PMC8650633_01
Preoperative T2W coronal (A) and T1W coronal image after contrast administration (B) showing large sellar mass with bilateral parasellar involvement more prominent on the left, with partial encasement of the internal carotid artery with preserved flow void within the vessel (white arrows). Postoperative T1W coronal (C) and T2W (D) showing the reduction of the tumor volume in the sella and no significant changes in the parasellar components of the residual tumor.
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MRI showed the presence of a large sellar mass (16 x 28 x 19 mm) with bilateral parasellar involvement ( Figure 1 ). Transsphenoidal surgery was performed in February 2009 with partial tumor resection leaving residual tumor in both cavernous sinuses ( Figure 1 ). The MRI of the neck revealed a tumor mass in the left submandibular region as well as a smaller lesion in the ipsilateral masticator space ( Figure S1 ). A nodular soft tissue lesion in the body of the second lumbar vertebra consistent with metastasis was detected on the MRI performed due to back pain ( Figure S1 ).
T2W coronal (A), T1W coronal (B), and T1W axial (C) after contrast administration showing size increase of the left cavernous sinus residual tumor with mass effect to the left temporal lobe and signs of subcortical vasogenic edema were evident (white arrows). Tumor extension to the left orbit through the orbital fissure was documented (black arrow).
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The MRI showed a significant tumor progression (from 22 x 23 x 12 mm to 42 x 35 x 27 mm in 3 years) with tumor extension to the left orbit through the inferior orbital fissure ( Figure 2 ). In December 2019, 68Ga-DOTANOC PET/CT was performed (application 191 MBq) and showed the full extent of the disease ( Figure S2 ).
Hematoxylin-eosin staining revealed tumor composed of lobuli of uniform tumor cells surrounded by fibrous septa (A) with the evidence of invasion into surrounding brain parenchyma (B). Immunohistochemical analysis with synaptophysin (C) confirmed the neuroendocrine nature of the tumor and the presence of S100-positive sustentacular cells (D) was typical for paraganglioma. Cell proliferation was increased with Ki67 index reaching 10% (E). Tumor cells were strongly positive for SSTR2A (F). ATRX was preserved in endothelial cells; however, there was no ATRX nuclear immunolabeling in the tumor cells (G). TP53 was negative (H). Insert in H shows TP53 expression in the positive control tissue from a p53 mutated carcinoma (magnification is 200x for all microphotographs except (A) that has 400x and (B) that has 100x).
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There were signs of tumor invasion into surrounding brain tissue ( Figures 3A-E ). Immunohistochemical analyses performed according to standard protocols at the Department of Clinical Pathology, Uppsala University Hospital showed strong expression of somatostatin receptors (SSTR) type 2A ( Figure 3F ) and 3 in all tumor cells, whereas SSTR1 and SSTR5 were negative. ATRX antibody (HPA001906, Atlas Antibodies; dilution 1:100; incubation time 20 min) demonstrated the lack of immunolabeling in the tumor cells with preserved staining in non-neoplastic cells, strongly suggesting an ATRX gene mutation ( Figure 3G ). ATRX immunolabeling was negative both in the specimen from the primary sellar tumor from 2017 and in the specimen from submandibular tumor deposit from 2019. Figure 4 ). Following the molecular genetic finding of a TP53 variant, immunohistochemical analysis of TP53 (DAKO, monoclonal antibody, clone D0-7, catalogue number GA616; ready-to-use; incubation time 20 min) was performed showing a negative result ( Figure 3H ).
ATRX and TP53 mutations in a patient with metastatic primary sellar paraganglioma. NGS sequencing using a panel with 20 genes commonly mutated in gliomas identified two tumor suppressor mutations: a nonsense mutation in ATRX and missense mutation in TP53 with frequencies of 85% and 50%, respectively. Coverage and pile-up of sequencing raw data visualized using a genome browser depict the mutations in red (lower panels; minus orientation), and healthy donor controls (upper panels) were included for comparison. Schematic diagrams show ATRX and TP53 exon structures with positions of mutations indicated. Only exons containing coding sequence were included (ATRX: ex. 1 through ex. 35; TP53: ex. 2 through ex. 11). The large exon 9 of ATRX, depicted with stippled lines, is compressed for clarity. Protein domains are highlighted in light colors (ADD: ATRX-DNMT3-DNMT3L). The ATRX c.4048G>T mutation results in pre-termination of ATRX at G1350 in the central portion of the 2492-residue protein, whereas the c.847C>T mutation of TP53 causes an R283C substitution in the C-terminus of the DNA binding domain.
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Figure 4 ). Following the molecular genetic finding of a TP53 variant, immunohistochemical analysis of TP53 (DAKO, monoclonal antibody, clone D0-7, catalogue number GA616; ready-to-use; incubation time 20 min) was performed showing a negative result ( Figure 3H ).