Abstract
A wide spectrum of malignant tumors originate from the pseudostratified ciliated columnar epithelium lining the nasal cavity and sinonasal tract. These include sinonasal squamous cell carcinoma, adenocarcinoma, undifferentiated carcinoma, neuroendocrine tumors, SWI/SNF family of tumors, NUT carcinoma, and HPV-related multiphenotypic sinonasal carcinoma. This chapter discusses the characteristic histology, immunophenotype, and molecular features of sinonasal carcinomas of different types.
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Keywords
- Sinonasal
- Squamous cell carcinoma
- Adenocarcinoma
- Undifferentiated carcinoma
- Neuroendocrine tumors
- NUT carcinoma
- HPV-related multiphenotypic sinonasal carcinoma
- SMARCB1 deficient carcinoma
- SMARCA4 deficient carcinoma
- DEK
- AFF2
- IDH1/2
8.1 Introduction
Malignant epithelial tumors of sinonasal tract have seen a major improvement in understanding of their pathogenesis due to advances in molecular pathology during the last decade or so resulting into introduction of many new distinct tumor entities.
WHO 2022 classification of tumors of nasal cavity and paranasal sinuses has integrated clinical, radiological, and molecular pathology features of each of these tumors (Table 8.1) for better diagnosis and management of patients [1].
8.2 Squamous Cell Carcinoma
Keratinizing squamous cell carcinoma (KSCC) is a surface epithelial malignancy with squamous differentiation and keratinization (Fig. 8.1).
About half of sinonasal (SN) tract malignancies are KSCCs. Genomically p53, KRAS, and EGFR mutations have been identified in them. EGFR exon 20 mutation has been detected in tumors arising from inverted papillomas. Human papilloma virus (HPV) infection is not implicated in pathogenesis of most of KSCC [1, 2].
Non-keratinizing squamous cell carcinoma (NKSCC) is another subtype of surface SCC with no or minimal keratinization (Figs. 8.2, and 8.3).
WHO 2022 classification subtyped NKSCC, based on molecular etiopathogenesis, into two subtypes: HPV-associated squamous cell carcinoma and DEK::AFF2 carcinoma [1, 3, 4].
HPV association varies in different ethnicities being highest in Western countries and a low frequency in Asia [5]. Most of HPV negative NKSCC of SN tract have been shown to carry fusions between the DEK gene on chromosome 6p22.3 and the AFF2 gene on chromosome Xq28 [6].
Morphologically, NKSCC show surface proliferation with downward pushing invasion of tumor cell nests without much desmoplasia [1].
Other variants of SCC such as acantholytic, adenosquamous, basaloid, spindle, and verrucous are rare in SN tract in comparison to other head and neck sites. Papillary subtype needs to be tested for HPV and DEK::AFF2 fusion as these tend to show papillary exophytic growth pattern (Fig. 8.4).
The DEK::AFF2 fusion carcinomas show bland cytomorphology with exophytic and endophytic proliferation. The tumor cells are oval to fusiform in some examples with monotonous appearance [4, 6] (Figs. 8.5, 8.6, and 8.7). Some reported cases show prominent neutrophilic infiltration which brings NUT carcinoma in differential; however, cytomorphology of NUT carcinoma is high grade.
Similar to squamous cell carcinoma of other body sites, all variants and subtypes are immunopositive for high molecular weight keratins, p40 and p63.
8.3 Sinonasal Lymphoepithelial Carcinoma
Sinonasal lymphoepithelial carcinoma (SNLEC) is an undifferentiated variant of squamous cell carcinoma, mostly occur in Asia in endemic form, associated with Epstein–Barr Virus (EBV) infection.
Tumor grows in syncytial appearance and tumor cells show abundant eosinophilic to amphophilic cytoplasm. The tumor cells show round nuclei with vesicular chromatin and prominent nucleoli. Although lymphoplasmacytic infiltrate is diagnostic, it is less prominent in SN tract in comparison to the nasopharyngeal counterpart (Fig. 8.8).
Keratin, p63, p40 and in-situ hybridization for EBV-encoded small RNA (EBER) is positive especially in endemic form [7, 8].
8.4 NUT Carcinoma
NUT (Nuclear protein in testis) carcinoma is a poorly differentiated carcinoma with squamous differentiation which is characterized by translocation/fusion involving the NUTM1 gene on chromosome 15q14 with various partner genes, commonly BRD4 [t (15;19)], leading to formation of an oncoprotein [9].
NUT carcinoma is a high-grade tumor with “malignant small round blue” cell morphology comprising of sheets of primitive appearing undifferentiated cells. The cells possess uniform vesicular nuclei and prominent nucleoli. Foci of abrupt keratinization (keratinized squamous cells with or without keratin pearls and cytoplasmic clearing) are classical and can be seen in about a third of NUT carcinoma cases.
Immunohistochemistry with the NUT antibody is specific for the diagnosis only with diffuse (>50% of tumor cells) granular/speckled positivity. The tumor cells are immunopositive for pancytokeratin, p40 and p63 (more sensitive than p40) (Figs. 8.9, 8.10, 8.11, 8.12, 8.13, and 8.14). These tumors have an aggressive clinical course with a mean survival of 12 months [10].
8.5 HPV-Related Multiphenotypic Sinonasal Carcinoma (HMSC)
As the name indicates, this tumor is characterized by morphological and immunophenotypical characteristics of a salivary type carcinoma (ductal and myoepithelial differentiation) and squamous cell carcinoma. HMSC is limited to sinonasal tract.
Histology resembles solid to cribriform areas reminiscent of adenoid cystic carcinoma. The surface respiratory epithelium shows dysplasia. Immunohistochemistry shows p16 positivity, though HPV association needs to be confirmed by molecular methods. Transcriptionally active high-risk HPV type 33 is implicated in pathogenesis in most of the cases. The presence of high-risk HPV and absence of MYB gene fusion distinguishes it from the close differential of adenoid cystic carcinoma (Fig. 8.15, 8.16, 8.17, and 8.18).
These tumors behave indolently without much frequency of distant metastasis and tumor-related deaths [11].
8.6 Adenocarcinoma
Sinonasal adenocarcinomas (showing glandular differentiation) can be salivary type (see Chap. 9) and non-salivary adenocarcinomas. The latter are further subdivided into intestinal and non-intestinal-type adenocarcinomas.
8.6.1 Intestinal-Type Adenocarcinomas (ITAC)
This group of tumors resembles the adenocarcinoma/adenoma of the intestine or rarely normal intestinal mucosa. ITAC originate from intestinal metaplasia of surface epithelium. Exposure to wood and leather dust are implicated occupational risk factors. These tumors commonly involve the ethmoid sinuses and nasal cavity.
Histologically, tumors range from well-differentiated papillary adenocarcinomas to poorly differentiated/solid and mucinous carcinomas (Figs. 8.19 and 8.20).
On immunohistochemistry, these tumors are positive for CK20, CDX2, SATB2, and villin and variably positive for CEA and CK7 [12].
Genomically, ITAC show frequent p53 mutations.
Clinical course is aggressive with frequent local recurrences, metastasis, and death.
8.6.2 Non-intestinal-Type Adenocarcinomas
This group includes tumors that does not show characteristics of minor salivary gland or intestinal-type adenocarcinomas. Unlike ITAC there are no known occupational risk factors. Nasal cavity and maxillary sinuses are commonly involved. These are further subdivided into low-grade and high-grade tumors.
On immunohistochemistry, these tumors are immunonegative for CK20, CDX2, and villin.
Markers of seromucinous differentiation, S100, DOG1, and SOX10, are expressed in the majority of non-intestinal-type adenocarcinomas [1, 13].
Low-grade non-intestinal-type adenocarcinomas show a back to back arrangement of uniform glands lined by single layer of cuboidal or columnar cells. Low-grade tumors may arise in association with benign lesions (sinonasal papillomas and respiratory epithelial adenomatoid hamartomas) [2] (Fig. 8.21).
High-grade tumors show solid growth pattern with nuclear pleomorphism or malignant infiltrating glands with atypical mitoses in desmoplastic stroma [1, 2] (Fig. 8.22).
A subset of low-grade carcinomas show uniform population of cuboidal to columnar cells with glycogen-rich clear cytoplasm which is reminiscent of renal cell carcinoma and have been named as sinonasal renal cell-like adenocarcinoma. Renal cell-like adenocarcinoma expresses CK7, CAIX, and CD10, whereas negative for vimentin, RCCMa (renal cell carcinoma marker), and PAX8 (Fig. 8.23) (Table 8.2).
A subset of low-grade tumors carry ETV6::NTRK3/RET fusions. Interestingly, most cases of secretory carcinomas show same translocation involving ETV6 and NTRK3 genes. However, secretory carcinomas rarely involve sinonasal tract (Fig. 8.24). Rarely, CTNNB1 and BRAF mutations are reported [14].
8.7 SWI/SNF Complex Deficient Sinonasal Carcinoma
The SWI/SNF complex is a family of chromatin remodelling genes that function as tumor suppressors. Inactivating mutations lead to four distinct categories of tumors—SMARCB1(INI-1) deficient carcinoma, SMARCB1 deficient adenocarcinoma, SMARCA4 deficient carcinoma, and SMARCA4 deficient sinonasal teratocarcinosarcoma.
8.7.1 SMARCB1 Deficient Sinonasal Carcinoma
SMARCB1 (INI-1) deficient sinonasal carcinoma is a type of undifferentiated carcinoma with definitional inactivation of the SMARCB1 gene on chromosome 22q11 due to biallelic deletion of SMARCB1 gene in most of the cases. Monoallelic deletion or mutations occur in minority of cases. These tumors usually involve paranasal sinuses (ethmoids).
Histology shows mostly basaloid morphology with or without scattered rhabdoid cells. The other cytomorphologic subtype is oncocytoid/ plasmacytoid in which tumor cells possess abundant dense eosinophilic cytoplasm with central to eccentrically placed nuclei. This pattern can be present in solid sheets or complex tubuloglandular pattern which lead to diagnosis of SMARCB1 deficient adenocarcinoma. Rarely tumors show yolk-sac like patterns along with variable yolk-sac carcinoma immunophenotype in the form of SALL-4, glypican 3, and hep-par 1 positivity [14,15,16].
Immunohistochemistry for INI-1(SMARCB1) shows loss of expression in all variants while it is expressed in the nuclei of normal cells such as stromal fibroblasts, endothelial cells, and inflammatory cells. The tumor cells show immunopositivity for pankeratin with variable immunoreactivity for p63, p40, and neuroendocrine markers (Figs. 8.25, 8.26, and 8.27).
8.7.2 SMARCA4 Deficient Sinonasal Carcinoma
The SMARCA4 gene is located on chromosome 19p13.2, inactivation of which leads to a group of aggressive carcinomas. SMARCA4 deficient SN carcinomas are also poorly to undifferentiated carcinomas with morphologic resemblance to neuroendocrine (NE) carcinomas. Similar to high-grade NE carcinomas, the tumor cells show nuclear molding, spindling, crushing, and stippled chromatin (small cell carcinoma phenotype). Some tumors show more cytoplasm, squared off edges, and prominent nucleoli and thus resemble large cell neuroendocrine carcinoma. Rare rhabdoid cells can be recognized on close search of tumor specimens. A characteristic cytologic monomorphism is maintained in these tumors also which is a diagnostic feature of all SWI/SNF family of tumors [17, 18] (Figs. 8.28, 8.29, 8.30, and 8.31).
A variation on this theme is identified in sinonasal teratocarcinosarcomas (TCS) which exhibit complete or partial loss of SMARCA4 (BRG1 protein) in about 70% of cases. SMARCA4 deficient or proficient tumors show CTNNB1 mutations in a subset of cases. TCS are an admixture of carcinoma (epithelial), sarcoma (mesenchymal), and primitive neuroepithelium [19, 20] (Figs. 8.32, 8.33, 8.34, and 8.35).
IHC of SMARCA4 deficient carcinoma shows BRG1 loss with retention of other family proteins viz. SMARCA2 (BRM) and SMARCB1 (INI1). Focal reactivity to neuroendocrine markers is present.
TCS show positivity for keratins, p40 and p63 in epithelial component, NE markers in NE elements and mesenchymal component stains according to type of differentiation. When present, the degree of BRG1 loss may vary in the three components.
8.8 Sinonasal Undifferentiated Carcinomas (SNUC)
Sinonasal undifferentiated carcinomas are a diagnoses of exclusion where tumors do not show any lineage commitment either on morphology or on immunophenotyping.
Morphologically these tumors are undifferentiated high-grade tumors with frequent necrosis and mitosis (Fig. 8.36). Aside from simple keratins and epithelial membrane antigen (EMA), they do not show any consistent immunophenotype. No viral associations are reported. Differential diagnoses on morphology range from basaloid carcinoma, NUT carcinoma, SWI/SNF deficient tumors to high-grade neuroendocrine carcinomas [2].
Pathogenetically, IDH2 hotspot mutations are identified in a significant number of SNUC cases (Fig. 8.37). Although IDH1/2 mutation-specific IHC is available, it is neither sensitive nor specific to identify all reported variants. Sequencing or PCR-based testing is suitable for mutation testing [21, 22].
8.9 Sinonasal Neuroendocrine Tumors
WHO 2022 classification of head and neck tumors has unified the grading and nomenclature of neuroendocrine tumors at different sites. Sinonasal neuroendocrine tumors are subdivided into:
Grade 1: lack necrosis and have <2 mitoses per 2mm2.
Grade 2: necrosis (often punctate or coagulative) and/or 2–10 mitoses per 2mm2.
The use of Ki67 proliferation index is encouraged which is generally <20% in low-grade tumors. These tumors do not show abnormal p53 staining indicative of p53 mutation and retain rb (retinoblastoma protein) immunoexpression.
Neuroendocrine carcinomas can have small cell or large cell morphology with mitoses >10/2 mm2, and Ki-67 > 20% (Fig. 8.38).
Morphology of these tumors is same as at any other body site. It is important to exclude SMARCA4 deficient SN carcinomas if neuroendocrine markers are focal, weak and not consistent in an otherwise morphologically compatible NE carcinoma [1, 18].
Table 8.3 summarizes all basaloid (malignant blue cell morphology) appearing carcinomas of sinonasal tract.
8.10 Conclusion
Sinonasal carcinomas are an important category of tumors which needs thorough workup of cases to establish a correct diagnosis. Before labelling a case as SNUC, a battery of ancillary testing needs to be performed to provide a correct diagnosis as it has significant clinical implications.
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Acknowledgement
The authors thank Dr. Divya Kannan for help with the images in Fig. 8.1.
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Jain, D., Bishop, J.A. (2023). Malignant Epithelial Tumors of Sinonasal Tract. In: Jain, D., Bishop, J.A. (eds) Atlas of Sinonasal Tract Pathology. Springer, Singapore. https://doi.org/10.1007/978-981-19-7315-4_8
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