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%) ([@b1-mco-0-0-1870]). 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) ([@b2-mco-0-0-1870]). 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 ([@b3-mco-0-0-1870]). Such discrepancies include female preponderance, limited role of UV (ultraviolet) light, and mutation status ([@b4-mco-0-0-1870]). The different makeup of mutation landscape is thought to be the impetus that drives the divergence between the two ([@b5-mco-0-0-1870]--[@b7-mco-0-0-1870]).

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 \[[www.thesis.de](www.thesis.de)\], 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* ([@b8-mco-0-0-1870]). 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) ([@b9-mco-0-0-1870]).

### 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 I^2^ statistic. The assumption of homogeneity was considered valid if I^2^ 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) ([@b10-mco-0-0-1870]) flow diagram of the search strategy, and characteristics of the included studies are given in [Fig. 1](#f1-mco-0-0-1870){ref-type="fig"} and [Table I](#tI-mco-0-0-1870){ref-type="table"}, 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.

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](#f2-mco-0-0-1870){ref-type="fig"}).

### 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 (I^2^=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](#tII-mco-0-0-1870){ref-type="table"}).

### 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 (I^2^=26.41; [Fig. 3](#f3-mco-0-0-1870){ref-type="fig"}).

### 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](#f4-mco-0-0-1870){ref-type="fig"}).

### 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](#tIII-mco-0-0-1870){ref-type="table"}).

### 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](#tIV-mco-0-0-1870){ref-type="table"}).

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](#tV-mco-0-0-1870){ref-type="table"}).

### 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](#f5-mco-0-0-1870){ref-type="fig"}).

### 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](#f6-mco-0-0-1870){ref-type="fig"}) for overall survival. No inter-study heterogeneity was found across the studies (I^2^=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* ([@b11-mco-0-0-1870]), 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 ([@b12-mco-0-0-1870]). 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) ([@b13-mco-0-0-1870]) 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 ([@b14-mco-0-0-1870]). This notion has been backed by the authors\' findings, that neither thickness nor depth of invasion is a significant determinant of survival ([Table IV](#tIV-mco-0-0-1870){ref-type="table"}).

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 ([@b15-mco-0-0-1870],[@b16-mco-0-0-1870]), 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.

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.

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

![Flowchart of search strategy, adopted from the PRISMA Group, 2009 ([@b10-mco-0-0-1870]).](mco-11-02-0116-g00){#f1-mco-0-0-1870}

![Forest plots for advanced age. DSS, disease-specific survival; CI, confidence interval.](mco-11-02-0116-g01){#f2-mco-0-0-1870}

![Forest plots for the lethality of mucosal melanoma vs. cutaneous melanoma (DSS). MM, mucosal melanoma; CM, cutaneous melanoma; DSS, disease-specific survival; CI, confidence interval.](mco-11-02-0116-g02){#f3-mco-0-0-1870}

###### 

Forest plots for TNM staging (DSS): (A) T4 vs. T3 disease, (B) N1 vs. N0 disease, and (C) M1 vs. M0 disease. DSS, disease specific survival; CI, confidence interval; TNM, tumor-node-metastasis.

![](mco-11-02-0116-g03)

![](mco-11-02-0116-g04)

![](mco-11-02-0116-g05)

###### 

Forest plots for adjuvant therapy (DSS): (A) Chemotherapy and (B) radiation therapy. DSS, disease-specific survival; CI, confidence interval; Adj., adjuvant.

![](mco-11-02-0116-g06)

![](mco-11-02-0116-g07)

![Forest plots for immunotherapy (OS): CI, confidence interval; OS, overall survival.](mco-11-02-0116-g08){#f6-mco-0-0-1870}

###### 

Characteristics of included studies.

  Author, year                Country^[b](#tfn2-mco-0-0-1870){ref-type="table-fn"}^   Location                                                          No. of patients                                     Follow-up            Ref.
  --------------------------- ------------------------------------------------------- ----------------------------------------------------------------- --------------------------------------------------- -------------------- ------
  Abugideiri *et al*, 2016    USA                                                     H&N                                                               39 (SRT=27; S=12)                                   Median 8.1 years     17
  Ahn *et al*, 2010           Korea                                                   H&N                                                               32 (SRT=16; S=16)                                   Median 25.3 months   18
  Aiempanakit *et al*, 2018   Thailand                                                All mucosal                                                       17 (S=14, UN=3)                                     Median 18.2 months   19
  Ajmani *et al*, 2017        USA                                                     SN                                                                704 (SRT=399; S=305)                                NR                   20
  Amit *et al*, 2018          USA                                                     SN                                                                198 (SRT=81; S=79; SCRT=24; C or CRT=14)            Median 26 months     21
  D\'Angelo *et al*, 2016     USA                                                     All mucosal                                                       889 (ipilimumab and nivolumab)                      6.2 months           22
  Benlyazid *et al*, 2010     France                                                  H&N                                                               160 (SRT=78; S=82)                                  Median 65.2 months   23
  Bishop and Olszewski 2014   USA                                                     All, including CM^[a](#tfn1-mco-0-0-1870){ref-type="table-fn"}^   229,976 (NR)                                        NR                   24
  Chiu and Weinstock, 1996    USA                                                     OC                                                                40,320 (NR)                                         NR                   25
  Ciarrocchi *et al*, 2017    Italy                                                   Anorectum                                                         208 (SRT=32; S=167)                                 Median 14 months     26
  Ercelep *et al*, 2016       Turkey                                                  All mucosal                                                       229,976 (NR)                                        Median 27 months     27
  Harada *et al*, 2016        Japan                                                   Oesophagus                                                        10 (S=10)                                           NR                   28
  Hasebe *et al*, 2017        Japan                                                   H&N                                                               85 (RT=85)                                          Median 42.5 months   29
  Heinzelmann-                Australia                                               Vulva                                                             33 (NR)                                             NR                   30
  Schwarz *et al*, 2014                                                                                                                                                                                                          
  Heppt *et al*, 2017         Germany                                                 All mucosal                                                       444 (NR)                                            NR                   31
  Hughes *et al*, 2013        Australia                                               All, including CM^[a](#tfn1-mco-0-0-1870){ref-type="table-fn"}^   485 (Lymphadenectomy)                               Median 17.4 months   32
  Jang *et al*, 2014          Korea                                                   All, including CM^[a](#tfn1-mco-0-0-1870){ref-type="table-fn"}^   206 (S=197; C=46; RT=31)                            NR                   33
  Kang *et al*, 2018          China                                                   All mucosal                                                       60 (NR)                                             Median 36 months     34
  Khan *et al*, 2014          USA                                                     SN                                                                567 (NR)                                            NR                   35
  Kirchoff *et al*, 2016      USA                                                     All mucosal                                                       227 (S=53; S + other=174)                           NR                   36
  Kirschner *et al*, 2013     USA                                                     Vagina                                                            201 (SRT=53; S=87; RT=30)                           Median 14 months     37
  Kong *et al*, 2016          China                                                   All, including CM^[a](#tfn1-mco-0-0-1870){ref-type="table-fn"}^   412 (NR)                                            Median 31 months     38
  Konuthula *et al*, 2017     USA                                                     SN                                                                695 (SRT=271; S=206; SC=29; SCRT=49; C=21; RT=42)   NR                   39
  Koto *et al*, 2017          Japan                                                   H&N                                                               260 (RT=105; CRT=155)                               Median 22 months     40
  Kuk *et al*, 2016           Korea                                                   OC                                                                39 (S=22; S + C or RT=17)                           NR                   41
  Lansu *et al*, 2018         Netherlands                                             SN                                                                63 (SRT=63)                                         Median 23 months     42
  Lawaetz *et al*, 2016       Denmark                                                 H&N                                                               98 (SRT=26; S=49; SC=2; SCRT=2; RT=8; None=8)       Median 24.5 months   43
  Lee *et al*, 2017           Korea                                                   H&N                                                               31 (SRT=13; S=9; SC=7; SCRT=2)                      Mean 9 months        44
  Lee *et al*, 2017           USA                                                     OC                                                                232 (NR)                                            NR                   45
  Lombardi *et al*, 2016      Italy                                                   SN                                                                58 (SRT=13; S=42; SCRT=3)                           Median 30 months     46
  Mücke *et al*, 2009         Germany                                                 OC                                                                10 (NR)                                             NR                   47
  Nakamura *et al*, 2018      Japan                                                   All mucosal                                                       45 (checkpoint inhibitors)                          NR                   48
  Oba *et al*, 2011           Japan                                                   All, including CM^[a](#tfn1-mco-0-0-1870){ref-type="table-fn"}^   78 (NR)                                             Median 40 months     49
  Pandey *et al*, 2002        India                                                   H&N                                                               60 (SRT=6; S=17; SC=3; SCRT=1; C=8; RT=7)           NR                   50
  Pfeil *et al*, 2011         Germany                                                 All mucosal                                                       172 (NR)                                            Median 24 months     51
  Plavc *et al*, 2016         Slovenia                                                H&N                                                               61 (SRT=14; S=17; C=1; RT=15)                       Median 16.5 months   52
  Roh *et al*, 2016           Korea                                                   All mucosal                                                       392 (NR)                                            Mean 55.4 months     53
  Samstein *et al*, 2016      USA                                                     SN                                                                78 (SRT=64; S=14)                                   Median 21 months     54
  Sanchez *et al*, 2016       USA                                                     Genitourinary tract                                               1,586 (NR)                                          NR                   55
  Schaefer *et al*, 2017      Germany                                                 All mucosal                                                       75 (checkpoint inhibitors)                          NR                   56
  Schmidt *et al*, 2017       USA                                                     H&N                                                               1,368 (SRT=704; S=566; RT=98)                       Median 55.2 months   57
  Shoushtari *et al*, 2017    USA                                                     All mucosal                                                       81 (NR)                                             NR                   58
  Shuman *et al*, 2011        USA                                                     H&N                                                               52 (SRT=15; S=13; SC=18; NR=6)                      Median 97 months     59
  Song *et al*, 2016          China                                                   OC                                                                62 (NR)                                             Median 32.5 months   60
  Sun *et al*, 2014           China                                                   SN                                                                65 (SRT=13; S=18; SC=9; C=6; RT=4; CRT= 2)          NR                   61
  Tchelebi *et al*, 2016      USA                                                     Rectum                                                            63 (SRT=18; S=45)                                   Median 17 months     62
  Thariat *et al*, 2011       France                                                  SN                                                                155 (NR)                                            Median 37 months     63
  Wang *et al*, 2013          China                                                   OC                                                                81 (NR)                                             NR                   64
  Wen *et al*, 2017           China                                                   All mucosal                                                       52 (checkpoint and PD-1 inhibitors)                 NR                   65
  Won *et al*, 2015           Korea                                                   SN                                                                155 (NR)                                            NR                   66
  Yeh *et al*, 2006           USA                                                     Anorectum                                                         46 (S=23; C=23)                                     Median 29 months     67
  Yi *et al*, 2011            Korea                                                   All, including CM^[a](#tfn1-mco-0-0-1870){ref-type="table-fn"}^   95 (NR)                                             Median 41 months     68

Included for purpose of comparison with mucosal melanoma

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.

###### 

Hazard ratios for non-Caucasian ethnicities.

  Ethnicity comparison          Survival   No. of studies   Pooled HR   95% CI       Z-value   P-value   I^2^
  ----------------------------- ---------- ---------------- ----------- ------------ --------- --------- --------
  Non-Caucasian vs. Caucasian   DSS        5                1.12        1.05--1.20   3.354     0.001     0.0001
  Non-Caucasian vs. Caucasian   OS         3                1.39        1.06--1.82   2.358     0.018     0.0001
  Afro-American vs. Caucasian   DSS        6                1.13        0.95--1.34   1.421     0.155     4.451
  API vs. Caucasian             DSS        2                1.09        0.80--1.49   0.563     0.574     91.47

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

###### 

Hazard ratios for clinical/macro-morphological features.

  Feature comparison                 Survival   No. of studies   Pooled HR   95% CI       Z-value   P-value   I^2^
  ---------------------------------- ---------- ---------------- ----------- ------------ --------- --------- -------
  Elevated LDH vs. WNL               DSS        4                2.06        1.56--2.72   5.104     0.001     0.001
  PS\>1 vs. PS\<0                    OS         4                1.71        1.32--2.21   4.112     0.001     0.001
  Ulceration vs. no ulceration       DSS        3                1.32        0.91--1.90   1.465     0.143     6.401
  Ulceration vs. no ulceration       OS         4                1.44        1.04--2.01   2.191     0.215     32.95
  Pigmentation vs. no pigmentation   OS         3                0.93        0.70--1.25   0.464     0.642     0.001
  Necrosis vs. no necrosis           DSS        2                1.29        0.96--1.73   1.708     0.088     0.001
  Necrosis vs. no necrosis           OS         2                0.96        0.55--1.68   0.013     0.989     72.12

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

###### 

Hazard ratios for microscopic features.

  Feature comparison                        Survival   No. of studies   Pooled HR   95% CI       Z-value   P-value   I^2^
  ----------------------------------------- ---------- ---------------- ----------- ------------ --------- --------- -------
  (+) Margin vs. (−) margin                 DSS        10               1.85        1.34--2.54   3.759     0.001     23.84
  (+) Margin vs. (−) margin                 OS         10               1.59        1.21--2.08   3.365     0.001     44.22
  Breslow \>1 mm vs. Breslow \<1 mm         DSS        6                1.07        0.99--1.19   1.755     0.079     29.63
  Breslow \>1 mm vs. Breslow \<1 mm         OS         3                1.07        0.99--1.17   1.621     0.105     11.23
  Invasion \>2 mm vs. invasion \<2 mm       DSS        3                2.02        0.68--6.03   1.259     0.208     81.02
  Invasion \>2 mm vs. invasion \<2 mm       OS         4                2.02        1.26--0.23   2.913     0.004     0.001
  Mitosis (+) vs. mitosis (−)               DSS        4                1.09        1.03--1.15   2.875     0.004     0.001
  Mitosis (+) vs. mitosis (−)               OS         4                1.06        1.01--1.12   2.405     0.016     0.001
  PNI vs. PNI (−)                           DSS        2                2.08        0.97--4.4    1.884     0.06      42.65
  Lymphovascular invasion vs. no invasion   DSS        3                1.24        0.94--1.64   1.537     0.124     0.001
  Epithelioid type vs. non-epithelioid      DSS        3                1.29        0.94--1.78   1.561     0.118     0.001

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

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Hazard ratios for different modalities of treatment.

  Modality comparison               Survival   No. of studies   Pooled HR   95% CI       Z-value   P-value   I^2^
  --------------------------------- ---------- ---------------- ----------- ------------ --------- --------- -------
  Radical op. vs. Conservative Tx   OS         5                2.61        2.04--3.34   15.079    0.001     55.35
  Op. alone vs. SC/SRT              DSS        11               1.78        1.55--2.05   8.192     0.001     30.85
  RT alone vs. SRT                  DSS        5                1.29        1.08--1.54   2.831     0.005     19.37
  RT alone vs. SRT                  OS         4                1.52        1.35--1.70   7.087     0.001     26.97

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.
