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Twelve retrospective studies that examined a total of 1593 patients were included
in the current investigation. All of these studies were descriptive cohort studies,
and they provided moderately strong evidence. Given that HNMM is rare and is associated
with an extremely poor prognosis, the results of this study can nonetheless provide
significant guidance in making clinical treatment decisions regarding this disease.

The preferred treatment method: surgical resection

The subjects included in the current study were patients with a history of past surgical
treatment; for mucosal melanoma surgery achieves better results than other therapeutic
approaches with respect to treatment and local control. Moreover, surgery was the
first treatment for many patients in the vast majority of examined publications. In
an examination of 815 HNMM patients, Thomas et al. 6] found that compared with patients who received surgery alone, the relative risk ratios
for patients who received simple radiotherapy or no treatment were 1.56 (95 % CI,
1.35–1.72) and 2.38 (95 % CI, 2.09–2.59), respectively. The clinical significance
of these findings was that compared with the administration of surgical treatment,
the administration of radiotherapy alone and the administration of no treatment increased
the risk of death by 56 and 138 %, respectively. Thus, patients who underwent surgical
treatment (with or without postoperative radiotherapy) had better prognoses and longer
survival times than patients who did not receive surgical treatment. In a study by
Andersen et al., all surviving patients had received surgical treatment; however,
the non-surgical treatment approach involving chemoradiotherapy alone had little or
no therapeutic effect 5].

Furthermore, the 2012 National Comprehensive Cancer Network (NCCN, an American organization)
guidelines recommend surgery as the preferred treatment for mucosal melanoma patients;
in particular, the optimal objective for surgical treatment is en bloc resection that
effectively achieves tumor-free margins (NCCN Guidelines Version 1.2012, Mucosal Melanoma
of the Head and Neck). However, surgical treatment is only suitable for patients with
stage III–IVA cancer in the American Joint Committee on Cancer (AJCC) staging system
(7th edition). In these stages, cancer is limited to the mucosal layer or exhibits
moderate progression; that is, the tumor may have invaded deep soft tissues, cartilage,
bone or surface skin covering the tumor, but there is no lymph node metastasis or
DM 19].

Unfortunately, most HNMM patients are already at an advanced clinical and pathological
stage of the disease when they are first diagnosed; as a result, their prognoses are
far worse than the prognoses of cutaneous melanoma patients, for whom surgical treatment
is also the preferred therapeutic approach 21], 22]. When cutaneous melanoma patients are first diagnosed, the percentage of patients
at stages 0, I, II, III, and IV (using AJCC staging) are 14.9, 47.7, 23.1, 8.9 and
5.3 %, respectively; many patients undergo surgery or other effective interventions
at the early stages of this disease. A survey of 84,836 melanoma patients indicated
that 91.5 % of cutaneous melanoma patients underwent surgery, and that the 5-year
survival rate for cutaneous melanoma was 80.8 % 1]. However, for HNMM, because of complexities associated with the anatomical location
of the primary tumor, it is often difficult to achieve negative safety margins during
the microscopic resection of this tumor 4]. In particular, it is very difficult to completely resect paranasal sinus mucosal
melanomas that are located near the cribriform plate or the skull plate, or that have
invaded the anterior skull base 23]. Therefore, many researchers believe that it is unwise to attempt to achieve complete
resection at the expense of increasing surgical risk and reducing postoperative quality
of life 24], 25]. However, a lack of complete resection increases postoperative complications and
thereby affects patient prognosis.

Postoperative radiotherapy is effective for local control, but does not reduce the
risks of DM and death

In the present study, a random-effects model was used for the meta-analysis of the
effects of postoperative radiotherapy on the local control (assessed in terms of LR)
of HNMM. Relative to surgery alone, surgery combined with postoperative radiotherapy
can reduce the risk of LR by 45 % (five NRSs with a total of 336 patients; HR, 0.55;
95 % CI, 0.32–0.93; p??0.05). However, postoperative radiotherapy did not reduce the risk of postoperative
death in HNMM patients (nine NRSs with a total of 1465 patients; HR, 1.07; 95 % CI,
0.95–1.02). Postoperative radiotherapy also did not reduce the risk of death in cases
of SNMM (five NRSs with a total of 341 patients; HR, 1.04; 95 % CI, 0.79–1.36).

Because HNMM is multicentric, the clinical boundaries of this disease are blurred
and unclear; infiltration occurs, particularly submucosal lymphoid infiltration involving
melanoma cells 26], resulting in a high rate of postoperative LR (31–85 %) 27]. Therefore, even if HNMM is diagnosed early and aggressive surgical treatment is
administered, postoperative adjuvant treatment remains necessary. Among the possible
adjuvant treatments, postoperative radiotherapy is one of the earliest examined adjuvant
therapies; it has been used in a relatively large number of clinical cases. The purpose
of radiotherapy is to reduce the postoperative invasion of residual tumors into the
surrounding normal tissues. The NCCN has noted that postoperative radiotherapy is
suitable in cases with extra capsular lesions, the invasion of two or more neck or
parotid gland lymph nodes, a single nodule ?3 cm and neck dissection without distant
invasion or postoperative LR. The use of conventional radiotherapy doses (2 Gy per
fraction, at a total dose of 60–66 Gy or 70 Gy) is recommended. In addition, secondary
damage from radiotherapy is regarded as acceptable. The current study confirmed that
although the adjuvant treatment approach outlined above produced good local control
effects, it did not reduce the risk of death. The reasons for this phenomenon are
analyzed below.

First, HNMM is a radiotherapy-resistant tumor; that is, HNMM tumors exhibit extremely
strong sublethal damage repair capacities. Therefore, although conventional radiotherapy
doses can achieve local control, traditional radiotherapy is ineffective in controlling
the disease as a whole. For this reason, stereotactic intensity-modulated radiation
therapy (IMRT), PT and CIT have recently been developed for the adjuvant treatment
of HNMM. Although these novel approaches have exhibited enhanced efficacy relative
to conventional radiotherapy, they remain at the clinical trial stage; thus, numerous
clinical trials and prospective studies will be required to determine the long-term
efficacy of these treatments.

Second, mucosal melanoma is a systemic disease that readily invades vascular and lymphoid
tissues and therefore characteristically tends to produce DM. Thus, it is difficult
for local radiotherapy to achieve good control of the hematogenous metastasis of this
disease 24]. Notably, many mucosal melanoma patients die from the spread of the disease rather
than from LR. Rinaldo et al. 27] have demonstrated that in contrast to primary squamous cell carcinoma of the nasal
cavity and the paranasal sinuses, which mainly exhibits posterior pharyngeal wall
and mandibular lymph node metastasis, mucosal melanoma more frequently exhibits lung
and brain metastasis 28]. Consequently, although postoperative adjuvant radiotherapy has relatively strong
local control effects, it is not a protective factor for HNMM because the main cause
of death in certain HNMM patients is DM.

Finally, because of the rarity of HNMM, it is extremely difficult to conduct large-sample
RCTs for the examination of this disease. Therefore, selection bias in the meta-analysis
of cohort studies will have caused uncertainty in the results of the present study.
In other words, in the included retrospective studies, most patients who received
postoperative radiotherapy were late-stage cases involving failed en bloc resection,
positive safety margins, lymphatic vascular invasion and/or DM. However, it was determined
that for these patients, postoperative radiotherapy could still achieve local control
but did not reduce the risk of death.

Value of other treatment methods in non-surgical therapy

As discussed above, surgical treatment is difficult to implement in HNMM cases because
of various issues including: complications associated with the anatomical location
of a tumor (particularly in the case of SNMMs located near important organs); the
advanced stage of the disease upon initial diagnosis; patient refusal of surgical
treatment; and the comprehensive consideration of surgical risk and postoperative
quality of life. Consequently, to increase survival rates and prolong patient survival
times in HNMM cases, many researchers advocate the use of radiotherapy, chemotherapy
and/or biological therapy alone as alternatives to surgical treatment.

Evaluation of the therapeutic efficacy of simple radiotherapy for HNMM

In recent years, with the continuous advancement of radiotherapy techniques and the
upgrading of relevant equipment, clinicians have gradually begun to increase the use
of radiotherapy alone in the treatment of primary HNMM. Although the development of
specific therapeutic strategies remains controversial, studies have already proven
the efficacy of this approach and have demonstrated that the side effects of the radiotherapy
are within manageable ranges.

Douglas et al. 29] recommended radiotherapy as the preferred treatment approach for HNMM patients who
cannot withstand surgery or refuse surgical treatment. In a retrospective study of
68 HNMM patients, 13 patients received palliative radiotherapy, 30 received radiotherapy
at therapeutic doses and 25 received surgical treatment with or without postoperative
radiotherapy. Radical treatment mainly using radiotherapy achieved relatively good
local control effects and a 5-year DSS of 25 %. However, there have been few relevant
reports on the use of radiotherapy at therapeutic doses, and these reports have involved
small sample sizes. These limitations occurred because HNMM is a radiotherapy-resistant
tumor with extremely effective sublethal repair capabilities. Therefore, therapeutic
hypofractionated radiotherapy (HF-RT) with an ?/? ratio of 4–6 Gy per fraction has
been used to overcome this radiotherapy resistance. The basic dose for the treatment
of uveal melanomas is 1.5–26.2 Gy, with an average of 10 Gy, and the basic dose for
cutaneous melanomas is 1.6–6 Gy, with an average of 2.5 Gy; however, the dose for
mucosal melanoma remains unknown 30]. Wada et al. 31] performed high-dose HF-RT with doses ?3 Gy in 31 HNMM patients. They found that compared
with conventional postoperative radiotherapy, HF-RT delivered better local control
and survival; in particular, HF-RT resulted in 1- and 3-year DSS rates of 73 and 33 %,
respectively. Moreover, increased radiotherapy doses produced better therapeutic effects
with respect to local control and survival. However, with the aforementioned radiotherapy
regimen, the occasional occurrence of lethal side effects, such as mucosal ulceration
and massive hemorrhage, is inevitable. Christopherson et al. 32] administered therapeutic doses of radiotherapy or postoperative radiotherapy to 21
patients. They found that three patients (17 %) experienced serious complications,
including the need for hospitalization and/or surgical intervention, failing to complete
the entire radiotherapy regimen, and death. Two of these patients received PT alone,
and one patient received photon therapy and PT. The manifestations of the complications
included bilateral blindness, severe mucositis and skin necrosis. Thus, numerous clinical
studies involving HF-RT are still required to develop regimens with optimal therapeutic
effects and ensure that the side effects of these regimens are manageable.

Given the side effects of HF-RT, local dose-escalated IMRT, another improved photon
radiotherapy technique, has been used in clinical practice. In a study on the treatment
of malignant tumors of the paranasal sinuses, Madani et al. 33] reported that IMRT was the gold standard for radiotherapy approaches for these tumors,
and that IMRT could be used alone or as an adjuvant treatment. Combs et al. 34] used IMRT to treat eight SNMM patients and found a 5-year OS of 80 %, a 3-year local
progression-free survival rate of 28.6 % and a 3-year distant progression-free survival
rate of 28.6 %. In addition, during the 27 months (12–71 months) of follow-up, radiotherapy-related
side effects were within acceptable ranges. No vision loss or blindness occurred,
and additional therapeutic intervention was not required. However, both the aforementioned
HF-RT approach and this IMRT approach produced non-ideal effects with respect to the
control of DM.

At present, PT and CIT particle therapies achieve better local control of melanomas
than surgery alone, conventional photon radiotherapy, or a combination of surgery
and photon radiotherapy. Therefore, the use of PT or CIT particle radiotherapy alone
for HNMM is attracting widespread attention. Because PT and CIT can provide precisely
distributed radiation doses, these techniques can be used to specifically deliver
high doses of radiation to tumors with a reduced risk of radiation exposure to normal
tissues; this characteristic is particularly relevant for malignant tumors located
in or near important tissues and organs 28], 35]. In contrast to the high levels of attenuation characteristic of the traditional
photon beams used for radiotherapy upon penetrating soft tissues, proton beams exhibit
tremendous energy deposition in targeted tumors but minimal energy deposition in the
preceding or subsequent normal tissues; consequently, proton beams can be used to
accurately deliver radiation to tumors with relatively little effect on the surrounding
normal tissues 36], 37]. This characteristic is highly suitable for the treatment of paranasal sinus melanomas
because the radiotherapy dose required for the treatment of these tumors is extremely
similar to the doses that affect the surrounding normal tissues, such as the eyes,
the optic nerves, brain tissues and the skull. Compared with photon beam radiotherapy,
PT is associated with lower risks regarding the development of secondary malignant
tumors 33], 34]. In an examination of 11 cases treated with PT, the initial disease control rate
was 85.7 %, the 3-year survival rate was 58.0 % and the mean disease-free time to
progression was 25.1 months (with a mean follow-up time of 36.7 months); there were
two cases of unilateral vision loss but no blindness events 38]. In addition, in 72 cases treated using CIT, the 5-year local control rate for the
disease was 84.1 %; 94.4 % of the patients who exhibited good local control received
radiotherapy with ?3.6 Gy/fraction. However, by the end of the follow-up, DM had occurred
in 40 cases; LR had not occurred in 34 of these cases (85.0 %). These results confirmed
that the tumors had often already invaded their microenvironment before treatment
had begun and that the examined radiotherapy approach did not produce good control
of HNMM that underwent early-stage hematogenous DM 39]. In contrast, compared with proton beams, carbon-ion beams have a better penumbra
and higher relative biological effectiveness. However, Demizu et al. 40] demonstrated that PT and CIT did not exhibit significant differences regarding therapeutic
effectiveness in the treatment of HNMM; in particular, the 2-year survival rates among
patients treated with PT and CIT were 58 and 62 %, respectively (p?=?0.399; Kaplan-Meier [K-M] curve analysis). PT and CIT also had no significant differences
regarding local control effects; these treatments resulted in local control rates
of 83 and 59 %, respectively (p?=?0.569; K-M curve analysis). In addition, the radiotherapy side effects of PT and
CIT did not differ significantly. Although CIT and PT particle therapies had excellent
local control effects (with an effective 2-year local control rate of 78 %), their
outcomes regarding OS were not ideal (a 2-year DSS of 31 %). The analysis appeared
to indicate that this phenomenon could be attributed to a relatively high incidence
of DM. Thus, although the toxic side effects of radiotherapy could be controlled to
within tolerable levels, the effects of particle radiotherapy with respect to controlling
DM were not ideal.

In summary, the value of radiotherapy in the treatment of HNMM should receive extensive
attention in future studies. With the advancement of radiotherapy techniques and constant
upgrading of the relevant equipment, solutions that address the issue of radiotherapy
side effects may be developed in the near future. Numerous controlled clinical studies
and prospective studies are still required to establish radiotherapy regimens that
achieve therapeutic objectives, but produce manageable side effects. In addition,
because mucosal melanoma is a systemic disease, therapeutic approaches that combine
radiotherapy with chemotherapy or immunobiological therapy can be designed to compensate
for the deficiencies of radiotherapy alone, with respect to controlling the high incidence
of DM in cases of mucosal melanoma.

Immunobiological therapy

Compared with cutaneous melanoma, mucosal melanoma involves more chromosomal abnormalities
and abnormal gene copies 41]. At present, gene therapies targeting the mutation hotspots of malignant melanoma
have already entered clinical trials. In particular, a phase III clinical trial has
confirmed that vemurafenib, a selective BRAF inhibitor, produces a higher response
rate (48 % vs 5 %) and 6-month OS (84 % vs 64 %) compared with decarbonizes, another
systemic chemotherapeutic agent 42]. In a phase II clinical trial, imatinib, a targeted therapeutic agent for melanomas
designed to be effective in cases involving KIT mutations, exhibited outstanding performance;
it achieved a significantly higher response rate in melanomas with KIT mutations than
in wild-type melanomas (40 % vs 0 %; p?=?0.005) 43]. A recent phase II clinical trial confirmed that patients with NRAS (neuroblastoma
RAS viral [v-ras] oncogene homolog) mutations could benefit from treatment with MEK1/2
inhibitors (MAP/ERK kinases 1 and 2) 44]. The mutation rates of KIT, NRAS, and BRAF mutations among SNMM patients were 7.91 %
(11/139), 12.9 % (18/139) and 2.16 % (3/139), respectively 43], 45]–48]. Analysis of the above data revealed that there are relatively low rates of KIT and
BRAF mutations among SNMM patients. Consequently, few SNMM patients will benefit from
chemotherapeutic drugs that target these two genes.

Rosenberg et al. 49] demonstrated that the transfer of lymphokine-activated killer (LAK) cells induced
by interleukin-2 (IL-2) could increase the survival rate of patients with malignant
tumors. In addition, mucosal melanoma is a systemic disease that readily undergoes
DM; thus, LAK immunobiological therapy can help to improve the prognosis of mucosal
melanoma patients. LAK cellular therapy is an emerging treatment modality that has
been applied to mucosal melanoma in recent years 49], 50]–52]. The core steps in this treatment are the collection of venous blood, the in vitro incubation of these blood samples with a certain concentration of IL-2, and the subsequent
transfusion of the blood back into patients; patients are then treated with sustained
administration of an appropriate concentration of IL-2 to maintain LAK activity 52], 53]. Kanetaka et al. 54] examined postoperative treatment with IL-2 and LAK in 13 HNMM patients and found
that the 5-year DSS rates of the group receiving the immunobiological treatment and
the untreated group were 67 and 33 %, respectively. DM is regarded as an important
cause of death among HNMM patients. Although surgery, radiotherapy and chemotherapy
are the most common treatment approaches, they do not produce particularly strong
effects with respect to controlling DM. Thus, although biological therapy for HNMM
is uncommon, this type of treatment approach nonetheless has potential research value
as an adjuvant therapy.

Moreover, in recent years, it has been confirmed that immunobiological therapy produces
certain radiation-sensitizing effects on radiotherapy-resistant tumors. The local
tissue hypoxia caused by the strong metabolic activity of tumor cells can induce local
immunosuppressive effects, which are manifested as tumor-promoting disruptions in
normal innate immunity 19]. Tissue hypoxia can induce the local downregulation of the interferon-? (IFN-?) immune
response pathway and thereby inhibit the activation of various mediating factors,
such as CD4+/CD25+ regulatory factors (where CD represents a cluster of differentiation),
IL-10 and transforming growth factor-b. A study has demonstrated that the phenotype
of activated IFN?+?CD8+ T cells was associated with a 1.8-fold increase in tumor sensitivity
to radiotherapy 55]. Therefore, IFN-??+?CD8+ T cells serve as a bridge between immune and radiotherapy
responses, and can produce targeted radiosensitization effects. Clinically available
immunological adjuvants and tumor vaccines can become effective tools to simultaneously
stimulate tumor immunosurveillance and enhance radiotherapy responses. Although HNMM
is highly malignant, has a low incidence, and occurs through molecular mechanisms
that have not yet been fully elucidated, there are nonetheless broad prospects for
the potential use of biological therapies in the treatment of this disease.

Study limitations

Potential bias in the included NRSs

Greater potential biases exist in NRSs than in RCTs 18] Among these biases, selection bias is a major concern because factors that influence
prognosis occurred unevenly across different groups in the selected studies. In addition,
commonly observed imperfections in the NRSs remain present in the reports, and in
descriptions of research protocols and the evaluations of measurements that affect
prognoses and results. These flaws all contribute to uncertainties in meta-analyses.
In particular, because a meta-analysis is a non-experimental observation study, completely
uniform control standards could not be achieved in the current meta-analysis; one
specific manifestation of this issue is that uniform quality control cannot be performed
in each case. Therefore, subgroup analysis (such as separate examinations of different
radiotherapy regimens, different clinical and case stages, and cases involving lymphatic
vascular invasion) cannot be performed. These issues caused selection bias in evaluations
regarding the efficacy of postoperative adjuvant radiotherapy, because in the included
retrospective studies postoperative radiotherapy was mostly used in patients with
a positive safety margin, local metastasis, DM and/or primary tumors with larger scopes.

Side effects of radiotherapy

HNMM lesions are located near various important tissues and organs, such as the optic
nerves and brain tissues. Therefore, during the course of surgery and radiotherapy
patients may experience various adverse effects, including optic nerve damage and
mucositis, which will affect prognosis. However, the relevant data of the included
publications were incomplete, and these publications did not use uniform quality control
standards; consequently, the prognostic impact of radiotherapy-related side effects
on prognosis was not analyzed. However, relevant reports have indicated that certain
side effects affect patient prognoses and survival times.

Radiotherapy subgroup analysis

In the present study the influence of radiotherapy on prognosis, local control and
metastasis was analyzed. However, recent advances in radiotherapy techniques and upgrades
to radiotherapy equipment have led to the development of novel radiotherapy strategies,
such as PT and CIT. In the context of HNMM, these novel strategies are superior to
conventional radiotherapy because they can both control LR and improve patient survival.
In addition, compared with conventional radiotherapy, these emerging radiotherapy
approaches clearly produce reduced side effects. However, there are few relevant reports
regarding these approaches, the extant reports involve small sample sizes, and studies
of many potential novel radiotherapy regimens remain in the experimental stage. Therefore,
future research will be required to address this topic.