI

54 

Samstein RM, Carvajal RD, Postow MA, Callahan MK, Shoushtari AN, Patel SG, Lee NY and Barker CA: Localized sinonasal mucosal melanoma: Outcomes and associations with stage, radiotherapy, and positron emission tomography response. Head Neck. 38:1310–1317. 2016. View Article : Google Scholar : PubMed/NCBI

55 

Sanchez A, Rodríguez D, Allard CB, Bechis SK, Sullivan RJ, Boeke CE, Kuppermann D, Cheng JS, Barrisford GW, Preston MA, et al: Primary genitourinary melanoma: Epidemiology and disease-specific survival in a large population-based cohort. Urol Oncol. 34:166.e7–166.e14. 2016. View Article : Google Scholar

56 

Schaefer T, Satzger I and Gutzmer R: Clinics, prognosis and new therapeutic options in patients with mucosal melanoma: A retrospective analysis of 75 patients. Medicine (Baltimore). 96:e57532017. View Article : Google Scholar : PubMed/NCBI

57 

Schmidt MQ, David J, Yoshida EJ, Scher K, Mita A, Shiao SL, Ho AS and Zumsteg ZS: Predictors of survival in head and neck mucosal melanoma. Oral Oncol. 73:36–42. 2017. View Article : Google Scholar : PubMed/NCBI

58 

Shoushtari AN, Bluth MJ, Goldman DA, Bitas C, Lefkowitz RA, Postow MA, Munhoz RR, Buchar G, Hester RH, Romero JA, et al: Clinical features and response to systemic therapy in a historical cohort of advanced or unresectable mucosal melanoma. Melanoma Res. 27:57–64. 2017. View Article : Google Scholar : PubMed/NCBI

59 

Shuman AG, Light E, Olsen SH, Pynnonen MA, Taylor JM, Johnson TM and Bradford CR: Mucosal melanoma of the head and neck: Predictors of prognosis. Arch Otolaryngol Head Neck Surg. 137:331–337. 2011. View Article : Google Scholar : PubMed/NCBI

60 

Song H, Jing G, Wang L, Guo W and Ren G: Periodic acid-Schiff-positive loops and networks as a prognostic factor in oral mucosal melanoma. Melanoma Res. 26:145–152. 2016. View Article : Google Scholar : PubMed/NCBI

61 

Sun CZ, Li QL, Hu ZD, Jiang YE, Song M and Yang AK: Treatment and prognosis in sinonasal mucosal melanoma: A retrospective analysis of 65 patients from a single cancer center. Head Neck. 36:675–681. 2014. View Article : Google Scholar : PubMed/NCBI

62 

Tchelebi L, Guirguis A and Ashamalla H: Rectal melanoma: Epidemiology, prognosis, and role of adjuvant radiation therapy. J Cancer Res Clin Oncol. 142:2569–2575. 2016. View Article : Google Scholar : PubMed/NCBI

63 

Thariat J, Poissonnet G, Marcy PY, Lattes L, Butori C, Guevara N, Dassonville O, Santini J, Bensadoun RJ and Castillo L: Effect of surgical modality and hypofractionated split-course radiotherapy on local control and survival from sinonasal mucosal melanoma. Clin Oncol (R Coll Radiol). 23:579–586. 2011. View Article : Google Scholar : PubMed/NCBI

64 

Wang X, Wen W, Wu H, Chen Y, Ren G and Guo W: Heparanase expression correlates with poor survival in oral mucosal melanoma. Med Oncol. 30:6332013. View Article : Google Scholar : PubMed/NCBI

65 

Wen X, Ding Y, Li J, Zhao J, Peng R, Li D, Zhu B, Wang Y and Zhang X and Zhang X: The experience of immune checkpoint inhibitors in Chinese patients with metastatic melanoma: A retrospective case series. Cancer Immunol Immunother. 66:1153–1162. 2017. View Article : Google Scholar : PubMed/NCBI

66 

Won TB, Choi KY, Rhee CS, Jin HR, Yi JS, Dhong HJ, Kim SW, Choi JH, Kim JK, Chung YJ, et al: Treatment outcomes of sinonasal malignant melanoma: A Korean multicenter study. Int Forum Allergy Rhinol. 5:950–959. 2015. View Article : Google Scholar : PubMed/NCBI

67 

Yeh JJ, Shia J, Hwu WJ, Busam KJ, Paty PB, Guillem JG, Coit DG, Wong WD and Weiser MR: The role of abdominoperineal resection as surgical therapy for anorectal melanoma. Ann Surg. 244:1012–1017. 2006. View Article : Google Scholar : PubMed/NCBI

68 

Yi JH, Yi SY, Lee HR, Lee SI, Lim DH, Kim JH, Park KW and Lee J: Dacarbazine-based chemotherapy as first-line treatment in noncutaneous metastatic melanoma: Multicenter, retrospective analysis in Asia. Melanoma Res. 21:223–227. 2011. View Article : Google Scholar : PubMed/NCBI

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APA
Hahn, H.M., Lee, K.G., Choi, W., Cheong, S.H., Myung, K.B., & Hahn, H.J. (2019). An updated review of mucosal melanoma: Survival meta‑analysis. Molecular and Clinical Oncology, 11, 116-126. https://doi.org/10.3892/mco.2019.1870
MLA
Hahn, H. M., Lee, K. G., Choi, W., Cheong, S. H., Myung, K. B., Hahn, H. J."An updated review of mucosal melanoma: Survival meta‑analysis". Molecular and Clinical Oncology 11.2 (2019): 116-126.
Chicago
Hahn, H. M., Lee, K. G., Choi, W., Cheong, S. H., Myung, K. B., Hahn, H. J."An updated review of mucosal melanoma: Survival meta‑analysis". Molecular and Clinical Oncology 11, no. 2 (2019): 116-126. https://doi.org/10.3892/mco.2019.1870