Complete response of hereditary leiomyomatosis and renal cell cancer (HLRCC)-associated renal cell carcinoma to nivolumab and ipilimumab combination immunotherapy by: a case report

Iribe, Yasuhiro; Furuya, Mitsuko; Shibata, Yosuke; Yasui, Masato; Funahashi, Makoto; Ota, Junichi; Iwashita, Hiromichi; Nagashima, Yoji; Hasumi, Hisashi; Hayashi, Narihiko; Makiyama, Kazuhide; Kondo, Keiichi; Tanaka, Reiko; Yao, Masahiro; Nakaigawa, Noboru

doi:10.1007/s10689-020-00195-0

Cited by 20 publications

(16 citation statements)

References 31 publications

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“…Patients may also benefit from specific clinical trials/adjuvant therapies, adding further importance to correct diagnosis. 13,15,23,24 Ultimately, when encountering an RCC with heterogeneous FH loss, we recommend having a low threshold to perform immunohistochemistry for 2SC and/ or molecular testing, as both are useful ancillary methods to confirm an FH-deficient RCC diagnosis.…”

Section: Discussionmentioning

confidence: 99%

A Clinicopathological and Molecular Analysis of Fumarate Hydratase (FH)-deficient Renal Cell Carcinomas with Heterogeneous Loss of FH Expression

et al. 2022

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Aims. Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a rare aggressive renal malignancy associated with hereditary leiomyomatosis and RCC syndrome (HLRCC). Tumors exhibiting heterogeneous (ie, patchy) FH loss by immunohistochemistry have rarely been described, may be diagnostically challenging, and have never been the focus of a study. We aimed to investigate the FH mutational status of FH-deficient RCC with heterogeneous versus complete FH loss, to characterize additional genetic drivers, and to evaluate 2SC immunohistochemistry in this setting. Methods and Results. We studied FH-deficient RCC with heterogeneous ( n = 3) and complete ( n = 4) FH loss. Targeted next-generation sequencing (NGS) was performed on all tumors. No patients had a known history of HLRCC. All tumors had histological features within the morphologic spectrum described for FH-deficient RCC. All 7 tumors were immunoreactive for 2SC. Molecularly, all 7 tumors revealed multiple hits involving the FH locus resulting in complete loss of wild-type alleles. All tumors with heterogeneous FH loss harbored FH missense variants within domain 2 of the protein, and each had concomitant copy neutral loss of heterozygosity (CN-LOH). In complete FH loss tumors, FH alterations included splice variants with concomitant loss of heterozygosity ( n = 2) and homozygous gene deletions ( n = 2). Other non-recurrent alterations included biallelic alterations of TP53, NF2, SMAD4 and activation of PIK3CA. Conclusions. Our series highlights how heterogeneous FH loss (patchy positive staining) is an important staining pattern to recognize since it is compatible with a diagnosis of FH-deficient RCC and should prompt additional ancillary studies (confirmatory 2SC immunohistochemistry and/or molecular testing) and genetic evaluation.

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Section: Discussionmentioning

confidence: 99%

A Clinicopathological and Molecular Analysis of Fumarate Hydratase (FH)-deficient Renal Cell Carcinomas with Heterogeneous Loss of FH Expression

et al. 2022

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“…Antitumor efficacy has been achieved by targeted therapy and ICI combinations in patients with variant histology RCC (6,7). A recent study reported the achievement of CR in a patient with HLRCC-RCC after 31 weeks of ICI combination treatment (nivolumab plus ipilimumab) (8). Another study showed that ICI treatment led to improved progression-free survival compared with antiangiogenic monotherapy (9).…”

Section: Discussionmentioning

confidence: 99%

“…A multicenter phase II study of atezolizumab and bevacizumab for patients with metastatic RCC involving variant histology revealed an overall response rate in PD-L1-positive patients of 60% (n = 9) vs. 19% (n = 4) in PD-L1negative patients (16). In the report of CR after combined ICI treatment, approximately half of the tumor cells exhibited PD-L1 expression (8). The immunohistochemical staining in our patient showed strong PD-1/PD-L1 expression.…”

Section: Discussionmentioning

confidence: 99%

Complete Response of Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC)-Associated Renal Cell Carcinoma to Pembrolizumab Immunotherapy: A Case Report

Wang

Huang

et al. 2021

Front. Oncol.

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Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare autosomal dominant disorder that results from a germline mutation in the fumarate hydratase (FH) gene; it manifests as cutaneous leiomyomas, uterine fibroids, and renal cell cancer (RCC). Patients with HLRCC-associated RCC (HLRCC-RCC) have aggressive clinical courses, but there is no standardized therapy for advanced HLRCC-RCC. Here, we describe aggressive HLRCC in a 26-year-old man who presented with RCC that exhibited a novel heterozygous germline insertion mutation in exon 2 of the FH gene (c.191dupA: p.N64fs). Systemic lymph node metastasis had already occurred. The patient underwent robot-assisted laparoscopic resection of the right kidney, but new metastases appeared within 5 months postoperatively. Histological staining of the resected tumor showed high expression levels of programmed cell death-ligand 1 (PD-L1) and programmed cell death-1 (PD-1). The patient was treated with anti-PD-1 antibody as first-line therapy. After 2 years of immune checkpoint inhibitor (ICI) treatment, all lesions had disappeared; this response was maintained at 51 months. To our knowledge, this is the first successful treatment of HLRCC-RCC with single-agent immunotherapy. Our approach might be effective for patients with advanced HLRCC-RCC.

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“…Individuals with FH mutations are also at risk of developing renal cell carcinoma. Patients with HLRCC and associated renal cell carcinoma have aggressive clinical courses [13,15].…”

Section: Assessmentmentioning

confidence: 99%

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2022

Ro Med J.

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Uterine fibroids represent the most commonly encountered benign tumors among women at childbearing age which might significantly influence their capacity of carring a normal pregnancy. Therefore, due to the significant impact which might be encountered, attention was focused on determining which are the most important risk factors for developing such lesions. In this respect, nowadays particular attention was given to genetic factors. In this article we discuss the implications of genetic chromosomal abnormalities aswell as chromosomal rearrangements in the formation of fibroids. We also report diseases that should not be overlooked when differentially diagnosing leiomyomatosis (MCUL1 and HLRCC).

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Complete response of hereditary leiomyomatosis and renal cell cancer (HLRCC)-associated renal cell carcinoma to nivolumab and ipilimumab combination immunotherapy by: a case report

Cited by 20 publications

References 31 publications

A Clinicopathological and Molecular Analysis of Fumarate Hydratase (FH)-deficient Renal Cell Carcinomas with Heterogeneous Loss of FH Expression

A Clinicopathological and Molecular Analysis of Fumarate Hydratase (FH)-deficient Renal Cell Carcinomas with Heterogeneous Loss of FH Expression

Complete Response of Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC)-Associated Renal Cell Carcinoma to Pembrolizumab Immunotherapy: A Case Report

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