Metastatic SMARCA4-Deficient Undifferentiated Carcinoma of the Oral Cavity: A Case Report and Review of Literature

Abstract

Purpose

SMARCA4-deficient high-grade malignancies are increasingly recognized across various anatomic sites, namely the genitourinary tract thorax, gastrointestinal tract, head and neck, and central nervous system. Within the head and neck region, the sinonasal tract is most commonly affected. These tumors are aggressive, often presenting with local or distant metastases at diagnosis, and median survival ranges from 4 to 7 months. We report a rare case of SMARCA4-deficient carcinoma presenting as a metastasis to the oral cavity, highlighting key histopathologic and clinical features.

Case report

A 63-year-old woman presented with a 3.0 × 2.0 × 2.0 cm exophytic mass involving teeth #25–28 and a 4 cm poorly defined radiolucency in the mandible. Histologically, the tumor was composed of diffuse sheets of large polygonal epithelioid cells with indistinct borders, pale eosinophilic cytoplasm, vesicular pleomorphic nuclei, prominent nucleoli, and numerous atypical mitotic figures and apoptotic bodies. Immunohistochemistry showed focal positivity for pankeratin, CAM5.2, and claudin-4. The tumor was negative for S100, SOX10, and SMARCA4 (BRG1), confirming SMARCA4-deficiency. A CT scan revealed a 5.5 cm mandibular lesion and a 16 cm right upper lobe lung mass, with additional nodules in the contralateral lung, thyroid, kidney, and widespread lymphadenopathy. The findings were consistent with a primary thoracic SMARCA4-deficient undifferentiated tumor with diffuse metastases. The patient died within two months of initial diagnosis of the oral metastasis.

Conclusion

To our knowledge, this is the first reported case of this unusual tumor metastasizing to the oral cavity. Given the aggressive nature and metastatic potential of these tumors, it is essential to evaluate for a distant primary malignancy when such a lesion is encountered in the head and neck.

Introduction

Recent breakthroughs in molecular pathology have significantly improved our understanding and classification of tumors that had been diagnosed in the past with a descriptive diagnosis or not otherwise specified. Among these are the SMARCA4-deficient malignancies, a group of heterogeneous neoplasms that share the same genetic mutation but exhibit a variety of clinical presentations as well as microscopic features. SMARCA4 (previously known as BRG1) is one of the two catalytic ATPase subunits of a multiprotein complex named switch/sucrose-nonfermentable (SWI/SNF) chromatin remodeling complex, which plays a crucial role in transcriptional regulation and tumor suppression. Since their first description in the late 2010 s, SMARCA4-deficient tumors have been reported from various anatomic sites including the lungs, ovaries, and the head and neck [1–3]. To date, however, only one primary oropharyngeal SMARCA4-deficient carcinoma, one primary SMARCA4-deficient carcinoma of the salivary glands, and one metastatic thoracic SMARCA4-deficient undifferentiated carcinoma to the maxilla have been described in the English literature [4–6]. Herein, we report a case of a 63-year-old female patient who presented with a poorly differentiated carcinoma of the mandible, which was confirmed to be metastatic from a primary lung malignancy, characterized as SMARCA4-deficient.

Case Report

A 63-year-old female patient presented to an oral and maxillofacial surgeon with the chief concern of painful mandibular swelling. The pain was described by the patient as gnawing in nature and limited to the right jaw. Medical history was significant for chronic obstructive pulmonary disease, dyslipidemia and osteoarthritis. She also reported a 40 pack-year smoking history. Extraoral examination did not reveal lymphadenopathy. Intraoral examination revealed an erythematous, exophytic and fungating mass of the lower right quadrant, causing mobility of the involved, right mandibular incisors and canine (Fig. 1A and B). The mass measured approximately 3 × 2 × 2 cm. The panoramic radiograph revealed an ill-defined radiolucency surrounding the roots of the right mandibular lateral incisor and canine (Fig. 1C).

Fig. 1.

Clinical appearance at initial presentation (A) and 2 months later (B). The panoramic radiograph reveals an ill-defined unilocular radiolucency surrounding the roots of the right mandibular lateral incisor and canine (C). Computed tomography of the head and neck and chest revealed a 5.5 × 4.2 cm mass centered in the right parasymphyseal mandibular ridge (D) and solid lung mass of the right upper lobe measuring approximately 16 × 7.8 cm (E)

An incisional biopsy was performed and revealed a tumor composed of sheets of large polygonal epithelioid cells with indistinct cell borders and abundant pale, eosinophilic to amphophilic cytoplasm (Fig. 2A and B). The tumor cells exhibited large, atypical and vesicular nuclei with variably prominent and multiple nucleoli. Marked pleomorphism, many atypical mitotic figures, apoptotic bodies, and areas of tumor necrosis were present (Fig. 2C). Immunohistochemistry (IHC) revealed that the tumor cells were multifocally positive for CAM5.2 (Fig. 2E), pan-keratin (Fig. 2F) and claudin-4, and negative for S100 protein and SOX10. The tumor cells showed complete nuclear loss of SMARCA4 (Fig. 2D), confirming the final diagnosis of SMARCA4-deficient undifferentiated carcinoma.

Fig. 2.

Hematoxylin and eosin-stained section demonstrates sheets of large epithelioid cells with indistinct cell borders and ample amounts of pale cytoplasm. Marked pleomorphism and many atypical mitotic figures are noted (A–C). The tumor cells exhibit complete nuclear loss of SMARCA4 (D) and are positive for CAM 5.2 (E) and pan-keratin (F)

Computed tomography of the head, neck and chest confirmed the presence of a 5.5 cm mandibular mass and revealed a16 cm lung mass of the upper right lobe, another 6 cm lung mass of the left lower lobe, 5 cm right thyroid mass and 2.7 cm left renal mass (Fig. 1D and E). It also confirmed bilateral level Ib, right level II and III, and right supraclavicular adenopathy as well as scattered pulmonary nodules with enlarged hilar and mediastinal lymph nodes. Core biopsy of the right thyroid mass and fine needle biopsy of multiple lymph nodes confirmed presence of SMARCA4-deficient malignancy. The findings were consistent with diffuse and extensive metastatic disease. The patient was started on palliative radiation and chemotherapy. However, patient elected to discontinue radiation treatment and chemotherapy, and succumbed to the disease within 2 months of the initial diagnosis of the mandibular mass.

Discussion

Recent breakthroughs in molecular pathology have revealed a high prevalence of mutations in genes encoding subunits of the SWI/SNF chromatin-remodeling complex. This ATPase-dependent complex is composed of approximately 15 protein subunits and serves key roles in cell proliferation and differentiation, transcriptional regulation, and DNA damage repair [7]. Its core members include SMARCB1 (also known as SNF5, BAF47, and INI1), SMARCC1 (BAF155), SMARCC2 (BAF170), SMARCA2 (BRM), and SMARCA4 (BRG1) [8]. SWI/SNF complexes represent the one of the most commonly mutated chromatin modulators in cancer, occurring in over 20% of all human malignancies. SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 or SMARCA4 is one of the two catalytic subunits of the SWI/SNF complex that modulate cellular processes by interacting with key regulatory proteins such as RB, p53, and beta-catenin [9]. Therefore, SMARCA4 plays a crucial role in tumor suppression as well as DNA repair mechanisms and its alteration can result in carcinogenesis.

Malignancies with SMARCA4 deficiency have been reported in various anatomic locations, including the SMARCA4-deficient undifferentiated carcinoma of ovaries (small cell carcinoma, hypercalcemic type, or SCCOHT), thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UT), and SMARCA4-UT of the genitourinary tract [10]. These entities share the molecular alteration of SMARCA4, characterized by loss of nuclear expression of SMARCA4 by IHC. However, there exists a wide spectrum of biological, histomorphologic, and immunohistochemical features within different anatomic sites.

SMARCA4 deficient carcinomas involve the head and neck, especially the sinonasal tract, with the nasal cavity being the most frequently affected site. The first case of SMARCA4-deficient sinonasal carcinoma was reported in 2017 by Agaimy and Weichart involving the right nasal cavity and the sinuses with extension into the skull base and periorbital tissue [11]. They described the tumor cells as “blue-appearing” small to medium sized cells with hyperchromatic nuclei and focal plasmacytoid features. They reported diffuse positive staining for cytokeratin and focal positive staining for neuroendocrine markers. This case was included in the subsequent series of 10 SMARCA4-deficient sinonasal carcinomas reported by Agaimy et al. in 2020 [3]. These tumors were initially diagnosed as neuroendocrine carcinomas (NEC) or poorly differentiated carcinomas. Histologically, the tumors were composed of nests and solid sheets of small basaloid or large epithelioid cells with extensive areas of necrosis, showing consistent expression of pankeratin and total loss of SMARCA4 by IHC. Of the six cases with available follow-up data, four patients succumbed to disease with median survival of 3 months. One patient presented with lung/mediastinal metastasis at presentation and two patients developed metastases, one patient with brain invasion and another with multiple metastases to the vertebrae and liver. Rooper et al. performed SMARCA4 IHC on 22 sinonasal teratocarcinosarcoma (TCS) and 153 other sinonasal tumors, and identified complete and partial loss of SMARCA4 expression in 15 and 3 cases, respectively [12]. In 2022, Kakkar et al. identified 12 cases of SMARCA4-deficient sinonasal carcinomas among a cohort of 299 cases of archival sinonasal carcinomas that were diagnosed as sinonasal undifferentiated carcinoma (SNUC), poorly differentiated carcinoma, NEC, or TCS [13]. Diffuse and complete loss of SMARCA4 expression was noted in 10 cases, while 2 cases showed severe reduction with focal retention of expression. There were eight cases with available information of clinical course, and five patients succumbed to disease.

More recently reported cases of SMARCA4-deficient carcinomas in the head and neck region further illustrate the aggressive nature of these tumors. Pasricha et al. reported the first case of primary SMARCA4-deficient carcinoma of the oropharynx in a 67-year-old man presenting with a painful tonsillar mass, whose tumor exhibited sheets of undifferentiated epithelioid cells with complete SMARCA4 loss and who died despite chemoradiotherapy [4]. Oestreicher et al. described the first salivary gland SMARCA4-deficient carcinoma in an 81-year-old woman with a parotid mass and widespread metastases; histolopathology showed rhabdoid-like cells with SMARCA4 loss confirmed by sequencing, and the patient received surgery, radiotherapy, and checkpoint inhibitor therapy [5]. Muller et al. described a case of metastatic thoracic SMARCA4-deficient undifferentiated carcinoma presenting as a soft tissue mass of the anterior maxillary gingiva in a 58-year-old man associated with bilateral neck swelling, dyspnea, and weight loss [6]. Imaging revealed a maxillary mass, extensive involvement of cervical lymph nodes, a lung mass, and diffuse metastatic disease. Histolopathology showed a high-grade malignant epithelioid neoplasm with rhabdoid features and reduced to absent SMARCA4 expression, leading to the diagnosis of metastatic SMARCA4 deficient thoracic sarcomatoid tumor (now referred to as thoracic SMARCA4-deficient undifferentiated carcinoma) [6]. More recently, Zhu and Liu reported two cases of SMARCA4-deficient carcinoma with skull base invasion: one in a 36-year-old man with a nasal mass extending to the orbit and anterior skull base who died one month after discharge, and another in a 64-year-old man with extensive bony destruction at the skull base and progressive symptoms despite surgery and chemotherapy [14]. The clinical and immunohistochemical characteristics of these reported cases are summarized in Table 1.

Table 1.

SMARCA4-deficient carcinomas of the head and neck

	Agaimy et al	Rooper et al	Kakkar et al	Zhu and Liu	Muller et al	Pasricha et al	Oestreicher et al
n =	10	22	12	2	1	1	1
M:F	7:3	13:9	10:2	2:0	1:0	1:0	0:1
Median age	44 (20–67)	45 (18–67)	36 (22–70)	49 (34–64)	58	67	81
Locations	Nasal cavity (6), nose and sinuses (2), sinonasal unspecified (2)	Nasal cavity and paranasal sinuses	Nasal cavity and paranasal sinuses	Left nasal cavit and skull base	Right anterior maxilla	Right tonsillar fossa	Left parotid
SMARCA4	Loss (10/10)	Loss (15/22), reduced (3/22), intact (4/22)	Loss (12/12)	Loss (2/2)	Reduced to absent	Loss	Loss
SMARCB1	Retained (10/10)	Reduced (6/15), intact (9/15)	Retained (12/12)	Retained (2/2)	N/A	Retained	Retained
SMARCA2	Retained (5/8), reduced (2/8), loss (1/8)	Reduced (14/15), intact (1/15)	Retained (11/11)	N/A	N/A	N/A	N/A
Claudin-4	N/A	Variable (15/15)	N/A	N/A	N/A	N/A	N/A
Pankeratin	Positive (10/10)	N/A	Positive (9/12), focal (3/12)	N/A	Negative	Positive	Positive
CK5/6	0/10	N/A	Focal (2/8)	N/A	N/A	N/A	N/A
CK7	Focal (2/6)	N/A	Focal (1/4)	N/A	N/A	N/A	N/A
p16	0/5	N/A	0/12	N/A	N/A	N/A	N/A
NUT	0/8	N/A	0/12	N/A	N/A	Negative	N/A
Chromogranin	Focal (4/10)	N/A	Focal (8/10), postive (2/10)	N/A	N/A	Negative	Negative
Synaptophysin	Weak to positive (9/10)	N/A	Focal (8/12), positive (3/12), negative (1/12)	N/A	Weak	Negative	Focal and weak
CD56	Focal (3/5)	N/A	Focal (3/3)	N/A	N/A	N/A	Negative

It appears that SMARCA4-deficient malignancies are characterized by aggressive clinical behavior with frequent distant metastases and an unfavorable prognosis, with a reported median survival of approximately 3 months. Histologically, these tumors exhibit a broad morphologic spectrum, including sheets of large polygonal or rhabdoid cells with abundant eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli; basaloid patterns with hyperchromatic nuclei and scant cytoplasm; neuroendocrine-like features such as nested or trabecular growth with rosette-like structures; and high-grade undifferentiated or sinonasal undifferentiated carcinoma (SNUC)-like morphology. This variability can complicate diagnosis and highlights the importance of correlating morphology with immunohistochemical loss of SMARCA4 expression.

Although metastasis to the oral cavity is rare, comprising less than 1% of all oral tumors, the mandible is the most commonly affected subsite within the oral cavity [15]. Thus, it is imperative to consider or rule out a metastatic process as differential diagnosis of mandibular tumors, particularly those presenting with histologicfeatures that do not correspond to know primary neoplasia within the oral cavity. The more frequent primary sites for mandibular metastasis in males include the lungs, kidneys, and liver, while in females, these are the breast, genital organs, and kidneys. This underscores the importance of a comprehensive approach to diagnosis, incorporating molecular pathology and thorough evaluation of primary tumor sites, to guide appropriate management and improve patient outcomes.

Conclusion

This is a case report of a metastatic SMARCA4-deficient carcinoma in the mandible of a 63-year-old female patient. SMARCA4 is one of the ATPase subunits of SWI/SNF chromatin remodeling complex and its deficiency results in development of clinically aggressive malignancy in various anatomic sites. Metastatic disease must be considered and ruled out in cases with atypical clinical and histologic findings for appropriate management.

Author Contributions

M.K. wrote the manuscript and created the figures. P.H. gathered the clinical data. S.W. reviewed the histopathology slides and supervised the project. All authors reviewed and approved the final manuscript.

Funding

This study was not supported by any funding.

Data Availability

No datasets were generated or analysed during the current study.

Code Availability

Not applicable.

Declarations

Conflict of interests

The authors declare no competing interests.

Ethical Approval

This article does not contain any studies with human participants performed by any of the authors.

Consent to Participate

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Consent for Publication

Consent for publication was obtained for every individual person’s data included in the study.