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Biphenotypic sinonasal sarcoma (BSNS) is an emerging subtype of sinonasal malignancy. It has not been previously well-studied but has characteristic gene fusion products and associated phenotypic features unique to it. Although rare, it has the potential to become large and infiltrate into bone over a prolonged period, with nonspecific preceding symptoms. It was first described in 2012, and more studies are needed before definitive decisions can be made regarding adjuvant treatments in addition to surgery. This activity reviews the evaluation, management, and overarching principles of BSNS and highlights the role of the healthcare team in evaluating and treating patients with this condition. Objectives: Identify the typical presentation of biphenotypic sinonasal sarcoma and its distinctions from other sinonasal malignancies. Evaluate the typical immunohistochemical findings for biphenotypic sinonasal sarcoma. Assess new developments in the identification of biphenotypic sinonasal sarcoma via molecular testing methods. Access free multiple choice questions on this topic.

Sinonasal malignancies only constitute 1-5% of head and neck malignancies but have a wide differential diagnosis and relatively non-specific symptoms.[1][2][3][4] Sinonasal malignancies are most frequently diagnosed as squamous cell carcinoma (36 to 58%), followed by adenocarcinoma, mucosal melanoma, adenoid cystic carcinoma, and esthesioneuroblastoma.[2][5] A lesser-known and recently classified entity is biphenotypic sinonasal carcinoma (BSNS), is reviewed in this topic. BSNS was first described in 2012 as "low-grade sinonasal sarcoma with neural and myogenic features" and was first recognized in the 2017 4th edition of the World Health Organization Classification of Head and Neck Tumors.[6][7] Although it is a slow-growing and low-grade upper aerodigestive tract malignancy, BSNS is locally aggressive.[8][6][9][10] About 20% of patients already have bony invasion at presentation in areas like the orbit (25%) and the cribriform plate (10%).[6][9][5][11] Cervical nodal metastasis is rarely demonstrated in any sinonasal malignancy and has not yet been demonstrated in patients with BSNS.[2] The tumors can approach up to 4 cm and are most commonly found in the nasal cavity or ethmoid sinus, followed by the sphenoid sinus, in frequency.[9][12][8][6] The maxillary sinus is the most common site for any sinonasal primary, but the ethmoid sinus contains the primary in 5 to 15% of patients.[2][5] In BSNS, however, the incidence of ethmoid involvement is significantly greater but has not yet been quantified.[2][5] Unlike squamous cell carcinoma, with an anticipated 5-year survival of only 25 to 50%, there have been no patients with BSNS who developed metastases, and only 1 death has been recorded in the literature.[9][6][8] It is unclear what percentage of sinonasal malignancies are later diagnosed as BSNS, as the malignancy was previously classified under various entities, including but not limited to pseudofibrosarcoma, angiofibroma, and leiomyosarcoma.[8][7][13][6] Just over 100 cases have been described in the existing literature, representing a combination of cases derived from retrospective reviews of specimens and more current case reports.[10]

There are no specific risk factors for the development of BSNS. Broadly, hazardous industrial chemicals used in textiles, furniture, and leather processing and production are risk factors for all tumors of the paranasal sinuses.[5] At the genetic level, fluorescence-in-situ hybridization is remarkable for a characteristic PAX3-MAML fusion protein that leads to the development of BSNS pathology.[8][9][12]

Multiple studies have demonstrated a female preponderance to BSNS, with a ratio of 1.8:1 up to 2.27:1 in females versus males.[8][9][6][14] While the mean age is 50-52, the range is between mid-20s and mid-80s.[8][9]

PAX3 is a gene that develops skeletal muscle, the central nervous system, and neural crest cells. In BSNS, fusion proteins due to the interaction of PAX3 with MAML drive amplification of neuroepithelial expression.[15]

The histopathologic examination of BSNS demonstrates hypercellular, uniform, long spindle-shaped cells in a fascicular pattern that is occasionally described as a "herringbone" configuration.[6] Nuclei appear tapered; despite the hypercellularity, there are almost no mitoses. Necrosis, ulceration, and hemorrhage are not common.[8][9][7] The cytoplasm of involved cells is scant and pale, and the tumor appears unencapsulated.[11] Foci of respiratory epithelium can be entrapped in tumor cells, creating a pseudoglandular appearance.[8][9] Infiltrative tumors are embedded in a bony matrix.[8] Vascular staghorn formations are common but can confound the diagnosis by expanding the differential diagnosis.[8][9][7][15] Identifying elements of both neural and myogenic differentiation with immunophenotyping, patchy or diffuse S-100 smooth muscle actin expression, and SOX-10 negativity are key in confirming the diagnosis.[6][8][9] Genetic features displayed by BSNS involve chromosomal translation t(2,4) and a fusion protein formed by the interaction of the PAX3-MAML genes.[6][8] The PAX3-MAML fusion is highly reliable in diagnosing BSNS, as it is present in 79 to 96% of cases.[8] The fusion of PAX3 with other genes, NCOA1 and FOXO1, suggests a more aggressive rhabdomyoblastic variant due to different amplification targets downstream.[8][9][15]

The most common presenting symptoms are progressive nasal obstruction, intermittent nasal congestion, anosmia, facial swelling and pain, epistaxis, anosmia, periorbital numbness, intermittent blurry vision, and rhinorrhea.[8][11][10][13] Patients with advanced tumors may also have epiphora, diplopia, proptosis, and cerebrospinal fluid rhinorrhea, depending on specific subsite involvement.[8][2][11][1] In some patients, the presentation can be confused with sinusitis, as patients present with secondary mucopurulent sinonasal drainage.[2] Given these nonspecific symptoms, patients are usually diagnosed at an advanced stage, similar to many other sinonasal tumors. Trismus due to invasion into the pterygoids, cranial nerve palsies, and hearing loss due to eustachian tube invasion may be associated with advanced disease and a worse prognosis.[5]

Both computed tomography and magnetic resonance imaging are used in assessing sinonasal tumors to detect their presence, size, and invasiveness. In patients with BSNS, computed tomography generally demonstrates a sinonasal mass with areas of hyperostosis, erosion of adjacent bony structures, and often post-obstructive sinus opacification.[8] On magnetic resonance imaging, the tumor is isointense on T1 and T2, appearing similar to gray matter on T2. BSNS enhances heterogeneously with contrast.[14][12] The enhancement pattern is likely due to the admixture of glandular components, which can be directly visualized histologically.[12] There is restriction on diffusion-weighted imaging. Positron emission tomography scans may be ordered to determine the presence of metastases; however, the utility is limited in BSNS as these tumors display none-to-low positron emission tomography avidity, and they rarely, if ever, metastasize either locally or distantly.[8][12]

The differential diagnosis for BSNS includes other uncommon sinonasal tumors, and it has been incorrectly diagnosed previously due to paucity of knowledge and resultant gaps in histopathological study. Sinonasal tumors with similar presenting features include solitary fibrous tumors, fibromatosis, myofibrosarcoma, schwannoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumors with or without rhabdomyoblastic features (Triton tumor), glomangiopericytoma, and inverted papilloma.[8][9][7][11][10] Although difficult to separate visually due to overlapping presentation, the histopathological analysis provides a definitive ability to classify rare sinonasal tumors. In preparation for these comparisons between BSNS and other tumors in the differential diagnosis, recall briefly the features of BSNS - hypercellular, spindle-shaped, patchy or diffuse S100 and smooth muscle actin staining, lack of SOX10 staining, PAX3-MAML fusion, and rare mitoses or necrosis. Solitary fibrous tumors, unlike BSNS, express cytokeratin.[8] Fibrosarcomas are less cellular and not S-100 positive.[1] Schwannomas and nerve tumors stain positive for SOX1.[9] Leiomyosarcoma does not demonstrate S-100 positivity, and features include perinuclear halos around cigar-shaped nuclei.[1] Synovial sarcoma can mimic BSNS due to the presence of pseudoglandular structures.[9] However, unlike BSNS, it also has positive cytokeratin expression and thick collagen bundles.[9] The chromosomal translocation in synovial sarcoma t(x;19)(p11;q11) leads to a characteristic SS18 rearrangement diagnostic for synovial sarcoma. It is diffusely S100 positive.[8] Fibromatosis, specifically neurofibromatosis type 1, is strongly associated with Triton tumor. While Triton tumor has features of rhabdomyosarcoma in addition to neural features, it is seen in patients slightly younger than those with BSNS.[11] The studied age range falls between 30 and 50 years of age.[11] Its presentation is characterized by rapid growth and resultant mass effect, while histology demonstrates hyperchromasia, nuclear atypia, widespread mitoses, and necrosis. Despite these differences from BSNS, lower-grade peripheral nerve sheath tumors may look nearly identical under the microscope.[1] Glomangiopericytoma is more epithelioid, does not stain positive for S100, and has a short instead of long fascicular pattern with round or ovoid nuclei.[9][1]

Fibromatosis, specifically neurofibromatosis type 1, is strongly associated with Triton tumor. While Triton tumor has features of rhabdomyosarcoma in addition to neural features, it is seen in patients slightly younger than those with BSNS.[11] The studied age range falls between 30 and 50 years of age.[11] Its presentation is characterized by rapid growth and resultant mass effect, while histology demonstrates hyperchromasia, nuclear atypia, widespread mitoses, and necrosis. Despite these differences from BSNS, lower-grade peripheral nerve sheath tumors may look nearly identical under the microscope.[1] Glomangiopericytoma is more epithelioid, does not stain positive for S100, and has a short instead of long fascicular pattern with round or ovoid nuclei.[9][1] The invaginated respiratory epithelial component of BSNS is also seen in inverted papilloma, but inverted papilloma has a significantly more prominent glandular pattern and no spindle cell proliferation.[3][1] None of the listed etiologies in the differential demonstrate PAX3-MAML fusion on fluorescence in-situ hybridization, which is diagnostic for BSNS. Synovial sarcoma, fibrosarcoma, and low-grade malignant peripheral nerve sheath tumors are most often misdiagnosed in place of BSNS.[9]

Surgical resection is the primary therapy for BSNS. However, the operative surgeon may need to leave positive margins of the tumor to limit the violation of critical structures like the orbit or skull base.[8][4][2][9] Both endoscopic and open-surgical approaches have been described, and the most appropriate approach depends on the location and extent of the tumor and the surgeon's preference. Open approaches include bifrontal craniotomy and lateral rhinotomy.[10][13] If present, resulting skull base defects may be repaired with autologous tissue, such as a pedicled pericranial flap or synthetic dural repair grafts.[13] Due to the low rate of nodal metastasis for all sinonasal malignancies, elective neck dissection is not recommended.[4]

There is no guidance regarding neoadjuvant, adjuvant, or salvage radiation dosing or technique for BSNS. Treatment plans have been very case-specific, and radiation has thus far been utilized as adjuvant therapy, both prophylactically and for positive surgical margins.[8][12] Due to the few cases reported in the literature and the lack of BSNS-specific photon radiotherapy or proton beam therapy studies, no specific recommendations can be made regarding adjuvant photon radiation or proton beam therapy. However, based on broad studies of all sinonasal tumors, adjuvant radiation (photon or proton beam) may be considered in patients with advanced T-stage, bony or neural invasion, dural or intracranial involvement, positive margins, or tumors that cannot be completely resected due to high surgical morbidity.[2][4] Given the low nodal metastatic rate, prophylactic cervical irradiation is not recommended.[4]

Chemotherapy has been used in treating 12% of patients with BSNS, although there is no guiding evidence.[14] Some reported regimens include cisplatin, carboplatin, or 5-fluorouracil with concurrent radiotherapy. However, these regimens were studied in patients with unresectable T4b sinonasal tumors and lymphoma, sarcoma, melanoma, and esthesioneuroblastoma.[16] There are no representative studies on chemotherapeutic outcomes in the management of BSNS.

Before establishing the American Joint Committee on Cancer staging system, Ohngren attempted to classify infrastructure versus suprastructure tumors based on a theoretical line drawn between the angle of the mandible to the medial canthus. By separating the superomedial/superolateral and inferomedial/inferolateral sites of the paranasal sinuses, he theorized that those with suprastructure involvement of the eye, skull base, pterygoid musculature/bone, and infratemporal fossae had a poorer prognosis.[5] The 8th edition of the American Joint Committee on Cancer Cancer Staging Manual describes primary tumor staging for sinonasal tumors of the maxillary sinus and nasal cavity/ethmoid sinus only since the involvement of the frontal or sphenoid sinuses automatically qualifies the tumor as being T4a.[5] Only staging for the nasal cavity and ethmoid subsites should be reviewed since BSNS has not been reported in the maxillary sinus. A T1 tumor involves only the nasal cavity or an isolated ethmoid sinus and may or may not invade bone.[5] A T2 tumor involves adjacent structures in the nasoethmoidal complex and may or may not invade bone or multiple subsites within a single region. A T3 tumor invades high-risk structures immediately adjacent to the ethmoid sinus, including the medial wall or floor of the orbit, maxillary sinus, palate, and cribriform plate.[5] Tumors within the T4 category are divided into T4a and T4b. T4a involves anterior orbital contents, the skin of the nose or cheek, and, to a minimal extent, the anterior cranial fossa, pterygoids, frontal sinuses, or sphenoid sinuses. T4b indicates that the tumor has extended into the cranial vault, involving the orbital apex, cranial nerves, nasopharynx, dura, brain, middle cranial fossa, or the clivus.

Only staging for the nasal cavity and ethmoid subsites should be reviewed since BSNS has not been reported in the maxillary sinus. A T1 tumor involves only the nasal cavity or an isolated ethmoid sinus and may or may not invade bone.[5] A T2 tumor involves adjacent structures in the nasoethmoidal complex and may or may not invade bone or multiple subsites within a single region. A T3 tumor invades high-risk structures immediately adjacent to the ethmoid sinus, including the medial wall or floor of the orbit, maxillary sinus, palate, and cribriform plate.[5] Tumors within the T4 category are divided into T4a and T4b. T4a involves anterior orbital contents, the skin of the nose or cheek, and, to a minimal extent, the anterior cranial fossa, pterygoids, frontal sinuses, or sphenoid sinuses. T4b indicates that the tumor has extended into the cranial vault, involving the orbital apex, cranial nerves, nasopharynx, dura, brain, middle cranial fossa, or the clivus. Nodal staging guides overall staging. Metastasis to a single node on the same side as the tumor, as long as it measures less than 3 cm, is staged as N1.[5] However, if 1 ipsilateral node measures 3 and 6 cm, the tumor is classified as N2a.[5] Once the patient develops multiple ipsilateral nodes, all less than 6 cm, the tumor is staged as N2b. N2c entails metastasis to contralateral or bilateral nodes, still less than 6 cm in the greatest dimension.[5] Any lymph node greater than 6 cm qualifies as N3. An overall stage is assigned based on the tumor, nodal, and metastasis staging. A T1N0M0 tumor is stage 1, and T2N0M0 is stage 2. Stage 3 includes both T3N0M0 tumors and T1/2/3 tumors with N1 nodal staging.[5] Stage 4 is divided into A/B/C to convey tumor extent. Stage 4A tumors include T4aN0M0, T4aN1M0, or T4aN2M0, and N2 nodal staging for T1/2/3 without metastasis.[5] Stage 4B tumors are any T stage with N3 nodal status and T4b tumors with any nodal status N0/1/2/3, without metastasis. If the patient has a distant metastasis, they are staged as M1 with an overall stage of 4C, regardless of the T or N staging.[5]

Based on the limited studies into the behavior of BSNS, the prognosis is unclear. However, the 5-year survival is much likely higher than the reported 25-50% 5-year survival for SCC in the paranasal sinuses.[5] Out of around 100 cases discussed in the literature, the reported recurrence rate is 32 to 40%.[12] Only 1 death has occurred due to a second recurrence and intracranial invasion.[8][13][9][3] The recurrence-free range was 1 year to 9 years.[11] In 1 series of 5 patients, 2 had a recurrence treated with revision surgery, and 1 additionally underwent adjuvant proton beam therapy.[12] The biologic potential is unknown due to ongoing study of the downstream effects of gene fusion that lead to the characteristic presentation of BSNS.[9]

There are few reported direct complications of BSNS due to its slow growth pattern. The most commonly reported surgical morbidity is recurrence.[8] Other postoperative complications include blurry vision, loss of vision, cerebrospinal fluid leak, pneumocephalus, postoperative infection, autologous skull base repair flap necrosis, continued nasal congestion, and frontal sinus outflow obstruction. Regarding skull base defect repair failure, revision defect repair can be completed with alternative autologous tissue flaps or grafts, including a pericranial flap, nasoseptal flap, or tensor fascia lata graft.[13]

If the tumor displays orbital or intracranial invasion, ophthalmology and neurosurgery should be consulted. If there is extensive disease or positive margins, radiation oncology should be consulted for further adjuvant treatment planning. As with any other malignancy, all new BSNS cases should be presented at a multidisciplinary tumor board.

There is ongoing research on BSNS and the gene rearrangements that cause it, which could further elucidate the behavior of this particular pathology. The tumor is often mistaken for other pathologies. Therefore, its genetic composition and staging should be closely examined to provide the patient with an accurate prognosis and treatment plan.

Although surgery is the primary treatment modality, optimal treatment of any sinonasal malignancy, BSNS included, involves collaboration with other services and members of an interprofessional healthcare team. It is important to review imaging for these tumors with a radiologist, specifically a neuroradiologist if available, to help determine tumor extent and possible involvement of adjacent structures. If the tumor is extensive at the time of presentation, which it often is, consultations for ophthalmology and neurosurgery should be considered to help in surgical planning. Furthermore, as with any other malignancy, all new BSNS cases should be formally discussed at a multi-disciplinary tumor board meeting. Post-operatively, the patient may require an intensive care unit stay for frequent neurologic monitoring. Communication between the hospitalist medicine team, nursing staff, and floor technicians is vital for excellent patient care in any post-operative admission.