18 May 2023: Articles
SMARCB1-Deficient Sinonasal Carcinoma: Case Report and Review of the Literature
Mistake in diagnosisNasser M. AlMadan 1ABEF*, Ebtehal A. AlEssa2BEF, Doaa A. AlGhamdi 3ABEF
Am J Case Rep 2023; 24:e939244
BACKGROUND: SMARCB1-deficient sinonasal carcinoma is a rare neoplasm with inactivation of the SWI/SNF complex, with an aggressive clinical course as most of the lesions present as advanced in pT3/T4 stages with frequent recurrence, and many patients succumb to the disease. Reported initially in 2014, the lesion has male predominance, with an age range of 19 to 89 years and predilection for the ethmoid sinus and nasal cavity. Histopathological findings show a proliferation of small- to medium-sized monomorphic basaloid cells with indistinctive cytoplasmic borders and round variably prominent nuclei with scattered cells that show rhabdoid morphology. Cytoplasmic vacuoles are common. It has similar morphological findings to a wide array of neoplasms in the sinonasal area.
CASE REPORT: We report a case of SMARCB1-deficient sinonasal carcinoma in a 30-year-old man referred to our hospital with a preliminary diagnosis of sinonasal adenocarcinoma, intestinal type. Computed tomography showed a huge destructive soft tissue mass in the left maxillary sinus, extended to involve the left nasal cavity with extension to the skull base and perineural spread along the foramen rotundum. Histological examination revealed a malignant basaloid neoplasm embedded in a myxoid stroma that showed loss of SMARCB1 stain. The patient was treated with induction chemotherapy using etoposide and cisplatin for disease control.
CONCLUSIONS: SMARCB1-deficient sinonasal carcinoma is a rare neoplasm with an aggressive clinical course and high-grade behavior despite having uniform cytological features. This poses complex diagnoses, especially in small biopsies. Incorporating morphological findings with ancillary tests is required to identify this high-grade malignancy.
Keywords: SMARCB1 protein, human, Carcinoma, Sinonasal Undifferentiated Carcinoma
Sinonasal tumors with inactivation of the switch/sucrose nonfermentable (SWI/SNF) complex are rare neoplasms, with most of the tumors showing loss of SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily B, member 1 (SMARCB1; also known as integrase interactor 1 [INI1]), with a subset of these lesions showing a loss of SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4; also known as Brahma-related gene 1 [BRG1]) . SMARCB1-deficient sinonasal carcinoma was reported initially in 2014 by 2 independent authors from Germany and the United States [2,3]. Pathological findings include a proliferation of small- to medium-sized monomorphic basaloid cells with indistinctive cytoplasmic borders and round nuclei, with variably prominent nuclei. Rhabdoid features and cytoplasmic vacuoles are commonly seen. Tumor cells are usually positive for pan-cytokeratin, while P63, CK5, and CK7 are positive in one-half of cases. A characteristic finding is SMARCB1 (INI1) expression loss in tumor cells.
SMARCB1-deficient sinonasal carcinoma is usually managed using surgery and radiochemotherapy . We report a case of SMARCB1-deficient sinonasal carcinoma in a 30-year-old man referred to our hospital with a preliminary diagnosis of sino-nasal adenocarcinoma, intestinal type, with emphasis on histological and immunohistochemical findings.
A 30-year-old man without a medical history was referred to our hospital for an enlarging left facial swelling of 8 months. The patient had no family history of malignancy and no smoking history. The lesion was associated with dental pain, decreased oral intake, left nasal obstruction, frequent left nasal epistaxis, and oral bleeding. Clinical examination revealed left facial swelling extending to the orbit and loss of sensation over the cheek. Intra-oral examination showed a mass extending to the hard palate. Lymph nodes were examined and were unremarkable.
An unenhanced computed tomography (CT) scan was done and compared with the previous CT from the referring hospital. It showed significant interval progression of a huge destructive soft tissue mass seen in the left maxillary sinus, extended to involve the left nasal cavity (Figure 1). The tumor was also seen involving the skull base, with perineural spread along the left foramen rotundum and a small enhancing component seen along the anterior aspect of the cavernous sinus. No significantly enlarged or suspicious lymph nodes were identified in the neck. A positron emission tomography scan showed a left maxillary sinus soft tissue mass causing mass effect, with no other suspicious fluorodeoxyglucose-avid disease elsewhere.
Histopathological examination revealed unremarkable sinonasal respiratory-type mucosa with underlying basaloid neoplastic growth. The neoplastic cells were arranged in solid nests, cords, and cribriform patterns embedded in a myxoid stroma. The cells had cytoplasmic vacuoles, with frequent cells showing rhabdoid morphology. Frequent mitotic figures (8/10 per high-power field) were identified. There were multiple foci of necrosis and bone invasion (Figure 2). Tumor cells were positive for CKAE1/AE3, cam5.2, and CK7. Focal positivity for synaptophysin, P16, and NSE were identified, while there was negative results for CD99, S100, CK20, HMB45, P63, CK5/6, chromogranin, CD56, EBER-1, GATA3, and androgen receptor, with loss of SMARCB1 (INI1) expression (Figure 3).
The differential diagnosis for our case included, but was not limited to, poorly differentiated non-keratinizing squamous cell carcinoma, basaloid squamous cell carcinoma, human papillomavirus (HPV)-related multhiphenotypic sinonasal carcinoma, sinonasal undifferentiated carcinoma, SMARCB1-deficient sinonasal carcinoma, small cell neuroendocrine carcinoma, melanoma, and Ewing sarcoma. The absence of surface dysplasia ruled out poorly differentiated squamous cell carcinoma, basaloid squamous cell carcinoma, and HPV-related multiphenotypic sinonasal carcinoma. Additionally, no stromal hyalinization and comedo necrosis was seen in our case. Moreover, unlike the lesion in our case, all of the above-mentioned lesions are reactive to P63 and CK5/6. Melanoma usually has in situ components and shows positivity to S100 and Sox10, which were negative in our case. Small cell neuroendocrine carcinoma has small cells with scant cytoplasm, finely granular nuclear chromatin, nuclear molding, and extensive necrosis, and very high mitotic activity. It shows reactivity with synaptophysin, chromogranin, and CD56. Regarding Ewing sarcoma, it has diffuse membranous positivity to CD99, unlike our case, which was negative.
The overall morphology and immunohistochemistry stains were consistent with SMARCB1-deficient sinonasal carcinoma. The patient was treated with induction chemotherapy using etoposide and cisplatin for disease control and was planned for radiation therapy after completing the course of chemotherapy; however, the patient opted to complete the therapy in his hometown outside Saudi Arabia.
The SWI/SNF family of chromatin-remodeling complexes, also known as BRG1/BRM-associated factor complexes, is a critical component in chromatin modification through the regulation of nucleosome positioning . Inactivation of the SWI/SNF complex is reported in rare neoplasms, with most of the tumors showing SMARCB1 (INI1) showing SMARCA4 loss (stands SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4), (BRG1) . It is reported that several soft tissue, central nervous system, genitourinary, and sinonasal neoplasms could show SWI/SNF complex loss, such as epitheliod sarcoma, atypical teratoid tumor, and myoepithelial carcinoma [4–6]. Many SWI/SNF complex entities exist in the sinonasal region, including SMARCB1-deficient carcinoma, SMARCB1-deficient adenocarcinoma, SMARCA4-deficient carcinoma, and SMARCA4-deficient sinonasal teratocarcinosarcoma .
SMARCB1-deficient sinonasal carcinoma was reported by Agaimy and Bishop in 2 independent papers [2,3]. The lesion has male predominance, with a patient age range of 19 to 89 years, and predilection for the ethmoid sinus and nasal cavity. It usually behaves in an aggressive manner, as most of the lesions present as advanced lesions in pT3/T4 stages with frequent recurrence, and many patients succumb to the disease . Histological features show nests or trabeculae of monotonous blue cells with instinctive cytoplasm, high nuclear to cytoplasmic ratio, and prominent nucleoli on desmoplastic stroma. The neoplasm does not rise from the surface epithelium, with no evident surface dysplasia; however, occasional tumor cells could infiltrate the lining in a pagetoid pattern. Tumor cells can show palisading, and it has abundant cytoplasmic vacuoles with no squamous or glandular differentiation. Another variant shows plasmacytoid cell proliferation with eccentric nuclei and hyaline eosinophilic cytoplasm. Brisk mitosis is usually identified with extensive necrosis [2–4]. Tumor cells are usually positive for pan-cytokeratin, while P63, CK5, and CK7 are positive in one-half of cases. Other markers that could be positive to a less extent include synaptophysin, chromogranin, CD56, CD117, and P16; however, it is negative for HPV, using in situ hybridization for HPV. Tumor cells are negative for Epstein Barr virus in situ hybridization and nuclear protein in testis (NUT) immunohistochemistry. A characteristic finding is SMARCB1 (INI1) expression loss in tumor cells .
Another tumor with SMARCB1 loss is SMARCB1-deficient sinonasal adenocarcinoma, a high-grade tumor with a distinct male predilection . The nasal cavity is the most common location, followed by the maxillary and ethmoid sinus . The tumor is characterized by the proliferation of oncocytic/plasmacytoid cells in a tubular or cribriform pattern embedded in the myxoid stroma, with some basaloid, squamous, clear, or spindle cells being identified. It shows clear nuclear pleomorphism, with increased mitosis and necrosis. Foci of intraluminal or intracellular mucin could be identified, with 1 case showing signet ring morphology. A unique pattern that could be identified is the reticular microcystic proliferation of tumor cells reminiscent of the yolk sac tumor [7,8]. Tumor cells were positive with CK7 in the majority of cases, while positivity for CK20, CDX2, and P40 was seen in the minority, and they were negative for S100. Regarding the yolk sac-like area, these areas exhibited strong positivity for Glypican-3 in most cases. Less staining was seen for SALL4 and Her par1, and it rarely stained Plap and AFP [7,8].
Malignant rhabdoid tumor of the head and neck is another tumor that shows SMARCB1 loss, with some cases having SMARCA4 loss. Malignant rhabdoid tumor is a disease of children, with all of the reported cases under 3 years. The oral cavity and neck are the most common sites, and the disease is characterized by a fatal course if left untreated. Histologically, it is composed of small- to medium-sized cells, with some cells showing rhabdoid or non-descript blue cells proliferating in the submucosa in a diffuse sheet pattern. Some cells show anaplastic epithelioid cells or an abrupt transition to clear cell components, which can pose a diagnostic difficulty, especially in small biopsies. Tumor cells are usually positive for vimentin in a characteristic paranuclear dot-like pattern and could be positive for pan-cytokeratin and EMA .
Another pathway that could be mutated is SMARCA4. This pathway is altered on 2 lesions on the sinonasal cavity, including SMARCA4-deficient carcinoma and sinonasal teratcarcinosarcoma.
SMARCA4-deficient carcinoma has a slight male predilection, with a mean patient age of 44 years, with most cases reported in the nasal cavity, followed by multiple combined sinuses. It has a more clinically aggressive course than SMARCB1-deficient carcinoma, with more than one-half of patients succumbing to disease after a few months. The tumor is characterized by the proliferation of basaloid cells, with a large epithelioid anaplastic cell with rounded hyperchromatic nuclei and indistinctive nucleoli growing in nested or solid patterns within fibrotic stroma, with no true glandular or squamous differentiation. The tumor shows brisk mitosis and frequent coagulative necrosis. Some cases showed abortive rosette formation, with neuropil formation. In contrast to SMARCB1-deficient sinonasal carcinoma, basaloid or rhabdoid features are rarely encountered. Tumor cells show positivity to squamous and neuroendocrine markers. All cases were positive for pan-cytokeratin in a diffuse manner, while CK7 stained a minority of cases. Synaptophysin was focally positive in most cases, while chromogranin was focally weak-positive in one-half of the cases and CD56. All cases were negative for P63, CK5/6, NUT, TTF1, and P16 [9,10]. The positivity for neuroendocrine markers could pose a diagnostic pitfall, especially in small biopsies, and it could be mistaken for poorly differentiated neuroendocrine carcinoma of the sinonasal tract. Both entities could show large cells; however, SMARCA4 rarely shows basaloid cells, while poorly differentiated neuroendocrine carcinoma could show small cell morphology. Both are negative for squamous markers, while neuroendocrine markers are positive in both focal distributions in SMARCA4-deficient carcinoma and diffuse in poorly differentiated neuroendocrine carcinoma. The most important distinguishing marker is SMARCA4, which is lost in SMARCA4-deficient carcinoma, while retained in poorly differentiated neuroendocrine carcinoma .
Teratocarcinosarcoma is a malignant sinonasal tumor with a very aggressive clinical course and triphasic growth. It is composed of teratoma-like, carcinomatous, and sarcomatous elements, with characteristic SMARCA4 loss. It shows a myriad of cellular components with prominent epithelial formation in the form of squamous or glandular differentiation along with primitive neuroepithelial elements and infrequent neuropils with rosette formation. The squamous component could show immature fetal-like clear cells with rare areas of more mature keratin-forming squamous differentiation. The glandular formation usually shows a resemblance to intestinal mucinous glands. The mesenchymal element usually shows undifferentiated fibroblastic spindle cell, rhabdomyoblastic, osteoblastic, or chondroblastic differentiation. There is obvious cytological atypia with increased mitotic counts, apoptotic bodies, and frequent necrosis. Tumor cells show a loss of SMARCA4, with a reduction of SMARCA2 in most cases, while SMARCB1 is intact in almost one-half of cases and reduced in the other half. An interesting finding is that claudin 4 showed variable positivity in all cases. This finding could imply that teratocarcinosarcomas are of epithelial origin [11,12].
Finally, it is necessary to mention the evolution of sinonasal undifferentiated carcinoma. Recently, Jo et al identified recurrent genetic mutation on IDH2 R172X. This subset of tumors has a slight male predilection, with frequent involvement of the nasal cavity, followed by multiple combined sinuses and a tendency to involve the cranial cavity. Most cases are diagnosed at a high stage and managed with surgery, followed by adjuvant chemoradiotherapy or chemotherapy. It is characterized histologically by a sheet-like and nested proliferation of medium- to large-sized cells, with hyperchromatic cells with vesicular nuclei, prominent nucleoli, and scant-to-moderate palely eosinophilic cytoplasm, with no squamous or glandular differentiation. No rhabdoid cells could be identified in addition to the absence of surface dysplasia. All cases showed a high mitotic count, evident necrosis, prominent lymphovascular spread, and perineural invasion .
SMARCB1-deficient sinonasal carcinoma is usually managed using surgery and radiochemotherapy . Currently, many clinical trials are testing the inhibitors of EZH2 in SMARCB1-deficient sinonasal carcinoma .
SMARCB1-deficient sinonasal carcinoma is a rare neoplasm with an aggressive clinical course and high-grade behavior despite having uniform cytological features. This poses complex diagnoses, especially in small biopsies. Incorporating morphological findings with ancillary tests is required to identify this high-grade malignancy.
FiguresFigure 1.. Unenhanced computed tomography scan in (A) axial and (B) coronal plane shows destructive soft tissue mass seen in the left maxillary sinus measuring approximately 5.8×6.6 cm and extended to involve the left nasal cavity, ethmoid air cells, upper alveolar ridge, hard palate, and orbital floor, with intraorbital extraconal infiltration with no ocular involvement. Figure 2.. (A) Anastomosing nests of basaloid cells in myxoid stroma. (B) Tumor cells show invasion into surrounding bone. (C) Monotonous proliferation of basaloid cells with prominent cytoplasmic vaculation. (D) Some tumor cells showed rhabdoid features with nuclei pushed to periphery. (E) Lymphovascular invasion. Figure 3.. Tumor cell are positive for (A) CK 7, (B) CK AE1/AE3, and negative for (C) P63, (D) Synaptophysin, with loss of SMARCB 1 (INI 1) in tumor cells with the (E) background cells acting as positive internal control. (F) KI-67 shows a high proliferation index.
1.. Agaimy A, Proceedings of the North American Society of Head and Neck Pathology, Los Angeles, CA, March 20, 2022: SWI/SNF-deficient Sinonasal Neoplasms: An Overview: Head Neck Pathol, 2022; 16(1); 168-78
2.. Agaimy A, Koch M, Lell M, SMARCB1 (INI1)-deficient sinonasal basaloid carcinoma: A novel member of the expanding family of SMARCB1-deficient neoplasms: Am J Surg Pathol, 2014; 38(9); 1274-81
3.. Bishop JA, Antonescu CR, Westra WH, SMARCB1 (INI-1)-deficient carcinomas of the sinonasal tract: Am J Surg Pathol, 2014; 38(9); 1282-89
4.. Agaimy A, Hartmann A, Antonescu CR, SMARCB1 (INI-1)-deficient sinonasal carcinoma: A series of 39 cases expanding the morphological and clinicopathological spectrum of a recently described entity: Am J Surg Pathol, 2017; 41(4); 458-71
5.. Mittal P, Roberts CWM, The SWI/SNF complex in cancer – biology, biomarkers and therapy: Nat Rev Clin Oncol, 2020; 17; 435-48
6.. Schaefer IM, Hornick JL, SWI/SNF complex-deficient soft tissue neoplasms: An update: Semin Diagn Pathol, 2021; 38(3); 222-31
7.. Shah AA, Jain D, Ababneh E, SMARCB1 (INI-1)-deficient adenocarcinoma of the sinonasal tract: A potentially under-recognized form of sino-nasal adenocarcinoma with occasional yolk sac tumor-like features: Head Neck Pathol, 2020; 14(2); 465-72
8.. Zamecnik M, Rychnovsky J, Syrovatka J, Sinonasal SMARCB1 (INI1) deficient carcinoma with yolk sac tumor differentiation: report of a case and comparison with INI1 expression in gonadal germ cell tumors: Int J Surg Pathol, 2018; 26(3); 245-49
9.. Agaimy A, Bishop JA, SWI/SNF-deficient head and neck neoplasms: An overview: Semin Diagn Pathol, 2021; 38(3); 175-82
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11.. Rooper LM, Uddin N, Gagan J, Recurrent loss of SMARCA4 in sinonasal teratocarcinosarcoma: Am J Surg Pathol, 2020; 44(10); 1331-39
12.. Schaefer IM, Agaimy A, Fletcher CD, Claudin-4 expression distinguishes SWI/SNF complex-deficient undifferentiated carcinomas from sarcomas: Mod Pathol, 2017; 30(4); 539-48
13.. Jo VY, Chau NG, Hornick JL, Recurrent IDH2 R172X mutations in sino-nasal undifferentiated carcinoma: Mod Pathol, 2017; 30(5); 650-59
14.. Shaverdashvili K, Azimi-Nekoo E, Cohen P, INI-1 (SMARCB1)-deficient undifferentiated sinonasal carcinoma: Novel paradigm of molecular testing in the diagnosis and management of sinonasal malignancies: Oncologist, 2020; 25(9); 738-44
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