Nasal cavity, paranasal sinuses, nasopharynx
Sinonasal carcinoma
Sinonasal undifferentiated carcinoma
Authors: Abeer Salama, M.D., Bin Xu, M.D., Ph.D.
Resident / Fellow Advisory Board: Kyle Devins, M.D.
Deputy Editor-in-Chief: Kelly Magliocca, D.D.S., M.P.H.
Last author update: 14 July 2021
Last staff update: 14 July 2021
Copyright: 2004-2022, PathologyOutlines.com, Inc.
PubMed Search: Sinonasal undifferentiated carcinoma [title] pathology
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Etiology | Clinical features | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Negative stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Salama A, Xu B. Sinonasal undifferentiated carcinoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/nasalsnuc.html. Accessed August 11th, 2022.
Definition / general
- WHO definition: undifferentiated carcinoma lacking evidence of differentiation (such as squamous, glandular or neuroendocrine differentiation) by histology and immunohistochemistry (El-Naggar: WHO Classification of Head and Neck Tumours, 4th Edition, 2017)
- Diagnosis of exclusion
Essential features
- Undifferentiated carcinoma demonstrating epithelial differentiation but lacking specific squamous, glandular, neuroectodermal, mesenchymal, melanocytic or other lines of differentiation
- Lacks specific viral etiologies, such as HPV and EBV
- Lacks other specific genotypes, such as NUT (NUTM1) fusions, SWI/SNF deficiency and others (JNCI Cancer Spectr 2019;4:pkz094, Semin Diagn Pathol 2021;38:175, Hum Pathol 2020;104:105)
- Lacks neuroendocrine differentiation that would justify for high grade neuroendocrine carcinoma, including large cell and small cell neuroendocrine carcinoma
- Displays oncogenic IDH2 or IDH1 mutations in 80% of cases: IDH2 R172T is the most common mutation (Mod Pathol 2019;32:205, Am J Surg Pathol 2018;42:1067)
Terminology
- Sinonasal undifferentiated carcinoma (SNUC)
ICD coding
Epidemiology
- Rare; 3 - 5% of all sinonasal carcinomas (Nat Rev Clin Oncol 2014;11:460)
- Median age at presentation: 50 - 60 years (Curr Oncol Rep 2019;21:26)
- Male predominance with M:F = 2 - 3:1 (Curr Oncol Rep 2019;21:26)
- No clear clinical risk factors documented to date
Sites
- Nasal cavity most common; may also affect paranasal sinus, such as ethmoid sinus and maxillary sinus (Am J Surg Pathol 2002;26:371)
Etiology
- No consistent etiology has been reported
Clinical features
- Presenting symptoms are variable, including nasal obstruction, epistaxis, facial pain and headache to severe visual symptoms (proptosis, diplopia and impaired visual acuity) and cranial nerve palsies (J Otolaryngol Head Neck Surg 2013;42:2)
- Usually presents with stage 4 disease and involves the skull base and orbit (Curr Oncol Rep 2019;21:26)
Radiology images
Contributed by Bin Xu, M.D., Ph.D. and Abeer Salama, M.D.
MRI
Prognostic factors
- Dismal prognosis
- Overall, 5 and 10 year relative survival rates for SNUC patients were 34.9% and 31.3%, respectively (J Neurol Surg B Skull Base 2015;76:94)
Case reports
- 50 year old woman with SNUC of maxillary sinus metastasizing to the liver (Oncol Lett 2019;17:5811)
- Man in his early to mid 50s with SNUC presenting with bilateral compressive optic neuropathy (JAMA Ophthalmol 2016;134:e155494)
- 60 year old man with a SNUC of maxillary sinus metastasizing to brain, lung and periaortic area (Autops Case Rep 2020;10:e2020222)
- 63 year old woman with SNUC arising in sinonasal inverted papilloma in the left maxillary sinus (Medicine (Baltimore) 2017;96:e8584)
- 80 year old man with SNUC arising in the left anterior nasal cavity involving the ethmoid, sphenoid and maxillary sinuses with brain metastasis (Cureus 2018;10:e2320)
Treatment
- Multimodal therapy regimens incorporating intensified radiotherapy or chemotherapy after surgery (Head Neck 2017;39:1819)
Gross description
- Usually > 4 cm
- Tend to be fungating, with ill defined borders and frequent invasion into adjacent structures (Arch Pathol Lab Med 2009;133:699, Radiology 1997;202:477)
Microscopic (histologic) description
- Nests, lobules, trabeculae and sheets of medium sized cells
- Cells contain small amounts of eosinophilic cytoplasm, medium to large sized hyperchromatic to vesicular nuclei, inconspicuous to prominent nucleoli and poorly defined cell membrane
- Mitotic activity is very high
- Tumor necrosis and apoptoses are frequent
- Lymphovascular invasion and perineural invasion are common
- Lacks any definite lineage of differentiation
- Squamous differentiation (e.g. keratin pearls and intracellular bridges)
- Glandular differentiation (e.g. glandular lumen or acinar architecture)
- Neuroectodermal differentiation (e.g. neurofibrillary material and true neural rosettes)
- Reference: Adv Anat Pathol 2020;27:51
Microscopic (histologic) images
Contributed by Bin Xu, M.D., Ph.D. and Abeer Salama, M.D.
Lobules and sheets of malignant cells
Cytologic features of malignant epithelial cells
High grade features: mitosis and apoptosis
Cytokeratin AE1 / AE3
IDH2 R172T immunohistochemistry
Positive stains
- Pancytokeratin AE1 / AE3, low molecular weight cytokeratin (CAM 5.2)
- CK7: expressed in half of SNUC (Am J Surg Pathol 2002;26:1597)
- Retain (i.e. no aberrant loss) of SWI/SNF complex, including SMARCB1 / INI1, SMARCA4 / BRG1 and SMARCA2 / BRM
- IDH mutation protein such as IDH2 R172T can be detected by immunohistochemistry in 70% (Mod Pathol 2019;32:205, Am J Surg Pathol 2018;42:1067)
Negative stains
- Minimal to absent expression of lineage markers, such as:
- Neuroendocrine markers: synaptophysin, chromogranin and INSM1 (Am J Surg Pathol 2001;25:156)
- Squamous markers: e.g. CK5/6, p63 and p40 (Ann Diagn Pathol 2014;18:261)
- NUT
- Negative for immunomarkers specific for sarcoma (e.g. CD99, desmin and myogenin), lymphoma (e.g. CD45), melanoma (e.g. MelanA and HMB45)
Molecular / cytogenetics description
- IDH2 or IDH1 mutations in > 80% cases, the most common being IDH2 R172 mutation (Mod Pathol 2019;32:1447)
- IDH2 mutant large cell neuroendocrine carcinoma is genetically similar to the IDH2 mutant SNUC
- In situ hybridization for high risk HPV and EBV is consistently negative
Sample pathology report
- Nasal cavity, biopsy:
- Poorly differentiated carcinoma, most consistent with sinonasal undifferentiated carcinoma (SNUC), at least 1.15 cm in greatest dimension, invading bone (see comment)
- Comment: Immunohistochemical stains show that the tumor cells are focal staining of AE1 / AE3, Cam 5.2 and IDH2 R172S, while they are negative for CK5/6, synaptophysin, chromogranin, IDH1-R132H, calretinin, NUT, P40, S100 and calponin. The immunostaining for BAF47, BRM and BRG1 is retained in the tumor. In situ hybridization for high risk HPV and EBV (EBER) are negative in the tumor.
Differential diagnosis
- Differential diagnoses of SNUC are broad and encompass a wide range of poorly differentiated carcinomas, sarcoma, melanoma and lymphoma
- Squamous cell carcinoma:
- Adenocarcinoma:
- Shows glandular differentiation by histology
- High grade salivary gland carcinoma:
- Shows histologic, immunohistochemical and molecular characteristics of salivary gland carcinoma
- High grade neuroendocrine carcinoma:
- Large cell neuroendocrine carcinoma has coarse or specked chromatin, prominent nucleoli
- Small cell undifferentiated neuroendocrine carcinoma has salt and pepper chromatin and nuclear molding
- Nonfocal immunoexpression of neuroendocrine markers (e.g. synaptophysin, chromogranin and INSM1)
- Like SNUC, might harbor IDH2 mutation
- Olfactory neuroblastoma:
- SWI/SNF deficient sinonasal carcinoma:
- NUT carcinoma:
- Detection of NUT (NUTM1) fusion by molecular testing or abnormal diffuse speckled NUT nuclear immunopositivity by immunohistochemistry
- HPV related multiphenotypic sinonasal carcinoma:
- Shows salivary / myoepithelial differentiation by histology
- Positive for high risk HPV
- Sarcoma
- Melanoma:
- Lymphoma:
- CD45 positive
Board review style question #1
Which of the following statement about sinonasal undifferentiated carcinoma (SNUC) is true?
- 20% of SNUC are positive for high risk HPV
- It is a diagnosis of exclusion
- It is commonly diffusely positive for synaptophysin
- SMARCB1 (INI1) immunostain is lost in this tumor
Board review style answer #1
B. It is a diagnosis of exclusion. SNUC can be focally positive for neuroendocrine markers (e.g. synaptophysin). However, diffuse synaptophysin positivity hints towards olfactory neuroblastoma, paraganglioma or neuroendocrine neoplasm. SMARCB1 loss is characteristic for SMARCB1 deficient sinonasal carcinoma. SNUC has no association with high risk HPV. The correct answer is B (SNUC is a diagnosis of exclusion).
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Reference: Sinonasal undifferentiated carcinoma
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Board review style question #2
Which of the following sinonasal carcinoma harbors frequent IDH2 mutation?
- Nasopharyngeal carcinoma
- NUT carcinoma
- Sinonasal undifferentiated carcinoma (SNUC)
- SMARCA4 and SMARCB1 deficient carcinoma
Board review style answer #2
C. Sinonasal undifferentiated carcinoma (SNUC)
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