SMARCB1 (INI1)‐deficient sinonasal carcinoma manifesting as oral lesions: A report of two cases

Sinonasal carcinomas represent a rare group of malignancies, accounting for less than 5% of all head and neck cancers and a worldwide incidence of less than 1 case per 100 000 inhabitants annually. Despite the restricted anatomical location, sinonasal carcinomas harbor some of the most histologically and molecularly diverse groups of tumors. SMARCB1 (INI1)‐deficient sinonasal carcinomas are locally aggressive tumors commonly detected late, leading to devastating morbidity and mortality.

3%-5% of all head and neck cancers, with squamous cell carcinoma (SCC) being the most common malignant neoplasm. 1,2Sinonasal carcinomas encompass a variety of morphologically different malignant neoplasms, including tumors of epithelial, neuroectodermal, mesenchymal, and lymphoproliferative origins. 2 Historically, a unique group of tumors from this region that shared similar histopathological features lacking squamous or glandular differentiation were collectively grouped into a category called sinonasal undifferentiated carcinoma (SNUC) and shown to be unrelated to HPV or EBV. 3,4Over the years, molecular studies have identified a distinct subset of previously called undifferentiated tumors that showed loss of expression of SWI/SNF-related, matrix-associated actin-dependent regulator of chromatin (SMARC) subfamily B member 1 (SMARCB1, INI1), and this new entity was initially described in the literature in 2014 by Agaimy et al. 5 These locally aggressive tumors share morphologic features resembling a basaloid variant of SCC admixed with isolated rhabdoid cells. 6,7All cases showed inactivation of SMARCB1, a tumor suppressor gene located on chromosome 22q11.2and part of the SWI/SNF nucleosome remodeling complex.[6]8 Advanced molecular studies have further elucidated other subtypes of SNUC, including NUT carcinoma and SMARCA4 (BRG1)deficient sinonasal carcinoma, 3 which are essential to distinguish from the SMARCB1-deficient sinonasal carcinoma.
SMARCB1-deficient sinonasal carcinoma usually arises in the nasal cavity or paranasal sinuses and frequently involves the skull base.The presenting symptoms include nasal obstruction, headaches, proptosis, and epistaxis.Still, many cases remain asymptomatic and only develop symptoms at late stages, as the presence of a large cavity allows unimpeded growth.Here, we report two cases of SMARCB1-deficient sinonasal carcinoma that presented initially as radiolucent lesions with swelling of the left anterior maxilla which were initially investigated as odontogenic lesions.

| CASE 1
A 70-year-old woman presented to the dentist for assessment of a painful swelling in the left maxillary edentulous ridge for the past month, and an inability to wear her denture.A detailed history of the symptoms preceding the visit to the dentist could not be collected due to challenges in communication.The main clinical concern and diagnostic hypothesis was a potential odontogenic lesion in the maxilla.After assessment by her dentist, she was referred to an oral medicine specialist (OM) for diagnosis.When assessed by the OM, she described that the swelling gradually increased in size and was affecting her eyesight.There was no history of epistaxis or rhinorrhea; she denied paresthesia or dyspnea.Her medical history was reviewed and was non-contributory.Extraoral examination showed no cervical lymphadenopathy, facial asymmetry, or swelling.Intraoral examination revealed a 15 Â 10 Â 7 mm exophytic mass on the left anterior edentulous maxillary ridge, with erythema.The lesion was tender to palpation, and the surface was irregular and showed focal ulceration (Figure 1A).A panoramic radiograph revealed a poorly defined radiolucent lesion of the left maxilla, causing effacement of the sinus cortex and opacification of the left maxillary sinus (Figure 1B).
An incisional biopsy was performed, and the results revealed parakeratinized stratified squamous epithelium covering dense fibrous connective tissue.Within the connective tissue was a nonencapsulated, infiltrative neoplasm composed of back-to-back islands and cords of basophilic round cells with open chromatin and eosinophilic cytoplasm.There was no evidence of squamous or glandular differentiation, or necrosis.Mitotic activity was brisk, including atypical ones.Focal areas of dystrophic calcification associated with multinucleated giant cells and hemorrhage were also noted (Figure 2A-C).The tumor cells were positive for pancytokeratin (AE1/AE3), p40 and p63.CK 5/6 highlighted the mucosal epithelium only, and the lesional cells were negative for p16, CD45, CK7, CK20, and S100.Loss of SMARCB1 expression was confirmed via immunohistochemistry (Figure 2D-F), while internal controls, including mucosal epithelium and peripheral lymphocytes, show preserved expression.The histopathological features and molecular profile were consistent with a SMARCB1-deficient sinonasal carcinoma.
The patient was referred to a specialized head and neck cancer center, and a CT scan was performed.The CT head scan revealed a 4.0 Â 3.5 Â 4.2 cm mass at the edentulous left maxillary alveolar ridge, with evidence of perineural invasion along the infraorbital nerve (images unavailable).A CT scan of the chest showed no evidence of metastatic disease.The patient was staged at pT3 pN1 cM0 and underwent multimodal treatment, including radical surgical resection and adjuvant radiotherapy.Unfortunately, local control was not achieved, and she died of the disease 1 year after the diagnosis.

| CASE 2
A 37-year-old male developed discomfort and sensitivity of the maxilla, prompting a visit to an emergency dental clinic to evaluate a presumed dental infection.He also reported, at the time, a reduced sensation between the left maxillary cuspid and first molar and was prescribed an antibiotic for a presumed odontogenic abscess.After 4 days of improvement, his symptoms returned, and he was informed on follow-up that endodontic therapy would be required.He returned to his general dentist and was advised that he did not need a root canal.He was instructed to see an oral and maxillofacial surgeon or go to the hospital emergency service.The patient followed the dentist's instructions and immediately presented to a hospital emergency department (ED).During the initial assessment at the ED, he was given a preliminary diagnosis of sinus infection and prescribed additional antibiotics, but imaging was not obtained then.As his symptoms did not improve, he returned to the same hospital after 4 days and was referred to oral and maxillofacial surgery (OMFS) for further evaluation.By the time he was assessed by OMFS, the chief complaint had progressed from discomfort to a hard swelling on the left upper gums, causing noticeable swelling of the ala and hypoesthesia of the upper left teeth.His medical history was reviewed and was non-contributory.
Clinical evaluation by OMFS revealed a wellappearing male in no acute distress.Extraoral examination did not reveal a palpable mass, and normal sensation was elicited by light touch in the distribution of the left maxillary division of the trigeminal nerve.Intraoral examination revealed expansion of the left lateral maxilla involving the vestibule.The lesion was hard and nontender to palpation.A panoramic radiograph (Figure 3A) revealed a well-defined radiolucent entity located at the left maxilla, extending from the periapical region of the left maxillary canine to the first molar and into the left maxillary sinus.This was associated with opacification of the adjacent maxillary sinus.
Further imaging with CBCT (Figure 3B,C) showed an infiltrative and destructive expansile soft tissue mass measuring at least 2.8 Â 3.0 Â 3.8 cm in dimension.There was loss of the antral cortical floor and perforation of the buccal and lateral wall of the antrum.There was no resorption or displacement of the teeth in the area.The findings were interpreted as suspicious of malignancy.An incisional biopsy was performed under local anesthesia and conscious sedation, with exposure to the lateral alveolar process and maxillary sinus via sulcular incision.
The biopsy revealed a malignant infiltrate composed of round basaloid cells with a high nuclear-to-cytoplasmic ratio and scant cytoplasm, arranged in nests.The tumor showed a highly infiltrative pattern in a background of collagenous stroma.Brisk mitotic figures were seen, with 20 mitotic figures per 10 high-power fields (Figure 4A-C).The tumor was positive for AE1/AE3 and p63, and loss of SMARCB1 was confirmed by immunohistochemistry (Figure 4D,E).Molecular analyses (TruSight RNA Fusion Panel) showed no actionable or diagnostic gene fusions, including those seen in Ewing's sarcoma or NUT carcinoma.A diagnosis of undifferentiated malignant basaloid neoplasm consistent with SMARCB1-deficient sinonasal carcinoma was made.The patient was referred to a head and neck cancer center for oncologic management.
Upon transfer of care to the head and neck surgery team, multiple imaging studies were completed for staging.Head and neck CT confirmed the presence of an infiltrative destructive expansile mass centered at the left maxillary alveolar process and the left maxillary sinus, with extension into the malar soft tissues anteriorly, and superiorly to the level of the infraorbital foramen.There was no involvement of the infraorbital foramen, pterygopalatine fossa, orbit, or skull base.A chest CT showed no evidence of metastases.A head and neck MRI with contrast was performed as part of the surgical planning and revealed no disease progression compared to the CT scan, and there was no evidence of perineural tumor involvement in the infraorbital nerve.A PET CT showed a metabolically active extensive primary tumor with no evidence of metastatic disease.The patient underwent surgical resection, which consisted of a left partial maxillectomy with partial excision of the anterior orbital rim and infraorbital nerve via a lateral rhinotomy approach, left neck dissection, left scapular free flap reconstruction, and tracheostomy.Histopathological analysis of the resection specimen confirmed the diagnosis of a SMARCB1-deficient sinonasal carcinoma involving the left maxillary sinus and left maxillary process, with a maximum tumor size of 4.7 cm, stage IVA, pT4a pN1 cM0.The tumor was mostly composed of undifferentiated basaloid cells growing in sheets, lobules, and rounded nests, with focal peripheral palisading.Some tumor cells had a light eosinophilic cytoplasm, while others had cytoplasmic clearing.Rare tumor cells with rhabdoid features were seen.There were abundant apoptotic cells and confluent necrosis, with a mitotic count of 12 per 10 HPFs.The tumor cells were strongly and diffusely positive for AE1/AE3 and p40.They were negative for SOX10, CDX2, TTF1, CK7, CK18, CD56, chromogranin, synaptophysin, S100 and p16.SMARCB1 expression was lost based on immunohistochemistry (Figure 4D,E).Lymphovascular, perineural, and maxillary bone invasion were noted, with the lateral mucosal margin focally positive for malignancy.One of the 31 nodes was positive for malignancy.Subsequently, the patient underwent adjuvant chemoradiotherapy of 66 Gy in 33 fractions with two cycles of high-dose cisplatin.The patient recently underwent reconstruction with implants and was alive without disease when this manuscript was completed (2.5 years post-diagnosis).

| DISCUSSION
SMARCB1/INI1-deficient sinonasal carcinoma is a rare and aggressive malignancy first described in the past 10 years.This tumor often presents as a sinonasal mass with nasal symptoms in individuals aged 17-89 years old. 9The disease is commonly diagnosed at a late stage, and due to the locally aggressive nature of the tumor, local destruction of surrounding structures is usually the first diagnostic feature. 4The treatment usually involves a combination of surgery with adjuvant chemoradiation, but unfortunately, the prognosis is poor.Further studies are required to investigate factors associated with improved survival. 6,9MARCB1-deficient sinonasal carcinomas presenting as oral lesions: The oral presentation of these tumors represents a significant challenge for otolaryngologists, oral surgeons, oral pathologists, physicians, and dentists, as they can mimic various entities.Among all SMARCB1/ INI1-deficient sinonasal carcinoma reported in the literature, only a few cases were first diagnosed as oral lesions.Larger series also show few cases involving the maxillary sinus and alveolar process; for example, Agaimy et al. reported only 4/39 cases involving the maxillary sinuses. 61][12] Within the reported cases, none were reported to manifest as a possible periapical inflammatory lesion, odontogenic infection, or sinus infection.
These findings are particularly important as the aggressive and destructive clinical behavior of this entity, combined with the location at the floor of the maxillary sinus, created the possibility of the tumor being first observed within the oral cavity or maxillary dentition.In this scenario, the clinical differential diagnosis is broader and includes odontogenic infection or abscess, 13 sinusitis, 14 and inflamed odontogenic lesions.These lesions occur with a much higher incidence 15 than any malignant disease and can have significant overlapping symptoms, including swelling, pain, and bone destruction. 16

| What can we learn from these cases?
Careful evaluation of the clinical history, clinical exam including dental exam, and adequate radiographic imaging are critical to prevent unnecessary treatments such as antibiotic therapy or tooth extraction.These cases also highlight the importance of the dentist in diagnosing these entities and considering aggressive malignant sinus diseases such as SMARCB1-deficient sinonasal carcinomas in the differential diagnosis of maxillary lesions.Dentists are well trained and are increasingly detecting more oral cancer and premalignant lesions 15 , but primarily intraosseous malignancies or aggressive lesions extending from adjacent structures such as the cases reported here are far more challenging to diagnose. 17,18he cases reported here illustrate the need to keep an open differential diagnosis when encountering similar lesions, and build on a systematic diagnostic approach that should be emphasized during dental and medical training.It also shows the importance of a multidisciplinary team that includes general dentists, otolaryngologists/head and neck surgeons, oral medicine and oral pathology, oral and maxillofacial surgery, and surgical pathologists.In both cases, the original pathology report was signed out by an oral and maxillofacial pathologist and further confirmed by an anatomical pathologist.
As seen in Case 1, the first clinical concern noted may be a poorly fitting denture due to swelling of the alveolar ridge and vestibule, and if not investigated thoroughly with proper radiographic imaging, may lead to unnecessary delays in treatment.In our case, a complete previous history of symptoms could not be completed for our first patient due to communication barriers.As the tumor was diagnosed at a late stage, it is likely that the reported changes in her denture and local symptoms were present for more than 1 month, and we speculate that patient denial, among other factors, may have contributed to a patient delay.The immediate referral to OM allowed prompt diagnosis and treatment.
In dentate patients such as Case 2, a critical starting point is evaluating the vitality of the associated teeth (e.g., cold or electrical pulp testing), as odontogenic infections are typically seen associated with non-vital teeth.Unfortunately, in cases of rapidly destructive tumors, nerve involvement can occur early and mimic negative pulp vitality testing, creating further challenges for the diagnosis.The dysesthesia of the affected dermatome is a vital clinical sign that favors a malignant entity and cannot be missed in this context.The next step in the diagnostic approach is to consider the use of advanced imaging, as typical intraoral plain film radiographs may not show the epicenter of the lesion and its destructive features beyond the alveolar bone. 19When interpreting radiographs, one must remember that infection is a great mimicker of malignancy.Finally, as seen in both cases, a timely biopsy to include viable and representative tumor tissue is required to confirm the diagnosis.Considering the minimal risks of the procedure and potential benefits, an oral manifestation of destructive lesions such as the ones presented here should be immediately biopsied via an oral cavity approach, even if the original suspicion favors an inflammatory process.][6][7] The intraoral presentations reported here present further challenges to the pathologist due to inflammation that can efface certain diagnostic features.In addition, Case 2 had limited material for histopathological analysis.The presence of dense inflammation and the small round blue cell appearance of the tumor favored a possible lymphoma at the top of our initial differential diagnosis 3,7,8,11 To add to the complexity, when presented with a poorly-differentiated carcinoma on histology in this location, it is critical to determine if this is an oral mucosal-origin carcinoma or sinusorigin carcinoma.Therefore, using different cytokeratins can help differentiate the origin of the tumor.In our case, the immunoreactivity to AE1/AE3 and lack of staining for CK5/6 supported a sinus origin rather than oral mucosa.These cases are an important reminder to pathologists to consider adding SMARCB1 IHC to the diagnostic panel of markers used in challenging poorly differentiated maxillary carcinomas, even if they appear as an intraoral tumor mass.

| CONCLUSIONS
SMARCB1-deficient sinonasal carcinomas can rarely present as an intraoral mass, posing clinical and histopathological diagnostic challenges.Collaboration with an interdisciplinary health care team including dentists, otolaryngologists, radiologists, and pathologists as well as careful oral examination, advanced imaging, and timely biopsy is critical to prevent delays in diagnosis.

1
Case 1. (A) A clinical photo showing the lesion affecting the left maxillary area.(B) A panoramic image for the same patient.

F I G U R E 3
Imaging for Case 2. (A) Panoramic image.(B) Axial CBCT cut.(C) Sagittal cut of CBCT.
T A B L E 1 Previous case reports of SMARCB1-deficient sinonasal carcinoma presenting intraoral symptoms.