Answer and Discussion
The antemortem sinonasal mass biopsy and sections from autopsy reveal pleomorphic epithelioid cells with prominent nucleoli in a primarily solid architecture. The tumor cells stain positive for Melan-A, HMB-45, and p16. The diagnosis is metastatic mucosal melanoma, likely arising from the nasal cavity. Mucosal melanomas often have lower somatic mutational burdens but are associated with higher rates of KIT mutations (Answer: 4) than their cutaneous counterparts, which harbor higher rates of BRAF and NRAS mutations.
Mucosal melanoma (MM) is a rare type of melanoma that primarily arises from the head and neck region and accounts for 1-2% of all melanomas. MM most often arises in the anterior nasal cavity but can also occur in the sinuses, specifically the maxillary sinus. Patients often present with nonspecific symptoms related to the affected regions including nasal and sinus congestion, rhinorrhea, and epistaxis. Less common locations where mucosal melanoma can arise include the larynx, the female genital tract, the anorectal region, and the urinary tract.MM is biologically distinct from cutaneous melanoma, with different risk factors and molecular associations. MM has a worse prognosis and often presents with more advanced disease than cutaneous melanoma. Formalin is cited as a known environmental risk, but MM is not believed to be associated with radiation and UV exposure, unlike cutaneous melanoma.
Histologically, the morphology of MM tumor cells varies greatly and may consist of undifferentiated, rhabdoid, epithelioid, plasmacytoid, and small cells. Tumor cells often exhibit a peritheliomatous pattern, in which they surround blood vessels. Additional architectural patterns include epithelioid, solid, organoid, fascicular, and meningothelial. Approximately 50% of cases are amelanotic, which can result in diagnostic difficulty.
MM expresses melanocytic markers (HMB-45, Melan-A, S100, SOX10), and it is recommended to have more than one positive melanocytic marker for diagnosis. Cytokeratins, neuroendocrine markers, and lymphocytic markers are negative in this entity. P16 over-expression, along with p53 over-expression, is thought to be associated with poorer outcomes in patients with MM, but this is controversial.
Overall, the prognosis of MM is poor. Multiple factors have been linked to a worse prognosis, including obstruction as a presenting symptom, nasopharynx involvement as opposed to the oral cavity, larger size (> 3 cm), and undifferentiated histology with a high mitotic rate.
Treatment includes surgical resection and palliative radiation, but local recurrence is common in these patients. Further, the five-year survival is estimated to be less than 25%.
The differential diagnosis of sinonasal MM is vast and includes olfactory neuroblastoma, sinonasal undifferentiated carcinoma, undifferentiated pleomorphic sarcoma, and spindle cell squamous cell carcinoma, among others. Immunohistochemistry plays a crucial role in distinguishing this entity from others in its differential:
Olfactory neuroblastoma is a neoplasm derived from specialized neuroepithelial olfactory cells and is primarily composed of small round blue cells that are slightly larger than lymphocytes. Additionally, pseudorosettes and true rosettes may be seen. The tumor cells will stain positive for neuroendocrine markers, including synaptophysin, chromogranin, and INSM1. As opposed to the diffuse positivity often seen in MM, S100 exhibits a sustentacular “meshwork-like” pattern in olfactory neuroblastoma.
Sinonasal undifferentiated carcinoma consists of pleomorphic cells in variable architectural patterns frequently associated with tumor necrosis. The tumor cells will stain negative for melanoma markers and should have keratin positivity. Neuroendocrine differentiation may be present in a portion of these tumors, with focal synaptophysin, chromogranin, and CD56 positivity.
Undifferentiated pleomorphic sarcoma is a high-grade entity that can occur post-radiation without specific differentiation and is a diagnosis of exclusion based on negative staining and molecular studies. Like mucosal melanoma, this entity has variability in microscopic patterns with numerous histologic subtypes, including spindled, epithelioid, and round cell. This entity stains positive for vimentin only.
Spindle cell squamous cell carcinoma is biphasic with an ill-defined threshold between spindled and squamous features. This entity should stain positive for p63, p40, and CK5/6, and should stain negative for SOX10 and S100, but epithelial markers can be negative in up to 30% of these cases.
References:
- WHO Classification of Tumours Editorial Board. Head and Neck tumours [Internet version]. Lyon (France): International Agency for Research on Cancer; 2022 [cited 10/10/2024]. (WHO classification of Tumours Series, 5th ed.; vol. 11). Available from: https://tumourclassification.iarc.who.int/chaptercontent/52/263
- Deerwester M, Smoller BR. Mucosal melanoma (genital, oral, sinonasal). PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/skintumormelanocyticmucosalmelanoma.html. Accessed October 10th, 2024.
- Spencer KR, Mehnert JM. Mucosal Melanoma: Epidemiology, Biology and Treatment. Cancer Treat Res. 2016;167:295-320. doi: 10.1007/978-3-319-22539-5_13. PMID: 26601869.
- Sergi MC, Filoni E, Triggiano G, Cazzato G, Internò V, Porta C, Tucci M. Mucosal Melanoma: Epidemiology, Clinical Features, and Treatment. Curr Oncol Rep. 2023 Nov;25(11):1247-1258. doi: 10.1007/s11912-023-01453-x. Epub 2023 Sep 29. PMID: 37773078; PMCID: PMC10640506.
- Chen H, Li Y, Long Y, Tang E, Wang R, Huang K, Xie C, Chen G. Increased p16 and p53 protein expression predicts poor prognosis in mucosal melanoma. Oncotarget. 2017 Jun 5;8(32):53226-53233. doi: 10.18632/oncotarget.18367. PMID: 28881806; PMCID: PMC5581105.
Board-type questions:
1. Where does mucosal melanoma most often arise?
A. Endometrium
B. Colon
C. Nasal cavity
D. Anogenital region
2. Which of the following is not associated with a poor prognosis in patients with
mucosal melanoma?
A. Obstruction as a presenting symptom
B. Primary site outside of nasopharynx
C. High mitotic count
D. Perineural invasion