—  SPECIALTY CONFERENCE  —

Head & Neck/Endocrine Pathology

Case 4 - Mucosal Melanoma of Eustachian Tube

Beverly Y. Wang, New York Univ/Medicine, New York, NY





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Introduction:
Primary malignant mucosal melanoma of the head and neck is rare. Complete removal of the tumors is difficult due to anatomic limitations. Diagnosis can be challenging, since melanomas can mimic many other types of malignant tumors. Treatment often requires adjuvant therapies. Recent clinical trials of Vemurafenib for treatment of BRAF gene mutation on metastatic cutaneous melanoma have prolonged survival rate.

Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
Histologically, the polypoid tumor was over-lined by ulcerated squamous mucosa and composed of pleomorphic, heavily pigmented spindle cells. Frequent mitoses were present. Immunohistochemical studies revealed that tumor cells were positive for S100 protein, HMB-45, Melan-A and PNL-2.

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PNL-2
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S100
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c-kit

Differential Diagnoses:
  • Sinonasal undifferentiated carcinoma

  • Sinonasal neuroendocrine carcinoma

  • Olfactory neuroblastoma

  • Rhabdomyosarcoma

  • Malignant lymphomas

Final Diagnosis:
Mucosal Melanoma of Eustachian Tube.

Case Discussion:
Melanoma is defined as a malignant tumor of melanocytes, which are cells derived from the neural crest that make the pigment melanin. Although most melanomas arise in the skin, they may also arise in mucosal surfaces or at other sites to which neural crest cells migrate. Estimated new cases and deaths from melanoma in the United States in 2011 were over 70,000 for new cases with over 8000 deaths (American Cancer Society 2011). Mucosal melanomas (MMs) represent 1.3% of all cutaneous and non-cutaneous melanomas. Among mucosal melanomas, 55% are located in the head and neck region (Chang 1998 and Wagner 2008). Approximately 15 to 20% of all malignant melanomas arise in head and neck sites: > 80% are of cutaneous origin, 20% are MMs, and most are of ocular origin.

The pathogenesis of MM is still unknown. Several speculated risk factors are thought to be related to MM, e.g. exposure to sunlight, human papillary virus, chronic irritants, and carcinogenic compounds (Brandwein 1997, Wagner 2008, Tomicic 2006). Recently, several studies have reported that pathogenesis of melanomas may be related to an altered immune system. Several immune genes have been studied in cutaneous melanoma, including CTLA-4, IL17, RORγt, and FoxP3. These genes are interesting because they function as immunomodulators (Wang 2008).

Clinically, MM of the nasal cavity and parasinuses affect men more than women, frequently during the 6th to 8th decades of life. Interestingly, MMs of the head and neck more frequently affect Asian patients. In contrast, cutaneous melanomas generally affect more of the light- skin population. In head and neck sinonasal tract, 0.5% to 3% of MM of all sites is located in following order: oral cavity > sinonasal tract > less common in nasopharynx, pharynx, larynx, and middle ear. Clinical staging is based on whether or not the tumor has spread to regional lymph nodes or distant sites. Melanoma can spread by local extension through lymphatics and/or by hematogenous routes to distant sites. While any organ may be involved by metastases, lungs and liver are the most common sites. Prognosis is affected by clinical and histological factors and by the anatomic location of lesions. Thickness and/or level of invasion of the melanoma, mitotic index, presence of tumor infiltrating lymphocytes, number of regional lymph nodes involved, and ulcertion or bleeding at the primary site affect the prognosis (Balch 2001, Fisher 2008).

Head and neck MM may appear macular, nodular, or polypoid, with colors ranging from white to dark brown to violaceous to pink. Cellular morphology is variable, ranging from epithelioid to plasmacytoid to spindly. However, immunostains for melanocytic markers can aid the diagnoses, including S100 protein, HMB-45 (human melanoma black-45), melan-A, micropthalmia transcription factor (MITF) and PNL-2. Ultimately, at the ultrastructural level, identified pre-melanosomes and/or melanosomes are diagnostic. Differential diagnoses of sinonasal mucosa melanoma include sinonasal tract undifferentiated carcinoma, sinonasal tract neuroendocrine carcinoma, olfactory neuroblastoma, rhabdomyosarcoma and malignant lymphoma.

Recently reported c-kit (CD117) gene activation can be detected in metastatic tumors of acral and MMs (Smalley 2009, Ashida 2009). Immunostain for c-kit is positive for most MM. This newly discovery can help clinically manage the treatment with Greevec.

Melanomas that have not spread beyond the site at which they developed are highly curable. The treatment of localized melanoma is surgical excision with clear margins proportional to the microstage of the primary lesion (AJCC 2010). For most melanomas with Breslow thickness of more than 2 mm to 4 mm, this means wide radical margins that should be considered for sentinel lymph node biopsy. Patients with melanomas that have a Breslow thickness of more than 4 mm should be considered for adjuvant therapy with high-dose interferon.

In a prospective randomized controlled trial, adjuvant high-dose interferon was shown to increase relapse-free survival and overall survival when compared to observation (Kirkwood 1996, Hancock 2004). Melanoma that has spread to distant sites is rarely curable with standard therapy and usually requires palliative therapy and adjuvant treatments. Adjuvant therapies include radiation, combination chemotherapy, biological response modifiers (such as specific monoclonical antibodies, interferons, IL- 2, or tumor necrosis factor-alpha), vaccine immunotherapy, and biochemotherapy (chemoimmunotherapy). Melanoma has been refractory to most standard systemic therapy. The two approved treatments, dacarbazine and interleukin-2 (IL-2), have not demonstrated an impact on overall survival in randomized trials. Response to IL-2 immunotherapy only showed that approximately 5% of patients may obtain a complete remission and become long-term survivors (Atkins 2000, Ewu 2009).

Review of the Literature/Treatment Options:

Current clinical trials for unresectable advanced staging melanomas:
The Eastern Cooperative Oncology Group, in collaboration with centers throughout the United States, is conducting a phase III randomized trial of ipilinumab versus placebo in stage III and stage IV patients who have advanced melanomas. Intratumoral injections of replication- competent oncolytic viruses of unresectable lesions are being tested in national clinical trials. Recently published data involving the meta-analysis of signal transduction inhibitors (Sorafenib and BRAF inhibitors) has shown improvement of overall survival rates (Hauschild 2009 and Flahery 2010).

Vemurafenib and BRAF inhibition:
FDA recently approved a new class of Vemurafenib for the treatment of BRAF V6000E mutant metastatic melanoma. Vemurafenib is a competitive small molecule serine- threonine kinase inhibitor that functions by binding to the ATP binding domain of mutant BRAF. BRAF V600E is the single most frequent mutation in the BRAF gene, with 60% to 70% of malignant melanomas harboring a single nucleotide transversion (Luke 2011). Clinical trials have shown that Zelboraf (Vemurafenib), for the treatment of BRAF V600E mutation-positive, inoperable or metastatic melanoma (skin cancer), causes an overall 84% improved survival rates at 6 months, compared to other regimens. Phase I and II clinical trials of the BRAF kinase inhibitor Vemurafenib (PLX4032) have shown response rates >50% in patients with metastatic melanoma with the BRAF V600E mutation. Vemurafenib produced improved rates of overall and progression-free survival in patients, who had previously untreated melanoma with the BRAF V600E mutation (Chapman 2011).

Conclusions:
  • MM of head and neck is uncommon and can mimic a variety of other types of tumors.

  • Improved survival with Vemurafenib and BRAF inhibition treatment for advanced melanoma is evidenced.

References:
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  3. Chang AE, Karnell LH, Menck HR. The National Cancer Data Base Report on cutaneous and non cutaneous melanoma. A summary of 84,836 cases from the past decade. Cancer 1998;83:1664-1678

  4. Brandwein MS, Rothstein A, Lawson W, et al. Sinonasal melanoma: a clinicopathologic study of 25 cases and literature meta-analysis. Arch Otolaryngol Head Neck Surg. 1997; 123: 20-296.

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  7. Balch CM, Buzaid AC, Soong SJ, et al.: Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 2001; 19:3635-48

  8. Fisher D, Kwong L, Chin L, et al.: Melanoma. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncolocy. Vol.1 & 2. 8th ed. Philadephia, Pa: Lippincott Williams & Wilkins, 2008, pp1889-1966.

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  13. Kirkwood JM, Strawderman MH, Ernstoff MS, et al.: Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin oncol 1996; 14:7-17

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  15. Atkins MB, Kunkel L, Sznol M, et al.: High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am 2000;6 (Suppl 1):S11-4

  16. Euw EV, Chodon T, Attar N, et al. CTLA4 blockade increases Th 17 cells in patients with metastatic melanoma. J Transl Med 2009; 7:35-48

  17. Hauschild A. Agarwala SS, Trefzer U, et al.: Results of phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxed as second-line treatment in patients with unresectable stage II or stage IV melanoma. J. Clint Once 2009; 27:2823-30

  18. Flaherty KT, Puzanov I, Kim KB, et al.: Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl J Med 2010; 363:809-19

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  20. Chapman PB, et al. Improved survival with Vemurafenib in melanoma with BRAF V600E mutation. N Eng J Med. 2011 Jun 30;364(26):2507-16. Epub 2011 Jun 5