Mucosal Melanoma

Author Credentials 

Liana Puscas, MD, MHS, MA
Associate Professor
Dept of Surgery, Division of Head and Neck Surgery & Communication Sciences
Duke University, Durham, NC

Nicholas B. Abt, MD
Resident
Department of Otolaryngology
Massachusetts Eye and Ear
Harvard Medical School, Boston, MA

Module Summary

Mucosal Melanoma is a rare cancer that is most often found in the head and neck. Patients generally present at an advanced stage since lesions produce non-specific symptoms, and the cancer biology is aggressive. Treatment goals include complete resection with postop radiation therapy. Unlike cutaneous melanoma, biologic treatments based on genetic analyses and sentinel lymph node biopsies are not mainstays of treatment. Prognosis remains poor and otolaryngologists must maintain a high index of suspicion to accurately diagnose this disease. 

Module Learning Objectives 
  1. Describe the unique characteristics that distinguish mucosal melanoma from cutaneous melanoma
  2. List the differential diagnosis for mucosal melanoma
  3. Describe the work up and staging system for mucosal melanoma
  4. Explain the treatment and prognosis of this disease entity

Embryology

Learning Objectives 
  • The embryologic origin of melanocytes as cells of neural crest origin results in their being found throughout the entire body. 
  • Melanoma is a “small blue cell tumor” and the differential diagnosis for these tumors is extensive. The mnemonic MR SLEEP has been developed to aid in this: melanoma, mesenchymal chondrosarcoma, rhabdomyosarcoma, sinonasal undifferentiated carcinoma, squamous cell carcinoma (including NUT carcinoma), small cell osteosarcoma, lymphoma, esthesioneuroblastoma (olfactory neuroblastoma), Ewing sarcoma/primitive neuroectodermal tumor, pituitary adenoma, and plasmacytoma. 
References 
  1. Coolen NA, Schouten KC, Middelkoop E & Ulrich MM. (2010). Comparison between human fetal and adult skin. Arch. Dermatol. Res. , 302, 47-55. 
  2. Thompson LD. “Small round blue cell tumors of the sinonasal tract: a differential diagnosis approach.” Mod Pathol. 2017 Jan;30(s1):S1-S26. 

Anatomy

Learning Objectives 

Mucosal melanoma is most often found in the head and neck and can affect the eye, ear, paranasal sinuses, and any portion of the upper aerodigestive tract.

References 
  1. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society.Chang AE, Karnell LH, Menck HR Cancer. 1998;83(8):1664.

Pathogenesis

Learning Objectives 

Unlike cutaneous melanoma, ultraviolet radiation does not play a role in the development of mucosal melanoma, nor are there any clear risk factors for developing this disease.

References 
  1. Garland CF, Garland FC, Gorham ED. Epidemiologic evidence for different roles of ultraviolet A and B radiation in melanoma mortality rates. Ann Epidemiol. 2003;13:395–404.
  2. Postow MA, Hamid O, Carvajal RD. Mucosal Melanoma: Pathogenesis, Clinical Behavior and Management. Curr Oncol Rep. 2012;14(5): 441-448.

Basic Science

Learning Objectives 
  • Mucosal melanoma has a low mutational burden when compared with cutaneous melanoma, likely related to no known environmental carcinogens versus UV radiation for cutaneous disease
  • Sites of mucosal melanoma are usually not associated with MALT, such as the oral cavity, vaginal tract, and anorectal areas
  • Lack of MALT plays a role in the local immunology of mucosal melanoma 
References 
  1. Brandtzaeg P, Kiyono H, Pabst R, et al. Terminology: nomenclature of mucosa-associated lymphoid tissue. Mucosal Immunol. 2008;1:31-7.

Incidence

Learning Objectives 
  • Less than 2% of Head and Neck melanomas are mucosal in origin, but head and neck mucosal melanomas comprise about 50% of all mucosal melanomas. 
  • Tumors are most commonly found in the nasal cavity (especially the septum) followed by the oral cavity, and of all sites, nasal sites of origin have a better prognosis, although it is still poor. 
  • Patients suffering from mucosal melanoma tend to present about 15 years later than those with cutaneous melanoma.
  • Although Caucasians still comprise the largest group of patients suffering from mucosal melanoma, the proportion of patients with mucosal melanoma is higher in African, Hispanic and especially Japanese ethnic groups.  
References 

Green B, Elhamshary A, Glomez R, et al. An update on the current management of head and neck mucosal melanoma. J Oral Path Med 2017; 46(7):475-479.

Genetics

Learning Objectives 
  • Specific genetic mutations are similar to cutaneous melanoma, although in decreased frequency. 
  • KIT, NRAS, and BRAF are most common, with KIT being much more common than cutaneous melanoma. BRAF is much less common in mucosal melanoma
  • Mucosal melanoma has a much higher rate of chromosomal instability, with gene amplifications rare in cutaneous melanoma, yet present in 85% of mucosal melanoma
References 

Lerner BA, Steward LA, Horowitz DP, et al. Muscoal melanoma: new insights and therapeutic options for a unique and aggressive disease. Oncology (Willisonton Park) 2017; 31(11):e23-e32.

Patient Evaluation

Learning Objectives 
  • Like all patients, a thorough history and head and neck exam are mandatory. A complete work up for melanoma occurring at other sites must be undertaken since mucosal melanoma is so much more rare than cutaneous melanoma.   
  • Fiberoptic nasopharyngoscopy is warranted during work up of all head and neck mucosal melanomas for complete assessment of the nose and the entire pharynx.
  • PET-CT may be helpful during primary workup, with sinonasal melanoma most commonly metastatic to the liver.
References 
  1. O'Regan K, Breen M, Ramaiya N, et al. Metastatic mucosal melanoma: imaging patterns of metastasis and recurrence. Cancer imaging; 13(4):626-32.

Imaging

Learning Objectives 
  • PET-CT may be helpful during primary workup, with sinonasal melanoma most commonly metastatic to the liver
  • Postoperatively, imaging every 3 months for the first two years is common
References 
  1. O'Regan K, Breen M, Ramaiya N, et al. Metastatic mucosal melanoma: imaging patterns of metastasis and recurrence. Cancer imaging; 2013 Dec; 13(4):626-32.

Pathology

Learning Objectives 
  • Up to 35% of mucosal melanomas are amelanotic
  • Ulceration is common with high rates of mitoses (>2 mitoses/mm2 correlates to rapid progression and worse survival)
  • Most mucosal melanomas are thick at diagnosis, with more than 80% having a depth greater than 1mm
  • Tumors are heterogenous and display epithelioid, spindled, and small cell cytomorphology
References 
  1. Cinotti E, Chevallier J, Labeille B, et al. Mucosal melanoma: clinical, histological and c-kit gene mutational profile of 86 French cases. J Eur Acad Dermatol Venereol; 2017 Nov; 31(11):1834-1840.
  2. Mochel MC, Duncan LM, Piris A, et al. Primary mucosal melanoma of the sinonasal tract: a clinicopathologic and immunohistochemical study of thirty-two cases. Head Neck Pathol; 2015 Jun; 9(2):236-43.

Treatment

Learning Objectives 
  • Surgery is the primary therapeutic intervention for mucosal melanoma
  • Radiotherapy is often used in the adjuvant setting and plays a role in definitive treatment in unresectable, locally advanced cases
References 
  1. 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 May;116(9):2215-23.

Medical Therapies

Learning Objectives 
  • Medical options for mucosal melanoma are limited, with standard chemotherapy regimens such as dacarbazine and paclitaxel/carboplatin demonstrating response rates similar to cutaneous melanoma
  • Immunotherapy is under active investigation in mucosal melanoma
  • Nivolumab combined with ipilimumab seem to have greater efficacy than either agent alone, with progression free survival of 6 months with a response rate of 37%
  • Grade 3 or 4 treatment-related adverse events increase from 8% to 40% from mono- to combination immunotherapy
References 
  1. Chang W, Lee SJ, Park S, et al. Effect of paclitaxel/carboplatin salvage chemotherapy in noncutaneous versus cutaneous metastatic melanoma. Melanoma Res. 2013;23:147-51
  2. D’Angelo SP, Larkin J, Sosman JA, et al. Efficacy and safety of nivolumab alone or in combination with ipilimumab in patients with mucosal melanoma: a pooled analysis. J Clin Oncol. 2017;35:226-35.

Surgical Therapies

Learning Objectives 
  • Complete surgical resection with negative margins is the goal of surgical therapy, and this may be accomplished through open or endoscopic approaches.
  • Neck dissection is performed for clinically or radiographically positive disease. 
  • Unlike cutaneous melanoma, sentinel lymph node biopsy has not been adopted as a mainstay of staging. 
  • Elective treatment of the cervical lymph nodes is advocated for those patients with an oral cavity primary site as the risk of occult disease is higher than for other sites in the head and neck.  

Radiation Therapy

  • While an improvement in locoregional control has been seen in some studies, there has not been an improvement in overall survival when adjuvant XRT is added to surgical therapy.
  • Primary XRT as a palliative therapy may be provided to those patients who are not surgical candidates.
References 
  1. Lopez F, Rodrigo JP, Cardesa A, et al. Update on primary head and neck mucosal melanoma. Head Neck. 2016 Jan; 38(1): 147–155.
  2. 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 May;116(9):2215-23.
  3. Caspers CJI, Dronkers EAC, Monserez D, et al. Adjuvant radiotherapy in sinonasal mucosal melanoma: A retrospective analysis. Clin Otolaryngol 2018;43(2):617.

Rehabilitation

Learning Objectives 
  • This depends on the location and extent of the surgical defect.

Staging

Learning Objectives 

To reflect the poor prognosis of the disease in most patients, the AJCC staging system begins at Stage III.

  • T stage
    • T3 Mucosal disease
    • T4a Moderately advanced disease. Tumor involving deep soft tissue, cartilage, one, or overlying skin.
    • T4b Very advanced disease. Tumor involving brain, dura, skull base, lower cranial nerves (IX, X, XI, XII), masticator space, carotid artery, prevertebral space or mediastinal structures References
  • N Stage
    • NX Regional lymph nodes cannot be assessed
    • N0 No regional lymph node metastases
    • N1 Regional lymph node metastases present
  • M Stage
    • M0 No distant metastasis present
    • M1 Distant metastasis present
  • Clinical Stage
    • Stage III T3 N0 M0
    • Stage IVA T4a N0 M0; T3-T4a N1 M0
    • Stage IVB T4b Any N M0
    • Stage IVC Any T Any N M1
References 
  1. AJCC Cancer Staging Manual 8th edition

Case Studies

  • Case studies:
    • 69 year old female presented with left maxillary alveolar ridge sore consistent with mucosal melanoma underwent wide surgical resection with bilateral cervical lymphadenectomy with clear margins with adjuvant radiation therapy. She had local recurrence 10 months later with subsequent resection followed by another recurrence with initiation on ipilimumab. Significant tumor progression was followed by sudden complete regression, with ultimate distant failure and subsequent death 2 years and 9 months from diagnosis.
    • 56 year old female with hard palate and maxillary gingiva pigmented lesion with detailed mucosal melanoma histopathologic analysis
References 
  1. Studentova H, Kalabova H, Koranda P, et al. Immunotherapy in mucosal melanoma: a case report and review of the literature. Oncotarget; 2018 April; 9(25):17971-17977. 
  2. Tlholoe MM, Khammissa RA, Bouckaert, et al. Oral mucosal melanoma: some pathobiological considerations and an illustrative report of a case. Head Neck Pathol; 2015 Mar; 9(1):127-34.

Complications

Learning Objectives 
  • Recurrence and distant disease are common possibly due to the rich vascularity and lymphatics of the head and neck.
  • The overall 5 year survival for patients with mucosal melanoma is 10-20%.
References 
  1. Schmalbach CE, Johnson TM, Bradford C. Cummings Otolaryngology Head and Neck Surgery. 5th edition. Ed: Flint et al. “The Management of Head and Neck Melanoma and Advanced Cutaneous Malignancies” 2010; Mosby Elsevier (Philadelphia): pp1108-1109.
  2. https://www.uptodate.com/contents/mucosal-melanoma#H32364903

Review

Review Questions 

1. What are some differences between cutaneous and mucosal melanoma?
2. What role does sentinel lymph node mapping play in mucosal melanoma?
3. What is the staging system for mucosal melanoma?
4. What is the preferred treatment option for mucosal melanoma?
5. What immunotherapy regimen is most efficacious in mucosal melanoma?

References 
  1. Lopez F, Rodrigo JP, Cardesa A, et al. Update on primary head and neck mucosal melanoma. Head Neck. 2016 Jan; 38(1): 147–155.
  2. https://www.uptodate.com/contents/mucosal-melanoma#H32364903
  3. Postow MA, Hamid O, Carvajal RD. Mucosal Melanoma: Pathogenesis, Clinical Behavior and Management. Curr Oncol Rep. 2012;14(5): 441-448.
  4. Green B, Elhamshary A, Gomez R, et al. An update on the current management of head and neck mucosal melanoma. J Oral Pathol Med. 2017 Aug;46(7):475-479.