PMC8149899_01
Three different tumors located in the patient's left kidney at first recurrence. Two years after radical right-kidney nephrectomy, the patient was diagnosed with three different tumors (A-C) in her left kidney on computed tomography examination. Yellow arrows show the three tumors. The patient underwent left-kidney partial nephrectomy for all tumors, and immunohistochemical analysis showed that their histopathological types were (D) angiomyolipoma, (E) clear cell renal cell carcinoma, and (F) papillary renal cell carcinoma. Magnification: 200x for hematoxylin and eosin staining.
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Two years after this, computed tomography (CT) imaging identified three tumors in her left kidney; the patient underwent left-kidney partial nephrectomy for these tumors ( Figures 1A-C ). AML, clear cell RCC (pT1a), and papillary RCC (pT1a) ( Figures 1D-F ). A periodic CT examination 3.5 years later revealed the tumor recurrence in her left kidney. Cancer Genome Atlas database ( Additional Figure 1 ). Regarding TSC1 and TSC2 mutations, TSC-associated papillary RCC harbored frameshift TSC1 mutation (c.2142del, p.Asn715fs), a pathogenic variant for patients with TSC reported in the ClinVar database. Conversely, TSC1 and TSC2 germline mutations were not found in our patient, implying that she may possess the phenotype with mosaic forms of TSC.
Radiographic evaluation at second recurrence. (A) Computed tomography examination shows typical findings of clear cell renal cell carcinoma in the left kidney. (B) Lung lymphangioleiomyomatosis. (C) Subependymal nodule at the left lateral ventricular wall of the brain.
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Upon initial visit to the Osaka University Hospital, abdominal CT scan showed a renal mass (diameter: 22 mm) with early enhancement in the left kidney ( Figure 2A ). Additional screening tests revealed the presence of lung cysts and calcifications in the left ventricular wall of the brain ( Figures 2B, C ), leading to the suspicion of TSC.
Immunohistochemical analysis identifies papillary renal cell carcinoma associated with tuberous sclerosis complex. (A) Main tumor nodule surrounded by thick fibrous stroma on low power; (B) Prominent papillary architecture lined by large clear cells with delicate eosinophilic cytoplasmic thread-like strands, which occasionally appeared more outstanding and aggregated to form eosinophilic globules on high power. Immunohistochemical analysis revealed positive staining for (C) CK7 and (D) CD10, whereas (E) SDHB and (F) AMACR were negative.
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We observed prominent papillary architecture lined by clear cells with delicate eosinophilic cytoplasmic thread-like strands that occasionally appeared more prominent and aggregated to form eosinophilic globules in the papillary RCC sample ( Figures 3A, B ). Immunohistochemical analysis revealed that CK7 and CD10 were positive, whereas succinate dehydrogenase subunit B (SDHB) and alpha-methylacyl-CoA racemase (AMACR) were negative ( Figures 3C-F ).
Mutational landscape of the three renal tumors in the patient's left kidney at first recurrence. We visualized the somatic mutation profiles of each tumor:angiomyolipoma (AML), clear cell renal cell carcinoma (RCC), and papillary RCC:as heat maps (black-colored genes indicate driver gene mutations in many cancer types). CDH11, Cadherin 11; CDK12, Cyclin Dependent Kinase 12; DICER1, Dicer 1; PABPC1, Poly(A) Binding Protein Cytoplasmic 1; PARP4, Poly(ADP-Ribose) Polymerase Family Member 4; PBRM1, Polybromo 1; POLQ, DNA Polymerase Theta; PTPN13, Protein Tyrosine Phosphatase Non-Receptor Type 13; PTPRK, Protein Tyrosine Phosphatase Receptor Type K; RET, Ret Proto-Oncogene; RPS3A, Ribosomal Protein S3A; SAMD3, Sterile Alpha Motif Domain Containing 3; SMARCA1, SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 1; SUSD2, Sushi Domain Containing 2; TSC1, TSC Complex Subunit 1; ZNF208, Zinc Finger Protein 208; ZNF721, Zinc Finger Protein 721.
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We found that 36.7% of these somatic mutations:including cancer driver genes such as PABPC1 and DICER1, which are common in parental clones of many cancer types:were shared among the three tumors (common mutations,  Figure 4 ).