A pleasant, 52-year-old female was referred to the department of otolaryngology head and neck surgery in OHSU, Oregon by her primary care physician, for the evaluation of an asymptomatic, unilateral nasal obstruction of 3-months duration. She had been suffering from chronic nasal congestion, rhinorrhea, and nasal drainage but denied the presence of epistaxis. Her symptoms only transiently improved following antibiotics coverage. She never smoked or used smokeless tobacco products and only reported occasional social alcohol consumption. A comprehensive and detailed systematic, clinical, and medical history review was unremarkable with exception of the sinonasal complaints and mild depression that has been effectively controlled with medications. Furthermore, she only reported foot surgery that was managed by metal screws. At the same time, a total systematic assessment of the patient did not show any abnormalities, except for the post-contrast imaging. T1 and T2 weighted MRI demonstrated a locally destructive, avidly enhancing mass with opacification of the maxillary sinus, prominent involvement of the right ethmoid sinus, and extension into the cranial base/cribriform plate. Hyperostosis was also seen accompanying the mass [Figure 1]. Following imaging studies, clinical examination revealed the presence of a well-defined erythematous polypoid mass, measuring approximately 4.5 cm and accompanied by mildly inflamed sinonasal membranes with no purulence drainage detected. The rest of the head and neck examinations, including orbital, ears, and neck, were noncontributory and within normal limits. [Display omitted] Based on the overall clinical presentation and signs and symptoms, coupled with the imaging presentation, several entities would be included in the differential diagnosis, which comprises sinonasal inflammatory conditions and tumors of epithelial, mesenchymal, and hematolymphoid differentiation and lineages, among others. A selective review of the entities will be discussed including sinonasal squamous cell carcinoma, adenocarcinoma, and recently described epithelial malignancies in this region. Solitary fibrous tumor, malignant peripheral nerve sheath tumor, olfactory neuroblastoma, glomangiopericytoma, and synovial sarcoma are discussed within the mesenchymal soft tissue lesions cohort. Sinonasal melanoma is also briefly discussed. Developmental conditions will not be addressed within the differential categories in this manuscript. Epithelial-derived malignancies; specifically, squamous cell carcinoma [SCC] and adenocarcinoma [Ad CA] constitute approximately 65% and 35% to 75% of all sinonasal cancers, respectively.1,2 SCC tends to involve patients in the 6th to 7th decade of life, shows 2: 1 female: male preference, and is histologically roughly divided into keratinizing and nonkeratinizing subtypes, with variations recognized within each category. Immunohistochemistry [IHC] staining including p53, p63, p16, and p40, cytokeratin types among others is commonly used to differentiate and distinguish between diverse types and categories. 3 In comparison, adenocarcinoma displays a pronounced and distinct male predilection [6; 1] and similarity to SCC where it involves patients during the 6th to the 7th decades of life. Sinonasal adenocarcinomas are divided into salivary-type and non-salivary-types, with the latter category further separated into intestinal, and non-intestinal-type adenocarcinomas. 4 In keeping with other pathologies involving the sinonasal region, SCC and Ad CA typically present with nonspecific signs and symptoms that include epistaxis, facial and sinus pain, rhinosinusitis, nasal blockage, earache, and others. Imaging of adenocarcinoma tends to be more heterogeneously enhancing and often involve the cribriform plate, ethmoid, and maxillary sinuses and exhibits bone resorption and calcification when compared to SCC, albeit with a more homogeneous imaging pattern. 5 Several, well-documented, common, and rare, previously diagnosed as well as more recently described malignancies of epithelial origin in the region may be also remotely added to the differential list, including human papillomavirus (HPV)-related multi-phenotypic carcinoma, sinonasal renal cell-like adenocarcinoma, NUT-midline carcinoma, sinonasal undifferentiated carcinoma (SNUC), and INI-1-deficient sinonasal carcinoma. 6 Several mesenchymal soft tissue tumors may be also included in the differential list. A solitary fibrous tumor [SFT] is a rare mesenchymal neoplasm that was first described in the 1930s.7 SFT may involve virtually any body site, with 5 to 27% of all cases encountered in the head and neck region [H&N]. 8,9 Approximately 6% of all cases that involve the H&N occur in the oral cavity and orbits combined, considered to be the most common H&N sites, but thyroid gland, hypopharyngeal, parapharyngeal space, infratemporal fossa, and salivary gland involvement are also well-documented. 10-11 Among all head and neck sites considered, sinonasal tract SFTs are rare, and their documentation is sparse, and mostly restricted to case reports or mini-series. 12,13 SFTs affect males and females equally with a wide age range; the mean being 49 years old. As typical to this region the signs and symptoms are nonspecific and include nasal obstruction and/or epistaxis with duration of symptoms averaging less than 2 years. Epiphora and visual disturbances may be also seen with involvement of the orbital region. 14,15 Histologically, the tumor demonstrates a monotonous spindle cell proliferation with alternating hypocellular-hypercellular zones, separated by thick hyalinized, often ropey, fibro-collagenous stroma supporting a well-vascularized background, typically displaying a staghorn pattern. The spindle cells are typically arranged in long streaming fascicular to storiform patterns of growth in areas, and multinucleated giant cells and/or a fatty component may be observed. 10, 16 The tumor can be distinguished from its mimickers by positive immunohistochemistry labeling with STAT6, CD34 BCL-2, β-Catenin, and CD99, and negative reactivity to smooth muscle actin [SMA], muscle-specific actin [MSA], Desmin, CD31, pan-cytokeratin and anti-S100 protein. 17-19 SFT is also characterized by NAB2- STAT translocation which may further help in securing the diagnosis when IHC staining is not helpful. 20 SFT appears as an enhancing heterogeneous mass with bony resorption and remodeling. 21 Glomangiopericytoma [GPC] is a rare, mesenchymal tumor of low-grade malignant potential that exclusively involves the sinonasal region, yet accounts for only 0.5% of all sinonasal neoplasms. 22,23 Since its first description by Stout and Murray, in 1952, 24 GPC underwent several terminological modifications: namely sinonasal type–hemangiopericytoma, sinonasal hemangiopericytoma, hemangiopericytoma–like tumor, and sinonasal glomus tumor. 25 The etiology of GPC is not well-understood, but previous, trauma, hypertension, pregnancy, and corticosteroid are implicated as contributors. 14 It most commonly involves the nasal cavity unilaterally, but bilateral nasal involvement is noted in up to 5% of cases, with extension into the paranasal sinuses often seen. 22,25 Tumors tend to affect older white adults, with an average age of 70 years old, and a female prevalence is observed. Signs and symptoms are non-specific and overlap with other sinonasal tumors. 25 The tumor typically reveals a well-confined, yet unencapsulated proliferation of uniform, round, to spindle cells that assume short fascicular, storiform, or palisaded growth patterns and are supported by a well-vascularized background, with many of the vessels exhibiting staghorn–branching morphology. 22-25 GPC characteristically expresses nuclear β-Catenin staining as well as diffuse staining with SMA, anti-CD99, cyclin D1, TLE-1, and patchy anti-CD34 staining. GPC reacts negatively to Desmin, pan-cytokeratin, SOX-10, anti-S100 protein, and STAT-6. The tumor also characteristically demonstrates CTNNB1 gene mutation. 25,26 MRI imaging shows an enhancing, locally destructive mass that reaches, or exceeds 4 cm in size and involves the nasal cavity, ethmoid sinuses, and may potentially extend to the cranial base/cribriform plate. 27 Benign and malignant neural tumors; schwannomas and neurofibromas must be also included in the differential. Approximately 50% of all benign schwannoma are diagnosed within the head and neck region with 4% of those diagnosed within the sinonasal region, with a wide age distribution, a preference for adults, and an equal gender distribution. As seen in GPC, sinonasal neural tumors most commonly involve the nasal cavity and ethmoids, with extension to the cribriform plate. The latter feature is best confirmed with MRI imaging, where the tumor appears as a locally destructive, heterogeneous soft tissue mass, with prominent post-contrast enhancement. 28 Microscopically, schwannoma appears as a well-delineated unencapsulated cellular spindle cell proliferation with 2 distinct intermingling patterns; the first is haphazardly arranged into compacted spindle cells and short streaming fascicles, and the second into an organoid, onion-like morphology with nuclear-palisaded pattern defining the so-called Antoni-A and Antoni B patterns, respectively. The tumor is supported by fibro-collagenous to neurofibrillary stroma and mitosis, though not atypical is often seen. The tumor cells react diffusely positively with anti-S-100 protein and SOX-10 and are less predictably and variably reactive to glial fibrillary acid protein [GFAP]. 29, 30 Neurofibromas typically show similar demographics to schwannoma, yet they are considered rarer than schwannomas in this region and unlike schwannoma, they typically present with unilateral nasal polypoid masses. Microscopically, neurofibroma shows an encapsulated spindle cell tumor that mimics the Antoni-A tissue component of schwannoma and stains positively with anti-S100 protein. Post-contrast CT imaging is reported to demonstrate an irregularly enhancing mass that occupies the paranasal sinuses with local expansion, albeit without noticeable bony destruction. 31 Malignant peripheral nerve sheath tumors [MPNSTs] of the head and neck in general and specifically those observed within the sinonasal region are rare aggressive mesenchymal tumors, representing only approximately 5% and up to 16% of all head and neck sarcomas. 5, 30-33 They also typically demonstrate a hypodense soft tissue mass that infiltrates the nose and paranasal sinuses, while on MRI, a heterogeneous signal is typically noted. 5 Low, intermediate, or high-grade histomorphologic spectrums may be seen but, the tumor demonstrates monotonous spindle cells with pink-eosinophilic cytoplasm, indistinct cell borders, and mildly hyperchromatic tapered to wavy nuclei that exhibit generalized pleomorphism. Mitosis varies from few in low-grade tumors to readily identified and abundant in the high-grade cohort. A short fascicular, whorly, wavy, and less commonly herringbone patterns of growth, with variable degrees of cellularity, may be observed within a single tumor. Perivascular orientation leading to the so-called "marbled appearance" on low power can help the pathologist consider the diagnosis on H&E. The tumor cells are characteristically positive for SOX-10 and may also retain anti-S100 positive IHC staining characteristics while staining for smooth muscle actin and β-catenin is usually negative. Variable reactivity to CD34, Desmin, and EMA may be seen which may create confusion with other pathologies. Loss of H3K27me3 staining however is pathognomonic and may help in the differential in challenging cases, when IHC staining fails to confirm the diagnosis. 30,32-33 Tumors that exhibit neuroendocrine differentiation can involve multiple head and neck sites but accounts for only 3- 5% of all sinonasal malignancies. 33-36 They are separated into those derived from epithelial [neuroendocrine carcinoma] or neuroectodermal origin; olfactory neuroblastoma [ONB]. 33, 36 [ONB] constitutes approximately 3% of all sinonasal tumors 37 and shows slight prevalence for males, with a wide age range, the peak being in the 5th to 6th decades of life. Further, in ONB extension from the nasal cavity into the cranial base/cribriform plate and adjacent paranasal sinuses are often readily seen and accompanied by regional lymph nodes as well as distant metastasis in up to 25% and 40% of patients, respectively. 5, 37, 38 CT imaging demonstrates a homogeneous soft tissue mass with or without calcification and is considered the best technique to confirm cribriform plate extension. MRI shows avidly enhancing homogeneous mass with scattered areas of hemorrhage and necrosis and possible cystification.38 The tumor may exist in one of 4 histomorphologic grades [Hyams grading]. Low-grade ONB is composed of lobules and nests of round to mildly oblong tumor cells with well-preserved round nuclei, inconspicuous nucleoli, and inconspicuous nuclei that possess finely stippled and dispersed chromatin, and inconspicuous nucleoli. The tumor nests are intimately surrounded by sustentacular cells, separated by thick fibro-collagenous septae, and are also supported by well-vascularized, dense fibro-collagenous to lose fibrillary backgrounds. While low-grade tumors show monotonous histomorphology, as the tumor increases in grade, necrosis, brisk mitotic activity, and nuclear pleomorphism become more evident. Homer-Wright pseudo rosettes, reflecting tumor cells' organization around pink fibrillary material, and Flexner rosettes [true rosettes], which are composed of tumor cells enclosing and forming true lumina are readily detected in low-grade and high-grade tumors, respectively.5, 37-41 Strong and diffuse positive reactivity to synaptophysin and chromogranin are the main IHC stains routinely used to confirm the diagnosis but staining for anti-S100 protein that delineates the sustentacular cells at the peripheral aspects of the tumor nests and lobules is also helpful and characteristic of low-grade PNB The identification of SHH pathway gene mutations [PTCH-1, GLI-1, and GLI-2 genes] in a quarter of the cases studied is also considered diagnostic and characteristic of this neoplasm. 33 Synovial sarcomas [SS] are extremely rare in the head and neck region, representing <0.1% of all head and neck malignancies and tumors involving the sinonasal complex are equally rare with only a handful of cases reported. The tumor shows certain distinct imaging characteristics that prompt including it in the differential diagnosis of sinonasal pathologies; specifically, the presence of the so-called "triple sign" defining alternating signal intensities, the identification of fluid, necrosis, hemorrhage on CT scan, and calcification on MRI imaging. 33,42,43 SS occurs as low, intermediate, or high-grade tumors that differ in the presence or absence of necrosis, pleomorphism, and mitotic index, and assumes one of several growth patterns, namely, the monophasic pattern that encompasses several variations [calcifying, spindle cell, myxoid, or poorly-differentiates] and the biphasic, that contains glandular or solid epithelial elements within. 34,44 Sinonasal melanomas are uncommon, highly malignant, and aggressive tumors of neuroectodermal derivation that constitute 0.5–2% of all melanomas and exhibit a slight preference for Caucasian middle-aged or slightly older males. 45-47 As observed with the majority of sinonasal tumors, signs, and symptoms are nonspecific but most patients present with epistaxis and nasal obstruction. CT imaging typically reveals a heterogeneously, post-contrast enhancing, markedly infiltrative mass within the nasal and paranasal spaces. MRI imaging may vary in intensity depending on the presence or absence of melanin and the degree of vascularity within the lesion. 48 Histologically melanomas are one of the greatest mimickers of different lesions of various embryologic derivations within this region, showing spindle cell to plasmacytoid to clear cell morphology, among others. Additionally, when compared to cutaneous melanoma where certain histomorphologic parameters [for example Clark and Breslow thickness scales]; coupled with the clinical presentation can predict prognosis, sinonasal melanomas are considered overall aggressive, with poor prognosis and lacks any dependable histomorphologic parameters to predict prognosis and/or survival rate. 49,50 A thorough clinical and imaging evaluation, which would be also supported by histomorphologic examination would delineate additional entities that would be considered in the differential, including deep fungal infection/allergic fungal sinusitis, 5,51,52 teratocarcinosarcoma, 53,54 rhabdomyosarcoma, 34, 55 bi-phenotypic sinonasal sarcoma 56,57 and sinonasal salivary gland tumors. 58 Histomorphologic examination of the large polypoid nasal mass revealed monotonous spindle cells that exhibited, oblong, tapered, to vesicular nuclei that lacked mitoses and demonstrated short to streaming fascicular patterns, with focal herringbone and swirly patterns in places. The growth patterns overlapped, merged, and even collided with each other. Immunohistochemistry staining for Ki-67 proliferative index was only 5%, and the tumor cells reacted positively; mostly in a patchy distribution, to anti-SMA, and anti-S100 protein while staining for pan-cytokeratin, STAT6, Desmin, CD34, CD99, β-Catenin, Melan-A, and SOX-10 were negative and noncontributory, however, patchy staining with TLE-1 was also noted and prompted the exclusion of the presence of SYT rearrangement by FISH [Fluorescence in situ-hybridization], which was confirmed [Figures 2-5]. [Display omitted] [Display omitted] [Display omitted] [Display omitted] The patient was taken to the operating room and under general anesthesia, underwent right endoscopic maxillary antrostomy with the removal of tissue from the maxillary sinus right endoscopic total ethmoidectomy, sphenoidotomy, frontal sinusotomy, right partial middle turbinate resection & excision of a pink to mildly hemorrhagic sinonasal polypoid mass that measured 4 cm in greatest dimensions. Following the confirmation of the diagnosis upon histomorphologic examination, the patient received adjuvant postoperative radiation therapy consisting of IMRT 60 cGy over 5 weeks duration to the tumor bed to minimize the potential for recurrence. The last follow-up was 5 years after initial presentation, when the patient exhibited no evidence of recurrence and was without symptoms. Although the head and neck and specifically the sinonasal region may be involved with a diverse group of pathologies of different cellular lineages and embryologic derivation, primary sinonasal malignancies are rare and constitute only 3% to 5% of all head and neck cancers. 59,60 SCC and adenocarcinoma are by far the most encountered pathologies in this region, constituting 65% and 35% to 75% of all sinonasal malignancies, respectively, 1, 2, 6 and by far more common than sarcomas, which account for approximately 1–3% of all head and neck malignancies and up to 15% and 30% to 35% of sarcomas involving adults and children in this region. 30,61-63 Nevertheless, malignant tumors of the paranasal sinuses constitute less than 1% of all malignancies and only 7% to 10% of all head and neck sarcomas, 9,30, 34, 63, 64 and are known for their high morbidity and mortality rates which are partially attributed to proximity to critical anatomic structures. Although any mesenchymal neoplasm may be encountered within the sinonasal region, a comprehensive review of literature that includes solitary case reports and/or small series reveals that glomangiopericytoma, juvenile angiofibroma, and bi-phenotypic sinonasal sarcoma are the only documented tumors that exclusively involve this region. 19,23,25,33, 63,64,56,66 Bi-phenotypic sinonasal sarcoma [BSNS] is a rare, locally aggressive low-grade sarcoma that was initially described as low-grade sinonasal sarcoma with neural and myogenic features, and then re-designated as Bi-phenotypic sinonasal sarcoma in 2012. 56 The tumor shows slight female predilection [2:1 F: M incidence] and tends to involve older adults, ranging in the 8th to 9th decades of life. The tumor most commonly presents as a locally destructive mass that involves the nasal cavity with extension to the maxillary sinus, ethmoid, and sphenoid sinuses, to the cribriform plate/cranial base, and the orbits. 19,56,63, 66 Microscopic examination reveals a well-delineated unencapsulated monotonous spindle cell growth exhibiting tapered to oblong morphology with indistinct cell border, lightly staining eosinophilic cytoplasm, and well-preserved round nuclei with inconspicuous nucleoli. The spindle cells are arranged in long and short fascicles that run into and collide with each other and often show swirling arrangements. Entrapment of benign native respiratory epithelium-lined sinonasal glands is typically seen and bone resorption is also common. Mitoses are rare and when found do not exceed 1 or 2/per 10 high-power fields. The spindle cell tumor is supported by a well-vascularized fibro-collagenous to myxoid background nourished by a rich vascular network that demonstrates staghorn-like morphology in many areas. The tumor stains positively for anti-smooth muscle actin and anti-S100 protein but variable focal positive labeling with Desmin, cytokeratin, β-Catenin, and TLE-1 have been reported. 19, 56,63, 66-70 In general, the monotonous, bland-appearing spindle cell morphologic pattern coupled with the dual myogenic and neural differentiation and limited local destructive nature of the lesion on clinical and imaging evaluations, can confidently secure the diagnosis of BSNS and exclude pathologies of the sinonasal tract including several spindle cell tumors which are generally more aggressive in behavior and histomorphologic presentation when compared to BSNS. Nevertheless, a comprehensive immunohistochemical panel and potentially obtaining molecular studies are important to confirm the diagnosis. 19, 71 The IHC panel includes TLE-1, pancytokeratin, CD99, CD34, STAT-6, β-catenin, SOX-10, anti-S-100 protein, and SMA. Although reports of positive reactivity to some of the comprehensive immunohistochemistry staining panels have been previously documented, the positive staining is patchy rather than diffuse which would further confirm the diagnosis of BSNS. 19, 63 Approximately 10% of cases exhibit focal rhabdomyoblastic differentiation on H&E examination or by IHC staining for desmin, myogenin, and MyoD-1 which may confuse BSNS with rhabdomyosarcoma; most specifically spindle cell type. However, when compared to BSNS, such differentiation, as well as positive staining to the stains, would be focal in BSNS, rather than as diffuse in rhabdomyosarcoma which would also show a more aggressive cytomorphology with abundance in mitoses and pleomorphism. The identification of PAX3-MAML3 fusion is considered pathognomonic and can help differentiate [BSNS] from mimickers especially when overlap in the immunohistochemistry staining profiles exists. 68,69 Nevertheless, it is noteworthy mentioning that PAX3-MAML3 fusion, as well as additional gene fusions; PAX3 - NCOA1 and PAX3 - FOXO1 have been also reported in BSNS with rhabdomyoblastic differentiation, more significantly reported and alveolar rhabdomyosarcoma (ARMS), which can further contribute to the diagnostic and classification confusion. 72 The confirmation of the presence of MYOD1 mutation should point toward the diagnosis of rhabdomyosarcoma. 73 Rhabdomyoblastic differentiation may be also detected in malignant "Triton tumor" of the sinonasal tract, which represents malignant peripheral nerve sheath tumor which contains heterologous muscle differentiation, 74 and displays histomorphologic and immunohistochemistry staining profile of MPNST, as described in the previous section with the addition of skeletal muscle immune profile. Although authorities in the field entertained the possibility that previously reported low-grade peripheral nerve sheath tumors of the sinonasal tract may represent examples of BSNS, constant and reproducible negative SOX-10 staining rule suggest neural differentiation. 68 BSNS must be distinguished from sinonasal synovial sarcoma [SS], monophasic type, showing a monotonous, tapered, spindle, or oblong cell shape with inconspicuous cell outlines and nuclei arranged in fascicular to intertwining swirling patterns of growth. The mitotic index is moderate at most, and the cells are supported by a faintly eosinophilic fibro-collagenous background that is rich in staghorn-like vasculature with an abundance of mast cells. Calcification is also evident, and it may be a point of distinction from other spindle cell neoplasms in the region. Patchy necrosis, cystification, and hemorrhage may also be observed in the background and may alert clinicians, radiologists, and pathologists to establish the diagnosis from the H&E examination as these features, aside from the indolent growth nature of the tumor, are not identified in BSNS. The tumor cells react positively with bcl-2, CD99, pan-cytokeratin, EMA, and CK7. CK7, anti-S100 protein, SMA, and vimentin defining the dual epithelial/mesenchymal differentiation. 75-78 It is well documented that diffuse positive nuclear staining to TLE-1 is an important marker which would distinguish synovial sarcoma from other histomorphologic mimickers, 77-79, and since TLE-1 may be observed in patchy distribution within BSNS, it is imperative to exclude the possibility of SS via documentation of chromosomal translocation t(X;18) and SYT-SSX gene fusion products which are characteristic of SS. In contrast, BSNS characteristically exhibits PAX 3–MAML 3 gene fusion. 68,76 The absence of SYT-SSX gene fusion was confirmed in the current case. Patchy, rather than diffuse positive immunohistochemistry staining to β-catenin may be seen in BSNS, while diffuse staining may confidently exclude the possibilities of glomangiopericytoma, solitary fibrous tumor, and synovial sarcoma among other head and neck tumors. Similarly, diffuse SOX-10 positive staining is seen in tumors of neural derivation including malignant peripheral nerve sheath tumor as well as in melanoma but not in BSNS, while the detection of CD34 and STAT-6 staining may confirm the diagnosis of a solitary fibrous tumor or glomangiopericytoma; excluding BSNS were no such labeling is seen. 19,33,63, 71 BSNS is best managed by complete surgical excision and some centers adopt the use of post-surgical adjuvant radiation and/or chemotherapy. The use of post-op chemotherapy is uncommon. Data confirmed the lack of additional benefit in reducing postsurgical recurrence between cases managed with surgery alone versus those that received adjuvant radiation therapy. An overall recurrence rate range is reported to be between 33% and 50%. 80 The tumor is locally aggressive with extension into the paranasal spaces and carries an insignificant risk of regional or distant metastases but is characterized by a high rate of recurrence even with adequate resection. 81 19 It is of significance that the disease recurrence-free intervals range from less than 1 year to more than 9 years, which directly emphasizes the necessity for long-term follow-up. 19,33,63 [ABSTRACT FROM AUTHOR]