First report of SMARCA4‐deficient carcinoma ex‐pleomorphic adenoma in salivary glands

Sir: The SMARCA4-deficient neoplasms are recently recognised, highly aggressive malignancies driven by the inactivation of SMARCA4 (BRG1) gene. SMARCA4 is a core subunit of the switch/sucrose non-fermentable (SWI/SNF) chromatin remodelling complex, increasingly implicated in the pathogenesis of several malignancies.1 Although rare, SMARCA4-deficient neoplasms have been reported in the ovaries, endometrium, thorax, gastrointestinal tract, and sinonasal tract. These are unified by undifferentiated/rhabdoid morphology and immunohistochemical loss of SMARCA4 expression.2, 3 To our knowledge, SMARCA4 loss in salivary gland neoplasms has not been demonstrated to date. Herein, we report a previously undescribed case of SMARCA4-deficient carcinoma ex-pleomorphic adenoma (CXPA) to alert readers to the rarity of such occurrences. A 60-year-old non-smoking man presented with a recently enlarging parotid mass that had persisted since his childhood, together with another swelling below his right mandible. A magnetic resonance scan revealed a 2.8 × 1.9 × 2.8 cm mass in the superficial parotid and multiple metastatic right level II nodes (Figure 1A). The total parotidectomy revealed a 2.4 × 2 × 1.8 cm circumscribed nodular tumour with a firm to hard cut-surface. Beyond this, and towards the parotid tail, the glandular parenchyma was reddish-brown, friable, and necrotic, merging with a large necrotic mass, measuring 5.4 cm at the level 1B/II region. Histological evaluation revealed a largely hyalinised pleomorphic adenoma (PA) from which arose a cellular tumour composed of sheets of a monotonous population of rhabdoid/plasmacytoid cells with eccentrically placed nuclei indented by globoid dense eosinophilic cytoplasmic inclusions (Figure 1B–F). The nuclei exhibited marked atypia, were hyperchromatic, pleomorphic, convoluted and bore prominent nucleoli. Multinucleated and bizarre tumour giant cells were frequently interspersed. Brisk mitotic activity (25/2 mm2), abundant necrosis, and karyorrhectic debris/apoptotic bodies was noted. The tumour was devoid of any squamous/glandular differentiation, mucin, zymogen granules, secretions, clearing, or vacuoles. No conventional salivary carcinoma was identified to indicate a high-grade transformation. The tumour was widely invasive, with extensive extraparenchymal spread into the peri-parotid soft tissues. Lymphovascular invasion was present, while perineural invasion was absent. Multiple metastatic lymph nodes were matted together to form a large metastatic mass with extensive extension into the soft tissues (regarded as extranodal extension). On immunohistochemistry (IHC) (Figure 2A–F), intracytoplasmic globoid keratin-positive inclusions were conspicuous (Figure 2D). Tumour cells were negative for androgen receptor, GATA3, GCDFP-15 (thus excluding rhabdoid salivary duct carcinoma), p40, p63, S100, SOX10, desmin, myogenin, MyoD1, CD34, SALL4, synaptophysin, INSM1 and HER2. Additionally, p53 overexpression (mutant pattern) was noted in the malignant component (wild-type in the PA), Given the rhabdoid morphology, SMARCB1 and SMARCA4 antibodies were added. While tumour nuclei retained SMARCB1, there was a complete loss of nuclear SMARCA4 in the tumour cells, with retained reactivity in the endothelial, stromal, and immune cells (Figure 2C). Hence, a diagnosis of SMARCA4-deficient carcinoma ex-PA was offered. The patient is currently scheduled to receive radiotherapy. Carcinoma ex-PA are rare neoplasms, accounting for approximately 12% of salivary gland malignancies.4 Nearly all known histological types of salivary malignancies have been reported to occur in CXPA, with SDC and myoepithelial carcinoma being the most common types. Exceptionally rare dual5 and triple malignancies6 may also occur. To the best of our knowledge, SMARCA4-deficient carcinoma has not been reported until now, either as a de-novo salivary gland carcinoma or as a CXPA. With this report, the salivary gland is appended to the evolving list of organs that may harbour a SMARCA4-deficient carcinoma. Undifferentiated rhabdoid/plasmacytoid morphology with high-grade nuclear atypia should prompt including SMARCA4 and SMARCB1 in the IHC panel. Rhabdoid morphology is less frequent in the sinonasal counterpart of SMARCA4-deficient carcinomas; the latter tends to show monotonous large cells with frequent neuroendocrine features. While rhabdoid cells are a clue to SMARCB1-deficient sinonasal carcinomas, their spectrum is wider and includes basaloid cells, glandular morphology, and yolk sac-like areas. Complete loss of SMARCA4 expression is the defining feature of SMARCA4-deficient neoplasms, essentially distinguishing it from other mimics. Most studies have demonstrated aggressive clinical behaviour of these tumours, irrespective of the site of origin. In summary, we report the first case of SMARCA4-deficient carcinoma ex-PA. This case is unique not only as first SMARCA4-deficient neoplasm to be reported in salivary glands but also as a here-to-fore unreported histological type of malignancy in CXPA. No conflicts of interest to disclose. No funding obtained. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.