SMARCA4-Deficient Carcinoma of Unknown Primary Presenting with Fatal Paraneoplastic Hypercalcemia in a Heart Transplant Recipient: First Report in a Male Patient

Abstract

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare SMARCA4-driven aggressive malignancy of young age characteristically associated with paraneoplastic hypercalcemia. Comparable neoplasms/presentations have not been reported in males. A 39-year-old male heart transplant recipient (HTX 40 months previously) presented with multiple liver nodules and hypercalcemic crisis. The serum parathyroid hormone-related protein (PTHrp) was significantly elevated (241 pg/ml; reference value < 57). Liver biopsy showed poorly differentiated partially rhabdoid neoplasm expressing pancytokeratin, CK20, and focally GATA3, SATB2, p63, and SALL4. The tumor cells showed dual loss of SMARCA4 and SMARCA2. He died of irreversible multiorgan failure one week after admission. To our knowledge, this is the first report highlighting the rare occurrence of paraneoplastic hypercalcemia associated with SMARCA4-deficient malignancies in males. Although the immunophenotype suggests urothelial or upper gastrointestinal tract origin, the exact primary tumor site could not be ascertained due to rapid death of the patient. SMARCA4 immunohistochemistry should be included in the workup of neoplasms associated with hypercalcemia irrespective of gender and site.

Figure 1

Patient's serum calcium values over the years (since his initial cardiac disease in 2007) showed significant hypercalcemia during his fatal disease.

Figure 2

(a) Liver biopsy showed tumor tissue diffusely infiltrating the liver parenchyma (normal liver is seen in lower left field). (b) Higher magnification showed anaplastic large epithelioid cells with prominent nucleoli. (c) Scattered rhabdoid inclusions are seen (arrows) as well as small cytoplasmic vacuoles possibly suggestive of abortive glandular differentiation. (d) In other areas, hemorrhage and spindling might be mistaken for a vascular neoplasm.

Figure 3

By immunohistochemistry, the neoplastic cells expressed strongly pancytokeratin with frequent paranuclear accentuation in the rhabdoid inclusions (a). The neoplastic cells were negative with HepPar-1 ((b) main image; see strongly stained hepatocytes) and CK7 ((b), inset; residual biliary tract epithelial cells are strongly stained). (c) CK20 was expressed in most of cells. (d) GATA3 was focally positive. Both of SMARCA4 (e) and SMARCA2 (f) are lost in the tumor cells (endothelial cells are strongly positive for both markers as internal control).