Table 1.

Clinicohistopathologic and genetic features of “small round cell tumors of the sinonasal area”

Diagnosis	Age (years)/Location	Histopathology/Architecture	Mitotic activity/necrosis	Cytomorphology	Anaplasia or marked atypia	Cytogenetic/molecular	Immunohistochemistry
Malignant epithelial sinonasal small round blue cell tumors
Small cell carcinoma neuroendocrine type	26–77/superior or posterior nasal cavity, maxillary, ethmoid sinuses	Sheets, ribbons, or nests of closely packed cells with nuclear molding	Frequent/common	Monotonous, small-sized cells with hyperchromatic nuclei, inconspicuous or absent nucleoli, and minimal cytoplasm	Variable		CD56 Cytokeratin (punctate perinuclear) Chromogranin (variable) NSE (variable) Synaptophysin (variable) TTF-1 (variable)
Sinonasal undifferentiated carcinoma	20–80/nasal cavity, maxillary antrum, ethmoid sinuses, often with extension into adjacent sites	Tumor cells may be arranged in nests, lobules, trabeculae, or sheets	Frequent/common	Medium-sized nuclei with prominent nucleoli surrounded by scant eosinophilic cytoplasm	Common	No recurrent cytogenetic change No c-kit activating mutations or gene amplification	Pankeratin CK7 CK8 CK19 Ki-67 (most cells, variable intensity) NSE (occasional) EMA (occasional) CD99 (rare) Synapthophysin (rare) S-100 protein (rare) Chromogranin (rare)
Squamous cell carcinoma (nonkeratinizing)	55–65/maxillary sinus, nasal cavity, ethmoid sinus, sphenoid and frontal sinuses	Ribbons, nests, or strands; underlying tissue invasion often features well delineated border	Variable/limited	Poorly differentiated form most difficult to distinguish from other undifferentiated, small round cell tumors such as neuroendocrine carcinoma or olfactory neuroblastoma	Common		Pankeratin EMA CK5/6 CK8 CK13 CK14 CK19
Neuroectodermal sinonasal small round blue cell tumors
Ewing sarcoma/primitive neuroectodermal tumor (PNET)	<30/maxillary sinus, nasal fossa	Sheets, lobules (less commonly cords or trabeculae may cause dx difficulty with carcinoid or undiff carcinoma) of uniformly round cells; ± Homer Wright rosettes	Variable/common	Small to intermediate sized cells with poorly defined, scant, or vacuolated cytoplasm and round nuclei with fine chromatin	Infrequent	t(11;22)(q24;q12) EWSR1-FLI1 (~95%) t(21;22)(q22;q12) EWSR1-ERG (~5%) Other EWSR1 or FUS variants (< 5%)	CD99 (membranous pattern) Vimentin FLI1 NSE (variable) Synaptophysin (variable) AE1/AE3 and CAM5.2 (occasional)
Mucosal Malignant Melanoma	40–70/nasal septum, paranasal sinuses (particularly maxillary)	Commonly deeply infiltrative with ulceration and frequent pseudopapillary architecture	Frequent/common	Amelanotic small round cell or larger melanotic epithelioid or spindle-shaped cells. Nuclear molding and/or prominent eosinophilic nucleoli may be present	Common	CDKN2A/p16 (9p21) PTEN (10q23) 1q+,6p+,8q+	S-100 protein Vimentin HMB45 (usually) Melan-A (usually) Microphthalmia transcription factor (variable) Tyrosinase (variable)
Olfactory neuroblastoma	Broad age range (< 10 to > 80)/roof of nasal cavity, cribiform plate	Localized to submucosa; lobular to solid growth pattern in higher grade neoplasms. Rosettes (Homer Wright and Flexner-Wintersteiner) may be present	Variable/variable	Uniformly, small-sized cells with scant cytoplasm and round nuclei with fine to coarse granular chromatin and occasional small nucleoli (grade dependent)	Variable (more common in high-grade tumors)	Complex with aCGH studies demonstrating gain of 13q, 20q and loss of Xp as most frequent in high stage tumors	Neuron-specific enolase CD56 Synaptophysin (usually) S-100 protein (supporting sustentacular cells) CD57 (Leu7) (variable) Chromogranin (variable) GFAP (variable) Keratin (occasional)
Mesenchymal sinonasal small round blue cell tumors
Desmoplastic small round blue cell (DSRCT)	15–35/sinonasal case reporta	Nests of undifferentiated cells embedded in a prominent desmoplastic stroma	Frequent/common	Small, round-oval cells with scant-moderate cytoplasm and hyperchromatic nuclei with inconspicuous nucleoli. Intracytoplasmic inclusions or vacuoles may be seen	Infrequent	t(11;22)(p13;q12) EWSR1-WT1	Desmin (perinuclear dot-like pattern) Pankeratin, EMA, AE1/AE3, CAM5.2 Vimentin WT1 NSE (usually) CD57 (usually) Synaptophysin (occasional) CD99 (occasional)
Rhabdomyosarcoma	<20 year/nasopharynx > sinonasal tract	Embryonal subtype (ERMS): alternating hyper- and hypocellular areas with myxoid or sparsely collagenized stroma Alveolar subtype (ARMS): collagenous fibrous septa separate nests of tumor cells with loss of central cohesion Solid ARMS: sheets of tumor cells without fibrous septa	Variable/limited	Small round cells with scant cytoplasm ± scattered cells with eosinophilic cytoplasm and cross-striations	Common	ERMS: gain of all or portions of chromosomes 2, 7, 8, 11, 12, 13 and/or 20 with or without loss of 22 11p15 LOH ARMS: t(2;13)(q35;q14) PAX3-FOXO1 (50–60%) t(1;13)(p36;q14) PAX7-FOXO1 (~20%) Other PAX3 variants (<1%) Fusion neg. (20–30%)	Desmin Myogenin (nuclear) myo-D1 (nuclear) Myoglobin (cytoplasmic) Vimentin (usually) CD56 (usually) Myosin (variable)
Synovial sarcoma (poorly differentiated)	<50/maxillary, sphenoid, ethmoid and frontal sinuses	Often solidly packed small round cells with richly vascular hemangiopericytoma like pattern; may be focal within a typical biphasic or monophasic synovial sarcoma or it may represent the predominant pattern. Other poorly differentiated forms include large (epithelioid) cell and high-grade spindle cell	Variable/variable	Poorly differentiated small cell pattern composed of small-sized cells with high nuclear to cytoplasmic ratios may be exceedingly difficult to distinguish from other small round cell tumors	Infrequent	t(X;18)(p11.2;q11.2) SYT-SSX1 or SYT-SSX2 (>99%)	EMA BCL2 TLE1 Vimentin Cytokeratin (variable) CD99 (variable) S-100 (occasional)
Hematolymphoid sinonasal small round blue cell tumors
Extramedullary plasmacytoma	35–75/nasal cavity, paranasal sinuses, nasal cavity	Diffuse infiltrate of uniform (well-differentiated) to pleomorphic (anaplastic) neoplastic plasma cells. Amyloid deposits (11–38%)	Variable/uncommon	Small to large (well to poorly differentiated) cells with fine to coarse nuclear chromatin and prominent nucleoli. Intracytoplasmic crystals, Dutcher bodies, and perinuclear hof may be present	Occasional	14q32 (IGH) [although in contrast to multiple myeloma lacks the t(11;14)] −13 or 13q-	Light chain restriction CD138 CD38 CD45 VS38 EMA (variable) CD79a (variable) CD31 (occasional) CD56 (occasional)
Extranodal NK/T cell lymphoma, nasal	50–75/nasal cavity, paranasal sinuses, nasopharynx	Diffuse neoplastic lymphoid proliferation with angiocentric/angiodestructive growth pattern, mucosal ulceration, pseudoepitheliomatous hyperplasia and frequent associated inflammatory infiltrate	Frequent/common	Small or medium-sized cells to large transformed cells with round, oval. or irregular nuclei and azurophilic cytoplasmic granules	Common	del(6)(q21-25) i(6)(p10) EBV (ISH) 10% with T cell receptor gene rearrangement, no immunoglobulin light or heavy chain rearrangements	CD2 CD3e (cytoplasmic) Granzyme B Perforin CD45 CD56 (cytoplasmic) (usually) TIA-1 (usually)

^aFinke et al. [18]