March 2023 – Surgical Pathology

Patient is a 50-year-old man with a sinonasal mass. In addition to the above ancillary studies, lesional cells express cytokeratin AE1/AE3 and p63 while negative for NUT, androgen receptor, synaptophysin, chromogranin, Melan-A, and mucicarmine. INI-1 and BRG-1 show retained nuclear expression. 

Figure 1: H&E Medium power
Figure 2: H&E High power
Figure 3: cytokeratin 7
Figure 4: S100
Figure 5: P16
Figure 6: HPV E6E7 ISH

Given the above information, what is the most likely diagnosis?

  • Adenoid cystic carcinoma
  • Squamous cell carcinoma, HPV-associated
  • Sinonasal undifferentiated carcinoma
  • HPV-related multiphenotypic sinonasal carcinoma

The correct answer is ...

HPV-related multiphenotypic sinonasal carcinoma.

By definition, HPV-related multiphenotypic sinonasal carcinoma (HMSC) is a high-risk HPV associated epithelial neoplasm that shows both surface and minor salivary gland derived elements. The tumor typically affects adults (mean age 54 years) with the vast majority occurring in the nasal cavity. Multiphenotypic refers to a mixed ductal and myoepithelial morphologic and immunophenotypic phenotype. 

By histomorphology, HMSC may resemble biphasic salivary gland carcinomas with tumor cells arranged in trabecular, cribriform, microcystic, or nested patterns. The myoepithelial component of the tumor is usually comprised of basaloid-appearing tumor cells. Myoepithelial cells with spindle, plasmacytoid, or clear cell change may be present. Myxohyaline stroma is frequently present in the background. A variable number of ducts are present, which may be difficult to observe due to compression by the surrounded myoepithelial cells or due to their sparse representation. The ducts typically contain more abundant eosinophilic cytoplasm. HMSC frequently shows high grade features including high mitotic activity and necrosis. Despite its high-grade appearance, HMSC exhibits indolent behavior though local recurrences are common (approximately 33%). 

Surface involvement by dysplasia or carcinoma in situ may be present. Identification of surface involvement is a useful finding in the differential diagnosis of HMSC. Bone invasion is frequently seen but perineural and lymphovascular invasions are rare.

Immunohistochemically, HMSC shows evidence of both myoepithelial and ductal differentiation. Myoepithelial cell differentiation can be highlighted with p40, SMA, calponin and p63. Stains for low molecular weight cytokeratin or CD117 may preferentially highlight ducts. Immunostains for S100 and SOX-10 may highlight both cell types of the tumor. Evidence of transcriptionally active high-risk HPV can be shown with block-like p16 expression (surrogate) and high-risk HPV in-situ hybridization studies.

By morphologic findings alone, HMSC may be difficult to distinguish from salivary gland carcinomas with biphasic differentiation such as adenoid cystic carcinoma (AdCC). However, AdCC (and other salivary gland tumors) are typically not associated with overlying dysplasia or carcinoma in situ. The presence of high-risk HPV (confirmed in situ hybridization) is characteristic of HMSC.

HPV-associated squamous cell carcinoma should not exhibit morphologic and immunophenotypic evidence of a dual cell population. In this case, CK7, p63, and S100 expression provide immunophenotypic evidence of ductal and myoepithelial differentiation.

Sinonasal undifferentiated carcinoma (SNUC) is by definition an undifferentiated carcinoma lacking squamous and glandular elements. SNUC carries a much higher mortality rate then HMSC. Though SNUC may show similar nested to lobular growth patterns, high-grade cytologic features, and keratin expression, these tumors are otherwise immunophenotypically distinct. SNUC is negative for p40 and CK5/6 (evidence of squamous differentiation). S100 and SOX-10 are also negative in SNUC. 


  1. Bishop, J. HPV-Related Multiphenotypic Sinonasal Carcinoma. World Health Organization, 
  2. Gnepp DR, Bishop J. Nonsquamous lesions of the nasal cavity, paranasal sinuses, and Nasopharynx. In: Gnepp DR, Bishop J., eds., Gnepp's Diagnostic Surgical Pathology of the Head and Neck, 3rd ed., Elsevier, Amsterdam, 2020. 
  3. Jo, VY. Sinonasal Undifferentiated Carcinoma. World Health Organization,
  4. Thompson LDR. HPV-related multiphenotypic sinonasal carcinoma. Ear Nose Throat J. 2020 Feb;99(2):94-95. doi:10.1177/0145561319871711. Epub 2019 Sep 2. PMID: 31476886.
  5. Thompson LDR, Bishop J. Malignant neoplasms of the nasal cavity, paranasal sinuses, and nasopharynx. In: Thompson LDR, Bishop J., eds., Head and Neck Pathology, A Volume in the Series: Foundations in Diagnostic Pathology, 3rd ed., Elsevier-Health Sciences Div, 2017.
Photo of Michael R. McCarthy, M.D.

Michael McCarthy, M.D.

Resident, Anatomic and Clinical Pathology
Mayo Clinic

Michael Rivera, M.D.

Consultant, Anatomic Pathology
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

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