SWI/SNF 复合体缺失型鼻腔鼻窦癌：SMARCB1（INI1）/SMARCA4（BRG1）与鉴别诊断SWI / SNF complex deficient sinonasal carcinoma

• SWI / SNF complex deficient sinonasal carcinomas encompass poorly differentiated to undifferentiated epithelial tumors in the sinonasal tract with loss of SMARCB1 (INI1) or SMARCA4 (BRG1) protein expression (Adv Anat Pathol 2023;30:95, AJNR Am J Neuroradiol 2023;44:1116)

• Arising from the sinonasal tract
• Defining feature is loss of SMARCB1 (INI1) or SMARCA4 (BRG1) protein expression
• 3 recognized subtypes
  • SMARCB1 deficient sinonasal carcinoma
  • SMARCB1 deficient sinonasal adenocarcinoma (at least focal glandular or yolk sac morphology is essential)
  • SMARCA4 deficient sinonasal carcinoma
• Aggressive clinical course

• Sinonasal undifferentiated carcinoma (previous terminology; currently not recommended)

• ICD-O: 8044/3 - SWI / SNF complex deficient sinonasal carcinoma
• ICD-10
  • C30.0 - malignant neoplasm of nasal cavity
  • C31.1 - malignant neoplasm of ethmoidal sinus
• ICD-11
  • 2C20.Z & XH1YY4 - malignant neoplasms of nasal cavity, unspecified & carcinoma, undifferentiated, NOS
  • 2C22.2 & XH1YY4 - malignant neoplasms of accessory sinuses, unspecified & carcinoma, undifferentiated, NOS

• Male predominance across all subtypes
• Broad age range (young adults to elderly) (Am J Surg Pathol 2017;41:458, Head Neck Pathol 2022;16:168)

• SMARCA4 deficient sinonasal carcinoma and SMARCB1 deficient sinonasal adenocarcinoma
  • Nasal cavity with multiple sinonasal sites (Head Neck Pathol 2022;16:168)
• SMARCB1 deficient sinonasal carcinoma
  • Paranasal sinuses (mainly ethmoid), variably involves nasal cavity (Am J Surg Pathol 2017;41:458)

• Switch / sucrose nonfermentable (SWI / SNF) chromatin remodeling complex functions as a tumor suppressor and is composed of proteins encoded by > 20 genes
• Several mutations are seen with gene specific clustering; 2 subunit alterations of most relevance to the sinonasal tract are SMARCB1 and SMARCA4
  • SMARCB1 deficiency from biallelic deletion or inactivation at chromosome 22q11.2
  • SMARCA4 deficiency from biallelic inactivation at chromosome 19p13.2 (Head Neck Pathol 2022;16:168)

• Not known

• Clinically mimics benign conditions with mild congestive symptoms
• Becomes clinically apparent due to mass effect with compression of cranial nerves and branches (Cancers 2022;14:3285)
• Locally aggressive, often presenting at T4 with invasion into the orbit and intracranium

• While cytology can theoretically be adequate for diagnosis, a cell block is required for pertinent immunohistochemistry
• Sampling issues render a cytology or histology based diagnosis difficult (Head Neck Pathol 2022;16:168)
  • Glandular or yolk sac elements are required for diagnosis of SMARCB1 deficient sinonasal adenocarcinoma
• Excision may allow more complete assessment of morphology when limited biopsy material is nondiagnostic
• WHO histological criteria for diagnosis
  • Essential: sinonasal tract location; undifferentiated carcinoma with SMARCB1 (INI1) or SMARCA4 (BRG1) loss but no features of other entities; unequivocal gland formation or yolk sac tumor-like features are required for the adenocarcinoma subtype
  • Desirable: presence of rhabdoid cells; yolk sac-like features for the adenocarcinoma variant

• T4 stage at presentation with involvement of multiple sinuses, adjacent orbital and intracranial compartments
• Avid enhancement, intermediate T2 signal intensity, moderate diffusion restriction and fluorodeoxyglucose (FDG) avidity
• Blurring of anatomic boundaries with osseous change
• CT imaging showing calcification likely reflects retained bone fragments or an aggressive periosteal reaction causing a hair on end appearance
• Reference: AJNR Am J Neuroradiol 2016;37:1925

• SMARCB1 deficient sinonasal carcinoma
  • Mortality rate of 56% at 16 months (Am J Surg Pathol 2017;41:458)
  • Unresectable disease and metastasis are the most common causes of death
  • T4 disease and male gender are associated with worse prognosis
• SMARCB1 deficient sinonasal adenocarcinoma
  • Not currently defined due to limited follow up data
• SMARCA4 deficient sinonasal carcinoma
  • Highly aggressive with comparable behavior to extrasinonasal counterparts
  • ~67% of patients are deceased within a year of diagnosis (Arch Pathol Lab Med 2022;146:1122)

• 53 year old man with endobronchial metastases (Acta Cytol 2019;63:431)
• 54 year old woman with persistent left sided symptoms including epistaxis, hemicrania and ocular symptoms (Pathol Int 2022;72:53)
• 58 year old man presented with right sided nasal congestion, decreased sense of smell and protrusion of the right eyeball (Diagn Pathol 2025;20:102)
• 64 year old man with worsening right sided headache and sixth nerve palsy (Cureus 2025;17:e77217)
• 72 year old man with left facial pain and nasal obstruction, develops lung metastasis (J Surg Case Rep 2021;2021:rjab161)

• Multimodal therapy: resection, chemotherapy and radiotherapy (Cancers 2022;14:3285)
  • Induction chemotherapy reduces the risk of distant metastasis and good response to induction chemotherapy is associated with a good subsequent response to radiotherapy
  • Patients who proceeded to definitive chemoradiotherapy had better survival outcomes than with a primary resection
  • In cases with a poor response to induction chemotherapy, resection was then pursued (J Clin Oncol 2019;37:504)
• Targeted therapies addressing downstream alterations related to SWI / SNF complex deficiency are under investigation
  • EZH2 activity is increased following loss of SMARCB1 protein expression, making EZH2 a therapeutic target for small molecule inhibitors (Cancers 2022;14:3285)

• Often presents as T4 disease with highly infiltrative growth and bony invasion of local structures (i.e., maxilla) (AJNR Am J Neuroradiol 2016;37:1925)
• Can have an exophytic papilliform surface (Am J Surg Pathol 2017;41:458)

• Undifferentiated high grade malignancy on frozen
• Can be used to assess margin status in the setting of a known diagnosis

SMARCB1 deficient sinonasal carcinoma (Head Neck Pathol 2022;16:168)

• Monomorphic with predominant basaloid morphology (60% of cases)
  • Peripheral palisading (indistinguishable from basaloid squamous cell carcinoma [SCC]) (Am J Surg Pathol 2017;41:458)
• Eosinophilic, plasmacytoid / rhabdoid morphology (30% of cases) (Am J Surg Pathol 2017;41:458)
• Absent squamous differentiation (lack of keratinization and conventional morphology)
• Rare clear and spindled cells
• Pagetoid spread along the mucosa (carcinoma in situ mimic) may occur but there should be no true surface dysplasia
• May exhibit papilliform growth with colonization of mucous glands imparting an inverted appearance

SMARCB1 deficient sinonasal adenocarcinoma (Head Neck Pathol 2020;14:465)

• Unequivocal gland formation defined by tubules, cribriform pattern and intraluminal or intracellular lumen documented in 5 - 100% of tumor
• Occasional yolk sac (microcystic / reticular in a myxoid background) appearance
• Predominant oncocytoid / plasmacytoid morphology with myxoid stroma
• High grade cytology with nuclear pleomorphism, necrosis and mitoses
• Rarely spindled, squamoid or clear cell in appearance

SMARCA4 deficient sinonasal carcinoma (Head Neck Pathol 2022;16:168)

• Sheets of large, epithelioid, anaplastic cells
• Variable nesting and trabecular pattern
• Lack of glandular and squamous differentiation
• Brisk mitotic activity and extensive necrosis
• Rarely can have abortive neuroendocrine-like rosettes
• Only a minority of cells should be basaloid and rhabdoid but these features can predominate

• High grade malignant neoplasm
• Hypercellular smears with clusters of cohesive polygonal cells
• Variable proportion of individual rhabdoid / plasmacytoid cells with abundant cytoplasm
• Most commonly presents with uniform nuclei with fine chromatin and small nucleoli
• No overt keratinization or other evidence of squamous differentiation (Diagn Cytopathol 2016;44:700)
• Apoptotic bodies common with abundant background necrotic debris (Cancer Cytopathol 2018;126:567)
• For SMARCA4 tumors, large epithelioid cells with a more pleomorphic appearance are expected

SMARCB1 deficient sinonasal carcinoma

• Pancytokeratins (97%)
• CK5 (64%), p63 (55%)
• May show strong p40 positivity

SMARCB1 deficient sinonasal adenocarcinoma

• CK7 (83%)
• Yolk sac markers regardless of morphological expression: glypican 3 (90%), SALL4 (50%), HepPar1 (50%)

SMARCA4 deficient sinonasal carcinoma

• Pancytokeratin
• Focal and weak neuroendocrine markers: synaptophysin (90%), CD56 (60%)

SMARCB1 deficient sinonasal carcinoma

• Defined by loss of nuclear SMARCB1 (INI1) expression with retained internal control
• Negative for myoepithelial stains (S100, SOX10, calponin, SMA)
• CK7 (48%)
• Usually negative for p16 (Am J Surg Pathol 2014;38:1282)
• Negative for IDH

SMARCA4 deficient sinonasal carcinoma

• Defined by loss of nuclear SMARCA4 (BRG1) expression with retained internal control
• Usually negative: p63, p16
• p40 and CK5/6 generally negative unless in squamous area
• Chromogranin (40%)
• INSM1 is mainly negative or focally positive with weak intensity (Arch Pathol Lab Med 2022;146:1122, Am J Surg Pathol 2020;44:703)
• Consistently negative for NUT, CD99

SMARCB1 deficient sinonasal adenocarcinoma

• p40 (33%) (Head Neck Pathol 2020;14:465)
• CDX2 (27%), CK20 (25%)
• Yolk sac markers regardless of morphological expression: PLAP (11%) and AFP (10%)

• SMARCB1 deficient sinonasal carcinoma
  • Defined by inactivating mutations of SMARCB1 gene, a tumor suppressor gene located on chromosome 22q11.2 (Am J Surg Pathol 2014;38:1274, Am J Surg Pathol 2014;38:1282)
  • FISH can detect biallelic (homozygous) or monoallelic (heterozygous) deletions affecting the SMARCB1 gene locus (not preferred due to IHC with greater sensitivity and multiple differentials that can be ruled out with next generation sequencing [NGS]) (Head Neck Pathol 2022;16:168)
• SMARCA4 deficient sinonasal carcinoma
  • IDH1 / 2 mutations are absent; reported IDH1 / 2 mutant antibody immunopositivity may not correlate with mutation testing (Am J Surg Pathol 2020;44:703, Arch Pathol Lab Med 2022;146:1122)
• In situ hybridization for high risk HPV and EBV is consistently negative (Am J Surg Pathol 2017;41:458)

• Nasal mass, hemimaxillectomy:
  • SMARCB1 deficient sinonasal carcinoma (see comment and synoptic report)
  • Comment: The sections from the hemimaxillectomy show features of a high grade undifferentiated neoplasm. It protrudes in an exophytic manner from the left nasal cavity and invades into the medullary bone of the maxilla.
  • The tumor is composed of rounded large nests with sheets of overlapping, monomorphic basaloid cells. They contain vesicular chromatin, high nuclear to cytoplasmic ratio and minimal cytoplasm. Necrosis and multiple mitoses are seen. Squamous differentiation is not seen.
  • Immunohistochemistry shows positive staining for p40, CK5/6 with retained SMARCA4 (BRG1) expression. There is focal staining for synaptophysin.
  • Immunohistochemistry for SMARCB1 (INI1) shows diffuse loss of nuclear expression in the tumor cells (with positive internal control).
  • The tumor is negative for p16, SOX10, CD99, desmin, MyoD1 and NUT.
  • The histological features and immunoprofile are in keeping with a SMARCB1 deficient sinonasal carcinoma.

• Nasal mass, biopsy:
  • SMARCA4 deficient sinonasal carcinoma (see comment)
  • The lesional fragments show features of a high grade, undifferentiated neoplasm.
  • It is composed of large, pleomorphic, epithelioid cells in a nested architecture. Features of differentiation (i.e., keratinization, pigmentation, glandular formation) are not seen. Additional components (mesenchymal and neuroepithelial) are also not seen.
  • Immunohistochemistry shows positive staining for p40, CK5/6 and SMARCB1 (retained).
  • There is focal staining for synaptophysin. The tumor is negative for p16, SOX10, CD99, desmin, MyoD1, NUT, CD45, CD56, CD20 and TdT.
  • Immunohistochemistry for SMARCA4 (BRG1) shows diffuse loss of nuclear expression in the tumor cells (with positive internal control).
  • The tumor is also negative for EBER in situ hybridization and HPV in situ hybridization.
  • Comment: While these features are most in keeping with a SMARCA4 deficient sinonasal carcinoma, a teratocarcinosarcoma cannot be excluded.

• Most mimics of SMARCA4 and SMARCB1 sinonasal carcinomas show retained nuclear immunostaining with SMARCB1 (INI1) and SMARCA4
  • High grade intestinal and nonintestinal adenocarcinoma:
    • Variable glandular component with more specialized cells present (i.e., goblet and Paneth)
    • CK7 and CEA are variably positive
    • SMARCB1 (INI1) is intact
  • Primary and metastatic yolk sac tumor:
    • Extremely rare and will be accompanied by a history of a primary
    • Resembles the yolk sac appearance of sinonasal carcinomas
    • Glypican 3 (less specific, more expression), SALL4, PLAP
    • AFP patchy positive
    • HepPar1 in glandular and hepatoid areas; CDX2 in glandular areas
    • SMARCB1 (INI1) retained
  • Metastatic hepatoid adenocarcinoma:
    • Hepatoid areas positive for hepatoid stains
    • Site specific stain (i.e., SATB2 positivity in gut)
  • Rhabdomyosarcoma:
    • Skeletal muscle markers: desmin, myogenin
    • Molecular: FOXO1 fusion
  • Ewing sarcoma (especially adamantinoma-like):
    • NKX2.2, CD99 positive
    • Diffuse positive in adamantinoma-like variant: p63 / p40, cytokeratin
    • Synaptophysin and chromogranin can be positive
    • Molecular: EWSR1 fusion
  • Lymphoma (i.e., diffuse large B cell lymphoma [DLBCL], extranodal NK / T cell lymphoma and ALL):
    • Broad spectrum lymphoid lineage marker: CD45
    • B cell markers: CD20
    • Precursor lymphoid marker: TdT
    • Extranodal NK / T cell lymphomas have an East Asian and Latin American predilection (Curr Hematol Malig Rep 2016;11:514)
    • NK / T cell lymphoma markers: T cell markers (i.e., CD56, CD2, CD3), EBER in situ hybridization positive
  • Melanoma:
    • May have pigmentation, may have in situ component if primary
    • Positive for HMB45, SOX10, MelanA, PRAME, S100
  • Nasopharyngeal carcinoma:
    • Can appear basaloid and high grade
    • Positive for squamous markers
    • Positive for EBER in situ hybridization
  • Sinonasal undifferentiated carcinoma:
    • High grade and undifferentiated
    • EBER in situ hybridization negative
    • IDH2 mutation may support sinonasal undifferentiated carcinoma; however, IDH immunohistochemistry should be interpreted with caution
  • HPV related sinonasal carcinoma:
    • Multiphenotypic type has a biphasic basal and ductal component
    • Positive for HPV in situ hybridization
  • Neuroendocrine carcinoma:
    • High grade with mitosis and necrosis, may retain speckled chromatin
    • Positive for neuroendocrine markers (chromogranin and synaptophysin)
    • Dot-like cytokeratin pattern
  • Olfactory neuroblastoma:
    • Small round cell tumor with rosettes around true tumor lumens (Flexner-Wintersteiner rosettes) or fibrillary matrix (Homer Wright rosettes) depending on level of differentiation
    • Based on the ethmoid sinus cribriform plate
    • Positive for neuroendocrine markers
    • S100 positive in sustentacular cells
  • NUT carcinoma:
    • Basaloid appearance with abrupt keratinization
    • Positive for NUT IHC
  • Myoepithelial carcinoma (Head Neck Pathol 2022;16:168):
    • Can show rhabdoid / plasmacytoid morphology
    • Subset shows loss of SMARCB1 (INI1)
    • Positive for myoepithelial markers S100, SOX10, SMA and calponin
• SMARCA4 deficient sinonasal teratocarcinosarcoma:
  • Triphasic growth with epithelial, mesenchymal and primitive neuroepithelial elements
  • Neuroepithelial component: predominant with rosettes and neuropil-like matrix; positive for chromogranin and synaptophysin
  • Epithelial component: squamous epithelium of varying maturity (clear cell fetal type to mature squamous) and glands (mucinous, intestinal type or ciliated); squamous component is positive for CK5/6
  • Mesenchymal component: undifferentiated fibroblastic to rhabdomyoblastic; can have foci of cartilage and bone
  • Heterologous, sarcomatoid or teratoid elements may be absent in limited biopsy material
  • SMARCA4 (BRG1) loss
  • Beta catenin nuclear positivity in epithelial cells

• WHO Classification of Tumours Editorial Board: Head and Neck Tumours, 5th Edition, 2024

1. BRG1 loss in tumor nuclei with positive controls is diagnostic of SMARCA4 deficient sinonasal carcinoma if no teratoid elements are present in the biopsy
2. Loss of BRG1 in tumor cells and respiratory epithelium supports the diagnosis of SMARCA4 deficient sinonasal carcinoma
3. Retained INI1 expression in tumor cells and internal control cells supports the diagnosis of SMARCB1 deficient sinonasal carcinoma
4. SMARCB1 deficient sinonasal adenocarcinoma can be diagnosed with only yolk sac differentiation and INI1 loss
5. Subepithelial rosettes and diffuse neuroendocrine expression support the diagnosis of SMARCB1 deficient sinonasal carcinoma

1. Characterized by diffuse positivity for p16 immunohistochemistry and high risk HPV RNA in situ hybridization
2. Defined by loss in BRG1
3. Demonstrates a true surface dysplasia in the form of a pagetoid distribution
4. May show basaloid cell nests with peripheral palisading and strong p40 positivity