case_images: PMC11224512_01
case_images: Diagnosis of hereditary smooth muscle tumor and renal cell carcinoma. (A) CT in January 2022 showed that the patient had subcutaneous nodules in both lungs and a subcutaneous nodule on the right back. (B) Immunohistochemistry showed PD-L1 expression TPS positive, TPS = 5%; PD-L1 expression CPS positive, CPS = 6. (C) PET-CT showed cystic lesions in the right kidney; unequal-sized nodules in both lungs; localized bone destruction and uneven density in the left scapula, part of the concha and adnexa, sacrum, and right ilium; bone metastasis was considered. (D) Immunohistochemistry showed that the metastatic tumor cells lacked the expression of 2SC; Hematoxylin-eosin staining showed that the metastatic tumor cells had large nuclei with obvious phagocytic nuclei and obvious halos around the nuclei; immunohistochemistry showed that the metastatic tumor cells lacked the expression of fumarate hydratase FH, which supported the diagnosis of renal cell carcinoma with FH deficiency. Information of antibodies for PD-L1, FH, 2SC is shown in Supplementary Table S2.
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case_images: F1
case_images: Computed tomography (CT) scans revealed small subcutaneous nodules on her right back and right buttock, along with variable-sized nodules in both lungs, suggestive of metastasis (Figure 1A). Immunohistochemistry revealed high expression of programmed cell death ligand 1 (PD-L1), with a TPS of 5% and a CPS of 6 (Figure 1B). Localized bone destruction, uneven density, and increased FDG uptake were observed in the left scapula, part of the concha and adnexa, sacrum, and right ilium, suggesting bone metastasis (Figure 1C). HE staining revealed enlarged nuclei with prominent eosinophilic nucleoli and a clear halo around the nucleolus (Figure 1D). FH showed loss of FH expression (Figure 1D). Following the patient's informed consent, whole exon sequencing was performed on the patient's tissue, revealing suspicious pathogenic mutations that could account for the patient's phenotype. PET-CT results in October 2022 demonstrated significant progression of bone metastases throughout the body compared to May 2022 (Supplementary Figure S1A).
case_images: Schematic diagram of Sanger sequencing validation results for the proband and wild-type FH variants. (A) Wild type. (B) The proband. (C) Pedigree of the family with three patients. The black symbols represent the affected members with renal carcinoma, and the arrow indicates the proband.
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case_images: F2
case_images: Results indicated that the patient's mother and one daughter harbored the same mutations at the identical sites within the FH gene (Figure 2A). Wild-type Sanger sequencing is depicted in Figure 2B. The patient's family pedigree is illustrated in Figure 2C.
case_images: CT of the patient at various stages after receiving treatment. (A) In April 2022, after 6 weeks of treatment with pembrolizumab in combination with sunitinib, the patient's metastases were significantly reduced. (B) In May 2022, after 5 weeks of treatment with pembrolizumab in combination with axitinib due to the patient's intolerance of sunitinib, the subcutaneous nodule on the right side of the back was enlarged compared with the previous one. (C) After eight cycles of the original regimen, a CT in January 2023 showed multiple metastases in both lungs that were significantly more advanced than before. (D) ACT in July 2023 showed a significant reduction in the patient's metastatic lesions.
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case_images: F3
case_images: Subsequent CT scans in April 2022 revealed significant reductions in the size of subcutaneous nodules and pulmonary metastases on the right back compared to previous scans (Figure 3A). In May 2022, CT scans indicated an increase in multiple small nodules in various subcutaneous areas and an increase in metastatic tumors in both lungs compared to April 2022 (Figure 3B). However, a CT scan in January 2023 revealed significant enlargement of bilateral lung metastases compared to October 2022 (Figure 3C). A CT reexamination in June 2023 showed a significant reduction in metastatic lesions, with the patient's condition stabilized (Figure 3D).
case_images: Timeline of the case. Red arrow indicates that the patient was diagnosed with FH-deficient renal cell carcinoma.
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case_images: F4
case_images: The timeline of the case is illustrated in Figure 4, with the top axis depicting the diagnostic process and the bottom axis showing the treatment process.