PMC8421801_01
Patient A: preoperative, axial T1 postcontrast weighted magnetic resonance (MRI) imaging showing enhancing disease (A); postoperative, axial T1 postcontrast weighted MRI imaging showing enhancing, residual disease (B); radiation therapy (RT) planning using volumetric arc therapy (VMAT) resulted in excellent coverage of the planning target volume (PTV) (red) by the 100% isodose line (yellow) corresponding to 5940 cGy (C); follow up gallium-68 dotatate positron emission tomography (PET) after more than 6 years showing hypermetabolic, recurrent disease in the left tentorial leaflet and physiologic uptake in the pituitary (D); Patient B: preoperative, axial T1 postcontrast weighted MRI imaging showing enhancing disease (E); postoperative, axial T1 postcontrast weighted MRI imaging showing enhancing, residual disease (F); postoperative PET showing hypermetabolic, residual disease (G); RT planning using VMAT resulted in excellent coverage of the 6000 cGy (red) and 5400 cGy (blue) PTVs by the 100% (yellow) and 90% (green) isodose lines, respectively (H).
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Figures 1A-D depicts a timeline for this patient presentation. Magnetic resonance imaging (MRI) of the brain with contrast revealed an infiltrating, contrast enhancing, roughly 5-cm mass centered in the left parasellar region with compression of the left temporal lobe, cavernous sinus, pons, and trigeminal nerve (Figure 1A). Postoperative MRI brain demonstrated significant surgical decompression with residual enhancement along the left petroclinoid ligament and region of the cavernous sinus (Figure 1B). An anisotropic expansion of 0-8 mm from the CTV was used to create a planning target volume (PTV) accounting for daily setup uncertainty while respecting dose constraints to the optic structures and brainstem (max dose less than or equal to 5400 cGy) (Figure 1C). MRI brain with contrast showed increased nodular enhancement along the anterior margin of the left tentorial leaflet correlating with increased uptake on gallium-68 dotatate positron emission tomography (PET) imaging (Figure 1D). Figures 1E-H depicts a timeline for this patient presentation. MRI Brain with contrast revealed a roughly 2.6 cm, enhancing left skull base mass involving the cerebellar-medullary angle cistern and centered around the jugular fossa with a tympanic component protruding into the middle ear cavity (Figure 1E). Postoperative MRI revealed residual tumor projecting into the cerebellomedullary angle, extending into the cerebellomedullary cistern and left jugular foramen, and tracking along the carotid sheath (Figure 1F) with corresponding increased uptake on gallium-68 dotatate PET (Figure 1G). Treatment was delivered via VMAT with 3 six MV arcs (Figure 1H) and was well tolerated with no significant adverse events. A family history of kidney cancer at age of 52 in Patient B's sister was discovered as well as lung cancer in patient B's father (Supplementary Figure 1).
Surgical pathology for Patient A H&E stained sections show numerous rhabdoid tumor cells with cytoplasmic hypereosinophilic inclusions (arrows) (400x) (A). Papillary features are also readily apparent (200x) (B). EMA highlights the tumor cells (200x) (C). The tumors cells label for vimentin (200x) (D). There is loss of BAP-1 immunoreactivity in the tumor cells with appropriate internal positive controls (endothelial cells) (100x) (E). Ultrastructural studies revealed cytoplasmic whorls of intermediate filaments (F).
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Many of the tumor cells showed eccentrically placed nuclei and round cytoplasmic inclusions of hypereosinophilic material consistent with rhabdoid morphology (Figure 2A). A significant component of papillary architecture was also present (Figure 2B). The tumor cells showed diffuse immunoreactivity for EMA (Figure 2C) and vimentin (Figure 2D). There was complete loss of BAP-1 immunoreactivity in the tumor cells (Figure 2E) with appropriate internal positive controls (endothelial cells, inflammatory cells, etc.). Ultrastructural studies (electron microscopy) confirmed the presence of cytoplasmic whorls of intermediate filaments in many of the tumor cells (Figure 2F).
Surgical pathology for Patient B H&E stained sections show areas of rhabdoid tumor cells with cytoplasmic hypereosinophilic inclusions (arrows) (400x) (A). Papillary arrangement of tumor cells (200x) (B). EMA highlights the tumor cells (200x) (C). Tumor cells are diffusely positive for vimentin (200x) (D). Focal immunoreactivity for progesterone receptor in the tumor cells (200x) (E). Diffuse loss of BAP-1 immunoreactivity in the tumor cells with appropriate internal controls (100x) (F).
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Rhabdoid features were noted including eccentrically placed nuclei and abundant eosinophilic cytoplasm (Figure 3A). Papillary architecture with epithelioid cells arranged in perivascular papillae was also noted (Figure 3B). In support of the diagnosis, the tumor cells were immunoreactive for EMA (Figure 3C), vimentin (Figure 3D), and progesterone receptor (patchy; Figure 3E). The tumor cells showed diffuse loss of immunoreactivity for BAP-1 (Figure 3F).
Biallelic inactivation of BAP1 by differing mechanisms. Aligned sequence data from Patient A show the pathogenic BAP1 variant is heterozygous in the germline (top track) and tumor (bottom track) (A); the second hit is a somatic frameshift mutation (B). In contrast, aligned sequence data from Patient B (C) show the germline variant approaching homozygosity in the tumor (D). VarScan tumor allele frequency plot for heterozygous germline variants on chromosome 3 of Patient B indicates chromosome-level LOH across chromosome 3.
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Patient A's tumor occurred through an 11-base pair frameshift mutation NM_004656.4:c.1092_1102del (p.His364GlnfsTer30) consistent with a loss of function BAP1 variant (Figures 4A, B). By contrast, Patient B's tumor exhibited LOH across the entirety of chromosome 3 including the second BAP1 allele (Figures 4C, D). Patient A's tumor had an additional 3 somatic coding mutations, and Patient B's displayed an additional 18 somatic coding mutations (Supplementary Table 1).