PMC8554149_01
Diagnosis of hereditary leiomyomatosis and renal cell cancer-associated renal cell carcinoma (HLRCC-RCC). (A) Transverse CT revealed a large mass in the lower middle part of the right kidney. (B) Pedigree of the family with three patients. The black symbols represent the affected members with renal carcinoma, and the arrow indicates the proband. (C, D) Genetic testing identified a novel fumarate hydratase (FH) germline mutation (c.191dupA:p.N64fs), which confirmed the diagnosis of HLRCC-RCC. (C) A heterozygous mutation was identified in blood, and (D) a homozygous mutation was identified in tumor tissue.
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Positron emission tomography (PET)-computed tomography (CT) showed that the right kidney volume was increased, the lower part of the right kidney contained an irregular cystic mass, and the internal glucose metabolism was uneven ( Figure 1A  and  Supplementary Figure 2A ). Because the patient's father and grandfather both died of kidney cancer ( Figure 1B ), HLRCC was suspected. Sanger sequencing confirmed these findings ( Figures 1C, D ) and supported a diagnosis of HLRCC-RCC. The microstructure was characterized by thick papillae lined with large tumor cells containing abundant, granular, and eosinophilic cytoplasm; large nuclei were present with prominent eosinophilic nucleoli surrounded by clear halos ( Figure 2A  and  Supplementary Figure 1A ). Figures 2C, D ). FH staining of the tumor tissue revealed the loss of FH expression ( Figure 2B  and  Supplementary Figure 1B ).
Histomorphological findings in our patient with hereditary leiomyomatosis and renal cell cancer syndrome. (A) Hematoxylin-eosin staining showed a renal cell carcinoma with papillary and tubular structures. (B) Immunohistochemistry revealed absence of fumarate hydratase (FH) expression in tumor cells, supporting the diagnosis of FH-deficient RCC. (C, D) There were few tumor-infiltrating lymphocytes (TILs). Approximately 30% of the tumor cells exhibited programmed cell death-ligand 1 (PD-L1) expression. TILs exhibited programmed cell death-1 (PD-1) expression (35%). Magnification, x100.
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Positron emission tomography (PET)-computed tomography (CT) showed that the right kidney volume was increased, the lower part of the right kidney contained an irregular cystic mass, and the internal glucose metabolism was uneven ( Figure 1A  and  Supplementary Figure 2A ). The patient underwent robot-assisted laparoscopic resection of the right kidney and retroperitoneal lymphadenectomy ( Supplementary Figure 2B ). The microstructure was characterized by thick papillae lined with large tumor cells containing abundant, granular, and eosinophilic cytoplasm; large nuclei were present with prominent eosinophilic nucleoli surrounded by clear halos ( Figure 2A  and  Supplementary Figure 1A ). Figures 2C, D ). FH staining of the tumor tissue revealed the loss of FH expression ( Figure 2B  and  Supplementary Figure 1B ).
The patient had new metastatic lesions postoperatively but showed a response during immunotherapy and eventually achieved complete response (CR). (A) At 4 months postoperatively, CT revealed metastatic lesions on retroperitoneal lymph nodes, peritoneum, and right pleural nodules. (B) After 8 months of pembrolizumab treatment, the patient's abovementioned metastatic lesions were significantly reduced or even disappeared. (C-E) Changes in patient's PET-CT. (C) Preoperative PET-CT showed multiple systemic lymph node metastases. (D) After 2 years of immunotherapy, PET-CT showed that the metastases had disappeared. (E) A third PET-CT in April 2021 confirmed the patient's CR maintenance status.
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There were multiple enlarged lymph nodes in the neck (zones III-V), bilateral clavicle areas, posterior mediastinum, and posterior phrenic angle space, as well as adjacent to the abdominal aorta and iliac vessels; all of these enlarged lymph nodes were considered malignant ( Figure 3C ). At 4 months postoperatively, CT revealed multiple nodules on the retroperitoneal lymph nodes, peritoneum, and right pleural nodules, suggestive of metastasis ( Figure 3A ). After 8 months of pembrolizumab treatment, the patient's abovementioned metastatic lesions were significantly reduced or even disappeared ( Figure 3B ). After 24 months of treatment, PET-CT showed that the fluorodeoxyglucose (FDG) metabolism of the lesions had normalized, indicative of CR ( Figure 3D ). A third PET-CT in April 2021 still showed no disease progression ( Figure 3E ).
Timeline of the case.
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The timeline is shown in  Figure 4 .