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Sinonasal melanoma: a systematic review of the prognostic factors
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Int. J. Oral Maxillofac. Surg. 2019; xxx: xxx–xxx https://doi.org/10.1016/j.ijom.2019.11.001, available online at https://www.sciencedirect.com
Systematic Review Head and Neck Oncology
Sinonasal melanoma: a systematic review of the prognostic factors F. S. C. Pontes, L. L. de Souza, M. C. de Abreu, L. A. Fernandes, A. L. M. Rodrigues, D. M. do Nascimento, V. C. S. Vasconcelos, C. D. Soares, D. L. Correˆa, F. P. Fonseca, B. A. B. de Andrade, H. A. R. Pontes: Sinonasal melanoma: a systematic review of the prognostic factors. Int. J. Oral Maxillofac. Surg. 2019; xxx: xxx–xxx. ã 2019 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Abstract. The objective was to evaluate the available published data on sinonasal melanoma and analyse its clinical features, treatment modalities, and prognostic factors. An electronic search was undertaken in March 2018 in multiple databases. Eligibility criteria included publications with sufficient clinical, histological, and immunohistochemical information to confirm the diagnosis. Seventy-three publications (439 cases) were included. The lesion was more prevalent in females than in males. There was a higher prevalence in the seventh and eighth decades of life. The lesions mainly presented as epistaxis and commonly involved the nasal cavity. Age (>67.6 years; P = 0.0012), primary location (middle turbinate; P = 0.0112), disease stage (advanced disease stage; P = 0.0026), treatment (radiotherapy; P = 0.0111), recurrence (recurrence presented; P = 0.0137), and distant metastasis (distant metastasis presented; P = 0.0011) were independently associated with a lower survival rate. Recurrence was significantly correlated with age (>67.6 years; P = 0.0021), sex (males tended to present a higher recurrence rate than females; P = 0.0051), disease stage (stages III and IV presented a higher recurrence rate than stages I and II; P = 0.0331), and histological type (amelanotic lesions presented a higher index of recurrence than melanotic lesions; P = 0.0095). In conclusion, sinonasal melanoma is a neoplasm with a poor prognosis, presenting a 30.69% possibility of survival after 5 years.
Mucosal melanomas are uncommon lesions that arise from melanocytes, presenting an aggressive clinical behaviour and a poor prognosis1–3. They can affect 0901-5027/000001+09
the aerodigestive tract, including the oral cavity, pharynx, larynx, nasal cavity, and paranasal sinuses4,5. Mucosal melanomas are also distinct from cutaneous melano-
F. S. C. Pontes1, L. L. de Souza1, M. C. de Abreu1, L. A. Fernandes1, A. L. M. Rodrigues2, D. M. do Nascimento2, V. C. S. Vasconcelos2, C. D. Soares3, D. L. Correˆa1, F. P. Fonseca3,4, B. A. B. de Andrade5, H. A. R. Pontes1,3 1
Joa˜o de Barros Barreto University Hospital (HUJBB), Federal University of Para´ (UFPA), Bele´m, Para´, Brazil; 2State University of Para´ (UEPA), Bele´m, Para´, Brazil; 3Oral Diagnosis Department, Semiology and Oral Pathology Areas, Piracicaba Dental School, University of Campinas (UNICAMP), Piracicaba, Sa˜o Paulo, Brazil; 4Department of Oral Surgery and Pathology, School of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; 5Department of Pathology, School of Dentistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
Key words: melanoma; amelanotic; sinonasal; survival; recurrence. Accepted for publication 4 November 2019
mas in their pathobiology and clinical course, since the former are not associated with exposure to solar radiation and also exhibit different cytogenetic alterations3,6.
ã 2019 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Pontes FSC, et al. Sinonasal melanoma: a systematic review of the prognostic factors, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.ijom.2019.11.001
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Approximately 50% of all mucosal melanomas are located in the head and neck region4. Primary malignant melanoma of the sinonasal tract is a rare variant and accounts for less than 1% of all head and neck tumours3,7. The most frequent symptoms are nasal obstruction, epistaxis or nasal discharge, polyp, and rarely pain, so they are often diagnosed in the late stages when the lesions are already large and lymph node metastases have developed1,6,8. Up to 10–30% of subjects with sinonasal melanomas will present positive lymphadenopathy at diagnosis, resulting in a poor prognosis9–11. Microscopically, the presence of melanin on the epithelial surface derived from neoplastic pigmented melanocytes is the main characteristic of this lesion12,13; however, there is an amelanotic variant that does not present melanin, which represents a diagnostic challenge for pathologists6. The clinical significance of this microscopic difference, if any, is unknown. Although many case reports are available in the literature, few series have been published to date. Consequently, the clinicopathological and survival features of patients affected by sinonasal melanoma remain to be better established. The aim of the present study was to integrate the available data on sinonasal melanoma into an updated comprehensive review of their clinical, histological, therapeutic, and prognostic factors.
Materials and methods
This study followed the PRISMA Statement guidelines (Preferred Reporting Items for Systematic Reviews and MetaAnalyses)14.
Inclusion and exclusion criteria
Inclusion criteria comprised cases of sinonasal melanoma with sufficient clinical, histological, and immunohistochemical information to confirm the diagnosis. The evaluation was done following the updated classification for mucosal melanoma of the World Health Organization, published in 201715. Randomized and controlled clinical trials, cohort studies, cross-sectional studies, case–control studies, case series, and case reports published in the English language were retrieved. Exclusion criteria were immunohistochemistry only studies, histomorphometric studies, radiological studies, genetic expression studies, histopathological studies, cytological studies, cell proliferation/apoptosis studies, and in vitro studies, unless any of these publication categories had reported any case with enough clinical, histological, and immunohistochemical information. Study selection
The titles and abstracts of all reports retrieved in the electronic search were independently read by four authors (LLS, ALMR, DMN, and VCSV). Those studies that fulfilled the inclusion criteria, as well as those with insufficient data in the title and abstract to make a clear decision, were fully assessed. Any disagreement was resolved by discussion between the professors (FSCP and HARP). The clinical and radiological aspects, as well as the histological description of the lesions reported in the publications, were thoroughly assessed by three authors (FSCP, FPF and HARP), who are experts in oral pathology, in order to confirm the diagnosis.
Search strategies
Data extraction
An electronic search without time restriction was conducted in March 2018. The following electronic databases were assessed: PubMed, Science Direct, and Web of Science. The search strategy used in all databases encompassed the following key words: (frontal sinus OR superior turbinate OR middle turbinate OR inferior turbinate OR vestibule OR anterior naris OR hard palate OR soft palate OR uvula OR pharyngeal tonsil OR choana OR sella turcica OR sphenoid sinus OR cribriform plate OR maxillary sinus OR ethmoid sinus OR nasal) AND (melanoma). Other published literature reviews on sinonasal melanoma were also checked for possible additional studies.
Four authors divided into two groups (LLS and ALMR; DMN and LAF) independently extracted data using specially designed data extraction forms, utilizing Microsoft Excel software. Any disagreement was resolved by discussion between the authors. For each selected study, the following data were then extracted from a standard form (when available): author and year of publication, country, number of patients, patient sex (male or female), age, evolution time, signs and symptoms, tumour location, loco-regional metastasis, radiographic aspects, diagnostic imaging examinations, histological type (melanotic or amelanotic), tumour staging, immunohistochemistry (positive and negative
antibodies), treatment used, lymph node dissection, recurrence, distant metastasis, and follow-up. Study authors were contacted for possible missing data.
Statistical analysis
The means and percentages are presented as descriptive data. Overall survival rates were estimated by Kaplan–Meier analysis and compared using a log-rank test to identify potential prognostic factors. A P-value of <0.05 was considered statistically significant. To investigate the clinicopathological features that may have a prognostic role for the affected patients, factors identified in the univariate analysis were introduced stepwise into a Cox proportional hazards model to identify the independent predictors of survival. Clinicopathological variables were investigated regarding their possible association with recurrence, using either the Student t-test or Mann–Whitney test. Fisher’s exact test was used for categorical variables. Statistical significance was set as P < 0.05. Data were analysed using IBM SPSS Statistics for Windows, version 23.0 (IBM Corp., Armonk, NY, USA). Results Literature search
The study selection process is summarized in Fig. 1. The search strategy returned 71,006 papers. Four authors independently screened the titles and abstracts for compliance of the manuscripts with the study objective. Of the 1807 studies identified, 713 were excluded for not being related to the topic, resulting in 1094 records. Of these, 781 articles were cited in more than one database (duplicates). The full-text reports of the remaining 313 articles were evaluated, leading to the exclusion of 240 articles because they did not report clinical and histological information. Thus, a total of 73 publications were included in the review (Supplementary Material, File S1).
Description of the studies and analyses
Seventy-three publications reporting 439 cases were included in this review. The epidemiological results are described in Fig. 2, which reveals the United States (119 cases), Switzerland (52 cases), France (52 cases), Italy (34 cases), and the United Kingdom (27 cases) to be the
Please cite this article in press as: Pontes FSC, et al. Sinonasal melanoma: a systematic review of the prognostic factors, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.ijom.2019.11.001
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Fig. 1. Study screening process.
Fig. 2. Countries with cases of sinonasal melanoma described in the literature and the number of cases in each country. The United States has reported the most cases, followed by Switzerland, France, Italy, and the United Kingdom.
Please cite this article in press as: Pontes FSC, et al. Sinonasal melanoma: a systematic review of the prognostic factors, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.ijom.2019.11.001
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Table 1. Demographic characteristics, clinical features, and survival analysis of cases of sinonasal melanoma described in the literature (N = 439). Variables
Survival analysis, P-values
N = 439
Age (years), n (%) 67.6 189 (43.1%) >67.6 238 (54.2%) ND 12 (2.7%) Sex, n (%) Male 171 (39.0%) Female 228 (51.9%) ND 40 (9.1%) Primary location, n (%) Ethmoid sinus 75 (17.1%) Inferior turbinate 28 (6.4%) Maxillary sinus 84 (19.1%) Middle turbinate 10 (2.3%) More than one location 24 (5.5%) Nasal cavity 155 (35.3%) Paranasal sinus 50 (11.4%) Sphenoid sinus 13 (3.0%) Disease stage, n (%) IA 20 (19.2%) IB 11 (10.6%) IIA 17 (16.3%) IIB 25 (24.0%) IIC 11 (10.6%) III 12 (11.5%) IV 8 (7.7%) Melanin presence, n (%) Melanotic 381 (86.8%) Amelanotic 58 (13.2%) Lymph node metastasis, n (%) Yes 62 (14.1%) No 34 (7.7%) ND 343 (78.1%) Treatment, n (%) RS 161 (36.7%) CT 13 (3.0%) RT 21 (4.8%) RS + CT 24 (5.5%) RS + RT 75 (17.1%) RS + LND 14 (3.2%) RS + RT + LND 6 (1.3%) CT + RT 6 (1.3%) RS + CT + RT 19 (4.3%) ND 100 (22.8%) Recurrence, n (%) Yes 141 (32.1%) No 121 (27.6%) ND 177 (40.3%) Distant metastasis, n (%) Yes 210 (47.8%) No 118 (26.9%) ND 111 (25.3%)
Univariate analysis
Multivariate analysis
0.0042*
0.0012*
0.1236
0.1179
0.0212*
0.0112*
0.0091*
0.0026*
0.1951
0.2837
0.3214
0.9429
0.0419*
0.0111*
0.0216*
0.0137*
0.0057*
0.0011*
CT, chemotherapy; LND, lymph node dissection; ND, not described; RS, radical surgery; RT, radiotherapy. * P < 0.05, significant result.
countries with the highest numbers of cases described. Table 1 presents the demographic and clinical data, as well as the results of the survival analysis. The lesions were more prevalent in females than in males, with a male to female ratio of 1:1.33. The mean
age of the patients was 67.6 years (range 26–97 years); females were older (mean age 69.6 years, range 35–97 years) than males (mean age 64.3 years, range 26–93 years). Sinonasal melanomas were most prevalent in the nasal cavity (n = 155, 35.3%), maxillary sinus (n = 84, 19.1%),
ethmoid sinus (n = 75, 17.1%), and paranasal sinus not specified (n = 50, 11.4%). The mean lesion size was 30 mm (range 5–100 mm). The tumour stage was reported in 104 cases: stage I was observed in 31 cases (IA in 20 cases (19.2%) and IB in 11 cases (10.6%)), stage II in 53 cases (IIA in 17 cases (16.3%), IIB in 25 cases (24.0%), and IIC in 11 cases (10.6%)), stage III in 12 cases (11.5%), and stage IV in eight cases (7.7%). Regarding regional lymph node metastasis, 62 (14.1%) patients presented positive nodes on clinical examination. Treatment was described for 339 patients and included radical surgery in 161 (36.7%), radical surgery and radiotherapy (RT) in 75 (17.1%), radical surgery and chemotherapy (CT) in 24 (5.5%), RT alone in 21 (4.8%), and radical surgery associated with CT and RT in 19 (4.3%). A small number of cases underwent radical surgery associated with lymph node dissection (n = 14, 3.2%), CT alone (n = 13, 3.0%), CT and RT (n = 6, 1.3%), and radical surgery associated with RT and lymph node dissection (n = 6, 1.3%). Concerning patients who underwent radiotherapy as a single treatment or associated with other treatment approaches, the mean radiation dose used was 43.5 Gy (range 1.5–59.8 Gy). Among the 62 patients who had regional lymph node metastasis, 24 underwent neck dissection, and of these, 12 patients (50%) died after a mean interval of 32 months (range 6–160 months). Figure 3 presents the distribution of the lesions according to the age, showing the highest prevalence in the seventh and eighth decades of life. The patients presented a mean duration of lesion evolution of 6.3 months (range 0.5–72 months). The lesions mainly presented as epistaxis, nasal obstruction, and blurry vision. Preoperative imaging studies were reported in 77 cases. The most common imaging modality was computed tomography (77.9%). Other imaging modalities reported included magnetic resonance imaging (MRI) (38.9%) and X-ray (2.6%). On computed tomography evaluation, the lesions mainly showed a heterogeneous hypodense image; on MRI, the lesions could present as heterogeneous hypointense or hyperintense images. Histological analysis revealed the melanotic subtype in 381 cases (86.8%) and the amelanotic subtype in 58 cases (13.2%). The immunohistochemistry panel for the lesions is shown in Table 2. Patient follow-up was described in 280 cases. The mean duration of fol-
Please cite this article in press as: Pontes FSC, et al. Sinonasal melanoma: a systematic review of the prognostic factors, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.ijom.2019.11.001
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Fig. 3. Distribution of sinonasal melanoma according to age and sex (ND, not described).
Table 2. Antibodies used in the diagnosis of the cases analysed (N = 439). Immunohistochemistry analysis Antibody
Positive
Negative
HMB-45 S-100 Melan-A Vimentin Tyrosinase CD68 EMA Desmin CD99 CK7 CD117 Fli-1
57.3% 53.1% 51.1% 22.9% 9.3% 2% 1% 1% 1% 1% 1% 1%
5.2% 7.3% 5.2% 4.1% 3.1% 0% 2% 1% 0% 0% 0% 0%
low-up was 33.6 months (range 1–217 months). Of these 280 cases, 73 (26.1%) patients were alive without evidence of disease at the end of follow-up, 27 (9.6%) patients were alive with disease, 154 (55%) patients had died of the disease, and 26 (9.3%) patients had died of
other causes. The 5-year survival rate achieved was 30.69% (Fig. 4). One hundred and forty-one patients (32.1%) had a local recurrence at a mean interval of 18.8 months (range 1–105 months). Of these, 100 died from the disease. Distant metastases affected 210 patients (47.8%) at a mean time of
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20.4 months (range 1–96 months), with metastasis occurring in the lungs (34%), liver (30%), central nervous system (17%), and bones (21%), and leading to 184 (87.6%) deaths. Univariate survival analysis of clinical variables revealed that age older than 67.6 years (P = 0.0042), primary location (middle turbinate) (P = 0.0212), advanced disease stage (P = 0.0091), treatment (radiotherapy) (P = 0.0419), recurrence (P = 0.0216), and distant metastasis (P = 0.0057) were significantly associated with a lower survival. Multivariate survival analysis also revealed that age, primary location, disease stage, treatment, recurrence, and distant metastasis were independently associated with survival. Logistic regression showed that the odds ratio of death was seven times higher among patients older than 67.6 years (P = 0.0012) (Fig. 5A). The odds ratio of death in patients with lesions in the middle turbinate was 19 times higher (P = 0.0112) than for lesions in the maxillary sinus (Fig. 5B). Logistic regression showed that the odds ratio of death in patients who presented disease stage IV was 26 times higher (P = 0.0026) than in patients who presented disease stage IA (Fig. 5C). The odds ratio of death in patients treated with radiotherapy (single or associated with other treatment approaches) was 13 times higher (P = 0.0111) than in those treated by radical surgery (Fig. 5D). Logistic regression showed that the odds ratio of death among patients who presented recurrence was three times higher (P = 0.0137) than in patients who did not present recurrence (Fig. 5E). Finally, the odds ratio of death in patients with distant metastasis was 13 times higher (P = 0.0011) than in patients who did not present distant metastasis (Fig. 5F). The correlation between recurrence and other clinicopathological data was statistically significant for age (patients older than 67.6 years; P = 0.0021), sex (men tended to present a higher recurrence index than women; P = 0.0051), disease stage (stages III and IV presented a higher recurrence possibility than stages I and II; P = 0.0331), and histological type (amelanotic lesions presented a higher index of recurrence than melanotic lesions; P = 0.0095) (Table 3). All results demonstrated an elevated Pearson’s correlation. Discussion
Fig. 4. Kaplan–Meier curve for overall survival indicating the reduced probability of survival over time. The overall survival probability is 74.79% at 1 year, 42.64% at 3 years, and 30.69% at 5 years.
Sinonasal melanoma is an aggressive and uncommon lesion, presenting an incidence of 0.2–1 case per million population16,17.
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Fig. 5. Kaplan–Meier curves showing statistically significant results for survival associated with (A) age (P = 0.0012), (B) primary location (P = 0.0112), (C) disease stage (P = 0.0026), (D) treatment (P = 0.0111), (E) recurrence (P = 0.0137), and (E) distant metastasis (P = 0.0011). (RS, radical surgery; CT, chemotherapy; RT, radiotherapy; LND, lymph node dissection.).
Sinonasal melanoma has been described to be more common in regions where cutaneous melanomas are less common12, which may be explained by the multiple factors associated with the disease, including genetic features4,18. It was observed in the present review that females were more affected than males. This differs from the results of some research studies, which have shown a male predominance or no sex difference2,9,19. Regarding age, the highest prevalence was found in the seventh and eighth decades of life16,20. This review revealed a lower mean evolution time until diagnosis (6.3 months) when compared to the previous literature, which reported considerably higher evolution times, probably because of the asymptomatic evolution of the tumour in some cases5,8. Regarding the location of the lesion, the nasal cavity was the most affected site, followed by the maxillary sinus, ethmoid sinus, and paranasal sinus not specified; this is in agreement with the literature1,11,21. The main symptoms observed were epistaxis, nasal obstruction, and blurry vision, which is in accordance with previous reports, and
these occur due to the expansive process of the tumour and neurovascular invasion6,22. Concerning tumour stage, 31 cases (29.8%) were classified as stage I, 53 (51.0%) as stage II, 12 (11.5%) as stage III, and eight (7.7%) as stage IV. Previous studies have demonstrated that patients with sinonasal melanomas generally present in the late stages2,3,8. However, the present review demonstrated that stages I and II were more commonly observed than stages III and IV. This may be explained due to the symptoms such as epistaxis and nasal obstruction, which led to a better investigation by the specialists2,4. Preoperative imaging examinations are the main means of diagnosis. In the present study, it was found that computed tomography was the most common imaging modality and the lesions presented a heterogeneous hypodense image17,23. MRI was less frequently used and the lesions were seen as heterogeneous hypointense or hyperintense images2,17,24. On microscopic analysis, the melanotic subtype was observed in 86.8% of the cases and the amelanotic subtype in 13.2%. This finding is consistent with those of other previous studies, which
showed that melanotic lesions are more often observed2,9,17. In malignant melanoma, most tumour cells appear pigmented and hence the diagnosis of melanin-rich melanoma is not difficult8,19. In contrast, a diagnostic challenge occurs in amelanotic melanoma11,12,24. In melanoma, tumour cells are arranged in sheets with oval to round nuclei and prominent nucleoli. A similar histological picture can be found in many other small round cell tumours and undifferentiated sinonasal cancers11,12,24. Immunohistochemistry using S-100 and HMB-45 is more sensitive in differentiating melanomas from other neoplasms. Concerning lymph node metastasis, 14.1% of patients presented positive nodes on clinical examination. Some studies have described a lower incidence of nodal involvement (5.15%25), while others have reported a much higher incidence (30%1,8). The submandibular, jugulodigastric, and retropharyngeal lymph nodes are most commonly involved, since they are evolved on the lymphatic drainage pathway of the nasal cavity. Early identification of cervical metastasis could help patients who are at high risk of distant
Please cite this article in press as: Pontes FSC, et al. Sinonasal melanoma: a systematic review of the prognostic factors, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.ijom.2019.11.001
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Sinonasal melanoma Table 3. Recurrence according to clinicopathological features and treatment for those lesions with information available for these factors. Variables Age (years), n (%) 67.6 >67.6 Sex, n (%) Male Female Primary location, n (%) Ethmoid sinus Hard palate Inferior turbinate Maxillary sinus Middle turbinate More than one location Nasal cavity Paranasal sinus Sphenoid sinus Disease stage, n (%) IA IB IIA IIB IIC III IV Melanin presence, n (%) Melanotic Amelanotic Lymph node metastasis, n (%) Yes No Treatment, n (%) RS CT RT RS + CT RS + RT RS + LND RS + RT + LND CT + RT RS + CT + RT Distant metastasis, n (%) Yes No
P-value 0.0021* 0.0051* 0.0728
0.0331*
0.0095* 0.0893 0.8511
0.9981
CT, chemotherapy; LND, lymph node dissection; RS, radical surgery; RT, radiotherapy. * P < 0.05, significant result.
metastasis, to allow for closer surveillance or earlier treatment with adjuvant chemotherapy; this could potentially improve the patient’s prognosis and reduce the number of patients who die due to distant metastasis26. However, in the current study, only eight cases (7.7%) were stage IV and 12 cases stage III (11.5%), which does not corroborate with the information that sinonasal cancers are diagnosed in the late stages where the tumour is very large and lymph nodes metastases have already developed. This indicates that the majority
of cases present in the early stages and hence neck dissection must be performed, considering the aggressive behaviour of the lesion1,6,8. Regarding the treatment approach, radical surgery is the main therapeutic strategy for sinonasal melanoma, despite surgical excision being challenging due to the proximity of critical structures such as the eyes and brain. An alternative is the transnasal endoscopic procedure, which provides a better quality of life for patients26,27. Radiotherapy when used in isolation is not effective because sinonasal melanoma is a radio-resistant tumour7,28. Irradiation is more often used in cases of sinonasal melanoma because of the difficulty obtaining satisfactory clear surgical margins in this region. Therefore, complete surgical removal of the tumour and postoperative radiation therapy is the standard of care for resectable lesions. Interestingly, in the current study, the mean radiotherapy dose used was 43.5 Gy. In addition, the current data showed that although radiotherapy is not the best treatment, it was demonstrated to be the second best long-term treatment approach28. Chemotherapy is reserved for surgical treatment failures and for metastatic patients and its efficacy is limited9,19,20,27,29. The prognosis of patients with sinonasal melanoma tends to be poor2,6,27. In the present study it was observed that of the 280 patients with a reported time of follow-up, 154 died due to the disease, which shows a high mortality index. Sinonasal melanomas are notorious for their high rate of local recurrence. In this study, it was found that 32.1% of the cases presented recurrence at a mean interval of 18.8 months, which corroborates the findings of other previous studies2,12,16. In addition, distant metastasis affected a large number of patients at a mean time interval of 20.4 months. These results are validated by other previous studies2,26,27. The main sites affected by distant metastasis were found to be the lungs, liver, central nervous system, and bones2,4,9. Regarding prognostic factors, this study found that patients older than 67.6 years had an odds ratio of death seven times higher than for the younger patients. The study demonstrated a higher death rate in the elderly due to death from melanoma specifically or death from other causes2,19. In addition, tumour location also demonstrated a significant result in the survival analysis. It appears that no previous study has shown the association between the patient prognosis and the tumour location. The odds ratio of death in patients with lesions in the middle turbinate was 19
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times higher than for lesions in the maxillary sinus. This may be explained by the fact that lesions in the turbinates tend to be misdiagnosed and confused with other pathologies such as polyposis and sinusitis6,19. Moreover, the present study found that patients at an advanced disease stage presented a higher possibility of death. The statistical analysis showed that the odds ratio of death in patients who presented disease stage IV was 26 times higher than in patients who presented disease stage IA. These results corroborate those of other studies2,9,30. Also related to the prognosis, the treatment modality revealed a significant result: the odds ratio of death in patients treated with radiotherapy (single and associated with other treatment approaches) was 13 times higher than in those treated by resective surgery. Previous studies have reported that the role of chemotherapy in the management of mucosal melanoma is considered to be limited3 and it is generally used in metastatic forms or as palliative treatment, with a restricted impact on survival; this is in agreement with the results of the present study2,26,27. In addition, the odds ratio of death among patients who presented recurrence was three times higher than in patients who did not present recurrence. Kalogirou et al.8 also observed that recurrence is a significant survival factor and they also evidenced a poor prognosis. Distant metastasis also showed statistically significant results in the present study: the odds ratio of death in patients with distant metastasis was 13 times higher than in patients who did not present distant metastasis, corroborating the results of other research4,8,17,31. Regarding recurrence, a correlation with patient age older than 67.6 years was observed, in agreement with the previous literature, which has associated advanced age and more frequent recurrence8. In addition, advanced disease stages and amelanotic histological type were correlated with recurrence. Breik et al.4 explained that this happens due to the aggressive behaviour of in situ mucosal melanoma, which is considered as T3 in the staging system, and hence should be treated like an invasive melanoma. They also observed that recurrence may be a result of the multifocal nature of the primary disease or the clinically unapparent lymphatic spread of mucosal melanoma cells. In addition, the amelanotic subtype may present an aggressive behaviour due to the difficulty in diagnosis, since it represents a rare variant. In the present study, it was observed that male patients
Please cite this article in press as: Pontes FSC, et al. Sinonasal melanoma: a systematic review of the prognostic factors, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.ijom.2019.11.001
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had a higher recurrence index than female patients. This is different from the results of previous studies in the literature, which did not find any significant relationship for this variable2,8. In conclusion, sinonasal melanoma is a neoplasm with a poor prognosis, presenting a 30.69% possibility of survival after 5 years. Patients older than 67.6 years, with lesions in the middle turbinate, disease at an advanced stage, in whom radiotherapy was used as the treatment approach, and who presented recurrence or distant metastasis, presented the worst prognosis. In addition, males older than 67.6 years who presented disease stage III or IV and the amelanotic histological subtype tended to present a higher rate of recurrence. Funding
No funding was given to this study. Competing interests
No conflict of interest is reported for this study. Ethical approval
This study did not involve human or animal subjects or records. Patient consent
Not applicable. Statement to confirm
All authors reviewed and agreed the final version of the paper.
Appendix A. Supplementary data
Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.ijom.2019. 11.001. References 1. Thariat J, Poissonnet G, Marcy PY, Lattes L, Butori C, Guevara N, Dassonville O, Santini J, Bensadoun RJ, Castillo L. Effect of surgical modality and hypofractionated splitcourse radiotherapy on local control and survival from sinonasal mucosal melanoma. Clin Oncol (R Coll Radiol) 2011;23:579–86. 2. Dre´no M, Georges M, Espitalier F, Ferron C, Charnole´ A, Dre´no B, Malard O. Sinonasal mucosal melanoma: a 44-case study and literature analysis. Eur Ann Otorhinolaryngol Head Neck Dis 2017;134:237–42.
3. Romano A, Iaconetta G, Pansini A, Mascolo M, Cieri M, Abbate V, Salzano G, Orabona GD, Califano L. Sinonasal mucosal melanoma extended to nose bridge: a one-time reconstruction treatment report. Oral Maxillofac Surg Cases 2018;4:1–5. 4. Breik O, Sim F, Wong T, Nastri A, Iseli TA, Wiesenfeld D. Survival outcomes of mucosal melanoma in the head and neck: case series and review of current treatment guidelines. J Oral Maxillofac Surg 2016;74:1859–71. 5. Snyers A, Janssens GO, Twickler MB, Hermus AR, Takes RP, Kappelle AC, Merkx MA, Dirix P, Kaanders JH. Malignant tumors of the nasal cavity and paranasal sinuses: long-term outcome and morbidity with emphasis on hypothalamic-pituitary deficiency. Int J Radiat Oncol Biol Phys 2009;73:1343–51. 6. Shin SH, Seok H, Kim SG, Hong SD. Primary sinonasal mucosal melanoma simulated as cystic lesions: a case report. J Korean Assoc Oral Maxillofac Surg 2018;44:29–33. 7. Stanimirov Rossi O, Vital D, Soyka MB, Roth TN, Huber GF, Holzmann D. Multilocular sinonasal malignant melanoma: a poor prognostic subgroup? Eur Arch Otorhinolaryngol 2015;272:123–9. 8. Kalogirou EM, Kalyvas D, Tosios KI, Tsiklakis K, Sklavounou A. Recurrence in a patient with a 10-year history of sinonasal mucosal melanoma manifesting as facial swelling. J Clin Exp Dent 2017;9:e1492–5. http://dx.doi.org/10.4317/jced.54466. 9. Gilain L, Houette A, Montalban A, Mom T, Saroul N. Mucosal melanoma of the nasal cavity and paranasal sinuses. Eur Ann Otorhinolaryngol Head Neck Dis 2014;131:365– 9. 10. Kondratiev S, Gnepp DR, Yakirevich E, Sabo E, Annino DJ, Rebeiz E, Laver NV. Expression and prognostic role of MMP2, MMP9, MMP13, and MMP14 matrix metalloproteinases in sinonasal and oral malignant melanomas. Hum Pathol 2008;39:337–43. 11. Singhvi A, Joshi A. A case of amelanotic malignant melanoma of the maxillary sinus presented with intraoral extension. Malays J Med Sci 2015;22:89–92. 12. Verma R, Lokesh KP, Gupta K, Panda NK. Sinonasal amelanotic malignant melanoma—a diagnostic dilemma. Egypt J Ear Nose Throat Allied Sci 2015;16:275–8. 13. de Souza LL, Pontes FSC, Pontes HAR, Neto NC, de Carvalho WRS, Guimara˜es DM. Central mucoepidermoid carcinoma: an up-to-date analysis of 147 cases and review of prognostic factors. J Craniomaxillofac Surg 2018;46:162–7. 14. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 2009;151:264–9. 15. Williams MD. Update from the 4th edition of the World Health Organization Classification of Head and Neck Tumours: Mucosal
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Melanomas. Head Neck Pathol 2017;11:110–7. Kerr EH, Hameed O, Lewis Jr JS, Bartolucci AA, Wang D, Said-Al-Naief N. Head and neck mucosal malignant melanoma: clinicopathologic correlation with contemporary review of prognostic indicators. Int J Surg Pathol 2012;20:37–46. Letievant JC, Poupart M, Ambrun A, Colin C, Pignat JC. Single-center retrospective series of fourteen patients with mucosal melanoma of the nasal cavity and paranasal sinuses. Eur Ann Otorhinolaryngol Head Neck Dis 2016;133:387–91. Furumoto K, Miyauchi Y, Ito D, Kitai T, Kogire M. Solitary metastatic gallbladder malignant melanoma originated from the nasal cavity: a case report. Int J Surg Case Rep 2013;4:965–8. Gasparyan A, Amiri F, Safdieh J, Reid V, Cirincione E, Shah D. Malignant mucosal melanoma of the paranasal sinuses: two case presentations. World J Clin Oncol 2011;2:344–7. Lie´tin B, Montalban A, Louvrier C, Kemeny JL, Mom T, Gilain L. Sinonasal mucosal melanomas. Eur Ann Otorhinolaryngol Head Neck Dis 2010;127:70–6. Tiwari D, Plater M, Partridge R, WestonSimons J. Primary malignant melanoma of the nose: a rare cause of epistaxis in the elderly. Age Ageing 2005;34:653–4. Sanderson AR, Gaylis B. Malignant melanoma of the sinonasal mucosa: two case reports and a review. Ear Nose Throat J 2007;86:287–9. 294. Shehata M, Gombos D, Bishop J, Zafereo ME. Sinonasal melanoma arising from conjunctival primary acquired melanosis. BMJ Case Rep 2015;2015. pii: bcr2014208522. Smith SM, Schmitt AC, Carrau RL, Iwenofu OH. Primary sinonasal mucosal melanoma with aberrant diffuse and strong desmin reactivity: a potential diagnostic pitfall! Head Neck Pathol 2015;9:165–71. Prasad HM, Suhas SS, Ravi D, Balaji NK, Madhuri MG. A case report of primary melanotic tumour of the nasal cavity. J Evol Med Dent Sci 2016;5:4049–51. Oldenburg MS, Price DL. The utility of sentinel node biopsy for sinonasal melanoma. J Neurol Surg B Skull Base 2017;78:425–9. Ledderose GJ, Leunig A. Surgical management of recurrent sinonasal mucosal melanoma: endoscopic or transfacial resection. Eur Arch Otorhinolaryngol 2015;272:351– 6. Schmidt MQ, David J, Yoshida EJ, Scher K, Mita A, Shiao SL, Ho AS, Zumsteg ZS. Predictors of survival in head and neck mucosal melanoma. Oral Oncol 2017;73:36– 42. Marinova L, Yordanov K, Sapundgiev N. Primary mucosal sinonasal melanoma—case report and review of the literature. The role
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Sinonasal melanoma of complex treatment—surgery and adjuvant radiotherapy. Rep Pract Oncol Radiother 2010;16:40–3. 30. Haerle SK, Soyka MB, Fischer DR, Murer K, Strobel K, Huber GF, Holzmann D. The value of 18F-FDG-PET/CT imaging for sinonasal malignant melanoma. Eur Arch Otorhinolaryngol 2012;269:127–33. 31. Sun S, Huang X, Gao L, Zhang Y, Luo J, Zhang S, Wang K, Qu Y, Wu R, Liu Q, Xiao
J, Xu G, Yi J. Long-term treatment outcomes and prognosis of mucosal melanoma of the head and neck: 161 cases from a single institution. Oral Oncol 2017;74:115–22.
Address: Lucas Lacerda de Souza Joa˜o de Barros Barreto University Hospital Department of Surgery and Oral Pathology Mundurucus Street
No. 4487 66073-000 Bele´m Para´ Brazil Tel.: +55 91 32016786 E-mail: [email protected]
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Int. J. Oral Maxillofac. Surg. 2019; xxx: xxx–xxx https://doi.org/10.1016/j.ijom.2019.11.001, available online at https://www.sciencedirect.com
Systematic Review Head and Neck Oncology
Sinonasal melanoma: a systematic review of the prognostic factors F. S. C. Pontes, L. L. de Souza, M. C. de Abreu, L. A. Fernandes, A. L. M. Rodrigues, D. M. do Nascimento, V. C. S. Vasconcelos, C. D. Soares, D. L. Correˆa, F. P. Fonseca, B. A. B. de Andrade, H. A. R. Pontes: Sinonasal melanoma: a systematic review of the prognostic factors. Int. J. Oral Maxillofac. Surg. 2019; xxx: xxx–xxx. ã 2019 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Abstract. The objective was to evaluate the available published data on sinonasal melanoma and analyse its clinical features, treatment modalities, and prognostic factors. An electronic search was undertaken in March 2018 in multiple databases. Eligibility criteria included publications with sufficient clinical, histological, and immunohistochemical information to confirm the diagnosis. Seventy-three publications (439 cases) were included. The lesion was more prevalent in females than in males. There was a higher prevalence in the seventh and eighth decades of life. The lesions mainly presented as epistaxis and commonly involved the nasal cavity. Age (>67.6 years; P = 0.0012), primary location (middle turbinate; P = 0.0112), disease stage (advanced disease stage; P = 0.0026), treatment (radiotherapy; P = 0.0111), recurrence (recurrence presented; P = 0.0137), and distant metastasis (distant metastasis presented; P = 0.0011) were independently associated with a lower survival rate. Recurrence was significantly correlated with age (>67.6 years; P = 0.0021), sex (males tended to present a higher recurrence rate than females; P = 0.0051), disease stage (stages III and IV presented a higher recurrence rate than stages I and II; P = 0.0331), and histological type (amelanotic lesions presented a higher index of recurrence than melanotic lesions; P = 0.0095). In conclusion, sinonasal melanoma is a neoplasm with a poor prognosis, presenting a 30.69% possibility of survival after 5 years.
Mucosal melanomas are uncommon lesions that arise from melanocytes, presenting an aggressive clinical behaviour and a poor prognosis1–3. They can affect 0901-5027/000001+09
the aerodigestive tract, including the oral cavity, pharynx, larynx, nasal cavity, and paranasal sinuses4,5. Mucosal melanomas are also distinct from cutaneous melano-
F. S. C. Pontes1, L. L. de Souza1, M. C. de Abreu1, L. A. Fernandes1, A. L. M. Rodrigues2, D. M. do Nascimento2, V. C. S. Vasconcelos2, C. D. Soares3, D. L. Correˆa1, F. P. Fonseca3,4, B. A. B. de Andrade5, H. A. R. Pontes1,3 1
Joa˜o de Barros Barreto University Hospital (HUJBB), Federal University of Para´ (UFPA), Bele´m, Para´, Brazil; 2State University of Para´ (UEPA), Bele´m, Para´, Brazil; 3Oral Diagnosis Department, Semiology and Oral Pathology Areas, Piracicaba Dental School, University of Campinas (UNICAMP), Piracicaba, Sa˜o Paulo, Brazil; 4Department of Oral Surgery and Pathology, School of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; 5Department of Pathology, School of Dentistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
Key words: melanoma; amelanotic; sinonasal; survival; recurrence. Accepted for publication 4 November 2019
mas in their pathobiology and clinical course, since the former are not associated with exposure to solar radiation and also exhibit different cytogenetic alterations3,6.
ã 2019 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
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Approximately 50% of all mucosal melanomas are located in the head and neck region4. Primary malignant melanoma of the sinonasal tract is a rare variant and accounts for less than 1% of all head and neck tumours3,7. The most frequent symptoms are nasal obstruction, epistaxis or nasal discharge, polyp, and rarely pain, so they are often diagnosed in the late stages when the lesions are already large and lymph node metastases have developed1,6,8. Up to 10–30% of subjects with sinonasal melanomas will present positive lymphadenopathy at diagnosis, resulting in a poor prognosis9–11. Microscopically, the presence of melanin on the epithelial surface derived from neoplastic pigmented melanocytes is the main characteristic of this lesion12,13; however, there is an amelanotic variant that does not present melanin, which represents a diagnostic challenge for pathologists6. The clinical significance of this microscopic difference, if any, is unknown. Although many case reports are available in the literature, few series have been published to date. Consequently, the clinicopathological and survival features of patients affected by sinonasal melanoma remain to be better established. The aim of the present study was to integrate the available data on sinonasal melanoma into an updated comprehensive review of their clinical, histological, therapeutic, and prognostic factors.
Materials and methods
This study followed the PRISMA Statement guidelines (Preferred Reporting Items for Systematic Reviews and MetaAnalyses)14.
Inclusion and exclusion criteria
Inclusion criteria comprised cases of sinonasal melanoma with sufficient clinical, histological, and immunohistochemical information to confirm the diagnosis. The evaluation was done following the updated classification for mucosal melanoma of the World Health Organization, published in 201715. Randomized and controlled clinical trials, cohort studies, cross-sectional studies, case–control studies, case series, and case reports published in the English language were retrieved. Exclusion criteria were immunohistochemistry only studies, histomorphometric studies, radiological studies, genetic expression studies, histopathological studies, cytological studies, cell proliferation/apoptosis studies, and in vitro studies, unless any of these publication categories had reported any case with enough clinical, histological, and immunohistochemical information. Study selection
The titles and abstracts of all reports retrieved in the electronic search were independently read by four authors (LLS, ALMR, DMN, and VCSV). Those studies that fulfilled the inclusion criteria, as well as those with insufficient data in the title and abstract to make a clear decision, were fully assessed. Any disagreement was resolved by discussion between the professors (FSCP and HARP). The clinical and radiological aspects, as well as the histological description of the lesions reported in the publications, were thoroughly assessed by three authors (FSCP, FPF and HARP), who are experts in oral pathology, in order to confirm the diagnosis.
Search strategies
Data extraction
An electronic search without time restriction was conducted in March 2018. The following electronic databases were assessed: PubMed, Science Direct, and Web of Science. The search strategy used in all databases encompassed the following key words: (frontal sinus OR superior turbinate OR middle turbinate OR inferior turbinate OR vestibule OR anterior naris OR hard palate OR soft palate OR uvula OR pharyngeal tonsil OR choana OR sella turcica OR sphenoid sinus OR cribriform plate OR maxillary sinus OR ethmoid sinus OR nasal) AND (melanoma). Other published literature reviews on sinonasal melanoma were also checked for possible additional studies.
Four authors divided into two groups (LLS and ALMR; DMN and LAF) independently extracted data using specially designed data extraction forms, utilizing Microsoft Excel software. Any disagreement was resolved by discussion between the authors. For each selected study, the following data were then extracted from a standard form (when available): author and year of publication, country, number of patients, patient sex (male or female), age, evolution time, signs and symptoms, tumour location, loco-regional metastasis, radiographic aspects, diagnostic imaging examinations, histological type (melanotic or amelanotic), tumour staging, immunohistochemistry (positive and negative
antibodies), treatment used, lymph node dissection, recurrence, distant metastasis, and follow-up. Study authors were contacted for possible missing data.
Statistical analysis
The means and percentages are presented as descriptive data. Overall survival rates were estimated by Kaplan–Meier analysis and compared using a log-rank test to identify potential prognostic factors. A P-value of <0.05 was considered statistically significant. To investigate the clinicopathological features that may have a prognostic role for the affected patients, factors identified in the univariate analysis were introduced stepwise into a Cox proportional hazards model to identify the independent predictors of survival. Clinicopathological variables were investigated regarding their possible association with recurrence, using either the Student t-test or Mann–Whitney test. Fisher’s exact test was used for categorical variables. Statistical significance was set as P < 0.05. Data were analysed using IBM SPSS Statistics for Windows, version 23.0 (IBM Corp., Armonk, NY, USA). Results Literature search
The study selection process is summarized in Fig. 1. The search strategy returned 71,006 papers. Four authors independently screened the titles and abstracts for compliance of the manuscripts with the study objective. Of the 1807 studies identified, 713 were excluded for not being related to the topic, resulting in 1094 records. Of these, 781 articles were cited in more than one database (duplicates). The full-text reports of the remaining 313 articles were evaluated, leading to the exclusion of 240 articles because they did not report clinical and histological information. Thus, a total of 73 publications were included in the review (Supplementary Material, File S1).
Description of the studies and analyses
Seventy-three publications reporting 439 cases were included in this review. The epidemiological results are described in Fig. 2, which reveals the United States (119 cases), Switzerland (52 cases), France (52 cases), Italy (34 cases), and the United Kingdom (27 cases) to be the
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Fig. 1. Study screening process.
Fig. 2. Countries with cases of sinonasal melanoma described in the literature and the number of cases in each country. The United States has reported the most cases, followed by Switzerland, France, Italy, and the United Kingdom.
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Table 1. Demographic characteristics, clinical features, and survival analysis of cases of sinonasal melanoma described in the literature (N = 439). Variables
Survival analysis, P-values
N = 439
Age (years), n (%) 67.6 189 (43.1%) >67.6 238 (54.2%) ND 12 (2.7%) Sex, n (%) Male 171 (39.0%) Female 228 (51.9%) ND 40 (9.1%) Primary location, n (%) Ethmoid sinus 75 (17.1%) Inferior turbinate 28 (6.4%) Maxillary sinus 84 (19.1%) Middle turbinate 10 (2.3%) More than one location 24 (5.5%) Nasal cavity 155 (35.3%) Paranasal sinus 50 (11.4%) Sphenoid sinus 13 (3.0%) Disease stage, n (%) IA 20 (19.2%) IB 11 (10.6%) IIA 17 (16.3%) IIB 25 (24.0%) IIC 11 (10.6%) III 12 (11.5%) IV 8 (7.7%) Melanin presence, n (%) Melanotic 381 (86.8%) Amelanotic 58 (13.2%) Lymph node metastasis, n (%) Yes 62 (14.1%) No 34 (7.7%) ND 343 (78.1%) Treatment, n (%) RS 161 (36.7%) CT 13 (3.0%) RT 21 (4.8%) RS + CT 24 (5.5%) RS + RT 75 (17.1%) RS + LND 14 (3.2%) RS + RT + LND 6 (1.3%) CT + RT 6 (1.3%) RS + CT + RT 19 (4.3%) ND 100 (22.8%) Recurrence, n (%) Yes 141 (32.1%) No 121 (27.6%) ND 177 (40.3%) Distant metastasis, n (%) Yes 210 (47.8%) No 118 (26.9%) ND 111 (25.3%)
Univariate analysis
Multivariate analysis
0.0042*
0.0012*
0.1236
0.1179
0.0212*
0.0112*
0.0091*
0.0026*
0.1951
0.2837
0.3214
0.9429
0.0419*
0.0111*
0.0216*
0.0137*
0.0057*
0.0011*
CT, chemotherapy; LND, lymph node dissection; ND, not described; RS, radical surgery; RT, radiotherapy. * P < 0.05, significant result.
countries with the highest numbers of cases described. Table 1 presents the demographic and clinical data, as well as the results of the survival analysis. The lesions were more prevalent in females than in males, with a male to female ratio of 1:1.33. The mean
age of the patients was 67.6 years (range 26–97 years); females were older (mean age 69.6 years, range 35–97 years) than males (mean age 64.3 years, range 26–93 years). Sinonasal melanomas were most prevalent in the nasal cavity (n = 155, 35.3%), maxillary sinus (n = 84, 19.1%),
ethmoid sinus (n = 75, 17.1%), and paranasal sinus not specified (n = 50, 11.4%). The mean lesion size was 30 mm (range 5–100 mm). The tumour stage was reported in 104 cases: stage I was observed in 31 cases (IA in 20 cases (19.2%) and IB in 11 cases (10.6%)), stage II in 53 cases (IIA in 17 cases (16.3%), IIB in 25 cases (24.0%), and IIC in 11 cases (10.6%)), stage III in 12 cases (11.5%), and stage IV in eight cases (7.7%). Regarding regional lymph node metastasis, 62 (14.1%) patients presented positive nodes on clinical examination. Treatment was described for 339 patients and included radical surgery in 161 (36.7%), radical surgery and radiotherapy (RT) in 75 (17.1%), radical surgery and chemotherapy (CT) in 24 (5.5%), RT alone in 21 (4.8%), and radical surgery associated with CT and RT in 19 (4.3%). A small number of cases underwent radical surgery associated with lymph node dissection (n = 14, 3.2%), CT alone (n = 13, 3.0%), CT and RT (n = 6, 1.3%), and radical surgery associated with RT and lymph node dissection (n = 6, 1.3%). Concerning patients who underwent radiotherapy as a single treatment or associated with other treatment approaches, the mean radiation dose used was 43.5 Gy (range 1.5–59.8 Gy). Among the 62 patients who had regional lymph node metastasis, 24 underwent neck dissection, and of these, 12 patients (50%) died after a mean interval of 32 months (range 6–160 months). Figure 3 presents the distribution of the lesions according to the age, showing the highest prevalence in the seventh and eighth decades of life. The patients presented a mean duration of lesion evolution of 6.3 months (range 0.5–72 months). The lesions mainly presented as epistaxis, nasal obstruction, and blurry vision. Preoperative imaging studies were reported in 77 cases. The most common imaging modality was computed tomography (77.9%). Other imaging modalities reported included magnetic resonance imaging (MRI) (38.9%) and X-ray (2.6%). On computed tomography evaluation, the lesions mainly showed a heterogeneous hypodense image; on MRI, the lesions could present as heterogeneous hypointense or hyperintense images. Histological analysis revealed the melanotic subtype in 381 cases (86.8%) and the amelanotic subtype in 58 cases (13.2%). The immunohistochemistry panel for the lesions is shown in Table 2. Patient follow-up was described in 280 cases. The mean duration of fol-
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Fig. 3. Distribution of sinonasal melanoma according to age and sex (ND, not described).
Table 2. Antibodies used in the diagnosis of the cases analysed (N = 439). Immunohistochemistry analysis Antibody
Positive
Negative
HMB-45 S-100 Melan-A Vimentin Tyrosinase CD68 EMA Desmin CD99 CK7 CD117 Fli-1
57.3% 53.1% 51.1% 22.9% 9.3% 2% 1% 1% 1% 1% 1% 1%
5.2% 7.3% 5.2% 4.1% 3.1% 0% 2% 1% 0% 0% 0% 0%
low-up was 33.6 months (range 1–217 months). Of these 280 cases, 73 (26.1%) patients were alive without evidence of disease at the end of follow-up, 27 (9.6%) patients were alive with disease, 154 (55%) patients had died of the disease, and 26 (9.3%) patients had died of
other causes. The 5-year survival rate achieved was 30.69% (Fig. 4). One hundred and forty-one patients (32.1%) had a local recurrence at a mean interval of 18.8 months (range 1–105 months). Of these, 100 died from the disease. Distant metastases affected 210 patients (47.8%) at a mean time of
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20.4 months (range 1–96 months), with metastasis occurring in the lungs (34%), liver (30%), central nervous system (17%), and bones (21%), and leading to 184 (87.6%) deaths. Univariate survival analysis of clinical variables revealed that age older than 67.6 years (P = 0.0042), primary location (middle turbinate) (P = 0.0212), advanced disease stage (P = 0.0091), treatment (radiotherapy) (P = 0.0419), recurrence (P = 0.0216), and distant metastasis (P = 0.0057) were significantly associated with a lower survival. Multivariate survival analysis also revealed that age, primary location, disease stage, treatment, recurrence, and distant metastasis were independently associated with survival. Logistic regression showed that the odds ratio of death was seven times higher among patients older than 67.6 years (P = 0.0012) (Fig. 5A). The odds ratio of death in patients with lesions in the middle turbinate was 19 times higher (P = 0.0112) than for lesions in the maxillary sinus (Fig. 5B). Logistic regression showed that the odds ratio of death in patients who presented disease stage IV was 26 times higher (P = 0.0026) than in patients who presented disease stage IA (Fig. 5C). The odds ratio of death in patients treated with radiotherapy (single or associated with other treatment approaches) was 13 times higher (P = 0.0111) than in those treated by radical surgery (Fig. 5D). Logistic regression showed that the odds ratio of death among patients who presented recurrence was three times higher (P = 0.0137) than in patients who did not present recurrence (Fig. 5E). Finally, the odds ratio of death in patients with distant metastasis was 13 times higher (P = 0.0011) than in patients who did not present distant metastasis (Fig. 5F). The correlation between recurrence and other clinicopathological data was statistically significant for age (patients older than 67.6 years; P = 0.0021), sex (men tended to present a higher recurrence index than women; P = 0.0051), disease stage (stages III and IV presented a higher recurrence possibility than stages I and II; P = 0.0331), and histological type (amelanotic lesions presented a higher index of recurrence than melanotic lesions; P = 0.0095) (Table 3). All results demonstrated an elevated Pearson’s correlation. Discussion
Fig. 4. Kaplan–Meier curve for overall survival indicating the reduced probability of survival over time. The overall survival probability is 74.79% at 1 year, 42.64% at 3 years, and 30.69% at 5 years.
Sinonasal melanoma is an aggressive and uncommon lesion, presenting an incidence of 0.2–1 case per million population16,17.
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Fig. 5. Kaplan–Meier curves showing statistically significant results for survival associated with (A) age (P = 0.0012), (B) primary location (P = 0.0112), (C) disease stage (P = 0.0026), (D) treatment (P = 0.0111), (E) recurrence (P = 0.0137), and (E) distant metastasis (P = 0.0011). (RS, radical surgery; CT, chemotherapy; RT, radiotherapy; LND, lymph node dissection.).
Sinonasal melanoma has been described to be more common in regions where cutaneous melanomas are less common12, which may be explained by the multiple factors associated with the disease, including genetic features4,18. It was observed in the present review that females were more affected than males. This differs from the results of some research studies, which have shown a male predominance or no sex difference2,9,19. Regarding age, the highest prevalence was found in the seventh and eighth decades of life16,20. This review revealed a lower mean evolution time until diagnosis (6.3 months) when compared to the previous literature, which reported considerably higher evolution times, probably because of the asymptomatic evolution of the tumour in some cases5,8. Regarding the location of the lesion, the nasal cavity was the most affected site, followed by the maxillary sinus, ethmoid sinus, and paranasal sinus not specified; this is in agreement with the literature1,11,21. The main symptoms observed were epistaxis, nasal obstruction, and blurry vision, which is in accordance with previous reports, and
these occur due to the expansive process of the tumour and neurovascular invasion6,22. Concerning tumour stage, 31 cases (29.8%) were classified as stage I, 53 (51.0%) as stage II, 12 (11.5%) as stage III, and eight (7.7%) as stage IV. Previous studies have demonstrated that patients with sinonasal melanomas generally present in the late stages2,3,8. However, the present review demonstrated that stages I and II were more commonly observed than stages III and IV. This may be explained due to the symptoms such as epistaxis and nasal obstruction, which led to a better investigation by the specialists2,4. Preoperative imaging examinations are the main means of diagnosis. In the present study, it was found that computed tomography was the most common imaging modality and the lesions presented a heterogeneous hypodense image17,23. MRI was less frequently used and the lesions were seen as heterogeneous hypointense or hyperintense images2,17,24. On microscopic analysis, the melanotic subtype was observed in 86.8% of the cases and the amelanotic subtype in 13.2%. This finding is consistent with those of other previous studies, which
showed that melanotic lesions are more often observed2,9,17. In malignant melanoma, most tumour cells appear pigmented and hence the diagnosis of melanin-rich melanoma is not difficult8,19. In contrast, a diagnostic challenge occurs in amelanotic melanoma11,12,24. In melanoma, tumour cells are arranged in sheets with oval to round nuclei and prominent nucleoli. A similar histological picture can be found in many other small round cell tumours and undifferentiated sinonasal cancers11,12,24. Immunohistochemistry using S-100 and HMB-45 is more sensitive in differentiating melanomas from other neoplasms. Concerning lymph node metastasis, 14.1% of patients presented positive nodes on clinical examination. Some studies have described a lower incidence of nodal involvement (5.15%25), while others have reported a much higher incidence (30%1,8). The submandibular, jugulodigastric, and retropharyngeal lymph nodes are most commonly involved, since they are evolved on the lymphatic drainage pathway of the nasal cavity. Early identification of cervical metastasis could help patients who are at high risk of distant
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Sinonasal melanoma Table 3. Recurrence according to clinicopathological features and treatment for those lesions with information available for these factors. Variables Age (years), n (%) 67.6 >67.6 Sex, n (%) Male Female Primary location, n (%) Ethmoid sinus Hard palate Inferior turbinate Maxillary sinus Middle turbinate More than one location Nasal cavity Paranasal sinus Sphenoid sinus Disease stage, n (%) IA IB IIA IIB IIC III IV Melanin presence, n (%) Melanotic Amelanotic Lymph node metastasis, n (%) Yes No Treatment, n (%) RS CT RT RS + CT RS + RT RS + LND RS + RT + LND CT + RT RS + CT + RT Distant metastasis, n (%) Yes No
P-value 0.0021* 0.0051* 0.0728
0.0331*
0.0095* 0.0893 0.8511
0.9981
CT, chemotherapy; LND, lymph node dissection; RS, radical surgery; RT, radiotherapy. * P < 0.05, significant result.
metastasis, to allow for closer surveillance or earlier treatment with adjuvant chemotherapy; this could potentially improve the patient’s prognosis and reduce the number of patients who die due to distant metastasis26. However, in the current study, only eight cases (7.7%) were stage IV and 12 cases stage III (11.5%), which does not corroborate with the information that sinonasal cancers are diagnosed in the late stages where the tumour is very large and lymph nodes metastases have already developed. This indicates that the majority
of cases present in the early stages and hence neck dissection must be performed, considering the aggressive behaviour of the lesion1,6,8. Regarding the treatment approach, radical surgery is the main therapeutic strategy for sinonasal melanoma, despite surgical excision being challenging due to the proximity of critical structures such as the eyes and brain. An alternative is the transnasal endoscopic procedure, which provides a better quality of life for patients26,27. Radiotherapy when used in isolation is not effective because sinonasal melanoma is a radio-resistant tumour7,28. Irradiation is more often used in cases of sinonasal melanoma because of the difficulty obtaining satisfactory clear surgical margins in this region. Therefore, complete surgical removal of the tumour and postoperative radiation therapy is the standard of care for resectable lesions. Interestingly, in the current study, the mean radiotherapy dose used was 43.5 Gy. In addition, the current data showed that although radiotherapy is not the best treatment, it was demonstrated to be the second best long-term treatment approach28. Chemotherapy is reserved for surgical treatment failures and for metastatic patients and its efficacy is limited9,19,20,27,29. The prognosis of patients with sinonasal melanoma tends to be poor2,6,27. In the present study it was observed that of the 280 patients with a reported time of follow-up, 154 died due to the disease, which shows a high mortality index. Sinonasal melanomas are notorious for their high rate of local recurrence. In this study, it was found that 32.1% of the cases presented recurrence at a mean interval of 18.8 months, which corroborates the findings of other previous studies2,12,16. In addition, distant metastasis affected a large number of patients at a mean time interval of 20.4 months. These results are validated by other previous studies2,26,27. The main sites affected by distant metastasis were found to be the lungs, liver, central nervous system, and bones2,4,9. Regarding prognostic factors, this study found that patients older than 67.6 years had an odds ratio of death seven times higher than for the younger patients. The study demonstrated a higher death rate in the elderly due to death from melanoma specifically or death from other causes2,19. In addition, tumour location also demonstrated a significant result in the survival analysis. It appears that no previous study has shown the association between the patient prognosis and the tumour location. The odds ratio of death in patients with lesions in the middle turbinate was 19
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times higher than for lesions in the maxillary sinus. This may be explained by the fact that lesions in the turbinates tend to be misdiagnosed and confused with other pathologies such as polyposis and sinusitis6,19. Moreover, the present study found that patients at an advanced disease stage presented a higher possibility of death. The statistical analysis showed that the odds ratio of death in patients who presented disease stage IV was 26 times higher than in patients who presented disease stage IA. These results corroborate those of other studies2,9,30. Also related to the prognosis, the treatment modality revealed a significant result: the odds ratio of death in patients treated with radiotherapy (single and associated with other treatment approaches) was 13 times higher than in those treated by resective surgery. Previous studies have reported that the role of chemotherapy in the management of mucosal melanoma is considered to be limited3 and it is generally used in metastatic forms or as palliative treatment, with a restricted impact on survival; this is in agreement with the results of the present study2,26,27. In addition, the odds ratio of death among patients who presented recurrence was three times higher than in patients who did not present recurrence. Kalogirou et al.8 also observed that recurrence is a significant survival factor and they also evidenced a poor prognosis. Distant metastasis also showed statistically significant results in the present study: the odds ratio of death in patients with distant metastasis was 13 times higher than in patients who did not present distant metastasis, corroborating the results of other research4,8,17,31. Regarding recurrence, a correlation with patient age older than 67.6 years was observed, in agreement with the previous literature, which has associated advanced age and more frequent recurrence8. In addition, advanced disease stages and amelanotic histological type were correlated with recurrence. Breik et al.4 explained that this happens due to the aggressive behaviour of in situ mucosal melanoma, which is considered as T3 in the staging system, and hence should be treated like an invasive melanoma. They also observed that recurrence may be a result of the multifocal nature of the primary disease or the clinically unapparent lymphatic spread of mucosal melanoma cells. In addition, the amelanotic subtype may present an aggressive behaviour due to the difficulty in diagnosis, since it represents a rare variant. In the present study, it was observed that male patients
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had a higher recurrence index than female patients. This is different from the results of previous studies in the literature, which did not find any significant relationship for this variable2,8. In conclusion, sinonasal melanoma is a neoplasm with a poor prognosis, presenting a 30.69% possibility of survival after 5 years. Patients older than 67.6 years, with lesions in the middle turbinate, disease at an advanced stage, in whom radiotherapy was used as the treatment approach, and who presented recurrence or distant metastasis, presented the worst prognosis. In addition, males older than 67.6 years who presented disease stage III or IV and the amelanotic histological subtype tended to present a higher rate of recurrence. Funding
No funding was given to this study. Competing interests
No conflict of interest is reported for this study. Ethical approval
This study did not involve human or animal subjects or records. Patient consent
Not applicable. Statement to confirm
All authors reviewed and agreed the final version of the paper.
Appendix A. Supplementary data
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