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.

Topic Completed: 14 July 2021

Minor changes: 14 July 2021

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PubMed Search: Sinonasal undifferentiated carcinoma [title] pathology

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Table of Contents

Cite this page: Salama A, Xu B. Sinonasal undifferentiated carcinoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/nasalsnuc.html. Accessed January 21st, 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

ICD-10:
- C30.0 - malignant neoplasm of nasal cavity
- C31.1 - malignant neoplasm of ethmoid sinus

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:
  - Shows squamous differentiation by histology (e.g. keratin pearls and intercellular bridges) or by immunohistochemistry (e.g. immunopositivity for p40 and CK5/6)
- 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:
  - Express neuroendocrine markers
  - Positive for S100 in a sustentacular pattern
  - Keratin expression is typically absent or focal (in less than 25% of cases)
- SWI/SNF deficient sinonasal carcinoma:
  - Mutation of SMARCB1, SMARCA2 or SMARCA4 detected by molecular testing or loss of immunoexpression of SMARCB1, SMARCA2 or SMARCA4 by immunohistochemistry
- 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:
  - MelanA, SOX10, S100 positive
- 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

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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Reference: Sinonasal undifferentiated carcinoma