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Mucosal melanoma of the head and neck: recurrence characteristics and survival outcomes
Vol. 120 No. 5 November 2015
Mucosal melanoma of the head and neck: recurrence characteristics and survival outcomes Faruk Kadri Bakkal, MD,a Adil Bas¸man, DMD,b Yusuf Kızıl, MD,a Özgür Ekinci, MD,c Mustafa Gümüs¸ok, DMD,d Mehmet Ekrem Zorlu, MD,a and Utku Aydil, MDa Gazi University School of Medicine, Ankara, Turkey
Objective. The aim of this study was to review oncologic outcomes and recurrence characteristics of head and neck mucosal melanomas (HNMMs) managed at a tertiary referral center. Study Design. Clinical records of 10 patients who were managed for HNMMs between 2001 and 2013 were retrospectively analyzed. Results. The median age was 66 years (range 28-76 years) and male/female (M/F) ratio was 1:5. The 3-year disease-free survival (DFS) rates and overall survival (OS) rates were 11.7% and 35%, respectively; and the 5-year DFS rates and OS rates 11.7% and 23.3%, respectively. The median DFS and OS periods were 12 months (range 2-36 months) and 17 months (range 7-96 months), respectively. The rates of development of local, regional, and systemic recurrences were 20%, 50%, and 80%, respectively. Lungs were involved in all patients who had distant metastasis. Conclusions. This study shows that HNMMs has a very aggressive course and that distant metastases are common. For this reason, systemic control of the disease is an important aim of treatment. (Oral Surg Oral Med Oral Pathol Oral Radiol 2015; 120:575-580)
Melanomas develop from melanocytes found mainly in the skin but also in the eyes and the meninges, as well as throughout the gastrointestinal system and the airway mucosa. Mucosal melanosis may have a role, but the exact etiology of the mucosal melanomas has not been clearly defined yet. Melanomas are grouped as cutaneous, ocular, mucosal, and unknown primaries, and the least frequent one is mucosal melanomas (1.3%), according to Chang et al.1 Head and neck mucosal melanomas (HNMMs) comprise 0.7% to 0.8% of all melanomas and less than 10% of all head and neck melanomas.1,2 However, HNMMs seem to be more common in some parts of Africa and Japan compared with Europe and North America.3 Within the upper aerodigestive tract, most commonly involved sites are the oral cavity and the sinonasal tract.1-4 Although rare, HNMMs are very aggressive malignant tumors, and the prognosis is worse compared with that for cutaneous and ocular melanomas.4 Since the entity is very rare, knowledge This study was presented at the XVII International Congress on Oral _ Pathology and Medicine, May 25e30, 2014, at Istanbul, Turkey. a Department of Otorhinolaryngology, Gazi University School of Medicine, Ankara, Turkey. b Department of Periodontics, Gazi University School of Medicine, Ankara, Turkey. c Department of Pathology, Gazi University School of Medicine, Ankara, Turkey. d Department of Dentomaxillofacial Radiology, Gazi University School of Medicine, Ankara, Turkey. Received for publication Dec 16, 2014; returned for revision May 22, 2015; accepted for publication Jun 25, 2015. Ó 2015 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2015.06.038
about HNMMs is mainly derived from case series. In this study, we report the recurrence characteristics and oncologic outcomes of HNMMs managed at our institution.
METHODS The records of the patients treated for HNMMs at our institution between the years 2001 and 2013 were retrospectively analyzed. The patients with a newly diagnosed and histopathologically confirmed mucosal melanoma located at any part of the upper aerodigestive tract mucosa were included in the study (Figures 1A and 1B; Figures 2A to 2D). Patients with a history of a melanoma located at any other part of the body, including skin, were excluded. Demographic features (e.g., age and gender), clinical data (e.g., site of involvement and staging), and treatment and follow-up data were obtained and assessed. Since the tumorenodeemetastasis (TNM) staging system by the American Joint Committee on Cancer (AJCC) is valid for HNMMs since 2010 January, clinical data were used for restaging of the tumors treated before 2010 (Table I).
Statement of Clinical Relevance Head and neck mucosal melanomas are rare cancers comprising less than 1% of all melanomas. This paper is prepared to document our clinical experience on this rare entity and offer some suggestions on management of patients. 575
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Fig. 1. A and B, Clinical view of the mucosal melanomas located at the hard palate and the upper alveolar ridge.
Fig. 2. A, Malignant melanoma invading into the superficial lamina propria. Abundant melanin pigment is seen (H&E, 100). B, The same area after digestion of melanin pigment. The cellular detail is better observed (H&E after melanin digestion, 100). C, HMB45 is focally present in the tumor. Immunoperoxidase, DAB as chromogen (100). D, Ki67 is positive in numerous tumor cells (red colored nuclei). Immunoperoxidase, AEC as chromogen (200).
All patients underwent incisional biopsy to confirm the diagnosis before any treatment and had surgery as an initial treatment. All patients underwent computed tomography (CT) or magnetic resonance imaging (MRI) for evaluation of the primary tumor and the neck and also had chest CT or positron emission tomography (PET)-CT to exclude metastasis. Statistical analyses were performed by using Statistical Package for the Social Sciences (SPSS) software. The main endpoints were disease-free survival (DFS), disease-specific survival (DSS) and overall survival (OS). DFS and OS were calculated from the diagnosis to the associated event, and Kaplan-Meier curves were used to calculate DSS and DFS.
RESULTS Ten patients managed for HNMM at our institution were all included in the study. Demographic and clinical features of the patients are provided in Tables II and III. The rate of oral to sinonasal involvement in our series was 2.3:1. TREATMENT All 10 patients underwent radical surgery as an initial treatment, but each anatomic site required a specific surgical approach. The primary goal was complete surgical removal of the tumor, and the extent of the surgery depended on tumor site and extension. Preoperative imaging studies were used to determine the
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Table I. Tumorenodeemetastasis staging of the mucosal melanoma of the head and neck Primary tumor T3 Mucosal disease T4 a Moderately advanced disease e tumor involving deep soft tissue, cartilage, bone, or overlying skin T4 b Very advanced disease e tumor involving brain, dura skull base, lower cranial nerves (IX, X, XI, XII), masticator space, carotid artery, prevertebral space, or mediastinal structures Regional Lymph Nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastases N1 Regional lymph node metastases present Distant metastasis M0 No distant metastasis M1 Distant metastasis present
Table II. Demographic and clinical characteristics of the patients n
10
Median age (years) Gender (M/F) Involved site Maxilla/Lateral nasal wall Oral cavity Stage III IVa
66 (28e76 years) 1.5 (6/4) 3 7 1 9
extent of the surgery, and intraoperative frozen biopsy specimens were used to assess the adequacy of the resections. Local control was considered crucial to prevent distant metastasis. Since removal of sinonasal melanomas with safe margins is difficult and surgical margins are less clear, all patients with sinonasal involvement had chemoradiation therapy (CRT) as adjuvant therapy. All of the 7 patients with oral melanoma had adjuvant therapy: 5 of the patients who had clear surgical margins had only adjuvant radiotherapy (RT), 1 subject who had microscopic residual disease had adjuvant concurrent CRT, and the last subject with the only T3 tumor of the series had both conventional chemotherapy and immunotherapy with interferon because all the cases treated earlier had had systemic recurrences. Although melanomas are considered radioresistant tumors, all but the last subject had T4 tumors; adjuvant RT or concurrent CRT was used to achieve better local control, according to our institutional treatment policy. Since there are no specific chemotherapy protocols for mucosal melanomas of the head and neck, institutional chemotherapy schemes for skin melanomas were used for the treatment of these patients. Either dacarbazine/cisplatin combination or paclitaxel were preferred for systemic treatment of the disease.
Recurrence patterns Interestingly, neither regional lymph node involvement nor systemic involvement was determined initially in any of the patients despite investigations with imaging modalities (see Table II). However, within the first year of follow-up, 50% of the subjects experienced lung metastasis, and 30% of all cases died. The overall rates of local recurrence, regional recurrence, and systemic recurrence were 20%, 50%, and 80%, respectively. The high rate of systemic recurrence despite high local control rate was striking. The most common site of systemic involvement was the lung, which was involved in all patients with systemic disease (see Table III). All except one subject experienced local and/ or regional recurrences together with systemic recurrence. Only one had three times local and two times regional recurrence in the absence of systemic metastasis and died because of locoregional disease. Oncologic outcomes At 10 months’ follow-up, only one subject was alive and free of disease. This was also the only subject with a T3 disease. The 3-year and 5-year DFS rates were 11.7% and 11.7% (Figure 3). The 3-year and 5-year OS rates were found to be 35% and 23.3% (Figure 4). The median DFS and the median OS periods were 12 months (range 2-36 months) and 17 months (range 796 months), respectively.
DISCUSSION Since HNMMs are rare malignancies, prospective and controlled studies on the efficacy of treatment modalities on locoregional and systemic control of the disease are lacking, and there are only limited data on treatment options. However, case series provide some useful information about the nature and the course of the disease, and the last edition of the TNM staging system by the AJCC has provided a new staging system for upper aerodigestive tract malignant melanomas (see Table I). Since even small HNMMs behave quite aggressively with high rates of recurrence and death, primary cancers limited to the mucosa are considered T3 (the earliest primary tumor stage) to reflect this aggressive behavior. Advanced HNMMs are classified as T4a and T4b accordingly. In situ mucosal melanomas are excluded, as they are extremely rare. Koivunen et al. reported that this new classification system can predict survival in HNMM cases with sinonasal involvement and provides a useful format.5 In our opinion, a separate staging system would be beneficial to predict prognosis and to establish useful treatment protocols. According to the present limited data and clinical treatment guidelines, surgery is the mainstay of the treatment of HNMM stages III through IVa.6
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Table III. Follow-up data of the study patients Local recurrence and TI (months)
Regional recurrence and TI (months) d d 12 26 Two times (12, 90) 12
Systemic recurrence, localization, and TI (months)
TI to death (months)
5 (lung) 36, 60 (lung, abdominal) 12 (lung) 18 (lung) d
7 69 14 28 96 17
Subject
Age/ Gender
1 2 3 4 5
41/m 49/m 72/f 76/f 75/m
Maxilla Maxilla Maxilla Palate Palate
T4 T4 T4 T4 T4
6
67/m
Palate
T4 aN0 M0
SxþRT
d d 12 d Three times (72, 84, 90) d
7 8
28/f 73/f
T4 aN0 M0 T4 aN0 M0
SxþRT SxþRT
d d
5 d
9 10
65/m 54/m
Palate Lower gingiva/buccal mucosa Palate Upper gingiva
12 (lung, inguinal nodes, abdomen wall) 8 (lung) 38 (lung)
T4 aN0 M0 T3 N0 M0
SxþRT SxþCTþINF
d d
d d
2 (lung) d
Site
TNM aN0 aN0 aN0 aN0 aN0
M0 M0 M0 M0 M0
Treatment SxþCRT SxþCRT SxþCRT SxþCRT SxþRT
9 40
7 alive
CRT, chemoradiation; CT, computed tomography; f, female; INF, interferon; m, male; RT, radiotherapy; Sx, surgery; TI, Time interval.
Fig. 3. Kaplan-Meier survival.
curve
representing
disease-free
A recent study has reported that there is a rapid increase in the incidence of HNMMs and that the most profound increase in incidence is among patients with sinonasal tumors and in white women.7 Since there is an increase in the incidence and the course of the disease is unfavorable, HNMMs deserves serious attention. Besides the poor oncologic outcome, most of the survivors will have sequelae with severe impact on quality of life. Keller et al. reported that HNMMs have the worst prognosis compared with other mucosal melanomas, such as gynecologic and anorectal melanomas.8 By using the United States Surveillance, Epidemiology, and End Results (SEER) registry, Jethanamest et al. reported that the 5-year and 10-year OS rates for patients with HNMM are 25.2% and 12.2%, respectively.9 According to this large cohort, indicators of poor survival were involvement of areas other than
Fig. 4. Kaplan-Meier curve representing overall survival.
oral and sinonasal sites, advanced age, tumor size, and regional and systemic metastases at presentation. Similar results were also reported by various authors from different regions. In a study from Finland, Koivunen et al. reported that the 5-year OS rate was 27% for sinonasal melanomas patients.5 Moreno et al. reported that the 5-year OS rates were between 16% and 27% for sinonasal melanomas other than septal ones, and 50% for melanomas located at the nasal septum in the MD Anderson Cancer Center series.10 From Queen Mary Hospital, Hong Kong, Chan et al. reported that the 5-year OS rate for HNMM patients was 22.9%.11 Mücke et al. reported that the 5-year OS rate was 30% in their oral cavity melanoma series from Germany.12 According to McLean et al., the 5year OS rate was 10% in a series from United States.13 Bachar et al. reported that the 5-year DFS and DSS rates were 8% and 28.7%, respectively, in the Princess Margaret Hospital, Canada, series.14 The
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5-year OS rate was 20.7% in a Chinese oral melanoma series reported by Sun et al.15 In our series, the 5-year OS rate was 23.3%, which is comparable with the previous studies. In our series, the median age was 66 years, and there was a male predominance with 1:5 M/F ratio. These findings are exactly same as those of some of the previous reports.10,11,13 However, some other studies have reported higher M/F ratios, equal frequencies among the genders, or even female predominance.3,14,16,17 Some studies also reported younger median ages between 55 and 59 years.3,16,17 Although, sinonasal involvement was 2.5 to 4.9 times higher compared with oral cavity involvement in previous reports, oral cavity involvement was more common in our series.9,11,13,14 Despite the use of imaging techniques, such as CT, MRI, and PET-CT, for staging, the absence of any regional or distant metastasis at presentation was very remarkable in our case series. In all of the previously reported case series, the rate of systemic metastasis at presentation is below 5%.3,10,11,13-15 However, there is an inconsistency in the rates of regional involvement at presentation. Although some studies have reported rates as low as 7%, some authors have reported that the frequency of regional involvement may be more than 20% and it was also reported to be as high as 76% in one study.3,10,11,13-15 All of the patients except the last one in our study had adjuvant RT to improve local control. Interestingly, one of the patients had three local recurrences and two regional recurrences but never had a systemic recurrence. This is probably because of the genetic incapability of the tumor cells to disseminate systemically. During the follow-up period, distant metastatic spread was encountered in a very high proportion (80%) of the patients, and the lungs were involved in all cases. Meleti et al. had reported a similar recurrence pattern previously.3 According to these authors, the most common recurrence pattern was systemic (71%), and the most commonly involved site was the lung. Moreno et al. also reported that the most commonly involved organ in metastatic disease is the lung and that systemic recurrence is more common compared with locoregional recurrence.10 In this study, it was also reported that although systemic recurrence is a statistically significant predictor of outcome, locoregional recurrence is not. A study by Bachar et al. indicated the importance of combined therapy for better local control.14 Since the proportion of the patients who had combined therapy was low in this series, local recurrence and systemic recurrence rates were 60% and 49%, respectively. The most common site for systemic recurrence was the liver. In the study
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by McLean et al., the reported rate of distant metastasis is unexpectedly lower than 30%.13 Mucosal melanoma has been considered a radioresistant malignancy; however, this does not mean that RT is not indicated as an adjuvant therapy. Local recurrence can be prevented by complete surgical excision of the primary tumor with adjunctive RT or CRT, as indicated by our results. According to previous studies, adjuvant RT improves locoregional control but does not affect overall survival.10,18-22 The patients with advanced disease typically received adjuvant RT. In our series, regional recurrences were relatively high. Although there is no indication as to its potential benefit in mucosal melanoma, elective neck dissection may be considered to improve regional control rates. Systemic recurrences were the most common and fatal pattern of recurrence in our series. Although half of the patients had systemic therapies, 80% of the patients experienced systemic recurrence, as indicated by our results. Adjuvant chemotherapy does not seem to be effective in preventing distant metastasis, and more beneficial methods should be explored to improve systemic control and survival. In a large series comprising sinonasal melanomas, Sun et al. reported that nearly 80% systemic control can be achieved by using biotherapies, including bacillus CalmetteeGuerin (BCG) vaccine, interleukin-II, and interferon-a-2b.15 In the absence of standardized treatment protocols for mucosal melanomas, tumor stage and extension are important determinants of the treatment planning process, particularly for sinonasal melanomas. Similar to cutaneous melanomas, systemic recurrence is the most common cause of death, but the therapeutic effect of chemotherapy is still being debated. The most commonly preferred chemotherapeutics for the treatment of HNMMs are dacarbazine, cisplatin, taxanes, and temozolomide.18,23 However, outcomes with conventional chemotherapeutics are disappointing as was seen in our study.10,20-22,24 At present, a common adjuvant treatment for HNMMs is immunotherapy, and interferon-a is usually given for this purpose. However, Lin et. al. reported that relapse-free survival and OS rates were significantly better in patients treated with temozolomide plus cisplatin compared with patients treated with high-dose interferon.25 A recent large study has shown that immunotherapy with ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyteassociated antigen, may improve survival in patients with metastatic melanoma.26 Molecular-targeted therapy, based on drugs targeting proteins those mediating proliferation and migration of the cancer cells (such as imatinib), may be more effective for systemic control of the disease.18 Although multicenter
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collaborative prospective trials are needed, the rare occurrence of the disease limits such efforts.
CONCLUSIONS Despite intensive efforts toward a cure, the prognosis of HNMM is still very poor. Initial therapy for a curative intent is surgery, but combined therapeutic regimens should be employed to improve oncologic outcomes. The combination of radical surgical resection and adjuvant RT seems to be highly effective for local control. The relatively low number of patients in our series and the retrospective nature of the study prevent us from making strong recommendations. However, our experience shows that efforts should be focused on the systemic control of the disease. REFERENCES 1. Chang AE, Karnell LH, Menck HR. The national cancer data base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. Cancer. 1998;83:1664-1678. 2. Andersen LJ, Berthelsen A, Hansen HS. Malignant melanoma of the upper respiratory tract and the oral cavity. J Otolaryngol. 1992;21:180-185. 3. Meleti M, Leemans CR, Mooi WJ, Vescovi P, van der Waal I. Oral malignant melanoma: a review of the literature. Oral Oncol. 2007;43:116-121. 4. Mihajlovic M, Vlajkovic S, Jovanovic P, Stefanovic V. Primary mucosal melanomas: a comprehensive review. Int J Clin Exp Pathol. 2012;5:739-753. 5. Koivunen, Bäck, Pukkila, et al. Accuracy of the current TNM classification in predicting survival in patients with sinonasal mucosal melanoma. Laryngoscope. 2012;122:1734-1738. 6. Marcus DM, Marcus RP, Prabhu RS, et al. Rising incidence of mucosal melanoma of the head and neck in the United States. J Skin Cancer. 2012;2012:231693. 7. Pfister DG, Ang KK, Brizel DM, et al. Mucosal melanoma of the head and neck. J Natl Compr Canc Netw. 2012;10:320-338. 8. Keller DS, Thomay AA, Gaughan J, et al. Outcomes in patients with mucosal melanomas. J Surg Oncol. 2013;108:516-520. 9. Jethanamest D, Vila PM, Sikora AG, Morris LG. Predictors of survival in mucosal melanoma of the head and neck. Ann Surg Oncol. 2011;18:2748-2756. 10. Moreno MA, Roberts DB, Kupferman ME, et al. Mucosal melanoma of the nose and paranasal sinuses, a contemporary experience from the M. D. Anderson Cancer Center. Cancer. 2010;116:2215-2223. 11. Chan RC, Chan JY, Wei WI. Mucosal melanoma of the head and neck: 32-year experience in a tertiary referral hospital. Laryngoscope. 2012;122:2749-2753. 12. Mücke T, Hölzle F, Kesting MR, et al. Tumor size and depth in primary malignant melanoma in the oral cavity influences survival. J Oral Maxillofac Surg. 2009;67:1409-1415.
OOOO November 2015 13. McLean N, Tighiouart M, Muller S. Primary mucosal melanoma of the head and neck. Comparison of clinical presentation and histopathologic features of oral and sinonasal melanoma. Oral Oncol. 2008;44:1039-1046. 14. Bachar G, Loh KS, O’Sullivan B, et al. Mucosal melanomas of the head and neck: experience of the Princess Margaret Hospital. Head Neck. 2008;30:1325-1331. 15. Sun CZ, Chen YF, Jiang YE, Hu ZD, Yang AK, Song M. Treatment and prognosis of oral mucosal melanoma. Oral Oncol. 2012;48:647-652. 16. Lourenço SV, Sangüeza AM, Sotto MN, et al. Primary oral mucosal melanoma: a series of 35 new cases from South America. Am J Dermatopathol. 2009;31:323-330. 17. Sun CZ, Li QL, Hu ZD, Jiang YE, Song M, Yang AK. Treatment and prognosis in sinonasal mucosal melanoma: a retrospective analysis of 65 patients from a single cancer center. Head Neck. 2014;36:675-681. 18. Lazarev S, Gupta V, Hu K, Harrison LB, Bakst R. Mucosal melanoma of the head and neck: a systematic review of the literature. J Radiat Oncol Biol Phys. 2014;90:1108-1118. 19. Benlyazid A, Thariat J, Temam S, et al. Postoperative radiotherapy in head and neck mucosal melanoma: a GETTEC study. Arch Otolaryngol Head Neck Surg. 2010;136:1219-1225. 20. Owens JM, Roberts DB, Myers JN. The role of postoperative adjuvant radiation therapy in the treatment of mucosal melanomas of the head and neck region. Arch Otolaryngol Head Neck Surg. 2003;129:864-868. 21. Temam S, Mamelle G, Marandas P, et al. Postoperative radiotherapy for primary mucosal melanoma of the head and neck. Cancer. 2005;103:313-319. 22. Krengli M, Masini L, Kaanders JH, et al. Radiotherapy in the treatment of mucosal melanoma of the upper aerodigestive tract: analysis of 74 cases. A Rare Cancer Network study. Int J Radiat Oncol Biol Phys. 2006;65:751-759. 23. Tacastacas JD, Bray J, Cohen YK, et al. Update on primary mucosal melanoma. J Am Acad Dermatol. 2014;71:366-375. 24. Shiga K, Ogawa T, Kobayashi T, et al. Malignant melanoma of the head and neck: a multi-institutional retrospective analysis of cases in northern Japan. Head Neck. 2012;34: 1537-1541. 25. Lian B, Si L, Cui C, et al. Phase II randomized trial comparing high-dose IFN-a2 b with temozolomide plus cisplatin as systemic adjuvant therapy for resected mucosal melanoma. Clin Cancer Res. 2013;19:4488-4498. 26. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-723.
Reprint requests: Yusuf Kızıl, MD Gazi Üniversitesi Tıp Fakültesi KBB AD. 06500 Bes¸evler Ankara Turkey [email protected]
Mucosal melanoma of the head and neck: recurrence characteristics and survival outcomes Faruk Kadri Bakkal, MD,a Adil Bas¸man, DMD,b Yusuf Kızıl, MD,a Özgür Ekinci, MD,c Mustafa Gümüs¸ok, DMD,d Mehmet Ekrem Zorlu, MD,a and Utku Aydil, MDa Gazi University School of Medicine, Ankara, Turkey
Objective. The aim of this study was to review oncologic outcomes and recurrence characteristics of head and neck mucosal melanomas (HNMMs) managed at a tertiary referral center. Study Design. Clinical records of 10 patients who were managed for HNMMs between 2001 and 2013 were retrospectively analyzed. Results. The median age was 66 years (range 28-76 years) and male/female (M/F) ratio was 1:5. The 3-year disease-free survival (DFS) rates and overall survival (OS) rates were 11.7% and 35%, respectively; and the 5-year DFS rates and OS rates 11.7% and 23.3%, respectively. The median DFS and OS periods were 12 months (range 2-36 months) and 17 months (range 7-96 months), respectively. The rates of development of local, regional, and systemic recurrences were 20%, 50%, and 80%, respectively. Lungs were involved in all patients who had distant metastasis. Conclusions. This study shows that HNMMs has a very aggressive course and that distant metastases are common. For this reason, systemic control of the disease is an important aim of treatment. (Oral Surg Oral Med Oral Pathol Oral Radiol 2015; 120:575-580)
Melanomas develop from melanocytes found mainly in the skin but also in the eyes and the meninges, as well as throughout the gastrointestinal system and the airway mucosa. Mucosal melanosis may have a role, but the exact etiology of the mucosal melanomas has not been clearly defined yet. Melanomas are grouped as cutaneous, ocular, mucosal, and unknown primaries, and the least frequent one is mucosal melanomas (1.3%), according to Chang et al.1 Head and neck mucosal melanomas (HNMMs) comprise 0.7% to 0.8% of all melanomas and less than 10% of all head and neck melanomas.1,2 However, HNMMs seem to be more common in some parts of Africa and Japan compared with Europe and North America.3 Within the upper aerodigestive tract, most commonly involved sites are the oral cavity and the sinonasal tract.1-4 Although rare, HNMMs are very aggressive malignant tumors, and the prognosis is worse compared with that for cutaneous and ocular melanomas.4 Since the entity is very rare, knowledge This study was presented at the XVII International Congress on Oral _ Pathology and Medicine, May 25e30, 2014, at Istanbul, Turkey. a Department of Otorhinolaryngology, Gazi University School of Medicine, Ankara, Turkey. b Department of Periodontics, Gazi University School of Medicine, Ankara, Turkey. c Department of Pathology, Gazi University School of Medicine, Ankara, Turkey. d Department of Dentomaxillofacial Radiology, Gazi University School of Medicine, Ankara, Turkey. Received for publication Dec 16, 2014; returned for revision May 22, 2015; accepted for publication Jun 25, 2015. Ó 2015 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2015.06.038
about HNMMs is mainly derived from case series. In this study, we report the recurrence characteristics and oncologic outcomes of HNMMs managed at our institution.
METHODS The records of the patients treated for HNMMs at our institution between the years 2001 and 2013 were retrospectively analyzed. The patients with a newly diagnosed and histopathologically confirmed mucosal melanoma located at any part of the upper aerodigestive tract mucosa were included in the study (Figures 1A and 1B; Figures 2A to 2D). Patients with a history of a melanoma located at any other part of the body, including skin, were excluded. Demographic features (e.g., age and gender), clinical data (e.g., site of involvement and staging), and treatment and follow-up data were obtained and assessed. Since the tumorenodeemetastasis (TNM) staging system by the American Joint Committee on Cancer (AJCC) is valid for HNMMs since 2010 January, clinical data were used for restaging of the tumors treated before 2010 (Table I).
Statement of Clinical Relevance Head and neck mucosal melanomas are rare cancers comprising less than 1% of all melanomas. This paper is prepared to document our clinical experience on this rare entity and offer some suggestions on management of patients. 575
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Fig. 1. A and B, Clinical view of the mucosal melanomas located at the hard palate and the upper alveolar ridge.
Fig. 2. A, Malignant melanoma invading into the superficial lamina propria. Abundant melanin pigment is seen (H&E, 100). B, The same area after digestion of melanin pigment. The cellular detail is better observed (H&E after melanin digestion, 100). C, HMB45 is focally present in the tumor. Immunoperoxidase, DAB as chromogen (100). D, Ki67 is positive in numerous tumor cells (red colored nuclei). Immunoperoxidase, AEC as chromogen (200).
All patients underwent incisional biopsy to confirm the diagnosis before any treatment and had surgery as an initial treatment. All patients underwent computed tomography (CT) or magnetic resonance imaging (MRI) for evaluation of the primary tumor and the neck and also had chest CT or positron emission tomography (PET)-CT to exclude metastasis. Statistical analyses were performed by using Statistical Package for the Social Sciences (SPSS) software. The main endpoints were disease-free survival (DFS), disease-specific survival (DSS) and overall survival (OS). DFS and OS were calculated from the diagnosis to the associated event, and Kaplan-Meier curves were used to calculate DSS and DFS.
RESULTS Ten patients managed for HNMM at our institution were all included in the study. Demographic and clinical features of the patients are provided in Tables II and III. The rate of oral to sinonasal involvement in our series was 2.3:1. TREATMENT All 10 patients underwent radical surgery as an initial treatment, but each anatomic site required a specific surgical approach. The primary goal was complete surgical removal of the tumor, and the extent of the surgery depended on tumor site and extension. Preoperative imaging studies were used to determine the
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Table I. Tumorenodeemetastasis staging of the mucosal melanoma of the head and neck Primary tumor T3 Mucosal disease T4 a Moderately advanced disease e tumor involving deep soft tissue, cartilage, bone, or overlying skin T4 b Very advanced disease e tumor involving brain, dura skull base, lower cranial nerves (IX, X, XI, XII), masticator space, carotid artery, prevertebral space, or mediastinal structures Regional Lymph Nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastases N1 Regional lymph node metastases present Distant metastasis M0 No distant metastasis M1 Distant metastasis present
Table II. Demographic and clinical characteristics of the patients n
10
Median age (years) Gender (M/F) Involved site Maxilla/Lateral nasal wall Oral cavity Stage III IVa
66 (28e76 years) 1.5 (6/4) 3 7 1 9
extent of the surgery, and intraoperative frozen biopsy specimens were used to assess the adequacy of the resections. Local control was considered crucial to prevent distant metastasis. Since removal of sinonasal melanomas with safe margins is difficult and surgical margins are less clear, all patients with sinonasal involvement had chemoradiation therapy (CRT) as adjuvant therapy. All of the 7 patients with oral melanoma had adjuvant therapy: 5 of the patients who had clear surgical margins had only adjuvant radiotherapy (RT), 1 subject who had microscopic residual disease had adjuvant concurrent CRT, and the last subject with the only T3 tumor of the series had both conventional chemotherapy and immunotherapy with interferon because all the cases treated earlier had had systemic recurrences. Although melanomas are considered radioresistant tumors, all but the last subject had T4 tumors; adjuvant RT or concurrent CRT was used to achieve better local control, according to our institutional treatment policy. Since there are no specific chemotherapy protocols for mucosal melanomas of the head and neck, institutional chemotherapy schemes for skin melanomas were used for the treatment of these patients. Either dacarbazine/cisplatin combination or paclitaxel were preferred for systemic treatment of the disease.
Recurrence patterns Interestingly, neither regional lymph node involvement nor systemic involvement was determined initially in any of the patients despite investigations with imaging modalities (see Table II). However, within the first year of follow-up, 50% of the subjects experienced lung metastasis, and 30% of all cases died. The overall rates of local recurrence, regional recurrence, and systemic recurrence were 20%, 50%, and 80%, respectively. The high rate of systemic recurrence despite high local control rate was striking. The most common site of systemic involvement was the lung, which was involved in all patients with systemic disease (see Table III). All except one subject experienced local and/ or regional recurrences together with systemic recurrence. Only one had three times local and two times regional recurrence in the absence of systemic metastasis and died because of locoregional disease. Oncologic outcomes At 10 months’ follow-up, only one subject was alive and free of disease. This was also the only subject with a T3 disease. The 3-year and 5-year DFS rates were 11.7% and 11.7% (Figure 3). The 3-year and 5-year OS rates were found to be 35% and 23.3% (Figure 4). The median DFS and the median OS periods were 12 months (range 2-36 months) and 17 months (range 796 months), respectively.
DISCUSSION Since HNMMs are rare malignancies, prospective and controlled studies on the efficacy of treatment modalities on locoregional and systemic control of the disease are lacking, and there are only limited data on treatment options. However, case series provide some useful information about the nature and the course of the disease, and the last edition of the TNM staging system by the AJCC has provided a new staging system for upper aerodigestive tract malignant melanomas (see Table I). Since even small HNMMs behave quite aggressively with high rates of recurrence and death, primary cancers limited to the mucosa are considered T3 (the earliest primary tumor stage) to reflect this aggressive behavior. Advanced HNMMs are classified as T4a and T4b accordingly. In situ mucosal melanomas are excluded, as they are extremely rare. Koivunen et al. reported that this new classification system can predict survival in HNMM cases with sinonasal involvement and provides a useful format.5 In our opinion, a separate staging system would be beneficial to predict prognosis and to establish useful treatment protocols. According to the present limited data and clinical treatment guidelines, surgery is the mainstay of the treatment of HNMM stages III through IVa.6
ORAL AND MAXILLOFACIAL SURGERY 578 Bakkal et al.
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Table III. Follow-up data of the study patients Local recurrence and TI (months)
Regional recurrence and TI (months) d d 12 26 Two times (12, 90) 12
Systemic recurrence, localization, and TI (months)
TI to death (months)
5 (lung) 36, 60 (lung, abdominal) 12 (lung) 18 (lung) d
7 69 14 28 96 17
Subject
Age/ Gender
1 2 3 4 5
41/m 49/m 72/f 76/f 75/m
Maxilla Maxilla Maxilla Palate Palate
T4 T4 T4 T4 T4
6
67/m
Palate
T4 aN0 M0
SxþRT
d d 12 d Three times (72, 84, 90) d
7 8
28/f 73/f
T4 aN0 M0 T4 aN0 M0
SxþRT SxþRT
d d
5 d
9 10
65/m 54/m
Palate Lower gingiva/buccal mucosa Palate Upper gingiva
12 (lung, inguinal nodes, abdomen wall) 8 (lung) 38 (lung)
T4 aN0 M0 T3 N0 M0
SxþRT SxþCTþINF
d d
d d
2 (lung) d
Site
TNM aN0 aN0 aN0 aN0 aN0
M0 M0 M0 M0 M0
Treatment SxþCRT SxþCRT SxþCRT SxþCRT SxþRT
9 40
7 alive
CRT, chemoradiation; CT, computed tomography; f, female; INF, interferon; m, male; RT, radiotherapy; Sx, surgery; TI, Time interval.
Fig. 3. Kaplan-Meier survival.
curve
representing
disease-free
A recent study has reported that there is a rapid increase in the incidence of HNMMs and that the most profound increase in incidence is among patients with sinonasal tumors and in white women.7 Since there is an increase in the incidence and the course of the disease is unfavorable, HNMMs deserves serious attention. Besides the poor oncologic outcome, most of the survivors will have sequelae with severe impact on quality of life. Keller et al. reported that HNMMs have the worst prognosis compared with other mucosal melanomas, such as gynecologic and anorectal melanomas.8 By using the United States Surveillance, Epidemiology, and End Results (SEER) registry, Jethanamest et al. reported that the 5-year and 10-year OS rates for patients with HNMM are 25.2% and 12.2%, respectively.9 According to this large cohort, indicators of poor survival were involvement of areas other than
Fig. 4. Kaplan-Meier curve representing overall survival.
oral and sinonasal sites, advanced age, tumor size, and regional and systemic metastases at presentation. Similar results were also reported by various authors from different regions. In a study from Finland, Koivunen et al. reported that the 5-year OS rate was 27% for sinonasal melanomas patients.5 Moreno et al. reported that the 5-year OS rates were between 16% and 27% for sinonasal melanomas other than septal ones, and 50% for melanomas located at the nasal septum in the MD Anderson Cancer Center series.10 From Queen Mary Hospital, Hong Kong, Chan et al. reported that the 5-year OS rate for HNMM patients was 22.9%.11 Mücke et al. reported that the 5-year OS rate was 30% in their oral cavity melanoma series from Germany.12 According to McLean et al., the 5year OS rate was 10% in a series from United States.13 Bachar et al. reported that the 5-year DFS and DSS rates were 8% and 28.7%, respectively, in the Princess Margaret Hospital, Canada, series.14 The
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5-year OS rate was 20.7% in a Chinese oral melanoma series reported by Sun et al.15 In our series, the 5-year OS rate was 23.3%, which is comparable with the previous studies. In our series, the median age was 66 years, and there was a male predominance with 1:5 M/F ratio. These findings are exactly same as those of some of the previous reports.10,11,13 However, some other studies have reported higher M/F ratios, equal frequencies among the genders, or even female predominance.3,14,16,17 Some studies also reported younger median ages between 55 and 59 years.3,16,17 Although, sinonasal involvement was 2.5 to 4.9 times higher compared with oral cavity involvement in previous reports, oral cavity involvement was more common in our series.9,11,13,14 Despite the use of imaging techniques, such as CT, MRI, and PET-CT, for staging, the absence of any regional or distant metastasis at presentation was very remarkable in our case series. In all of the previously reported case series, the rate of systemic metastasis at presentation is below 5%.3,10,11,13-15 However, there is an inconsistency in the rates of regional involvement at presentation. Although some studies have reported rates as low as 7%, some authors have reported that the frequency of regional involvement may be more than 20% and it was also reported to be as high as 76% in one study.3,10,11,13-15 All of the patients except the last one in our study had adjuvant RT to improve local control. Interestingly, one of the patients had three local recurrences and two regional recurrences but never had a systemic recurrence. This is probably because of the genetic incapability of the tumor cells to disseminate systemically. During the follow-up period, distant metastatic spread was encountered in a very high proportion (80%) of the patients, and the lungs were involved in all cases. Meleti et al. had reported a similar recurrence pattern previously.3 According to these authors, the most common recurrence pattern was systemic (71%), and the most commonly involved site was the lung. Moreno et al. also reported that the most commonly involved organ in metastatic disease is the lung and that systemic recurrence is more common compared with locoregional recurrence.10 In this study, it was also reported that although systemic recurrence is a statistically significant predictor of outcome, locoregional recurrence is not. A study by Bachar et al. indicated the importance of combined therapy for better local control.14 Since the proportion of the patients who had combined therapy was low in this series, local recurrence and systemic recurrence rates were 60% and 49%, respectively. The most common site for systemic recurrence was the liver. In the study
ORIGINAL ARTICLE Bakkal et al. 579
by McLean et al., the reported rate of distant metastasis is unexpectedly lower than 30%.13 Mucosal melanoma has been considered a radioresistant malignancy; however, this does not mean that RT is not indicated as an adjuvant therapy. Local recurrence can be prevented by complete surgical excision of the primary tumor with adjunctive RT or CRT, as indicated by our results. According to previous studies, adjuvant RT improves locoregional control but does not affect overall survival.10,18-22 The patients with advanced disease typically received adjuvant RT. In our series, regional recurrences were relatively high. Although there is no indication as to its potential benefit in mucosal melanoma, elective neck dissection may be considered to improve regional control rates. Systemic recurrences were the most common and fatal pattern of recurrence in our series. Although half of the patients had systemic therapies, 80% of the patients experienced systemic recurrence, as indicated by our results. Adjuvant chemotherapy does not seem to be effective in preventing distant metastasis, and more beneficial methods should be explored to improve systemic control and survival. In a large series comprising sinonasal melanomas, Sun et al. reported that nearly 80% systemic control can be achieved by using biotherapies, including bacillus CalmetteeGuerin (BCG) vaccine, interleukin-II, and interferon-a-2b.15 In the absence of standardized treatment protocols for mucosal melanomas, tumor stage and extension are important determinants of the treatment planning process, particularly for sinonasal melanomas. Similar to cutaneous melanomas, systemic recurrence is the most common cause of death, but the therapeutic effect of chemotherapy is still being debated. The most commonly preferred chemotherapeutics for the treatment of HNMMs are dacarbazine, cisplatin, taxanes, and temozolomide.18,23 However, outcomes with conventional chemotherapeutics are disappointing as was seen in our study.10,20-22,24 At present, a common adjuvant treatment for HNMMs is immunotherapy, and interferon-a is usually given for this purpose. However, Lin et. al. reported that relapse-free survival and OS rates were significantly better in patients treated with temozolomide plus cisplatin compared with patients treated with high-dose interferon.25 A recent large study has shown that immunotherapy with ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyteassociated antigen, may improve survival in patients with metastatic melanoma.26 Molecular-targeted therapy, based on drugs targeting proteins those mediating proliferation and migration of the cancer cells (such as imatinib), may be more effective for systemic control of the disease.18 Although multicenter
ORAL AND MAXILLOFACIAL SURGERY 580 Bakkal et al.
collaborative prospective trials are needed, the rare occurrence of the disease limits such efforts.
CONCLUSIONS Despite intensive efforts toward a cure, the prognosis of HNMM is still very poor. Initial therapy for a curative intent is surgery, but combined therapeutic regimens should be employed to improve oncologic outcomes. The combination of radical surgical resection and adjuvant RT seems to be highly effective for local control. The relatively low number of patients in our series and the retrospective nature of the study prevent us from making strong recommendations. However, our experience shows that efforts should be focused on the systemic control of the disease. REFERENCES 1. Chang AE, Karnell LH, Menck HR. The national cancer data base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. Cancer. 1998;83:1664-1678. 2. Andersen LJ, Berthelsen A, Hansen HS. Malignant melanoma of the upper respiratory tract and the oral cavity. J Otolaryngol. 1992;21:180-185. 3. Meleti M, Leemans CR, Mooi WJ, Vescovi P, van der Waal I. Oral malignant melanoma: a review of the literature. Oral Oncol. 2007;43:116-121. 4. Mihajlovic M, Vlajkovic S, Jovanovic P, Stefanovic V. Primary mucosal melanomas: a comprehensive review. Int J Clin Exp Pathol. 2012;5:739-753. 5. Koivunen, Bäck, Pukkila, et al. Accuracy of the current TNM classification in predicting survival in patients with sinonasal mucosal melanoma. Laryngoscope. 2012;122:1734-1738. 6. Marcus DM, Marcus RP, Prabhu RS, et al. Rising incidence of mucosal melanoma of the head and neck in the United States. J Skin Cancer. 2012;2012:231693. 7. Pfister DG, Ang KK, Brizel DM, et al. Mucosal melanoma of the head and neck. J Natl Compr Canc Netw. 2012;10:320-338. 8. Keller DS, Thomay AA, Gaughan J, et al. Outcomes in patients with mucosal melanomas. J Surg Oncol. 2013;108:516-520. 9. Jethanamest D, Vila PM, Sikora AG, Morris LG. Predictors of survival in mucosal melanoma of the head and neck. Ann Surg Oncol. 2011;18:2748-2756. 10. Moreno MA, Roberts DB, Kupferman ME, et al. Mucosal melanoma of the nose and paranasal sinuses, a contemporary experience from the M. D. Anderson Cancer Center. Cancer. 2010;116:2215-2223. 11. Chan RC, Chan JY, Wei WI. Mucosal melanoma of the head and neck: 32-year experience in a tertiary referral hospital. Laryngoscope. 2012;122:2749-2753. 12. Mücke T, Hölzle F, Kesting MR, et al. Tumor size and depth in primary malignant melanoma in the oral cavity influences survival. J Oral Maxillofac Surg. 2009;67:1409-1415.
OOOO November 2015 13. McLean N, Tighiouart M, Muller S. Primary mucosal melanoma of the head and neck. Comparison of clinical presentation and histopathologic features of oral and sinonasal melanoma. Oral Oncol. 2008;44:1039-1046. 14. Bachar G, Loh KS, O’Sullivan B, et al. Mucosal melanomas of the head and neck: experience of the Princess Margaret Hospital. Head Neck. 2008;30:1325-1331. 15. Sun CZ, Chen YF, Jiang YE, Hu ZD, Yang AK, Song M. Treatment and prognosis of oral mucosal melanoma. Oral Oncol. 2012;48:647-652. 16. Lourenço SV, Sangüeza AM, Sotto MN, et al. Primary oral mucosal melanoma: a series of 35 new cases from South America. Am J Dermatopathol. 2009;31:323-330. 17. Sun CZ, Li QL, Hu ZD, Jiang YE, Song M, Yang AK. Treatment and prognosis in sinonasal mucosal melanoma: a retrospective analysis of 65 patients from a single cancer center. Head Neck. 2014;36:675-681. 18. Lazarev S, Gupta V, Hu K, Harrison LB, Bakst R. Mucosal melanoma of the head and neck: a systematic review of the literature. J Radiat Oncol Biol Phys. 2014;90:1108-1118. 19. Benlyazid A, Thariat J, Temam S, et al. Postoperative radiotherapy in head and neck mucosal melanoma: a GETTEC study. Arch Otolaryngol Head Neck Surg. 2010;136:1219-1225. 20. Owens JM, Roberts DB, Myers JN. The role of postoperative adjuvant radiation therapy in the treatment of mucosal melanomas of the head and neck region. Arch Otolaryngol Head Neck Surg. 2003;129:864-868. 21. Temam S, Mamelle G, Marandas P, et al. Postoperative radiotherapy for primary mucosal melanoma of the head and neck. Cancer. 2005;103:313-319. 22. Krengli M, Masini L, Kaanders JH, et al. Radiotherapy in the treatment of mucosal melanoma of the upper aerodigestive tract: analysis of 74 cases. A Rare Cancer Network study. Int J Radiat Oncol Biol Phys. 2006;65:751-759. 23. Tacastacas JD, Bray J, Cohen YK, et al. Update on primary mucosal melanoma. J Am Acad Dermatol. 2014;71:366-375. 24. Shiga K, Ogawa T, Kobayashi T, et al. Malignant melanoma of the head and neck: a multi-institutional retrospective analysis of cases in northern Japan. Head Neck. 2012;34: 1537-1541. 25. Lian B, Si L, Cui C, et al. Phase II randomized trial comparing high-dose IFN-a2 b with temozolomide plus cisplatin as systemic adjuvant therapy for resected mucosal melanoma. Clin Cancer Res. 2013;19:4488-4498. 26. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-723.
Reprint requests: Yusuf Kızıl, MD Gazi Üniversitesi Tıp Fakültesi KBB AD. 06500 Bes¸evler Ankara Turkey [email protected]