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Diagnosis and Discussion: Case 1144

Final Diagnosis

Sinonasal Undifferentiated Carcinoma

Oncomine Test Results Summary

DNA Mutations:

  • IDH2 mutation p.R172T
  • TP53 mutation p.R280K

Copy Number Alterations:

  • RAD51 copy number LOSS
  • 9q, 13q, and 16p/16q region copy number LOSS
  • 8q, 10q, and 12p region copy number GAIN (~4 copies)

Discussion

Sinonasal Undifferentiated Carcinoma (SNUC) is a rare, aggressive epithelial malignancy representing 3-5% of sinonasal carcinomas (1). It typically presents with rapid clinical onset (weeks to months) and extensive infiltration at presentation, often involving multiple sites including the nasal cavity, paranasal sinuses, orbit, and skull base (2, 3). Despite aggressive multimodality therapy, SNUC has a poor prognosis with a median survival of 22 months and 5-year survival rates of approximately 35%.

Histologically, SNUC shows hypercellular proliferation with varied growth patterns including lobular, trabecular, sheet-like, and organoid arrangements. The cellular infiltrate consists of medium to large polygonal cells with round to oval nuclei, prominent nucleoli, and varying amounts of eosinophilic to clear cytoplasm. SNUC typically has a characteristically uniform appearance with relatively consistent nuclear size and shape despite its high-grade morphology. Key diagnostic features include a high mitotic count with atypical forms, prominent tumor necrosis (both confluent areas and individual cells), lymphovascular invasion, and neurotropism. By definition, SNUC lacks any identifiable squamous or glandular differentiation, and surface dysplasia is typically absent (4).

A significant subset of SNUCs harbor IDH2 mutations, predominantly at the R172 hotspot, with R172S being most common (5, 6). These mutations lead to overproduction of hydroxyglutarate, a potent oncometabolite that interferes with histone demethylation. IDH-mutant SNUCs demonstrate a hypermethylator phenotype. IDH2 mutations correlate with better disease-specific survival, providing important prognostic information and potential therapeutic targets for IDH inhibitors (7, 8). Though IDH mutations are found in up to 80% of cases, it is not required for diagnosis. Other potential driver mutations have been identified in IDH2-wildtype tumors, including inactivating mutations in the NOTCH1 PEST regulatory domain and TET2 loss-of-function mutations. This suggests there may be other potential genomically defined subsets within histologically defined SNUCs (6).

Immunohistochemistry is essential for diagnosis due to histologic overlap with other sinonasal tumors. SNUCs consistently show intense, diffuse positivity for pancytokeratins (AE1/AE3, CAM5.2) and simple keratins, while being negative or only focally positive for p40, p63, and CK5/6. Neuroendocrine markers (synaptophysin, chromogranin, CD56) may show limited and focal reactivity, but diffuse positivity in any of these markers excludes SNUC. Mutant IDH1/2 immunohistochemistry can identify a proportion of SNUCs with IDH mutations, though sequencing-based methods are more reliable for detecting the full range of mutations. Other immunohistochemical features include retained INI1 (SMARCB1) and BRG1 (SMARCA4) expression, with possible p16 and CD117 positivity. SNUCs are typically negative for S100, calretinin, hematolymphoid markers, melanocytic markers, CD99, EBER, and NUT.

The differential diagnosis requires systematic exclusion of various entities through specific immunophenotypic patterns. Olfactory neuroblastoma shows neuroendocrine marker positivity with S100-positive peripheral sustentacular cells and lacks diffuse cytokeratin staining. Neuroendocrine carcinomas demonstrate strong reactivity with at least one neuroendocrine marker and characteristic nuclear features. Squamous cell carcinomas express p40, CK5/6, and p63. Lymphoepithelial carcinoma is nearly always EBER-positive. Mucosal melanoma expresses S100, SOX10, and melanocytic markers while being negative for cytokeratins. Rhabdomyosarcoma shows positivity for desmin and myogenin. NUT carcinoma reveals areas of abrupt squamous differentiation with strong nuclear NUT immunoreactivity. SWI/SNF complex-deficient carcinomas show nuclear loss of INI1 or BRG1. The diagnosis of SNUC is therefore established through a combination of characteristic histomorphology, appropriate immunophenotype, and careful exclusion of other entities, with molecular testing for IDH mutations providing additional diagnostic and prognostic information.

References

  1. Llorente et al. (2014). Sinonasal carcinoma: clinical, pathological, genetic and therapeutic advances. Nature Reviews Clinical Oncology, 11(8), 460-472. https://doi.org/10.1038/nrclinonc.2014.97
  2. Reiersen et al. (2012). Meta‐analysis of treatment outcomes for sinonasal undifferentiated carcinoma. Otolaryngology, 147(1), 7-14. https://doi.org/10.1177/0194599812440932
  3. Ejaz et al. (2005). Sinonasal undifferentiated carcinoma. Advances in Anatomic Pathology, 12(3), 134-143. https://doi.org/10.1097/01.pap.0000163958.29032.56
  4. Bishop et al. (2023). Sinonasal undifferentiated carcinoma. WHO Classification of Tumours, 5th edition, volume 9. Head and neck tumours. Lyon (France): International Agency for Research on Cancer. https://tumourclassification.iarc.who.int/chapters/52.
  5. Dogan et al. (2017). Frequent IDH2 R172 mutations in undifferentiated and poorly-differentiated sinonasal carcinomas. The Journal of Pathology, 242(4), 400-408. https://doi.org/10.1002/path.4915
  6. Jo et al. (2017). Recurrent IDH2 R172X mutations in sinonasal undifferentiated carcinoma. Modern Pathology, 30(5), 650-659. https://doi.org/10.1038/modpathol.2016.239
  7. Guo et al. (2021). Biological roles and therapeutic applications of IDH2 mutations in human cancer. Frontiers in Oncology, 11. https://doi.org/10.3389/fonc.2021.644857
  8. Riobello et al. (2024). Next‐generation sequencing reveals remarkable genetic stability in primary and corresponding recurrent intestinal‐type sinonasal adenocarcinoma. Head & Neck, 46(8), 2010-2019. https://doi.org/10.1002/hed.27694