Cervical SMARCA4-Deficient Undifferentiated Tumor: A Rare Case Report and Literature Review

Abstract

Background:

The cervical switch (SWI)/sucrose non-fermentable (SNF) related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 (SMARCA4)-deficient undifferentiated tumor (SMARCA4-UT) constitutes a rare, highly aggressive malignancy that is currently unclassified by the World Health Organization (WHO). The published literature comprises predominantly sporadic case reports. Clinically characterized by an unfavorable prognosis, distinctive histopathological morphology, and specific immunophenotypic profiles, a cervical SMARCA4-UT exhibits relatively nonspecific molecular alterations that closely mirror those of a thoracic SMARCA4-UT. Notably, optimal therapeutic algorithms and management paradigms remain incompletely delineated.

Case:

We report a case of cervical SMARCA4-UT in a 58-year-old female presenting with persistent abnormal uterine bleeding. The initial clinical evaluation, including ultrasonography, identified a cervical mass. The patient was subsequently referred to a hospital. Comprehensive staging, using whole-body positron emission tomography-computed tomography (PET-CT) and pelvic magnetic resonance imaging (MRI), confirmed a large cervical neoplasm consistent with clinical stage IV disease, precluding radical surgical resection. Analysis of biopsy specimens demonstrated partial pan-cytokeratin [anti-epithelial cytokeratin 1 (AE1)/anti-epithelial cytokeratin 3 (AE3)] immunoreactivity, focal claudin-4 expression, and complete loss of SMARCA4 protein expression. Next-generation sequencing (NGS) identified a microsatellite instability-high (MSI-H) status, with mutations in genes such as phosphatase and tensin homolog deleted on chromosome ten (PTEN) and AT-rich interaction domain 1A (ARID1A), among others; notably, pathogenic SMARCA4 mutations were absent. A definitive diagnosis of SMARCA4-UT was established. Therapeutic intervention comprised percutaneous radioactive seed implantation followed by combination chemotherapy with etoposide-cisplatin (EP regimen) plus bevacizumab, complicated by bone marrow suppression. Therapy was transitioned to pembrolizumab combined with paclitaxel-carboplatin (TP regimen). Disease progression prompted the reversion to a reduced EP regimen with bevacizumab dosage. The patient demonstrated sustained disease control from her third discharge until the conclusion of the follow-up.

Conclusions:

Single-agent immunotherapy has shown limited efficacy in the inoperable setting, whereas combination chemotherapy regimens incorporating anti-vascular endothelial growth factor (VEGF) agents may have conferred a clinical benefit for tumor control.

Graphical abstract

Keywords

cervical cancer / immunotherapy / pathological diagnosis / prognosis / SMARCA4-deficient tumor

1. Introduction

Switch (SWI)/sucrose non-fermentable (SNF) related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 (SMARCA4)-deficient undifferentiated tumor (SMARCA4-UT) tumors were newly recognized as a distinct entity in the 2021 World Health Organization (WHO) Classification of Thoracic Tumors. These tumors are characterized by the loss of SMARCA4 tumor suppressor protein expression and predominantly arise in the anterior mediastinum. Patients diagnosed with SMARCA4-UT tumors have a median survival of approximately seven months [1]. Furthermore, SMARCA4 gene alterations have been implicated in various malignancies, including those of the central nervous system, head and neck, gastrointestinal tract, urogenital tract, soft tissues, and thoracic region. Although rare, there have been sporadic case reports describing SMARCA4-UT tumors occurring in the cervix [2, 3]. Notably, the most recent edition of the WHO Classification of Tumors of the Female Reproductive Tract did not include specific descriptions or classifications for SMARCA4-deficient undifferentiated cervical tumors. Furthermore, SMARCA4 deletion in most such tumors is confined to the protein level and remains undetected by next-generation sequencing (NGS), presenting significant diagnostic challenges for cervical SMARCA4-UTs. Given the markedly poor clinical prognosis and short survival periods associated with SMARCA4-UT, formulating effective treatment strategies has therefore become particularly urgent.

The present case study delineated a case of SMARCA4-UT, detailing its histological characteristics. Immunohistochemical analysis demonstrated positive anti-epithelial cytokeratin 1 (AE1)/anti-epithelial cytokeratin 3 (AE3) staining in distinct regions, focal Claudin-4 positivity, and complete absence of SMARCA4 protein expression. The differential diagnostic considerations and investigative approach are discussed. Additional genetic variants identified via NGS potentially expand the genotypic spectrum associated with this unique patient population. Therapeutic strategies were evaluated; immunotherapy demonstrated limited efficacy in this tumor subtype. However, chemotherapy combined with anti-vascular endothelial growth factor (VEGF) agents exhibited potential for inhibiting tumor growth, suggesting new therapeutic promise for this category of malignancies.

2. Case Presentation

The patient was a 58-year-old woman who experienced menarche at the age of 13, which is within the normal physiological range. She had regular menstrual cycles with moderate flow and experienced varying degrees of dysmenorrhea during menstruation. On December 16, 2024, the patient presented with abnormal menstruation, characterized by persistent dark-red vaginal bleeding accompanied by a small amount of abnormal vaginal discharge. Throughout this period, there were no obvious abdominal discomforts, such as abdominal pain or bloating. After medical consultation at a local hospital, detailed physical examination and gynecological ultrasound suggested possible cervical tumor lesions. Although initial pharmacological treatment resulted in partial control of vaginal bleeding, follow-up assessments showed no significant change in tumor size. As her condition progressed, she gradually developed new symptoms, including lower abdominal distension and intermittent dull pain.

The patient was referred to Ruijin Hospital, affiliated with Shanghai Jiao Tong University School of Medicine, on January 22, 2025, for further specialized diagnosis and management. Comprehensive positron emission tomography-computed tomography (PET-CT) whole-body imaging and pelvic magnetic resonance imaging (MRI) (specific findings shown in Fig. 1) revealed a bulky cervical tumor. Based on the International Federation of Gynecology and Obstetrics (FIGO) staging system, the tumor was clinically staged as stage IV.

Owing to the extensive tumor volume, the patient was deemed ineligible for radical surgical resection and subsequently underwent biopsy of a limited tumor tissue specimen for histopathological analysis. In this case, the limited quantity of biopsy tissues posed a significant challenge. Moreover, within the framework of the existing WHO classification for the female reproductive system, there had been no reported description of a similar case, and currently, case reports on this condition are scarce. The non-specific molecular characteristics further compounded the diagnostic difficulty. Given these circumstances, accurate diagnosis of this case was difficult.

The specimen sent to the pathology department consisted of fragmented grayish—brown tissue clumps with a volume of 2.0 \times 2.0 \times 1.0 cm. Hematoxylin and eosin (H&E) sections demonstrated an infiltrative neoplasm with solid, sheet-like growth and heterogeneous cellular density. Perivascular invasion and extensive necrosis were evident (Fig. 2A,B). High-power examination revealed monomorphic tumor cells exhibiting vesicular nuclei with hyperchromasia, prominent nucleoli, and eosinophilic cytoplasm. Rhabdoid morphology predominated (Fig. 2C), featuring eccentric nuclei, marked atypia, and readily identifiable mitoses in hyperchromatic cells. Stroma showed minimal inflammation with focal myxoid matrix (Fig. 2D).

During the pathological diagnostic process, we distinguished four distinct entities: (1) SMARCA4-deficient uterine sarcoma (SDUS); (2) Undifferentiated endometrial carcinoma (UDEC); (3) Ovarian hypercalcemic small cell carcinoma (SCCOHT); and (4) Conventional cervical carcinoma. Key differential diagnostic criteria comprised: (a) Imaging findings demonstrating a large cervical mass, effectively excluding SCCOHT as it represents a highly malignant ovarian tumor; (b) Immunohistochemical (Fig. 3 shows some of the immunohistochemical results) analysis revealing partial AE1/AE3 positivity, focal Claudin-4 immunoreactivity, complete loss of SMARCA4 protein expression, patchy p16 positivity, and tumor protein p53 (p53) positivity in 90% of tumor cells. SDUS characteristically exhibits negative Claudin-4 staining. The absence of SMARCA4 protein expression excluded conventional cervical carcinoma. In UDEC, approximately 34% of cases harbor tumor protein 53 (TP53) mutations and about 44% demonstrate microsatellite instability (MSI) [4], thereby differentiating it from SDUS. The H&E morphology of UDEC, featuring undifferentiated carcinoma or rhabdomyoid cells, resembled the current case. Immunohistochemical analysis similarly showed loss of SMARCA4 expression, AE1/AE3 positivity, Claudin-4 positivity, and p53 mutation. Nevertheless, differentiation from the present case remained challenging. In contrast, the primary lesion in this case was cervical in origin and demonstrated patchy p16 positivity (NOTE: Based on the experimental protocol, immunohistochemical staining was performed using the EnVision™ FLEX detection system (Standard, Dako/Agilent, Santa Clara, CA, USA, Cat. K8000; Patent EP1301268B1). Primary antibodies against SMARCA4 (rabbit monoclonal, clone EP235; dilution 1:150), pan-cytokeratin AE1/AE3 (mouse monoclonal, clone AE1/AE3-P; dilution 1:80), P16INK4a (mouse monoclonal, clone E6H4; dilution 1:1), TP53 (mouse monoclonal, clone DO-7; dilution 1:100) and CLDN4 (Claudin-4) (Rabbit monoclonal, clone EP145; dilution 1:200) were procured from Leica Biosystems (Leica Biosystems GmbH, Am Lustbühel 1, 69126 Heidelberg, Baden-Württemberg, Germany) and Agilent Dako (Dako Denmark A/S, Produktionsvej 42, 2600 Glostrup, Denmark), respectively. Based on these collective findings, the diagnosis was more consistent with a cervical SMARCA4-UT. Paraffin-embedded tissue samples were subjected to NGS, which revealed microsatellite instability-high (MSI-H) status and identified 12 distinct mutations across 688 tumor-related genes (results detailed in Table 1) [NOTE: The NGS reagents (Cat. No. SH-SEQ2025) were procured from Shihuo Biotech Co., Ltd. (Shanghai, China), and all experimental procedures, including library preparation and sequencing runs, were conducted in strict accordance with the manufacturer’s protocol (Version 3.1, issued 2024)].

On January 24, 2025, the patient underwent Implantable Venous Access Port (IVAP), followed by EP (cisplatin 75 mg/m² d1, etoposide 100 mg/m² d1–3) chemotherapy, combined with bevacizumab (15 mg/kg d1, q3w). However, significant myelosuppression occurred after treatment initiation, necessitating a switch to TP (T = 135 mg/m², P = 50 mg/m² d2) chemotherapy. Because of the MSI-H status that was detected by NGS, pembrolizumab (200 mg d1) was added to the therapeutic regimen. Nevertheless, imaging performed in March demonstrated tumor progression with increased volume, prompting modification of the treatment plan to reduced-dose EP chemotherapy while continuing bevacizumab therapy. From the third discharge in March 2025 until the most recent follow-up, the patient’s general condition remained stable, and she is currently surviving with tumor-bearing status.

3. Discussion

Brahma-related gene 1 (BRG1, SMARCA4) and Brahma homolog (BRM, SMARCA2), as the catalytic subunits of the mammalian switch/sucrose non-fermentable Chromatin Remodeling Complex (mSWI/SNF or BAF) complex, are highly evolutionarily conserved. This complex plays a central role in chromatin remodeling [5]. It regulates transcription by altering nucleosome topology through adenosine triphosphate (ATP)-dependent mechanisms. Cancer genomic study has revealed that more than 20% of human tumors harbor mutations in one or more components of the BAF complex [6]. Experimental evidence has demonstrated that most of these mutations contribute to increased tumorigenesis, supporting the tumor-suppressive function of the BAF complex under normal physiological conditions [7].

SMARCA4 (BRG1), as the ATPase core of the complex, provides the enzymatic driving force [8] and is therefore also recognized as a tumor suppressor. It encodes the BRG1 protein, which forms functional complexes essential for chromatin regulation. Moreover, SMARCA4 is among the most frequently mutated chromatin remodeling ATPases in cancer, accounting for approximately 5–7% of all human malignancies, with mutations predominantly located in evolutionarily conserved ATPase domains [9]. In a cohort study of SMARCA4-deficient non-small cell lung cancer (SMARCA4-dNSCLC), recurrent somatic mutations were identified in genes including SMARCA4, KRAS, and TP53 [10]. Notably, patients harboring alterations in SMARCA4, TP53, or serine/threonine kinase 11 (STK11) exhibited significantly shortened median overall survival compared to those without these genetic alterations [11].

SMARCA4 variations comprise two primary categories: Type I includes truncating mutations, gene fusions, and homozygous deletions, which result in complete loss of function; Type II comprises missense mutations that may exert dominant-negative or gain-of-function effects, either with or without functional loss [12]. An experimental study has demonstrated a high degree of consistency between the proportion of SMARCA4-subunit deletions and SMARCA4-gene mutations [13], leading researchers to suggest that genetic mutations may be the primary cause of protein expression loss. However, NGS has revealed that SMARCA4 gene mutations do not necessarily result in protein deficiency. For instance, missense mutations and allele mutations have been observed without corresponding protein expression loss [14], indicating that molecular sequencing is not essential for diagnosing SMARCA4-deficient tumors. Currently, the absence of SMARCA4 (BRG1) protein expression is widely used as a diagnostic marker for SMARCA4-UT.

Therefore, in clinical settings, immunohistochemical confirmation of SMARCA4 protein loss, as observed in this case, may be sufficient for diagnosis, particularly when NGS fails to detect typical SMARCA4 gene variants. According to recent data from The Cancer Genome Atlas (TCGA) [15, 16], such cases account for approximately 15–20% of SMARCA4-UT diagnoses.

The present case results were identified through NGS, which revealed an AT-rich interaction domain 1A (ARID1A) gene mutation. As the largest subunit of the BAF complex [17], ARID1A is characterized by frequent mutations across diverse human malignancies. These mutations impair the chromatin remodeling function of the complex, thereby promoting tumor-cell proliferation and invasiveness. Furthermore, by disrupting cell cycle regulatory pathways, these mutations drive aberrant cell proliferation [18]. A study reveals that the ARID1A-containing SWI/SNF complex (ARID1A/SWI/SNF) serves as a potent inhibitor of the pro-oncogenic transcriptional coactivators yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), effectively suppressing their activity and thereby curbing uncontrolled cell proliferation and tumor formation [19]. Evidence has confirmed that SMARCA4 deficiency frequently coexists with ARID1A mutations, and their concurrent occurrence in lung cancer may impair transcriptional regulation [20]. This may have accounted for the observed reduction in SMARCA4 protein expression despite the absence of detectable gene deletions. An alternative explanation involves limitations inherent in current detection methods: NGS technology exhibits restricted coverage for specific mutation classes, potentially leading to the oversight of pathogenic variants affecting SMARCA4.

SMARCA4-UT was first described in 2015 as a group of undifferentiated thoracic malignant neoplasms [21]. Initially classified as a sarcoma-like tumor, accumulating molecular evidence has led to its reclassification as a dedifferentiated or undifferentiated carcinoma [22]. Consequently, the WHO classification (5th Ed.) categorizes this entity under “other epithelial tumors”. SMARCA4-UT is a high-grade malignancy characterized by an undifferentiated or rhabdoid morphology and the absence of SMARCA4 expression [23]. A recent study has indicated that SMARCA4-UT can occur across multiple anatomical sites beyond the thorax, including the lung [24], gallbladder [25], paranasal sinuses [26], nasopharynx [27], gastrointestinal tract [28, 29, 30, 31], adrenal gland [31], urothelium [32], and skin [33].

As of 2020, the WHO classification of tumors of the female genital tract did not specifically describe SMARCA4-UT [34]. However, that does not imply the absence of SMARCA4 deficiency in tumors of the female reproductive system. In fact, SMARCA4 loss was first identified in ovarian small-cell carcinoma hypercalcemia type (SCCOHT) as early as 1982 [35]. SCCOHT is a rare aggressive ovarian malignancy associated with hypercalcemia in two-thirds of cases. Unlike most undifferentiated ovarian carcinomas with large cells and abundant cytoplasm, it has small cells [36]. SCCOHT shares similarities with rhabdoid tumors; both show SWI/SNF-complex mutations and poor response to conventional therapy [37]. Cervical SMARCA4-UT remains an extremely rare entity, with only limited reports published by the Sirák team [2] and the Yokoe team [3]. The histological features in case report were largely similar to those cases, although minor differences in immunohistochemical profiles were observed (Table 2, Ref. [2, 3]). Neither of the previously reported cases demonstrated SMARCA4 loss in molecular testing, and other molecular features were not fully characterized. The genetic findings presented herein may aid in better defining the molecular landscape of such rare tumors. The published case reports and the present case are comprehensively detailed in Table 2 with respect to the site of symptom onset, histological characteristics, immunohistochemical findings, therapeutic regimens, and prognostic outcomes.

In terms of treatment, surgical resection remains the primary therapeutic strategy for localized disease. In the case reported by Yokoe’s team [3], laparoscopic resection was performed with negative margins. Postoperative concurrent chemoradiotherapy (CCRT) was administered at a total dose of 50 Gy in 28 fractions. Weekly cisplatin (40 mg/m²) was given for six cycles without significant adverse events. Follow-up showed sustained serum carcinoembryonic antigen (CEA) levels below 5.0 ng/mL, and imaging along with vaginal cuff cytology revealed no signs of recurrence at a one-year post-treatment follow-up. However, prognosis tends to be poorer in inoperable cases. The patient reported by Sirák’s team [2] received two cycles of cisplatin plus etoposide as first-line therapy after radical hysterectomy was deemed unfeasible. Upon progression, extended pelvic radiotherapy (45 Gy in 25 fractions) was delivered, but the patient succumbed three months later.

In the present case, the large tumor burden precluded radical surgery, prompting treatment with percutaneous radioactive seed implantation (PORT). Subsequent chemotherapy with the etoposide-cisplatin (EP regimen) combined with bevacizumab was initiated. However, significant myelosuppression necessitated a switch to the paclitaxel-carboplatin (TP regimen). Given the MSI-H status detected via NGS, pembrolizumab was added to the treatment protocol. Three months later, imaging revealed tumor progression, leading to a revised regimen of reduced-dose EP chemotherapy with continued bevacizumab. From March 2025 (third discharge) until the latest follow-up, the patient remained clinically stable with tumor-bearing survival. These findings suggested that immunotherapy may offer limited efficacy in inoperable SMARCA4-UT, whereas chemotherapy combined with anti-VEGF agents may provide partial tumor growth inhibition.

During this therapeutic intervention, we administered bevacizumab, an anti-VEGF agent. This monoclonal antibody specifically binds to VEGF, thereby blocking its interaction with endothelial cell surface receptors [including fms-like tyrosine kinase 1 (Flt-1) and kinase insert domain receptor (KDR)], which consequently inhibits tumor angiogenesis and restricts malignant proliferation. Notably, investigations of colorectal cancer have demonstrated that SMARCA4 promotes VEGF-A expression and angiogenesis within tumor microenvironments, suggesting its potential as a therapeutic target [38]. However, this conclusion contradicts our current data. The investigators of that study also acknowledged this discrepancy, attributing it to the context-dependent dual biological functions of SMARCA4, which manifests either pro-tumorigenic or anti-tumor effects across distinct cancer types. This mechanistic divergence necessitates further investigation through molecular studies.

4. Conclusions

Cervical SMARCA4-UT represents an exceptionally rare and aggressive malignancy. Its low incidence, poorly differentiated morphology, and aggressive clinical behavior pose significant diagnostic and therapeutic challenges. The in-depth analysis of this case facilitated the formulation of more standardized and precise clinical approaches for the management of such rare tumors. Given the rarity of this tumor subtype, the present report constituted an isolated case study lacking large-scale clinical validation. Future multi-center clinical trials with substantial cohorts are warranted to establish therapeutic efficacy for cervical SMARCA4-UT, particularly in identifying specific patient subgroups deriving benefit from combined immunotherapy, chemotherapy, and anti-angiogenic agents. The correlation between molecular markers (such as SMARCA4 deletion status), MSI/mismatch repair (MMR) profiles, concomitant driver-gene alterations, and treatment response is a critical area that requires further investigation. This is evidenced by the significance of MSI/MMR as predictive biomarkers in immunotherapy, to clarify the molecular underpinnings of precision medicine in rare malignancies. Notably, the patient’s extended survival with persistent tumor burden demonstrated that sustained disease stabilization through personalized therapy, even without achieving complete remission, can significantly enhance quality of life and provide clinically relevant insights for managing inoperable advanced disease. However, clinical application should refrain from indiscriminately extrapolating individualized regimens due to the inherent limitations of single-case reports. For patients receiving chemotherapy combined with anti-angiogenic therapy, it is imperative to rigorously monitor treatment-related adverse events (e.g., myelosuppression) to ensure therapeutic safety and continuity.

Availability of Data and Materials

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

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