Biphenotypic Sinonasal Sarcoma

Etiology

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 (FISH) is remarkable for a characteristic PAX3-MAML fusion protein that leads to the development of BSNS pathology.[8][9][12]

Epidemiology

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 years old, the range is between the mid-20s to mid-80s.[8][9]

Pathophysiology

PAX3 is a gene involved in developing 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]

Histopathology

Histopathologic examination of BSNS demonstrates hypercellular, uniform, long spindle-shaped cells in a fascicular pattern occasionally described as a "herringbone" configuration.[6] Nuclei will appear tapered, and 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 itself appears unencapsulated.[11] There can be foci of respiratory epithelium entrapped in tumor cells, creating a pseudoglandular appearance.[8][9] 

Infiltrative tumors will be 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 and smooth muscle actin (SMA) 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]

History and Physical

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 (CSF) 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]

Evaluation

Both computed tomography (CT) and magnetic resonance imaging (MRI) are used in assessing sinonasal tumors to detect their presence, size, and invasiveness. In patients with BSNS, CT generally demonstrates a sinonasal mass with areas of hyperostosis, erosion of adjacent bony structures, and often post-obstructive sinus opacification.[8]

On MRI, 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 (PET) scans may be ordered to determine the presence of metastases; however, the utility is limited in BSNS as these tumors display none-to-low PET avidity, and they rarely, if ever, metastasize either locally or distantly.[8][12]

Treatment / Management

Treatment, as discussed further below, is primarily surgical. The utility of radiation therapy is unclear. Chemotherapy does not seem to add any therapeutic benefit.

Differential Diagnosis

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 tumor (SFT), fibromatosis, myofibrosarcoma, schwannoma, leiomyosarcoma, synovial sarcoma (SS), malignant peripheral nerve sheath tumor 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 SMA 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 additionally thick collagen bundles.[9] The chromosomal translocation in synovial sarcoma t(x;19)(p11;q11) leads to a characteristic SS18 rearrangement that is 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]

• 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 (FISH), 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 Oncology

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]

Radiation Oncology

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 (PBT) 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]

Medical Oncology

Chemotherapy has been used in treating 12% of patients with BSNS, although there is no guiding evidence for its use.[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.

Staging

Before establishing the AJCC 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 (AJCC) 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 and/or sphenoid sinuses automatically qualifies the tumor as being T4a.[5] 

Only staging for the nasal cavity and ethmoid subsites will 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 extends to involve adjacent structures in the nasoethmoidal complex and may or may not invade bone, or it invades 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 and/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, and/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 one ipsilateral node measures between 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 (TNM) 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, as well as 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]

Prognosis

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 one death has occurred due to a second recurrence and intracranial invasion.[8][13][9][3] 

The recurrence-free range was one year to 9 years.[11] In one series of 5 patients, two patients had a recurrence that was treated with revision surgery, and one of these patients 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]

Complications

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 (CSF) leak, pneumocephalus, postoperative infection, necrosis of autologous skull base repair flap, 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]