Top 10 Basaloid Neoplasms of the Sinonasal Tract

Abstract

Background

Basaloid neoplasms of the sinonasal tract represent a significant group of tumors with histological overlap but often with different etiologies (i.e., viral, genetics), clinical management, and prognostic significance.

Methods

Review.

Results

“Basaloid” generally refers to cells with coarse chromatin in round nuclei and sparse cytoplasm, resembling cells of epithelial basal layers or imparting an “immature” appearance. Tumors with this characteristic in the sinonasal tract are represented by a spectrum of benign to high-grade malignant neoplasms, such as adenoid cystic carcinoma, NUT carcinoma, sinonasal undifferentiated carcinoma, SWI/SNF complex-deficient carcinomas, and adamantinoma-like Ewing sarcoma.

Conclusion

In some instances, histology alone may be sufficient for diagnosis. However, limited biopsy material or fine-needle aspiration specimens may be particularly challenging. Therefore, often other diagnostic procedures, including a combination of histology, immunohistochemistry (IHC), DNA and RNA testing, and molecular genetics are necessary to establish an accurate diagnosis.

Index Case: High-Grade Tumor of the Paranasal Sinus

A sixty-nine-year-old man presented with a high-grade (HG) sinonasal tumor at an advanced stage with liver metastases. The tumor histologically exhibited an epithelial morphology with solid and trabecular patterns, but a somewhat papillary appearance at the edge. Occasionally, small foci of discrete keratinization were present (Fig. 1A). The tumor consisted of large, basaloid, and palisaded tumor cells along with the delicate basal membrane material (Fig. 1B). The tumor cells were round to oval with large, pleomorphic, and hyperchromatic nuclei with centrally located small nucleoli. There were 4 mitoses/10 high power fields (HPF) (1 HPF = 2.4 mm²). Lymphovascular invasion was identified. In some areas, tubular or glandular formations were intimated, lined by eosinophilic apocrine-like epithelium. The mucosa was ulcerated, but were intact, showed high-grade dysplasia of metaplastic squamous epithelium.

Fig. 1.

Non-keratinizing squamous cell carcinoma (NKSCC) composes of solid nests of bland basaloid cells exhibiting abortive squamous keratinization (A, B) with high-grade dysplastic superficial epithelium (B). Tumor cell nuclei are diffusely and strongly p63 positive (C) and approximately 70% of cells show p16 protooncogene positivity (D)

Based on these histologic findings, our diagnosis was non-keratinizing squamous cell carcinoma (NKSCC), an HPV-associated subtype with liver metastases (Stage 4).

The tumor cells were reactive with high molecular weight cytokeratins (OSCAR, AE1/3), p63 (Fig. 1C), and p16 (70% of tumor cells; Fig. 1D). Tumor cells were negative for: MYB, NUT, FLI1, CD99, and SOX10 helping to rule out adenoid cystic carcinoma, NUT carcinoma, Ewing sarcoma (including adamantinoma-like Ewing sarcoma), and HPV-related multiphenotypic carcinoma. Proliferative activity by MIB1 index was 50%. The molecular studies exhibited intact EWSR1, FLI1, MYB, MYBL1, and NFIB genes by fluorescence in situ hybridization (FISH), excluding (Adamantinoma-like) Ewing sarcoma and adenoid cystic carcinoma. Real-time polymerase chain reaction (RT-PCR) demonstrated high-risk HPV16 along with E6/E7 oncogenes.

Differential Diagnostic Consideration Includes a Spectrum of Diseases with Basaloid Morphology

The sampling procedure is often anatomically restricted in the sinonasal tract, may result in tissue fragmentation, and tumor necrosis and desmoplasia reduces diagnostic tumor cells. These pre-analytic and/or post-analytic aspects can lead to misdiagnosis including non-diagnostic material and reactive changes. The approach we take as pathologists must always be in the patient’s best interest and a logical examination sequence must be followed, especially when suboptimal amounts of material are available. Therefore, immunohistochemistry is usually the priority in the histological context of most cases, but if the morphology is highly suspicious of a particular tumor entity with a characteristic potentially targeted molecular etiology, molecular studies are recommended as a complement (see Scheme 1 and Table 1).

Scheme 1.

Differential for basaloid neoplasms

Table 1.

The panel of immunohistochemical markers

	pan CK	p63/p40	CK5/6	p16	Neuroendocrine markers	S100	SOX10	MYB	SMA	Other
Non-keratinizing squamous cell carcinoma	P	P/P	P	P	N	N	N	N	N
Solid variant of Adenoid cystic carcinoma	P	M/M	L	N	N	B	B	P	M	CK7 and DOG1
HPV-associated multiphenotypic sinonasal carcinoma	P	M/M	Pd	P	N	B	B	R	M
Sinonasal mucosal melanoma	R	N	R	N	N	P	P	N	N	Melan A, HMB45, MiTF, tyrosinase
SWI/SNF complex-deficient sinonasal (adeno)carcinomas	P	P/P	B	N	R and weak	N	N	N	N	SMARCB1 or SMARCA4 loss,CK7
NUT-carcinoma	P	P/R	N	N	R	N	N	N	N	NUT
Sinonasal undifferentiated carcinoma	P	R/N	N	R	R	N	N	N	N	CK8, CK18
Sinonasal teratocarcinosarcoma	P*	Pa/Pa	Pa	N	Pb	N	N	N	Pc	SMARCA4 lossβ-catenin (20%)
Adamantinoma-like Ewing sarcoma	P	P/P	N	N	R	R	N	N	R	CD99, NKX2.2
Olfactory neuroblastoma	F	F/F	F	R	P	P in sustentacular cells	N	N	N	SSTR2

^ain squamous component

^bin neuroepithelial elements

^cin spindle cell component

^dAuthors' own experience

Bi biphasic; F focal; P positive, N negative, L luminal; M myoepithelial/basal; R rare

Non-keratinizing Squamous Cell Carcinoma (NKSCC)

NKSCC is a distinct aggressive sinonasal epithelial malignancy that commonly arises in the sinonasal tract but can also involve the nasopharynx and middle ear/temporal bone. The highest incidence is in the 6th and 7th decades with a male predominance [1, 2]. NKSCC in up to 58% contains transcriptionally active high-risk HPV subtypes [3–6].

NKSCC is characterized by nested and/or ribbon-like (in a subset papillary) growth with delicate smooth muscle stroma with minimal desmoplasia despite the infiltrative and invasive growth [1]. The tumor cells have high-grade basaloid features, often palisaded at the tumor nest periphery (Fig. 1A, B). Central comedonecrosis, high mitotic activity, and pushing growth are often present.

A recently described molecular subtype of NKSCC, DEK::AFF2 fused carcinoma, has been identified in approximately half of all HPV-independent cases of NKSCC [7–11]. This entity is characterized by inverted anastomosing lobules of non-keratinizing squamous epithelium pushing into the stroma along with an exophytic (papillary) growth, while showing peripheral palisading, acantholytic change, and squamous pearl formation in less than 10% of overall tumor volume (Fig. 1A). The neoplastic cells are bland, typical of translocation-associated tumors and are quite uniform, basaloid, and polygonal. A recurrent feature is the presence of infiltrating neutrophils and stromal lymphocytes. Mitotic activity is usually low [7–10]. DEK oncogene is located on 6p22.3 and is upregulated in various carcinomas. AFF2 is on chromosome Xq28 and when transcriptionally regulated, causes intellectual disability [10].

The IHC profile of NKSCC (including DEK::AFF2 subtype) is positive with p63, p40 and high molecular weight cytokeratin (CK5/6), while negative with neuroendocrine markers, NUT, S100 protein and retained SWItch/Sucrose Non-Fermentable complex (SWI/SNF) family (INI1, BRG1) [1, 12]. NKSCC is positive for p16, especially if high-risk HPV-associated [13]. A nuclear IHC marker for AFF2 has been developed, showing 100% sensitivity and specificity for tumors with DEK::AFF2 fusion[14], but requires further evaluation.

NKSCCs are etiologically related to transcriptionally active HR-HPV in 36–58% [4–6, 15]. Currently, routine HPV testing is not recommended in NKSCC, given the high prevalence of HPV association, but it can be helpful for diagnosis and prognostic purposes. HPV-specific testing through in-situ hybridization (ISH) or PCR testing must be performed if p16 is initially reactive, as p16 alone is too non-specific in the sinonasal tract to establish HPV association [4, 16, 17]. With current standard of care treatments, studies show statistically significant improved survival in HPV-associated carcinomas compared to those that are not [4, 17–19]. Prognosis specific to DEK::AFF2 fusion carcinomas is incomplete, but report a local recurrence rate of 56%, distant metastasis of 35%, and death from disease of 25% [8–10, 20].

Solid Subtype Of Adenoid Cystic Carcinoma (AdCC)

The solid subtype of AdCC represents a biphasic epithelial-myoepithelial tumor of salivary gland origin [21] with almost equal genetic sex distribution and a peak incidence in the 5th decade of life [22]. AdCC has mixed histological features consisting of three basic subtypes: cribriform, tubular, and solid [21]. AdCC is graded according to predominant growth pattern (among other features), where the presence of more than 30% of solid component constitutes a high-grade tumor with a more aggressive clincal course [23, 24]. Recently, studies using a simplified 2-grade stratification found that the presence of any solid component is related to an overall reduced survival [25, 26].

The solid subtype is characterized by compact tumor nests or sheets of uniform basaloid cells with scant cytoplasm (Fig. 2A) settled in myxoid or hyaline background with high mitotic activity. Residual areas with tubular or cribriform growth are a clue to the diagnosis [27].

Fig. 2.

Adenoid cystic carcinoma (AdCC) is arranged in solid nests of basaloid cells with limited pseudocribriform pattern seen (A). AdCC is a biphasic malignancy with p63 positive abluminal cells (here in predominantly trabecular pattern) (B) and CK7 demonstrates cytoplasmic/membranous expression in luminal cells (C). Dual strong and diffuse MYB nuclear immunoreactivity (D)

The IHC profile supports the biphasic nature of AdCC, especially in cribriform and tubular growth patterns, which is identical to HPV-related multiphenotypic sinonasal carcinoma (HMSC). Cytokeratins are positive in both luminal and abluminal cells. Myoepithelial markers (Fig. 2B) are expressed in the abluminal layer, and CD117 and CK7 (Fig. 2C) typically show luminal expression [21]. The expression of MYB IHC is characteristic, but not specific for AdCC, with over 80% of AdCC positive (Fig. 2D), compared to 14% of MYB reactivity in non-AdCC neoplasms [28]. Although identification of a MYB gene rearrangement may support the diagnosis of AdCC, it can be seen in other tumor types and a lack of expression does not always rule it out [28]. The most common translocations involve chromosome 9, with approximately 50% harboring t(6;9) resulting in a MYB::NFIB fusion and 5% t(8;9) resulting in MYBL1::NFIB fusions [29–31]. Gene fusion and other modes of MYB or MYBL1 activation play an important role in AdCC pathogenesis and may be a potential therapeutic target [32–35] in a tumor associated with a prolonged clinical course, recurrences, and distant metastases, with a 10-year survival of 50% [36].

HPV-related Multiphenotypic Sinonasal Carcinoma (HMSC)

HMSC is another basaloid epithelial neoplasm driven by HPV especially serovar 33 [37, 38] (formerly HPV-related sinonasal carcinoma with adenoid cystic-like features), included as a separate sinonasal entity in the 5th edition of the WHO Classification of H&N tumors [39].

HMSC is a tumor of adults with a peak incidence in the 5th decade and with a slight female predominance [40]. HMSC has histologic and immunophenotypic features of both SCC and salivary gland carcinoma, specifically AdCC. The terminal excretory duct and its specific transition with surface epithelium are suspected to be the potential origin of HMSC [37, 40–42]. The tumor is composed of high-grade basaloid cells growing in solid and cribriform patterns, which imitate solid subtype of AdCC (Fig. 3A) [40, 42]. The surface epithelium usually develops high-grade squamous dysplasia, while foci of abrupt keratinization within the tumor may be encountered. Comedo-like necrosis and high mitotic activity are often present, but perineural and lymphovascular involvement are lacking, which corresponds to its potentially less aggressive clinical behavior [43].

Fig. 3.

HPV-related multiphenotypic sinonasal carcinoma (HMSC) shows nested architecture and is composed of high-grade basaloid cells with AdCC-like pseudocribriform features (A). Typical biphasic pattern of the epithelium is highlighted by p63 positive basal cells in areas of pseudoglandular structures, with the luminal cells being negative (B). SOX10 shows diffuse, strong nuclear positivity in both luminal and abluminal cells (C). Strong and diffuse expression of p16 protooncogene by immunohistochemistry is desirable for HMSC diagnosis (D)

The neoplastic cells display a biphasic pattern with cytokeratin expression in basal (myoepithelial) cells along with p63 (Fig. 3B), p40, calponin and smooth muscle actin positivity, while the luminal (ductal) cells are positive for keratins and CD117. The S100 protein and SOX10 (Fig. 3C) have mixed luminal/abluminal expression [40, 44, 45]. MYB is only weak and patchy in the abluminal layer, in contrast to a usual strong expression in the solid subtype of AdCC [45]. Transcriptionally active HPV33 can be detected in most cases, with rare cases harboring HPV16 [40]. The expression of p16 is usually strong and diffuse (Fig. 3D), but the same finding can be seen in AdCC, completely unrelated to HPV [46]. Therefore, p16 alone is not sufficient for distinguishing between HMSC and AdCC, with specific HPV testing required, typically through RT-PCR or RNA-ISH testing for high-risk HPV subtypes. Surgery is the treatment of choice, with or without radiation therapy in incompletely resected tumors. Approximately 1/3 of all reported cases have local recurrence, but lymph node and distant metastasis are quite rare [40].

Sinonasal Mucosal Melanoma (SMM)

SMM represents 4% of sinonasal malignancies [47], and is an aggressive tumor with high metastatic potential and dismal prognosis, showing a unique genetic profile unrelated to an UV signature [48–51]. This tumor has a peak incidence in the 7th decade without sex or race predilection [47, 52].

SMMs are heterogenous tumors and are most commonly composed of epithelioid (Fig. 4A) or plasmacytoid cells, while other morphologies include spindled (Fig. 4B), rhabdoid, clear (balloon cell subtype), and undifferentiated (microcystic subtype) cells [53]. The tumor cells are either loosely cohesive or arranged in solid nests, fascicles, storiform, or organoid formations that can mimic many sinonasal (mainly undifferentiated) tumors. General signs of malignancy are common, including distinct large nucleoli, high mitotic index, tumor necrosis, lymphovascular and perineural spread. The presence of cytoplasmic melanin is a helpful diagnostic clue together with intramucosal spread (Fig. 4C), but many SMMs are amelanotic and the mucosa frequently ulcerated or unsampled [53, 54]. The reactive IHC antibodies include S100 protein, HMB-45, SOX10, Melan A, tyrosinase, MiTF and PRAME, with a combination of antibodies more useful than individually (Fig. 4C, D) [53]. Aberrant cytokeratin, EMA, SMA, or neuroendocrine marker expression may complicate diagnostic interpretation [54–56].

Fig. 4.

Sinonasal mucosal melanoma (SMM) is a melanocytic malignancy with minimal melanin production composed of epithelioid (A) or spindle-shaped cells arranged in fascicular pattern (B). HMB45 exhibits strong immunoreactivity in the cytoplasm of malignant melanocytes which at the same time highlights their lentiginous spread in the overlying sinonasal mucosa (C). Strong nuclear immunoreactivity with SOX10 (D)

At least one mutation in NRAS, KIT, BRAF, and/or SF3B1 are found in varying frequency [57], while 6% harbor more than one mutation [58], recognizing specific inhibitor therapies can be matched to the mutation identified [57]. NRAS mutations have been shown to be a stage independent adverse predictor of survival [58]. In general, SMM has a poor prognosis overall prognosis with less than 30% 5-year survival rate. The standard treatment of sinonasal mucosal melanoma is surgical resection followed by radiation therapy. There is no consensus as of yet regarding adjuvant treatments, although immunotherapy for those with known mutations and at the advanced stage may provide survival benefits [59].

SWI/SNF Complex-Deficient Sinonasal (Adeno)Carcinomas

SWI/SNF-deficient sinonasal carcinomas are high-grade basaloid and poorly differentiated tumors previously categorized as sinonasal undifferentiated carcinomas (SNUC), but now classified as a unique tumor group in the 5th edition of the WHO classification of the H&N tumors [39, 60]. The SWI/SNF complex is currently recognized to be composed of 15 protein subunits, encoded by up to 29 genes. SMARCB1 (INI1) is a core subunit, the loss of which is seen in rhabdoid tumors of soft tissue, atypical teratoid/rhabdoid tumors, epithelioid sarcoma, renal medullary carcinoma, and epithelioid malignant peripheral nerve sheath tumors [61]. SMARCA4 (BRG1) is a catalytic subunit, the loss of which is seen in ovarian small cell carcinomas, undifferentiated uterine neoplasms, and undifferentiated thoracic neoplasms. This subunit forms a chromatin-remodeling complex that remodels nucleosomes and regulates DNA accessibility. Mutations of these subunits are common and may be seen in up to 25% of human cancers, with ARID1A being the most common [61]. There are three main categories of tumors associated with SWI/SNF alterations: (1) Tumors defined by the presence of SWI/SNF alterations, (2) Tumors with frequent, but not exclusive SWI/SNF alterations, and (3) Tumors with SWI/SNF alterations as part of differentiation [62].

SWI/SNF-deficient sinonasal carcinomas are defined by recurrent SMARCB1 and/or SMARCA4 inactivation [63, 64]. These tumors are more often in males and have wide age distribution with a peak incidence in the 6th decade for the SMARCB1-deficient category and the 4th decade for SMARCA4-deficient group [65, 66]. SMARCB1-deficient sinonasal carcinomas display a predominant basaloid (60%) morphology and a plasmacytoid/rhabdoid (33%) appearance [67–69]. SMARCB1-deficient carcinomas show histological overlap with NKSCC but without squamous cell features, keratinization, or glandular formations (Fig. 5A, B). By IHC, they show strong cytokeratin positivity, along with CK5 (Fig. 5C) (64%), p63 (55%) and CK7 (48%) expression [65]. SMARCB1 loss (in a subset of cases with SMARCA2 co-loss) is a defining feature (Fig. 5D). A small subset of tumors shows focal and weak immunoreactive for neuroendocrine markers, potentially bringing neuroendocrine tumors into the differential [67, 70]. Another potential mimic is a myoepithelial carcinoma, but SMARCB1-deficient carcinomas do not express myoepithelial markers [71].

Fig. 5.

SWI/SNF complex-deficient sinonasal (adeno)carcinomas are arranged in solid basaloid nests with relatively monomorphic cells and small comedo necrosis (A). Other tumors are of plasmocytoid appearance with few mini lumens and overlapping nuclei (B). Tumor cells are diffusely CK5/6 positive (C). SMARCB1 (INI1) is negative in tumor cells with internal positive control seen in lymphocytes and endothelium (D)

SMARCB1-deficient sinonasal adenocarcinomas show a histological predominance of oncocytoid and plasmacytoid cells with characteristic glandular formations, with yolk-sac features seen in about 25% of cases [64]. These tumors show CK7 and p40 reactivity, in addition to SMARCB1-loss. Yolk-sac markers identified include glypican-3, SALL4, PLAP, AFP and HepPar-1 [64].

SMARCA4-deficient sinonasal carcinomas are anaplastic, less basophilic tumors that have rather small-cell morphology with abortive pseudorosettes, while lacking squamous or glandular features [66, 72, 73]. SMARCA4-deficient carcinomas are defined by loss of SMARCA4 expression (BRG1), while usually immunoreactive for CK7 and negative for CK5, p63, p40, or p16. They might be focally positive for various neuroendocrine markers [66].

The SWI/SNF complex-deficient sinonasal neoplasm require aggressive multimodality therapy but have a dismal 5-year disease-free survival near 0%. Potential future treatments involve EZH2 inhibitors, which may be beneficial in inducing tumor cell cycle arrest and apoptosis; bromodomain inhibitors, which may cause downregulation of certain genes; and immune checkpoint inhibitors, which would enhance T-cell capacity to kill tumor cells [67, 74].

NUT Carcinoma (NC)

NC is a high-grade, aggressive and lethal monomorphic carcinoma of the H&N, particularly of the sinonasal area [75]. This tumor is defined by the presence of NUTM1 (Nuclear protein in testis) gene variants, located on 15q4 [75]. In about 80% of the cases, the translocation occurs between NUT and BRD4 on chromosome 19q13 (BRD4::NUT), with translocations with BRD3 (BRD3::NUT), NSD3 (NSD3::NUT) [76, 77] and others (ZNF532, ZNF592) or unidentified genes in the remaining cases.

NC is usually a malignancy of young adults age with an equal genetic sex distribution [77, 78]. NC has uniform morphology, typical of translocation tumors, consisting of sheets of primitive round cells with eosinophilic to basophilic cytoplasm, that may develop foci of abrupt keratinization juxtaposed to areas of a more undifferentiated component (Fig. 6A, B) [77]. These tumors are highly mitotically active and exhibit foci of tumor necrosis (Fig. 6A). The morphology alone has significant overlap with other tumors of the “small round blue cell category”, including lymphoma, melanoma, Ewing sarcoma, but also undifferentiated carcinomas and some of the aforementioned entities. Therefore, the diagnosis cannot be made by histology alone and appropriate IHC and/or genetic testing is essential.

Fig. 6.

NUT carcinoma (NC) is composed of solid growth pattern with large areas of necrosis and primitive round cells with eosinophilic to basophilic cytoplasm with marked nuclear pleomorphism noted (A). Classic areas of abrupt keratinization are a helpful clue in the recognition of this tumor (B). Strong nuclear NUT immunoreactivity is desirable (C) and high-molecular weight keratin positivity (AE1-AE3) is seen especially in foci of keratinization (D)

NCs are immunoreactive for NUT protein (Fig. 6C), with expression also reported in some CIC-rearranged sarcomas of the spinal cord, but not in any other carcinoma [79, 80]. NCs are variably positive for high- and low-molecular-weight keratins (Fig. 6D) (including AE1/3, CAM5.2 and CK7) and p63, but not p40 as reliably [81, 82]. NCs of H&N are usually negative for p16 and neuroendocrine markers. NCs are often positive for CD34 which may result in confusion with leukemia [78]. NUT carcinomas are highly aggressive, with a median survival of < one year, showing high rates of local recurrence and distant metastasis. Bromodomain inhibitors show promise [83], although blood-brain barrier issues in the skull base/sinonasal tract may limit response.

Sinonasal Undifferentiated Carcinoma (SNUC)

SNUC is a highly aggressive epithelial tumor without any specific line of epithelial differentiation (squamous or glandular) by histology and immunophenotyping, and therefore is considered a diagnosis of exclusion [60, 84], and as such specific entities have been separated out from this category with advances in IHC and molecular genetics [66–68, 85].

SNUCs are rare tumors with male predominance and peak incidence between the 5th and 6th decades of life [86]. SNUCs are composed of nests, sheets and trabeculae of large basaloid cells with prominent nucleoli and distinct cell borders (Fig. 7A, B). Mitotic activity is usually prominent, and tumor necrosis is usually present. The tumor may show signet ring cell morphology, but it lacks any mucin production [60, 84]. Tumor cells are positive for pancytokeratins and low-molecular-weight cytokeratins including CK7, CK8, CK18 and OSCAR (Fig. 7C) [87], but lack expression with CK5/6 and p40 [88], with p63 unreliable due to patchy and focal reactivity. SNUCs are usually positive for epithelial membrane antigen and typically show patchy positivity with synaptophysin (Fig. 7D) and chromogranin, but without histological neuroendocrine differentiation [89]. EBV is typically absent, especially in the western population, however, in the Asian population EBV was described as an environmental and geographical cofactor to SNUC [89, 90]. SNUCs frequently express p16 regardless of HPV status [16, 91]. Melanoma markers (S100 protein, SOX10, HMB45), lymphoid markers (CD45RB, CD20, CD3) and skeletal muscle markers (desmin, myogenin) are negative [60, 92].

Fig. 7.

Sinonasal undifferentiated carcinoma (SNUC) is composed of large nests and interconnected trabecular pattern of high-grade basaloid epithelial cells (A). High-grade nuclear features are illustrated by open chromatin, prominent nucleoli and multiple mitotic figures, including atypical mitoses (B). Strong and diffuse high-molecular-weight cytokeratin (AE1/AE3) positivity is typical (C) and synaptophysin positivity might be present (D)

A range of 50–88% of SNUCs have IDH2 mutations (hotspot mutations: R1725, R172T, R172G, and R172M) and can be identified by a mutant-specific immunohistochemical stain. The clinical significance is that IDH2-mutant carcinomas, no matter what phenotype, portend a better prognosis than SMARCB1-deficient carcinomas or other SNUCs with unclassified molecular alterations, and thus IDH2 mutations may be of treatment significance. Mutations in IDH1/2 genes alter enzyme activity to create an oncometabolite allowing IDH1/2 inhibitors to induce differentiation, which has been seen in other IDH1/2 mutant tumors such as leukemia, gliomas and chondrosarcoma [93], and thus separation as a distinctive entity may be warranted [94].

Sinonasal Teratocarcinosarcoma (TCS)

TCS is an aggressive neoplasm included in the differential diagnosis of basaloid tumors. TCS represents a rare mixed epithelial, mesenchymal and primitive neuroectodermal (blastema-like) neoplasm of adults in the 5th decade with predominance in male patients [95, 96]. Because of its low incidence and multiphenotypic histology, TSC might lead to diagnostic difficulties, especially in small biopsy samples, since not all diagnostic elements might be present [97]. The epithelial component is usually an admixture of keratinizing and/or non-keratinizing squamous epithelium and glandular epithelium (stratified/simple) including mucinous or ciliated cells (Fig. 8A). The squamous or glandular epithelium is often of a fetal-like to clear-cell nature. The mesenchymal component usually displays fascicular arrangement of spindled cells with potential participation of other mesenchymal derivates (Fig. 8A, B) (including rhabdomyosarcomatous, cartilaginous, osseous, or fatty) [98]. Neuroepithelial cells are round to oval, arranged in small nests, settled in the fibrillary background or growing in rosette-like formations. The immunoprofile mirrors characteristics of the basic elements: the epithelial component (less neuroepithelial cells) is positive for cytokeratins (Fig. 8C), and squamous epithelium can be highlighted by CK5/6, p40 and p63 [99]; stromal component may be positive for smooth muscle actin (Fig. 8D), desmin or myogenin, among other markers (SATB2, osteocalcin, SOX9). The neuroepithelial component is positive for neuron-specific enolase and neuroendocrine markers including chromogranin, synaptophysin, and INSM1 [99, 100]. A majority of sinonasal TSC belongs in the spectrum of SMARCA4-deficient tumors, with 82% showing partial loss and 68% exhibiting complete loss, confirmed by immunohistochemistry and/or next-generation sequencing. [101] A small subset of TSC showed aberrant nuclear β-catenin expression due to mutation, while still others exhibited PIK3CA mutation [102, 103]. All mutations reported thus far have been reported in sinonasal carcinomas with neuroendocrine differentiation. Germ cell markers are negative, except for SALL4 which has been reported in a subset of TSC [104]. SALL4 is a surrogate marker in SWI/SNF remodeling complex related alterations, particularly BAF60A which promotes the interactions between a microphthalmia-associated transcription factor and SWI/SNF complex by recruitment of SMARCA4 [105, 106]. Although the diagnosis of this rare tumor is primarily by the morphological characteristics, it likely belongs to the SWI/SNF family of tumors.

Fig. 8.

Sinonasal teratocarcinosarcoma (TCS) is composed of biphasic population: carcinomatous pattern with trabeculae of epithelium, and sarcomatous pattern illustrated by atypical mesenchymal cells (A). Fascicles of mesenchymal, somewhat chondroid, differentiation seen adjacent to epithelial component (B). Strong high-molecular weight cytokeratin (AE1-AE3) positivity in carcinomatous component and negativity in sarcomatous component (C). Weak actin S positivity in sarcomatous component and negativity in carcinomatous component (D)

Adamantinoma-Like Ewing Sarcoma (ALES)

ALES, originally described in the long bones [107], is categorized as a subtype of Ewing’s sarcoma (ES), but is predominantly localized in the H&N, where it histologically and immunohistochemically mimics the spectrum of basaloid, myoepithelial, and “small round blue cell” tumors [108–110]. Despite its monomorphic appearance, ALES is a high-grade, aggressive basaloid neoplasm that grows in compact lobules, nests or trabeculae with peripheral palisading of cells, surrounded by prominent fibrous stroma sometimes with myxoid change or basement membrane material deposits (Fig. 9A). A subset of cases may develop rosette formations (mimicking olfactory neuroblastoma) and abrupt keratinization with keratin pearls (mimicking NKSCC and NUT carcinoma). Despite the apparent epithelial differentiation including positivity for high-molecular-weight cytokeratins (Fig. 9B), p63 (Fig. 9C) and p40 (while classic ES are negative and show mostly low-molecular-weight cytokeratins in 25–30% of cases) [111], ALES show positivity for CD99 and NKX2.2, similar to the ES family tumors [108, 112, 113]. NKX2.2 is a very sensitive marker for ALES but not entirely specific, so should be used together with CD99 (Fig. 9D), cytokeratins and melanoma markers [112] as part of a panel. Synaptophysin, S100 protein and rarely p16 might be expressed in a subset of ALES, but HPV DNA is not detected [108].

Fig. 9.

Adamantinoma-like Ewing sarcoma (ALES) with nested and lobular architecture and cells with small round blue cell morphology and with a moderate amount of eosinophilic cytoplasm. Faint peripheral palisading of tumor cells is noted, and nests are embedded in a desmoplastic stroma (A). Tumor cells are positive for high molecular weight cytokeratin (AE1-AE3) (B), p63 (C) and show membranous positivity for CD99 (D)

ALES is characterized by recurrent t(11;22) EWSR1::FLI1 translocation, pathognomic for the ES family [107, 111]. The EWSR1 gene rearrangement alone is not sufficient for diagnosis of ALES, because soft tissue myoepithelial carcinomas carry the same EWSR1 rearrangements [114–117]. The fusion partner for ALES, FLI1, must be determined for definitive classification [107, 108]. Outcomes with surgery and adjuvant chemoradiation (using Ewing-specific protocols) are relatively good, but with 50% having persistent, recurrent or metastatic disease at six-month follow-up [100], especially when sinonasal tract cases are studied.

Olfactory Neuroblastoma (ONB)

ONB is a malignant neuroectodermal tumor [118], typically originating within the cribriform plate, superior turbinate and superior half of the nasal septum and with age distribution between the 5th and 6th decade and slight male predominance [119]. Histological classification considers the grading system developed by Hyams, which separates ONB into four grades according to architecture, mitotic activity, nuclear pleomorphism, presence of fibrillary matrix, (pseudo)rosettes and necrosis, with prognostic significance [120]. Low-grade ONB (grades 1 and 2) are non-necrotic lobular tumors with minimal atypia, prominent fibrillary matrix and Homer Wright psedorosettes. High-grade (grades 3 and 4) tumors show variable architecture with minimal or absent fibrillary matrix, presence of tumor necrosis, high-mitotic activity, significant pleomorphism and rarely, true Flexner-Wintersteiner rosettes (Fig. 10A). The IHC profile includes positivity for neuroendocrine markers (synaptophysin, INSM1, and chromogranin) (Fig. 10B, C) and reactivity of sustentacular cells with S100 protein/SOX10/GFAP (Fig. 10D). Somatostatin receptor 2 (SSTR2) is consistently positive in ONB (more intense in low-grade tumors) and thus may be implemented in imagining and therapeutic strategies [121]. Cytokeratin (CAM5.2, CK8) and p63 expression, if present, is usually focal and this may be a potential problem in separating ONB from other tumors including neuroendocrine carcinoma, adenocarcinoma, SNUC or TCS [122–124]. A subset of ONB may show muscle-specific marker reactivity (rhabdomyoblastic differentiated ONB) [125]. There is no defining molecular signature for ONB. Treatment depends primarily on the grade and stage of the tumor with resection, including neck dissection when indicated, followed by radiation and/or chemotherapy [126].

Fig. 10.

Olfactory neuroblastoma (ONB) is composed of sheets of pleomorphic basaloid neuroectodermal cells creating Homer Wright psedorosettes (A). Diffuse and strong synaptophysin (B) and chromogranin cytoplasmic staining in tumor cells (C). S100 protein highlights residual sustentacular cells (D)

Conclusion

When evaluating sinonasal tract basaloid neoplasms, histopathologic features that can be characteristic for a specific lesion are helpful in making the diagnosis without advanced testing. However, they are frequently shared by more than one tumor. Immunohistochemistry is very helpful as an adjunct testing to reach a diagnose, but a panel approach must be used to accurately classify these complex group of tumors. In the most challenging cases, molecular genetic testing may be required to reach the diagnosis and to aid in therapy selection. Importantly, understanding the genetic underpinnings of these basaloid tumors allows for potential reclassification and may serve as potential therapeutic targets.

Funding

This study was in part supported by study grant SVV 260539 from the Ministry of Education, Czech Republic, the Cooperatio Program, research area SURG and the project National Institute for Cancer Research – NICR (Programme EXCELES, ID Project No. LX22NPO5102) - Funded by the European Union - Next Generation EU.

Data Availability

Not applicable.

Code Availability

Not applicable.

Declarations

Conflict of interest

Both authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

All authors confirm they have meaningfully contributed to the research and read and approved the final manuscript.

Ethics Approval

No human participants were included in this invited review, but all materials were treated in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Consent to Participate

was waived by the IRB due to the retrospective nature of this review work.

Consent for Publication

was obtained when personally identifiable information was included.