Autopsy findings in a 6-month-old infant with rhabdoid tumor predisposition syndrome 1: Case report with literature review

To the Editor: Malignant rhabdoid tumor (MRT) and atypical teratoid (AT)/rhabdoid tumor (RT) are rare but aggressive pediatric malignancies. Classic rhabdoid cells found in both MRT and AT/RT show large eccentrically located nuclei with vesicular chromatin and viral inclusion-like nucleoli and dense eosinophilic cytoplasmic hyaline globules. Synchronous RTs in infants younger than 6-month old suggest the possibility of rhabdoid tumor predisposition syndrome (RTPS) (1). Recently, mutations, deletions, and other somatic alterations of integrase interactor 1 (INI1) gene, located on the long arm of chromosome 22, were identified in MRT, AT/RT, and several other malignancies including renal medullary carcinoma, epithelioid sarcoma, and others (2–4). In general, the median survival of less than 1 year is expected for patients with MRT and AT/RT (5, 6), and a 5-year survival is 28.3% (7). Patients usually present early in life with central nervous system, soft tissue, kidney, or liver tumors. Here, we report autopsy findings in a 6-month-old infant with undiagnosed RTPS1 who presented with progressive respiratory failure. At autopsy, he was found to have diffuse, predominantly intralymphatic involvement of the lungs, thymus, and epicardium, with subependymal brain involvement by RT. The patient, a 6-month-old boy, was admitted to the hospital for presumed pneumonia. The patient was born prematurely (28 weeks estimated gestational age) and had a complex history of intraventricular hemorrhage, recurrent respiratory infections, tracheomalacia, and bronchopulmonary dysplasia. During his hospital stay, he experienced progressive acute respiratory failure and was intubated. Bacterial (including mycobacterial) and fungal cultures showed no growth in blood. Cytomegalovirus was detected by PCR testing in blood. Diarrheal pathogens were not identified in stool by nucleic acid amplification testing. Cocksackie A virus, Cocksackie B virus, Echovirus, and Poliovirus were not detected by serology testing. A chest CT showed a large pneumothorax with depression of the right diaphragm and leftward mediastinal shift; diffuse bilateral pulmonary opacities were also noted. A computerized tomography scan of the head revealed an 11-mm hypodense lesion in the inferior aspect of the left cerebellar hemisphere with a more radiodense component extending toward the medulla; the imaging findings were consistent with a remote infarction or cystic intracranial mass (Fig. 1A). The patient’s respiratory status continued to decline despite vasopressors, antibiotics, and maximum mechanical respiratory support, and the family requested transition to comfort care. The patient passed away immediately on withdrawal of ventilatory support. The family requested an autopsy be performed. (A) Head CT. (B) Histologically, the brain tumor is composed of sheets of small round blue cells and focal spindled cells (not shown). (B, C) Rare rhabdoid cells were identified after thorough search. Mitotic activity is brisk. (D) Bilateral lungs showed diffuse, extensive, and predominantly intra-lymphatic involvement by a malignant neoplasm. (E) The architecture of the neoplasm is largely solid and trabecular, with a focal micropapillary pattern. The neoplastic cells are epithelioid and rhabdoid, with vesicular chromatin and prominent nucleoli. Scale bars: B, D = 100 µm and C, E = 20 µm. Examination of the thoracic organs at autopsy revealed minimal clear yellow pleural fluid in both pleural cavities and 20 mL of yellow-clear pericardial fluid. Both lungs showed severe diffuse consolidation and vague nodularity with a combined weight of 290 g (normal range: 110–171 g). The brain weighed 739 g (normal range: 684–890 g) (8) and contained a 1.8 cm × 0.5 cm × 0.5 cm well-circumscribed, tan-white right subependymal mass. The mass partially replaced the body of the caudate nucleus and abutted the right lateral ventricle. Interestingly, no anatomic correlation to the lesion on CT was identified. No additional gross abnormalities were found. No bacterial or fungal isolate was identified in lung tissue, pericardial fluid, or peritoneal fluid. Histopathologic sections from the brain tumor showed a well-circumscribed neoplasm composed of sheets of small round blue cells (Fig. 1B) with focally spindled morphology. A thorough search revealed rare cells with eccentric nuclei, vesicular chromatin, prominent nucleoli, and eosinophilic hyaline globule-like cytoplasm typical of the rhabdoid cells seen in MRT and AT/RT (Fig. 1C). Mitotic activity was brisk. The tumor cells were diffusely immunoreactive with anti-EMA and focally immunoreactive with anti-GFAP, -synaptophysin, and -S100 antibodies. Tumor cells showed no immunoreactivity for myogenin, CD99, pankeratin, desmin, CD34, FLI-1, or CD45. An INI1 stain showed loss of nuclear immunoreactivity in the malignant cells (Fig. 2A). INI1 immunohistochemistry shows loss of stain in brain tumor (A) and lung malignancy (B), respectively. Next-generation sequencing testing by using formalin-fixed paraffin-embedded tissue reveals significantly decreased copy numbers of the SMARCB1 gene in all types of analyzed tissue, indicating a partial germline deletion (C). Histopathologic sections from both lungs demonstrated diffuse, extensive, predominantly intralymphatic involvement by a malignant neoplasm composed of loosely cohesive epithelioid and rhabdoid cells with eosinophilic cytoplasm. The lymphatic channels were dilated. The architecture of the malignant process was largely solid, with focal micropapillary and corded patterns (Fig. 1D). The malignant nuclei showed vesicular chromatin with focally prominent eosinophilic nucleoli (Fig. 1E). The tumor cells were diffusely immunoreactive with pancytokeratin, CK7, and EMA, and focally immunoreactive with glypican-3 antibodies. Tumor cells showed no immunoreactivity for CD45, S100, CD163, AFP, TTF-1, PLAP, D2-40, CD31, CD30, CD117, Mart-1, OCT3/4, SALL4, β-hCG, or inhibin. An INI1 stain showed loss of nuclear immunoreactivity in the malignant cells (Fig. 2B). Sections from thymus and epicardium also showed multifocal, primarily intralymphatic involvement by tumor. Paraffin-embedded tissue from right lung, liver, right kidney, and subependymal mass was used for next-generation sequencing. The TruSight Oncology 500 kit (TSO500, Illumina, Inc., San Diego, CA) was used for library preparation and enrichment, followed by alignment and variant calling performed using the TSO500 bioinformatics pipeline. IGV_2.16.0 (9) was used to view and analyze the sequencing data. Significantly decreased copy numbers in exon 9 of the SMARCB1 gene were recovered from DNA from all examined tissue types, indicating a partial germline deletion of SMARCB1 in the infant (Fig. 2C). RTPS is a rare autosomal dominant cancer predisposition syndrome characterized by a high risk of developing RTs. RTPS is subclassified as RTPS1 when the mutation pathogenic variants are in the SMARCB1 gene and RTPS2 when mutations are in the SMARCA4 gene. It is estimated that 25%–35% of RT carry germline mutations of SMARCB1 (10). The typical clinical presentation of RTPS is an infant with synchronous or multifocal development of AT/RT and extracranial MRT (57% of the cases), AT/RT and RT of the kidney (RTK, 29% of the cases), or AT/RT, extracranial MRT, and RTK (14% of the cases) (11). According to Nemes et al (12), the diagnosis of RTPS should be considered in patients with RT, especially those with multiple primary tumors, and/or in individuals with a family history of RT. Molecular evidence showing SMARCB1 genetic alterations is required to make the diagnosis of RTPS. Patients with RTPS typically present with an AT/RT and 1 extracranial RT. The kidney is the most common extracranial site affected by this syndrome. However, non-renal extracranial RTs have been reported in various locations, including the liver, soft tissue, peripheral nerves, thymus, salivary glands, gastrointestinal tract, genitourinary tract, and heart. Intralymphatic RTs are exceedingly rare. To the best of our knowledge, our case represents the first reported instance of an extensive intralymphatic RT. Intravascular large B-cell lymphoma (ILCL) is a rare subtype of large-cell lymphoma characterized by the proliferation of lymphoma cells within the lumina of small blood vessels. Clinical manifestations often include symptoms related to organ dysfunction caused by the occlusion of blood vessels. ILCL typically affects the neurologic system and the skin. The primary presentation of ILCL in the lungs is uncommon, often mimicking pneumonia (13, 14). The definitive diagnosis of ILCL is usually made postmortem through autopsy. In an earlier publication, a case of lung ILCL was reported in a 35-year-old woman who presented with a 10-month history of progressive dyspnea on exertion and failed to respond to antibiotics. Following thorough examinations of various organs, including bone marrow, liver, lymph nodes, and lungs, an open lung biopsy confirmed ILCL (14). The clinical presentation of our case is similar to that described in the reported lung ILCL case, although our patient had a more aggressive clinical course with rapid deterioration. Both ILCL and our case pose significant diagnostic and treatment challenges, necessitating a high degree of suspicion and an extensive diagnostic workup. In conclusion, we report a 6-month-old infant with a unique clinical presentation who was found at autopsy to have an undiagnosed RPTS1 with diffuse, predominantly intralymphatic involvement of the lungs, thymus, and epicardium, and with focal subependymal brain involvement, clinically mimicking a presentation of pneumonia. All tumor cells showed loss of nuclear INI1 immunoreactivity but tumor morphology was variable between the brain and thoracic sites. NGS studies find a partial germline deletion of SMARCB1 in the infant, confirming the diagnosis of RPTS1. The authors have no conflicts of interest to declare.