RÉSUMÉ
Renal cell carcinoma (RCC) accounts for 2% of all cancer cases worldwide, and majority are sporadic. The latest World Health Organization (WHO) classification of renal cell tumors (fifth edition, 2022) has molecularly defined renal tumor entities, which includes fumarate hydratase (FH)-deficient RCC. FH-deficient RCC is an aggressive carcinoma caused by pathogenic alterations in FH gene, seen in 15% of patients with hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) syndrome. These tumors occur more frequently at a younger age and present at an advanced stage, carrying a dismal prognosis. We report a series of 10 cases of FH-deficient RCC. The mean age was 49.8 years, and all cases presented in advanced stages (III and IV). Morphologically, the cases had varied architectural patterns with characteristic eosinophilic macronucleoli and perinucleolar halo. On immunohistochemistry (IHC), all showed diffuse nucleo-cytoplasmic expression of S-(2-succino)-cysteine (2-SC), with loss of FH in seven cases. FH-deficient RCCs are aggressive neoplasms and can be diagnosed using specific IHC markers (FH and 2-SC). These patients should undergo germline testing for FH gene mutation, genetic counseling, and surveillance of family members.
Sujet(s)
Néphrocarcinome , Fumarate hydratase , Tumeurs du rein , Humains , Néphrocarcinome/génétique , Néphrocarcinome/anatomopathologie , Fumarate hydratase/déficit , Fumarate hydratase/génétique , Adulte d'âge moyen , Femelle , Mâle , Adulte , Tumeurs du rein/génétique , Tumeurs du rein/anatomopathologie , Immunohistochimie , Sujet âgé , Syndromes néoplasiques héréditaires/génétique , Syndromes néoplasiques héréditaires/diagnostic , Syndromes néoplasiques héréditaires/anatomopathologie , Mutation germinale , Marqueurs biologiques tumoraux/génétique , Marqueurs biologiques tumoraux/déficit , Cystéine/analogues et dérivés , Tumeurs cutanées , Tumeurs de l'utérus , LéiomyomatoseRÉSUMÉ
Background and Objectives: Mutations in succinate dehydrogenase (SDH) and fumarate hydratase (FH) give rise to various familial cancer syndromes, with these alterations being characteristic of certain types of histomorphologically specific leiomyomas that hold significant predictive value. Materials and Methods: This study presents two cases of uterine leiomyomas exhibiting rare histomorphological and genetic characteristics, which are crucial for prognosis and further treatment. Results: Distinct histopathological features such as marked nuclear atypia, intracellular eosinophilic globules, and abnormal intratumoral vessels raise suspicion for specific leiomyoma subtypes, which carry predictive significance for additional hereditary cancer syndromes. Immunohistochemical analysis confirmed FH/SDH deficiency in both patients, who underwent careful follow-up. Conclusions: This study describes two cases involving unusual leiomyomas, the histopathological characteristics of which may easily go unrecognized. These features hold predictive significance because their specific mutations point to additional hereditary cancer syndromes, highlighting the need for further examinations.
Sujet(s)
Fumarate hydratase , Léiomyome , Succinate Dehydrogenase , Tumeurs de l'utérus , Humains , Femelle , Fumarate hydratase/déficit , Fumarate hydratase/génétique , Tumeurs de l'utérus/génétique , Tumeurs de l'utérus/anatomopathologie , Succinate Dehydrogenase/déficit , Succinate Dehydrogenase/génétique , Adulte , Léiomyome/génétique , Léiomyome/anatomopathologie , Adulte d'âge moyenRÉSUMÉ
Leiomyoma is the most prevalent benign tumor of the female reproductive system. Benign metastasizing leiomyoma (BML) is a rare phenomenon that presents at distant sites, typically the lungs, exhibiting histopathological features similar to the primary uterine tumor in the absence of malignancy features in both. Fumarate hydratase-deficient uterine leiomyoma (FH-d UL) is an uncommon subtype among uterine smooth muscle tumors (0.5-2%), showing distinctive histomorphology and FH inactivation. The majority of FH-d ULs are sporadic, caused by somatic FH inactivation, while a minority of cases occur in the context of the hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome caused by germline FH inactivation. Metastasizing FH-d UL has not been well documented and might be under-reported. Here, we present two cases (21- and 34-year-old females) who presented with metastasizing FH-d UL after myomectomy/hysterectomy with histologically proven multiple lung metastases in both, in addition to multi-organ involvement in one case (cervical-thoracic lymph nodes, left kidney, perihepatic region, left zygomatic bone, and soft tissues). Pathological examination confirmed FH-d leiomyomas in the primary/recurrent uterine tumors, multiple lung lesions, and a renal mass. The minimal criteria for diagnosis of leiomyosarcoma were not fulfilled. Genetic testing revealed germline pathogenic FH variants in both cases (c.1256C > T; p.Ser419Leu in Case 1 and c.425A > G; p.Gln142Arg in Case 2). These novel cases highlight a rare but possibly under-recognized presentation of FH-d BML. Our study suggests that FH-d BML cases might be enriched for the HLRCC syndrome.
Sujet(s)
Fumarate hydratase , Léiomyome , Tumeurs du poumon , Tumeurs de l'utérus , Humains , Femelle , Tumeurs de l'utérus/anatomopathologie , Tumeurs de l'utérus/génétique , Fumarate hydratase/déficit , Fumarate hydratase/génétique , Adulte , Léiomyome/anatomopathologie , Léiomyome/génétique , Tumeurs du poumon/anatomopathologie , Tumeurs du poumon/génétique , Jeune adulte , Léiomyomatose/anatomopathologie , Léiomyomatose/génétique , Myomectomie de l'utérus , HystérectomieRÉSUMÉ
Women with germline pathogenic variants (PV) in the fumarate hydratase (FH) gene develop cutaneous and uterine leiomyomata and have an increased risk of developing aggressive renal cell carcinomas. Many of these women are unaware of their cancer predisposition until an atypical uterine leiomyoma is diagnosed during a myomectomy or hysterectomy, making a streamlined genetic counseling process after a pathology-based atypical uterine leiomyoma diagnosis critical. However, the prevalence of germline pathogenic/likely PVs in FH among atypical uterine leiomyomata cases is unknown. To better understand FH germline PV prevalence and current patterns of genetic counseling and germline genetic testing, we undertook a retrospective review of atypical uterine leiomyomata cases at a single large center. We compared clinical characteristics between the FH PV, FH wild-type (WT), and unknown genetic testing cohorts. Of the 144 cases with atypical uterine leiomyomata with evaluable clinical data, only 49 (34%) had documented genetic test results, and 12 (8.3%) had a germline FH PV. There were 48 IHC-defined FH-deficient cases, of which 41 (85%) had FH testing and nine had a germline FH PV, representing 22% of the tested cohort and 18.8% of the FH-deficient cohort. Germline FH PVs were present in 8.3% of evaluable patients, representing 24.5% of the cohort that completed genetic testing. These data highlight the disconnect between pathology and genetic counseling, and help to refine risk estimates that can be used when counseling patients with atypical uterine leiomyomata. PREVENTION RELEVANCE: Women diagnosed with fumarate hydratase (FH)-deficient uterine leiomyomata are at increased risk of renal cancer. This work suggests a more standardized pathology-genetic counseling referral pathway for these patients, and that research on underlying causes of FH-deficient uterine leiomyomata in the absence of germline FH pathogenic/likely pathogenic variants is needed.
Sujet(s)
Fumarate hydratase , Dépistage génétique , Mutation germinale , Léiomyome , Tumeurs de l'utérus , Humains , Femelle , Fumarate hydratase/génétique , Fumarate hydratase/déficit , Tumeurs de l'utérus/génétique , Tumeurs de l'utérus/anatomopathologie , Tumeurs de l'utérus/diagnostic , Adulte d'âge moyen , Études rétrospectives , Adulte , Léiomyome/génétique , Léiomyome/anatomopathologie , Léiomyome/diagnostic , Prédisposition génétique à une maladie , Conseil génétique , Léiomyomatose/génétique , Léiomyomatose/anatomopathologie , Léiomyomatose/diagnosticRÉSUMÉ
PURPOSE: Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare and lethal subtype of kidney cancer. However, the optimal treatments and molecular correlates of benefits for FH-deficient RCC are currently lacking. EXPERIMENTAL DESIGN: A total of 91 patients with FH-deficient RCC from 15 medical centers between 2009 and 2022 were enrolled in this study. Genomic and bulk RNA-sequencing (RNA-seq) were performed on 88 and 45 untreated FH-deficient RCCs, respectively. Single-cell RNA-seq was performed to identify biomarkers for treatment response. Main outcomes included disease-free survival (DFS) for localized patients, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) for patients with metastasis. RESULTS: In the localized setting, we found that a cell-cycle progression signature enabled to predict disease progression. In the metastatic setting, first-line immune checkpoint inhibitor plus tyrosine kinase inhibitor (ICI+TKI) combination therapy showed satisfactory safety and was associated with a higher ORR (43.2% vs. 5.6%), apparently superior PFS (median PFS, 17.3 vs. 9.6 months, P = 0.016) and OS (median OS, not reached vs. 25.7 months, P = 0.005) over TKI monotherapy. Bulk and single-cell RNA-seq data revealed an enrichment of memory and effect T cells in responders to ICI plus TKI combination therapy. Furthermore, we identified a signature of memory and effect T cells that was associated with the effectiveness of ICI plus TKI combination therapy. CONCLUSIONS: ICI plus TKI combination therapy may represent a promising treatment option for metastatic FH-deficient RCC. A memory/active T-cell-derived signature is associated with the efficacy of ICI+TKI but necessitates further validation.
Sujet(s)
Néphrocarcinome , Fumarate hydratase , Tumeurs du rein , Humains , Néphrocarcinome/traitement médicamenteux , Néphrocarcinome/génétique , Néphrocarcinome/anatomopathologie , Néphrocarcinome/immunologie , Néphrocarcinome/thérapie , Fumarate hydratase/déficit , Fumarate hydratase/génétique , Mâle , Femelle , Tumeurs du rein/traitement médicamenteux , Tumeurs du rein/génétique , Tumeurs du rein/anatomopathologie , Tumeurs du rein/immunologie , Tumeurs du rein/mortalité , Tumeurs du rein/thérapie , Adulte d'âge moyen , Sujet âgé , Adulte , Activation des lymphocytes/immunologie , Inhibiteurs de points de contrôle immunitaires/usage thérapeutique , Inhibiteurs de points de contrôle immunitaires/effets indésirables , Mémoire immunologique , Pronostic , Inhibiteurs de protéines kinases/usage thérapeutique , Inhibiteurs de protéines kinases/pharmacologie , Immunothérapie/méthodes , Cellules T mémoire/immunologie , Lymphocytes T/immunologieRÉSUMÉ
Deficiency of fumarate hydratase (FH) protein expression in uterine corpus leiomyomas may be attributable to either germline or somatic mutations of the FH gene, the former being definitional for the hereditary leiomyomatosis and renal cell cancer syndrome. The authors assess whether, using previously reported FH-associated morphologic features, FH protein-deficient uterine corpus leiomyomas associated with a pathogenic germline mutations of the FH gene (group 1) are distinguishable from FH protein-deficient uterine corpus leiomyomas without such mutations (and whose FH protein loss is presumed to be attributable to somatic/epigenetic inactivation or other unknown phenomena: group 2). Groups 1 and 2 were compared regarding a variety of clinicopathologic features, including 7 core "FH-associated" tumoral morphologic features: staghorn vasculature; alveolar-type edema; bizarre nuclei; chain-like tumor nuclei; hyaline cytoplasmic globules; prominent nucleoli, intranuclear inclusions, and perinucleolar halos; and prominent eosinophilic/fibrillary cytoplasm. Among 2418 patients diagnosed with uterine corpus leiomyoma during the study period, FH-associated morphologic features were reported in 1.5% (37 patients), and FH immunohistochemistry was performed in 29 (1.19%). Fourteen (48.27%) of the 29 patients showed FH protein deficiency by immunohistochemistry. Twelve patients underwent germline testing, of which 8 (66.7%) were classified as group 1 and 4 (33.3%) as group 2. FH protein-deficient tumors were larger (10.44 vs 4.08â cm, P = 0.01) and associated with younger patients (42.05 vs 47.97, P = 0.004) than 370 randomly selected uterine leiomyoma controls. Groups 1 and 2 showed no significant differences in patient age and tumor size. In group 1 tumors, the FH-associated morphologic features were generally present diffusely; all group 1 tumors displayed ≥5 FH-associated features, whereas all group 2 tumors displayed <5 FH-associated features (means 6.5 ± 0.53 vs 3.5 ± 1.00, P < 0.001). Notably, eosinophilic/fibrillary cytoplasm and alveolar-type edema were each significantly more prevalent in group 1 tumors than group 2 tumors (P = 0.018 for both). No single morphologic feature was found to be completely sensitive and specific in making the distinction between group 1 and 2 tumors. Our findings suggest that groups 1 and 2 are unlikely to be morphologically distinguishable by individual morphologic features. Whether there is a combination of features that can reliably make this distinction is unclear and will require additional studies with larger cohorts.
Sujet(s)
Néphrocarcinome , Fumarate hydratase/déficit , Tumeurs du rein , Léiomyomatose , Erreurs innées du métabolisme , Hypotonie musculaire , Troubles psychomoteurs , Tumeurs cutanées , Tumeurs de l'utérus , Humains , Femelle , Fumarate hydratase/génétique , Léiomyomatose/diagnostic , Léiomyomatose/génétique , Mutation germinale , Oedème , Cellules germinales , Tumeurs de l'utérus/génétiqueRÉSUMÉ
Objective: To investigate the clinicopathological features of fumarate hydratase (FH) deficiency uterine leiomyoma. Methods: The data of 38 patients with FH deficiency uterine leiomyoma were screened and analyzed. The expressions of FH, S-(2-succino)-cysteine (2SC), desmin, p16, p53, CD10 and cell proliferation associated nuclear antigen (Ki-67) proteins were detected by immunohistochemistry, and their clinicopathological features were analyzed retrospectively. Results: (1) Clinical features: the median age of the patients was (42.5±7.4) years old. Twenty-one cases (55%) of them were myomas found in physical examination, and the median maximum diameter of the tumor was 6.0 cm (range: 5.0-7.5 cm); myomectomy was performed in 23 cases (61%), total hysterectomy with or without bilateral appendages in 15 cases (39%); laparoscopic surgery in 27 cases (71%), open surgery in 11 cases (29%); none of the patients had renal cell carcinoma. (2) Histological features: atypical nuclear cells were distributed locally or diffusely, eosinophilic nucleoli and intranuclear inclusion bodies could be seen, glass like globules could be seen in the cytoplasm, nuclear division was 0-4/10 high power field (HPF), and antler like blood vessels and pulmonary edema-like changes could be seen in the stroma. Among 38 patients with FH deficiency uterine leiomyoma, FH was negative in 37 cases (97%), and positive in 1 case (3%); 2SC, desmin, p16, p53, CD10 and Ki-67 showed focal positive expression in 38 cases (100%), including 35 cases (92%) with Ki-67 index<10% and 3 cases (8%) with Ki-67 index ≥10%. (3) Follow-up: 4 cases (11%) recurred, and there was no death. There were significant differences in age, family history, distribution of atypical nuclei and mitosis number between recurrent group and non-recurrent group (all P<0.05). Conclusions: FH deficiency uterine leiomyoma is a rare tumor, which needs pathological examination,immunohistochemical examination and clinical history. Patients younger than 43 years old, with family history, histologically atypical diffuse nuclear distribution and mitotic number ≥3/10 HPF should be alert to the risk of recurrence.
Sujet(s)
Fumarate hydratase , Léiomyome , Tumeurs de l'utérus , Adulte , Desmine/métabolisme , Femelle , Fumarate hydratase/déficit , Fumarate hydratase/métabolisme , Humains , Antigène KI-67/métabolisme , Léiomyome/enzymologie , Léiomyome/anatomopathologie , Léiomyome/chirurgie , Erreurs innées du métabolisme/enzymologie , Adulte d'âge moyen , Hypotonie musculaire/enzymologie , Troubles psychomoteurs/enzymologie , Études rétrospectives , Protéine p53 suppresseur de tumeur , Tumeurs de l'utérus/diagnosticRÉSUMÉ
Introduction: Fumarase deficiency is a rare autosomal metabolic disease that curse with hypotonia, hyperlacticaemia and seizures. Diagnosis based in laboratory test might be done carefully, as most of metabolic diseases present similar symptomatology: hypotony, convulsions, lactic and pyruvic acidemia. Method: The objective is to analyse the pharmacological and nutritional approach of a neonate who presented symptoms of metabolic congenital disorders.Results:The patient is a three-month girl with heterozygote mutation in fumarase gene, who presented clinical manifestations of the altered enzyme function. She presented hyperlacticaemia, organic aciduria and alterations of amino acid levels. First diagnosis suspected was pyruvate dehydrogenase deficiency, so nutritional treatment with ketogenic diet was initiated. After medical discharge, she was hospitalized in emergency basis with cardiac arrest and metabolic decompensation. Genetic test revealed a heterozygote mutation in fumarase. Clinical symptomatology could have worsened because of the difficult diagnosis. Conclusions: Nutritional and pharmacological treatment of fumarase deficiency is considered essential for the patients evolution, but further researchers must be carried out to profoundly understand the mechanism underlying metabolic inborn errors. Multidisciplinary teams would manage the disease from the point of view of diverse clinician experts so the correct diagnosis and treatment would be decided with precision(AU)
Introducción: El déficit de fumarasa es una enfermedad rara del metabolismo, autosómica, que cursa con hipotonía, hiperlactacidemia y convulsiones. El diagnóstico basado en pruebas de laboratorio debe realizarse con precaución ya que la mayoría de enfermedades relacionadas con el metabolismo presentan la misma sintomatología: hipotonía, convulsiones y acidemia láctica y pirúvica. Método: Analizar retrospectivamente el manejo farmacológico y nutricional de un neonato con síntomas relacionados con errores del metabolismo congénitos.Resultados:La paciente de 3 meses de vida presentaba una mutación heterocigota en el gen de la fumarasa y síntomas relacionados con la alteración de la función enzima. La paciente presentaba hiperlactacidemia, aciduria orgánica y alteraciones analíticas de los aminoácidos. El primer diagnóstico supuesto fue un déficit de piruvato deshidrogenasa, por lo que se inició tratamiento nutricional con dieta cetogénica. Tras el alta de la paciente, volvió a ingresar por urgencias sufriendo una parada cardíaca y descompensación metabólica. El test genético reveló la presencia de una mutación heterocigota en el gen de la fumarasa. La sintomatología clínica pudo haber empeorado debido al difícil diagnóstico. Conclusiones: El tratamiento farmacológico y nutricional del déficit de fumarasa es esencial para la buena evolución del paciente, pero es necesario que se realicen más estudios para entender con profundidad el mecanismo de los errores congénitos del metabolismo Los equipos multidisciplinares permiten manejar la enfermedad desde distintos puntos de vista clínicos para un diagnóstico correcto y poder decidir el tratamiento adecuado con precisión(AU)
Sujet(s)
Humains , Femelle , Nourrisson , Fumarate hydratase/déficit , Erreurs innées du métabolisme/diétothérapie , Erreurs innées du métabolisme/diagnostic , Régime cétogène , Études rétrospectivesSujet(s)
Néphrocarcinome , Fumarate hydratase , Tumeurs du rein , Léiomyomatose , Syndromes néoplasiques héréditaires , Tumeurs de l'utérus , Néphrocarcinome/diagnostic , Néphrocarcinome/enzymologie , Néphrocarcinome/anatomopathologie , Femelle , Fumarate hydratase/déficit , Fumarate hydratase/génétique , Humains , Tumeurs du rein/diagnostic , Tumeurs du rein/enzymologie , Tumeurs du rein/anatomopathologie , Léiomyomatose/diagnostic , Léiomyomatose/enzymologie , Léiomyomatose/anatomopathologie , Syndromes néoplasiques héréditaires/diagnostic , Syndromes néoplasiques héréditaires/enzymologie , Syndromes néoplasiques héréditaires/anatomopathologie , Pronostic , Tumeurs de l'utérus/diagnostic , Tumeurs de l'utérus/enzymologie , Tumeurs de l'utérus/anatomopathologieRÉSUMÉ
Fumaric aciduria resulting from fumarate hydratase deficiency is a rare inherited disorder of the Krebs tricarboxylic acid cycle that is characterized by neurologic manifestations, a spectrum of brain abnormalities, and the excretion of fumaric acid in urine. We describe a 3 year old Sri Lankan boy who was referred at age 10 months with poor weight gain and hypotonia for further laboratory investigations. In addition to global developmental delay, there were noticeable dysmorphic features with a prominent forehead, low-set ears, micrognathia, and hypertelorism with persistent neutropenia. Urine organic acid assay revealed a massive elevation of fumaric acid on 2 occasions. Molecular analysis revealed a homozygous likely pathogenic missense variant, NM000143.3:c.1048C>T p. (Arg350Trp), in the FH gene, confirming the biochemical diagnosis. Our patient was the first patient in Sri Lanka molecularly diagnosed with fumaric aciduria. This case study highlights the importance of performing organic acid assays in children presenting with neurologic manifestations especially when these are suspected to have a metabolic basis.
Sujet(s)
Tests diagnostiques courants , Hypotonie musculaire , Enfant , Enfant d'âge préscolaire , Fumarate hydratase/déficit , Fumarate hydratase/génétique , Fumarate hydratase/métabolisme , Humains , Nourrisson , Mâle , Erreurs innées du métabolisme , Hypotonie musculaire/diagnostic , Hypotonie musculaire/génétique , Troubles psychomoteurs , Sri LankaRÉSUMÉ
Fumarate hydratase-deficient leiomyomas (dFH leiomyomas) often display atypical pathologic features yet exhibit a benign clinical course. Recent data suggest that dFH leiomyomas may be misclassified as smooth muscle tumors of uncertain malignant potential, a category that encompasses a heterogenous subgroup of uterine neoplasms with smooth muscle differentiation and atypical features that impart ambiguity regarding their expected clinical behavior. dFH leiomyomas can be seen in the context of hereditary leiomyomatosis and renal cell carcinoma syndrome or in the sporadic setting. In this retrospective study, we sought to examine the prevalence and clinicopathologic characteristics of dFH leiomyomas in 48 tumors previously diagnosed as smooth muscle tumors of uncertain malignant potential from 38 patients. Of these 48 tumors, 3 (6.3%) occurring in 2 patients were found to be deficient for FH by immunohistochemistry, including 1 uterine and 2 extrauterine (abdominopelvic) tumors. The 3 tumors showed histologic features typical of dFH leiomyomas, including hemangiopericytoma-like vessels, edema, macronucleoli, and atypia. Neither patient developed recurrent leiomyomas or renal cell carcinoma, and both were alive without disease at last follow-up. Our data suggest that dFH leiomyomas should be considered in the differential diagnosis of smooth muscle tumors of uncertain malignant potential, even in the context of extrauterine disease. Identification of FH deficiency in these tumors supports their classification as dFH leiomyomas despite their atypical morphologic features and/or clinical presentation. Importantly, detection of dFH in these cases may identify women at increased risk for hereditary leiomyomatosis and renal cell carcinoma who would benefit from genetic counseling and consideration for FH germline testing.
Sujet(s)
Néphrocarcinome , Tumeurs du rein , Léiomyomatose , Tumeurs cutanées , Tumeur du muscle lisse , Tumeurs de l'utérus , Néphrocarcinome/diagnostic , Diagnostic différentiel , Femelle , Fumarate hydratase/déficit , Fumarate hydratase/génétique , Humains , Tumeurs du rein/diagnostic , Léiomyomatose/diagnostic , Léiomyomatose/génétique , Léiomyomatose/anatomopathologie , Mâle , Erreurs innées du métabolisme , Hypotonie musculaire , Troubles psychomoteurs , Études rétrospectives , Tumeurs cutanées/anatomopathologie , Tumeur du muscle lisse/diagnostic , Tumeurs de l'utérus/anatomopathologieRÉSUMÉ
RATIONALE: Hereditary leiomyomatosis and renal cell carcinoma is an uncommon autosomal dominant disease caused by mutations in the fumarate hydratase (FH) gene. They usually demonstrated multiple uterine myomas and preformed surgical procedures for myomectomy and/or hysterectomy 10âyears earlier than sporadic myomas due to early development. This case report describes a woman with multiple uterine leiomyomas diagnosed with FH deficiency. PATIENT CONCERNS: A 37-year-old woman visited a gynecological clinic for the discovery of uterine leiomyoma for more than 1âyear. The size of the largest grew from 42â×â27â×â46 to 98â×â85â×â113âmm in 1 year. She had a history of surgery for breast cancer and thyroid cancer but denied a history of uterine leiomyoma in her family. DIAGNOSIS AND INTERVENTIONS: The patient underwent successful transabdominal hysterectomy. The pathological results showed multiple uterine leiomyomas (partly cellular leiomyomas) with scattered large bizarre giant cells. Immunohistochemistry results demonstrated FH deficiency. OUTCOMES: On follow-up, the patient did not have any complications. She was finally referred to the oncologists and urologists for follow-up. LESSONS: Gynecologists should be aware that early onset uterine leiomyoma presenting as large, multiple, and symptomatic lesion, may be associated with FH deficiency.
Sujet(s)
Fumarate hydratase/génétique , Léiomyome/chirurgie , Tumeurs de l'utérus/chirurgie , Adulte , Néphrocarcinome , Femelle , Fumarate hydratase/sang , Fumarate hydratase/déficit , Humains , Léiomyome/génétique , Erreurs innées du métabolisme/sang , Hypotonie musculaire/sang , Syndromes néoplasiques héréditaires/génétique , Syndromes néoplasiques héréditaires/chirurgie , Troubles psychomoteurs/sang , Tumeurs de l'utérus/génétiqueRÉSUMÉ
Fumarate hydratase (FH), encoded by the FH gene, is an enzyme which catalyses the conversion of fumarate to L-malate as part of the tricarboxylic acid cycle. Biallelic germline mutations in FH result in fumaric aciduria, a metabolic disorder resulting in severe neurological and developmental abnormalities. Heterozygous germline mutations in FH result in hereditary leiomyomatosis and renal cell carcinoma, a cancer predisposition syndrome. FH deficiency has multiple oncogenic mechanisms including through promotion of aerobic glycolysis, induction of pseudohypoxia, post-translational protein modification and impairment of DNA damage repair by homologous recombination. FH-deficient neoplasms can present with characteristic morphological features that raise suspicion for FH alterations and also frequently demonstrate loss of FH immunoreactivity and intracellular accumulation of 2-succinocysteine, also detected by immunohistochemistry.
Sujet(s)
Fumarate hydratase/déficit , Fumarate hydratase/métabolisme , Erreurs innées du métabolisme/enzymologie , Hypotonie musculaire/enzymologie , Tumeurs/enzymologie , Troubles psychomoteurs/enzymologie , Animaux , Fumarate hydratase/génétique , Régulation de l'expression des gènes codant pour des enzymes , Prédisposition génétique à une maladie , Humains , Léiomyomatose/enzymologie , Léiomyomatose/génétique , Léiomyomatose/anatomopathologie , Erreurs innées du métabolisme/génétique , Hypotonie musculaire/génétique , Mutation , Tumeurs/génétique , Tumeurs/anatomopathologie , Syndromes néoplasiques héréditaires/enzymologie , Syndromes néoplasiques héréditaires/génétique , Syndromes néoplasiques héréditaires/anatomopathologie , Phénotype , Troubles psychomoteurs/génétique , Tumeurs cutanées/enzymologie , Tumeurs cutanées/génétique , Tumeurs cutanées/anatomopathologie , Tumeurs de l'utérus/enzymologie , Tumeurs de l'utérus/génétique , Tumeurs de l'utérus/anatomopathologieRÉSUMÉ
Hereditary leiomyomatosis and renal cell carcinoma (HL (RCC)) entails cutaneous and uterine leiomyomatosis with aggressive type 2 papillary RCC-like histology. HLRCC is caused by pathogenic variants in the FH gene, which encodes fumarate hydratase (FH). Here, we describe an episode of young-onset RCC caused by a genomic FH deletion that was diagnosed via clinical sequencing. A 35-year-old woman was diagnosed with RCC and multiple metastases: histopathological analyses supported a diagnosis of FH-deficient RCC. Although the patient had neither skin tumors nor a family history of HLRCC, an aggressive clinical course at her age and pathological diagnosis of FH-deficient RCC suggested a germline FH variant. After counseling, the patient provided written informed consent for germline genetic testing. She was simultaneously subjected to paired tumor profiling tests targeting the exome to identify a therapeutic target. Although conventional germline sequencing did not detect FH variants, exome sequencing revealed a heterozygous germline FH deletion. As such, paired tumor profiling, not conventional sequencing, was required to identify this genetic deletion. RCC caused by a germline FH deletion has hitherto not been described in Japan, and the FH deletion detected in this patient was presumed to be of maternal European origin. Although the genotype-phenotype correlation in HLRCC-related tumors is unclear, the patient's family was advised to undergo genetic counseling to consider additional RCC screening.
Sujet(s)
Fumarate hydratase/déficit , Délétion de gène , Mutation germinale , Léiomyomatose/génétique , Erreurs innées du métabolisme/génétique , Hypotonie musculaire/génétique , Syndromes néoplasiques héréditaires/génétique , Troubles psychomoteurs/génétique , Tumeurs cutanées/génétique , Tumeurs de l'utérus/génétique , Adulte , Femelle , Fumarate hydratase/génétique , Dépistage génétique , HumainsRÉSUMÉ
We report a 62-year-old male with metastatic fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) without fumarate hydratase (FH) mutation (FH-deficient-like RCC). The International Metastatic RCC Database Consortium risk score was intermediate, and immunotherapy with nivolumab and ipilimumab (Ipi/ Nivo) was initiated. Four cycles of Ipi/Nivo and 5 cycles of nivolumab resulted in a complete response of the metastases. Hypophysitis occurred as an immune-related adverse event after four cycles of Ipi/Nivo. The prognosis of patients with FH-deficient RCC is generally poor. Few reports of FH-deficient RCC successfully treated with Ipi/Nivo have been published. Ipi/Nivo can be effective for treating FH-deficient RCC.
Sujet(s)
Antinéoplasiques immunologiques/effets indésirables , Néphrocarcinome/thérapie , Ipilimumab/effets indésirables , Tumeurs du rein/traitement médicamenteux , Nivolumab/administration et posologie , Protocoles de polychimiothérapie antinéoplasique , Néphrocarcinome/imagerie diagnostique , Néphrocarcinome/génétique , Néphrocarcinome/anatomopathologie , Fumarate hydratase/déficit , Fumarate hydratase/génétique , Mutation germinale , Humains , Tumeurs du rein/imagerie diagnostique , Tumeurs du rein/anatomopathologie , Mâle , Adulte d'âge moyen , Néphrectomie , TomodensitométrieRÉSUMÉ
PURPOSE: Fumarate hydratase-deficient (FHdef) renal cell carcinoma (RCC) is a rare entity associated with the hereditary leiomyomatosis and RCC syndrome with no standard therapy approved. The aim of this retrospective study was to evaluate the efficacy of different systemic treatments in this population. METHODS: We performed a multicentre retrospective analysis of Fhdef RCC patients to determine the response to systemic treatments. The endpoints were objective response rate (ORR), time-to-treatment failure (TTF), and overall survival (OS). The two latter were estimated using the Kaplan-Meier method. RESULTS: Twenty-four Fhdef RCC patients were identified, and 21 under systemic therapy were included in the analysis: ten received cabozantinib, 14 received sunitinib, nine received "other antiangiogenics" (sorafenib, pazopanib, and axitinib), three received erlotinib-bevacizumab (E-B), three received mTOR inhibitors, and 11 received immune checkpoint blockers (ICBs). ORR for treatments were 50% for cabozantinib, 43% for sunitinib, 63% for "other antiangiogenics," and 30% for E-B, whereas ORR was 0% for mTOR inhibitors and 18% for ICBs. The median TTF (mTTF) was significantly higher with antiangiogenics (11.6 months) than with mTOR inhibitors (4.4 months) or ICBs (2.7 months). In the first-line setting, antiangiogenics presented a higher ORR compared with nivolumab-ipilimumab (64% versus 25%) and a significantly superior mTTF (11.0 months vs 2.5 months; p = 0.0027). The median OS from the start of the first systemic treatment was 44.0 months (95% confidence interval: 13.0-95.0). CONCLUSIONS: We report the first European retrospective study of Fhdef RCC patients treated with systemic therapy with a remarkably long median OS of 44.0 months. Our results suggest that antiangiogenics may be superior to ICB/mTOR inhibitors in this population.
Sujet(s)
Inhibiteurs de l'angiogenèse/usage thérapeutique , Marqueurs biologiques tumoraux/génétique , Fumarate hydratase/génétique , Inhibiteurs de points de contrôle immunitaires/usage thérapeutique , Tumeurs du rein/traitement médicamenteux , Inhibiteurs de protéines kinases/usage thérapeutique , Adulte , Inhibiteurs de l'angiogenèse/effets indésirables , Marqueurs biologiques tumoraux/déficit , Évolution de la maladie , Femelle , France , Fumarate hydratase/déficit , Prédisposition génétique à une maladie , Humains , Inhibiteurs de points de contrôle immunitaires/effets indésirables , Tumeurs du rein/enzymologie , Tumeurs du rein/génétique , Mâle , Adulte d'âge moyen , Thérapie moléculaire ciblée , Phénotype , Inhibiteurs de protéines kinases/effets indésirables , Études rétrospectives , Espagne , Sérine-thréonine kinases TOR/antagonistes et inhibiteurs , Sérine-thréonine kinases TOR/métabolisme , Facteurs temps , Échec thérapeutique , Jeune adulteRÉSUMÉ
PURPOSE: Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare, aggressive form of RCC associated with hereditary leiomyomatosis and RCC syndrome. Evidence for systemic therapy efficacy is lacking. EXPERIMENTAL DESIGN: We studied clinical and genomic characteristics of FH-RCC, including response [objective response rate (ORR)] to systemic therapies and next-generation sequencing (NGS). Patients with metastatic FH-RCC, defined by presence of pathogenic germline or somatic FH mutation plus IHC evidence of FH loss, were included. RESULTS: A total of 28 of 32 included patients (median age 46; range, 20-74; M:F, 20:12) underwent germline testing; 23 (82%) harbored a pathogenic FH germline variant. Five (16%) were negative for germline FH mutations; all had biallelic somatic FH loss. Somatic NGS (31/32 patients) revealed co-occurring NF2 mutation most frequently (n = 5). Compared with clear-cell RCC, FH-RCC had a lower mutation count (median 2 vs. 4; P < 0.001) but higher fraction of genome altered (18.7% vs. 10.3%; P = 0.001). A total of 26 patients were evaluable for response to systemic therapy: mTOR/VEGF combination (n = 18, ORR 44%), VEGF monotherapy (n = 15, ORR 20%), checkpoint inhibitor therapy (n = 8, ORR 0%), and mTOR monotherapy (n = 4, ORR 0%). No complete responses were seen. Median overall and progression-free survival were 21.9 months [95% confidence interval (CI): 14.3-33.8] and 8.7 months (95% CI: 4.8-12.3), respectively. CONCLUSIONS: Although most FH-RCC tumors are due to germline FH alterations, a significant portion result from biallelic somatic FH loss. Both somatic and germline FH-RCC have similar molecular characteristics, with NF2 mutations, low tumor mutational burden, and high fraction of genome altered. Although immunotherapy alone produced no objective responses, combination mTOR/VEGF therapy showed encouraging results.
Sujet(s)
Marqueurs biologiques tumoraux , Néphrocarcinome/génétique , Fumarate hydratase/déficit , Adulte , Sujet âgé , Allèles , Protocoles de polychimiothérapie antinéoplasique , Néphrocarcinome/diagnostic , Néphrocarcinome/traitement médicamenteux , Néphrocarcinome/mortalité , Biologie informatique , Variations de nombre de copies de segment d'ADN , Femelle , Mutation germinale , Humains , Immunohistochimie , Mâle , Adulte d'âge moyen , Mutation , Grading des tumeurs , Stadification tumorale , Pronostic , Études rétrospectives , Résultat thérapeutique , Jeune adulteRÉSUMÉ
BACKGOUND: Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a subtype of RCC that is increasingly recognized pathologically. The aim of this study was to evaluate the imaging features of FH-RCC on computed tomography (CT), magnetic resonance imaging (MRI), and fluorodeoxyglucose positron emission tomography (FDG PET), and to determine the pre-operative diagnostic potential of imaging. METHODS: This single-site retrospective study included patients with histologically confirmed FH-RCC or with a renal cancer and known germline FH mutation; imaging of the renal mass before treatment with contrast-enhanced CT, contrast-enhanced MRI, or FDG PET/CT between October 2007 and May 2019. Clinical information, pathological data, and imaging features were analyzed and reported descriptively. RESULTS: Sixteen patients with sixteen tumors were included (median age 46 years, interquartile range 38-53 years; 31 % female). Almost all tumors were unifocal (15/16, 94 %). Most tumors had infiltrative margins (14/16, 88 %); few were circumscribed (2/16, 12 %). A large cystic tumor component (> 75 % of tumor volume) was seen in 8/16 (50 %) of tumors. Involvement of renal sinus fat was seen in 13/16 (81 %) of tumors, involvement of the hilar collecting system in 8/16 (50 %), and renal vein tumor thrombus in 6/16 (38 %). All 12 tumors (100 %) imaged with MRI had heterogenous tumor enhancement and heterogenous T2 signal. Of those patients that had diffusion-weighted imaging, 11/11 (100 %) of tumors had diffusion restriction in the solid portions of the tumor. Of the patients who had PET, 3/3 (100 %) tumors showed high metabolic activity with mean maximum standardized uptake value (SUVmax) of 16.4 (range 9.6-21.9). Patients presented with retroperitoneal nodal metastases in 69 % of cases and distant metastases in 75 %. Of those four patients without metastatic disease at presentation, three (75 %) developed metastases within 4 years of diagnosis. CONCLUSIONS: In our study, the majority of tumors (≥ 75 %) were unifocal, had an infiltrative margin, invaded the renal sinus fat, and presented with distant metastases. On MRI, most tumors had heterogenous T2 signal and diffusion restriction in their solid components. The small number of cases that had PET imaging showed high metabolic activity.
Sujet(s)
Néphrocarcinome/imagerie diagnostique , Fumarate hydratase/déficit , Tumeurs du rein/imagerie diagnostique , Tomographie par émission de positons couplée à la tomodensitométrie/méthodes , Adulte , Néphrocarcinome/anatomopathologie , Femelle , Humains , Tumeurs du rein/anatomopathologie , Mâle , Adulte d'âge moyen , Études rétrospectives , Charge tumoraleRÉSUMÉ
Understanding the mechanisms of the Warburg shift to aerobic glycolysis is critical to defining the metabolic basis of cancer. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an aggressive cancer characterized by biallelic inactivation of the gene encoding the Krebs cycle enzyme fumarate hydratase, an early shift to aerobic glycolysis, and rapid metastasis. We observed impairment of the mitochondrial respiratory chain in tumors from patients with HLRCC. Biochemical and transcriptomic analyses revealed that respiratory chain dysfunction in the tumors was due to loss of expression of mitochondrial DNA (mtDNA)-encoded subunits of respiratory chain complexes, caused by a marked decrease in mtDNA content and increased mtDNA mutations. We demonstrated that accumulation of fumarate in HLRCC tumors inactivated the core factors responsible for replication and proofreading of mtDNA, leading to loss of respiratory chain components, thereby promoting the shift to aerobic glycolysis and disease progression in this prototypic model of glucose-dependent human cancer.
Sujet(s)
Néphrocarcinome/génétique , Cycle citrique , Altération de l'ADN , ADN mitochondrial/métabolisme , Fumarate hydratase/génétique , Tumeurs du rein/génétique , Léiomyomatose/enzymologie , Syndromes néoplasiques héréditaires/enzymologie , Tumeurs cutanées/enzymologie , Tumeurs de l'utérus/enzymologie , Adulte , Sujet âgé , Néphrocarcinome/étiologie , Néphrocarcinome/métabolisme , Réparation de l'ADN , Réplication de l'ADN , Femelle , Fumarate hydratase/déficit , Analyse de profil d'expression de gènes , Humains , Tumeurs du rein/étiologie , Tumeurs du rein/métabolisme , Léiomyomatose/complications , Mâle , Adulte d'âge moyen , Mitochondries/génétique , Mitochondries/métabolisme , Mutation , Syndromes néoplasiques héréditaires/complications , Tumeurs cutanées/complications , Tumeurs de l'utérus/complications , Jeune adulteRÉSUMÉ
PURPOSE: Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare but lethal subtype of RCC. Little is known about the genomic profile of FH-deficient RCC, and the therapeutic options for advanced disease are limited. To this end, we performed a comprehensive genomics study to characterize the genomic and epigenomic features of FH-deficient RCC. EXPERIMENTAL DESIGN: Integrated genomic, epigenomic, and molecular analyses were performed on 25 untreated primary FH-deficient RCCs. Complete clinicopathologic and follow-up data of these patients were recorded. RESULTS: We identified that FH-deficient RCC manifested low somatic mutation burden (median 0.58 mutations per megabase), but with frequent somatic copy-number alterations. The majority of FH-deficient RCCs were characterized by a CpG sites island methylator phenotype, displaying concerted hypermethylation at numerous CpG sites in genes of transcription factors, tumor suppressors, and tumor hallmark pathways. However, a few cases (20%) with low metastatic potential showed relatively low DNA methylation levels, indicating the heterogeneity of methylation pattern in FH-deficient RCC. Moreover, FH-deficient RCC is potentially highly immunogenic, characterized by increased tumor T-cell infiltration but high expression of immune checkpoint molecules in tumors. Clinical data further demonstrated that patients receiving immune checkpoint blockade-based treatment achieved improved progression-free survival over those treated with antiangiogenic monotherapy (median, 13.3 vs. 5.1 months; P = 0.03). CONCLUSIONS: These results reveal the genomic features and provide new insight into potential therapeutic strategies for FH-deficient RCC.