ABSTRACT
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare autosomal dominant syndrome caused by a germline mutation in the fumarate hydratase (FH) gene that manifests with 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. In this study, we described a case of aggressive HLRCC in a 33-year-old female who exhibited a novel heterozygous germline insertion mutation in exon 8 of the FH gene (c.1126 C > T; p.Q376*). The patient underwent laparoscopic resection of the right kidney, but metastases appeared within 3 months after surgery. Histological staining of the resected tumor revealed high expression levels of programmed cell death-ligand 1 (PD-L1). Therefore, the patient was treated with immunotherapy. The patient achieved a partial response to immunotherapy, and the treatment of metastatic lesions has continued to improve. A thorough literature review pinpointed 76 historical cases of HLRCC-RCC that had undergone immunotherapy. From this pool, 46 patients were selected for this study to scrutinize the association between mutations in the FH gene and the effectiveness of immunotherapy. Our results indicate that immunotherapy could significantly improve the overall survival (OS) of patients with HLRCC-RCC. However, no influence of different mutations in the FH germline gene on the therapeutic efficacy of immunotherapy was observed. Therefore, our study suggested that immunotherapy was an effective therapeutic option for patients with HLRCC regardless of the type of FH germline mutation.
Subject(s)
Fumarate Hydratase , Immunotherapy , Leiomyomatosis , Neoplastic Syndromes, Hereditary , Skin Neoplasms , Uterine Neoplasms , Humans , Female , Leiomyomatosis/genetics , Leiomyomatosis/pathology , Leiomyomatosis/therapy , Fumarate Hydratase/genetics , Adult , Neoplastic Syndromes, Hereditary/genetics , Neoplastic Syndromes, Hereditary/therapy , Neoplastic Syndromes, Hereditary/complications , Neoplastic Syndromes, Hereditary/pathology , Uterine Neoplasms/genetics , Uterine Neoplasms/pathology , Uterine Neoplasms/therapy , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Skin Neoplasms/therapy , Germ-Line Mutation , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Kidney Neoplasms/therapy , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/therapySubject(s)
Telangiectasia, Hereditary Hemorrhagic , Humans , Telangiectasia, Hereditary Hemorrhagic/complications , Telangiectasia, Hereditary Hemorrhagic/diagnosis , Intestinal Polyposis/congenital , Intestinal Polyposis/diagnosis , Intestinal Polyposis/complications , Intestinal Polyposis/genetics , Intracranial Arteriovenous Malformations/complications , Intracranial Arteriovenous Malformations/diagnostic imaging , Neoplastic Syndromes, Hereditary/complications , Neoplastic Syndromes, Hereditary/genetics , Neoplastic Syndromes, Hereditary/diagnostic imaging , Neoplastic Syndromes, Hereditary/diagnosis , Adult , Male , Female , Cerebral AngiographyABSTRACT
The aim of this study was to assess the histopathologic spectrum of renal tumors in patients with PTEN hamartoma tumor syndrome (PHTS), with a specific focus on potential features predictive of the underlying syndrome. A multi-institutional study was conducted to obtain clinical and pathologic data on renal tumors arising in patients with PHTS, either diagnosed by germline mutational analysis or clinical criteria for Cowden syndrome. Histologic sections of the renal tumors were re-reviewed for classification. Twelve renal epithelial tumors from 9 patients were identified (4 males and 5 females, with a mean age of 41.8 y), 7 of whom carried germline PTEN mutations. All 12 renal epithelial tumors were renal cell carcinomas (RCCs): 5 were chromophobe RCCs, 4 papillary RCCs, and 3 RCC not otherwise specified. Pathologic stage distribution was: 7 (59%) pT1a, 2 (17%) pT1b, 1 (8%) pT2a, 1 (8%) pT2b, and 1 (8%) pT3a. World Health Organization/International Society of Urological Pathology (WHO/ISUP) histologic grade was applicable in 7 (54%) nonchromophobe tumors: 4 (57%) G2, 2 (29%) G3, and 1 (14%) G4. An unexpected histologic finding was the presence of 2 patients with incidental microscopic collections of intrarenal adipocytes that had no features of angiomyolipoma (and were negative with 2 sensitive PEComa markers: cathepsin-K and GPNMB); both were classified as lipoma/"lipomatous hamartomas." The average follow-up interval was 67.8 months (13 to 172 mo): 5 patients had no evidence of disease, 2 were lost to follow-up, 1 died of other (non-PHTS) causes (ie, prostate cancer), and 1 was alive with metastatic RCC to the lung (RCC not otherwise specified with rhabdoid differentiation). All tumors showed loss of nuclear PTEN staining by immunohistochemistry. Fumarate hydratase was retained and 2SC was negative in all papillary RCCs. CK7 was moderate-strong/diffuse positive in 4 of 5 chromophobe RCCs and in 3 of 4 papillary RCCs. Renal epithelial tumors associated with PHTS represent a heterogeneous group of RCCs, but classic chromophobe and papillary RCC are most common. The majority have a favorable clinical behavior as would be predicted by subtype. In contrast to other hereditary renal neoplasia syndromes, morphologic features of the RCCs do not allow identification of PHTS-associated neoplasia with any degree of specificity in the absence of clinical setting and/or prior history, but the presence of microscopic "lipomas" within the kidney may provide a clue in rare cases. Therefore, clinical suspicion and genetic counseling with germline testing remain necessary for identifying PHTS-associated RCC.
Subject(s)
Carcinoma, Renal Cell , Hamartoma Syndrome, Multiple , Kidney Neoplasms , Lipoma , Neoplastic Syndromes, Hereditary , Male , Female , Humans , Adult , Carcinoma, Renal Cell/pathology , Hamartoma Syndrome, Multiple/complications , Hamartoma Syndrome, Multiple/genetics , Kidney Neoplasms/pathology , Neoplastic Syndromes, Hereditary/complications , PTEN Phosphohydrolase/genetics , Membrane GlycoproteinsABSTRACT
We report the case of a 42-year - old female with familiar form von Hippel-Lindau disease (VHL) and recurrent endolymphatic sac tumour (ELST), which was presented like non-homogenous, solid and cystic expansion of the left petrous temporal bone. Histologically, there was found lamellae of bone with adjacent ligament and with papillary projections with fibrovascular core. The papillae were lined by a single layer of cuboidal epithelium with hyperchromatic and lightly pleomorphic nuclei. Sporadically, small cystic formations with eosinophilic, PAS positive secretion were noted. Imunohistochemically, the cuboidal cells showed diffuse positivity for vimentin, epithelial membrane antigen (EMA), cytokeratin AE1/AE3 and S100 protein (weakly). Other markers examined, including TTF1, PAX8 and CD10, were negative. Endolymphatic sac tumour is rare low-grade malignant epithelial tumour arising from the endolymphatic sac in the temporal bone, which occurs in 1 out of 30 000 births, with just fewer than 300 cases reported in the literature. About one third of cases are associated with von Hippel- Lindau disease, an autosomal dominant familial cancer syndrome.
Subject(s)
Adenoma , Bone Neoplasms , Ear Neoplasms , Endolymphatic Sac , Neoplastic Syndromes, Hereditary , von Hippel-Lindau Disease , Humans , Female , von Hippel-Lindau Disease/complications , von Hippel-Lindau Disease/pathology , Endolymphatic Sac/pathology , Ear Neoplasms/complications , Ear Neoplasms/pathology , Neoplastic Syndromes, Hereditary/complications , Neoplastic Syndromes, Hereditary/pathology , Bone Neoplasms/complications , Adenoma/pathologyABSTRACT
CDC73 alterations are associated with three main parathyroid lesions according to the World Health Organization (WHO) classification of tumors of the endocrine system. These include hyperparathyroidism-jaw tumor (HPT-JT) syndrome-associated adenomas, atypical parathyroid tumors (APTs), and parathyroid carcinomas (PCs). The loss of nuclear parafibromin expression, which serves as a surrogate marker for the underlying CDC73 alteration, encompasses these tumors under the term parafibromin-deficient parathyroid tumors. They have distinct morphologic features of more abundant eosinophilic cytoplasm with perinuclear clearing surrounding a large nucleus as well as prominent dilated branching "hemangiopericytoma-like" vasculature and a thick capsule as well as variably sized cystic spaces. These tumors include cases that show unequivocal histologic features fulfilling the criteria for PCs with growing data indicating a higher rate of recurrence or metastasis compared with parafibromin intact PCs. More importantly, the loss of parafibromin expression can be used in clinical practice to recognize APTs that fall short of a conclusive diagnosis of PCs, but clinically behave akin to them. Moreover, recognizing these tumors can lead to an underlying germline mutation and a diagnosis of HPT-JT, which impacts long-term treatment and surveillance for patients and close family.
Subject(s)
Hyperparathyroidism , Jaw Neoplasms , Neoplastic Syndromes, Hereditary , Parathyroid Neoplasms , Humans , Parathyroid Neoplasms/diagnosis , Parathyroid Neoplasms/genetics , Parathyroid Neoplasms/pathology , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism , Hyperparathyroidism/pathology , Jaw Neoplasms/diagnosis , Jaw Neoplasms/genetics , Neoplastic Syndromes, Hereditary/complications , Transcription FactorsABSTRACT
Juvenile polyposis syndrome (JPS) is an autosomal dominant, inherited disorder caused by pathogenic germline variants of mainly SMAD4 or BMPR1A genes. Some patients with JPS, especially with SMAD4 variants, also develop hereditary, hemorrhagic telangiectasia (HHT). HHT is also an autosomal dominant inherited disorder. Herein, we identified a novel germline pathogenic variant of the SMAD4 in a Japanese family with JPS and HHT. A six-base pair deletion in the SMAD4 gene (NM_005359.6:c.1495_1500delTGCATA) was identified in the patients. Two amino acids are deleted from SMAD4 protein (p.Cys499_Ile500del), which are located in MSH2 domain essential for the binding with SMAD3. This is a novel variant that has not been registered in any database surveyed. Amino acid structural analysis predicted significant changes in the secondary and three-dimensional structures in the vicinity of the two amino acids' deletion. The variant is classified as 'Likely Pathogenic' according to the American College of Medical Genetics and Genomics guidelines.
Subject(s)
Intestinal Polyposis , Neoplastic Syndromes, Hereditary , Telangiectasia, Hereditary Hemorrhagic , Humans , Telangiectasia, Hereditary Hemorrhagic/genetics , Telangiectasia, Hereditary Hemorrhagic/complications , Smad4 Protein/genetics , East Asian People , Neoplastic Syndromes, Hereditary/genetics , Neoplastic Syndromes, Hereditary/complications , Intestinal Polyposis/genetics , Intestinal Polyposis/complications , Germ CellsSubject(s)
Intestinal Polyposis , Neoplastic Syndromes, Hereditary , Adenomatous Polyps , Humans , Intestinal Polyposis/complications , Intestinal Polyposis/congenital , Intestinal Polyposis/drug therapy , Neoplastic Syndromes, Hereditary/complications , Neoplastic Syndromes, Hereditary/drug therapy , Sirolimus/therapeutic use , Stomach NeoplasmsABSTRACT
Hereditary hemorrhagic telangiectasia (HHT) (Osler-Weber-Rendu Syndrome) is a rare autosomal dominant vascular disorder characterized by the presence of multiple arteriovenous malformations (AVMs) and recurrent bleeding episodes. The diagnosis is based on the Curacao criteria: (i) spontaneous recurrent epistaxis, (ii) mucocutaneous telangiectasia, (iii) AVMs of visceral organs, and (iv) first degree relatives with a similar condition (1). Due to a common genetic pathway and SMAD4 gene mutation, juvenile polyposis syndrome (JPS) may coexist with HHT (2). The disease burden is high in overlapping HHT/JPS, but digital clubbing may be the only physical finding. Continuous meticulous management may improve the quality of life and reduce the risk of complications. In 2000, a 15-year-old female patient was diagnosed with HHT based on epistaxis, multiple pulmonary AVMs, and a father who had similar symptoms. Other visceral AVMs were excluded. No telangiectasia was noted. On several occasions, pulmonary AVMs were managed with coil embolization (Figure 1), which successfully led to the resolution of dyspnea and cyanosis. Recurrent gastrointestinal bleedings led to severe transfusion-dependent anemia. Multiple polyps in the stomach, small intestine, and colon were repeatedly endoscopically removed, confirming the coexisting JPS. Genetic testing was not performed. Proctocolectomy was performed to prevent malignant transformation in the digestive tract. Telangiectasias are the dermatological hallmark of the HHT and occur in up to 90% of patients with the typical onset in childhood, becoming more apparent with increasing age. They are most frequently found on the face, with highest incidence on the nose, lips, tongue, and ears, followed by the fingertips, trunk, and feet; telangiectasia is recognized as the most common of the three criteria required for the diagnosis of HHT (1). Interestingly, no cutaneous telangiectasia developed in our patient during years of follow-up. However, pulmonary AVMs led to digital clubbing of her both fingers and toes (Figure 2). Digital clubbing is the focal enlargement of the connective tissue in the terminal phalanges, consequently changing the shape of nails, which become abnormally curved and shiny. It is associated with various infectious, neoplastic, inflammatory, and vascular conditions (3). Despite its well-known prevalence in certain conditions, the pathogenesis of this phenomenon remains elusive. Vascular, neural, and hormonal mechanisms have been considered, implicating the role of a wide range of substances, such as prostaglandins, bradykinin, estrogen, platelet-derived growth factor, hepatocyte growth factor, and growth hormone, however, none of these mechanisms provide a unifying explanation (4,5). In digital clubbing, the increased vascularity in the nail-bed leads to hyperplasia of fibrous tissue and edema, resulting in a loss of the hyponychial angle, fluctuance of the nail-bed, and an abnormal phalangeal depth ratio (5). The clinical assessment of the clubbing is based on the measurement of the distal phalangeal depth (DPD) of the finger (at the nail base) and the interphalangeal depth (IPD). A DPD/IPD ratio >1 is defined as clubbing, while a DPD/IPD ratio <1 is defined as normal (3). Clubbing is a potentially reversible phenomenon provided that the underlying condition is cured (4,5). In the context of pulmonary AVMs, abnormal communication between the pulmonary artery and pulmonary vein outside the capillary bed leads to right-to-left shunt physiology that clinically presents as dyspnea, cyanosis, and clubbing. Embolization of AVMs as the first-line therapy resolved systemic symptoms in our patient, and therefore no other treatment options were pulmonary considered further. However, 20 years later, despite the treatment, the severe clubbing of her both fingers and toes remained (Figure 2). Based on our findings, HHT should be considered in differential diagnosis of patients with digital clubbing resulting from AVMs, in particular when no skin telangiectasia is present.
Subject(s)
Intestinal Polyposis , Neoplastic Syndromes, Hereditary , Telangiectasia, Hereditary Hemorrhagic , Adolescent , Female , Humans , Intestinal Polyposis/congenital , Neoplastic Syndromes, Hereditary/complications , Neoplastic Syndromes, Hereditary/genetics , Quality of Life , Telangiectasia, Hereditary Hemorrhagic/complications , Telangiectasia, Hereditary Hemorrhagic/diagnosisABSTRACT
BACKGROUND: The effect of the genetic imprint on the emergency presentation of colon cancer remains unclear. The disparity between tumours evolving along different carcinogenetic pathways has not been studied systematically. This retrospective multicenter cohort study evaluates the association between mismatch repair status and the risk for acute surgery of colon cancer. PATIENTS AND METHODS: A retrospective multicenter cohort study including in total 870 patients from three different countries. Scandinavian cohort (Finland and Sweden), including a total of 412 patients operated between January 1, 1995 and December 31, 2010, was validated against a cohort from the Czech Republic, including a total of 458 patients, operated between January 1, 2018 and December 31, 2019. The proficiency or deficiency of mismatch repair was determined by immunohistochemistry. Primary outcome was the risk for acute colon cancer surgery given as the Odds Ratio (OR) in the univariable and multivariable analyses. Acute colon cancer surgery was defined as surgery performed during the same hospital admission as when the diagnosis of colon cancer was made. RESULTS: Of the 870 patients (399 females [46%]) included in the analyses, median age at surgery was 69 [interquartile range, 61-76] years, deficient Mismatch Repair (dMMR) status was found in 190 patients (22%), and 179 patients (21%) underwent acute surgery during the same hospital admission as when the diagnosis of colon cancer was made. In the Scandinavian cohort, a significant association between dMMR status and acute surgery was seen in both the univariable (OR 1.82, 95% CI 1.11-3.02, P = 0.017) and the multivariable (OR = 2.21, 95% CI 1.28-3.95, P = 0.005) analyses. This was confirmed in the Czech validation cohort in both the univariable (OR = 1.94, 95% CI 1.09-3.26, P = 0.022) and the multivariable (OR = 1.77, 95% CI 1.15-3.18, P = 0.021) analyses. CONCLUSION: This multicenter study reveals a strong association between acute colon cancer surgery and dMMR tumour status.
Subject(s)
Brain Neoplasms/complications , Colonic Neoplasms/genetics , Colonic Neoplasms/surgery , Colorectal Neoplasms/complications , Neoplastic Syndromes, Hereditary/complications , Adult , Aged , Aged, 80 and over , Colonic Neoplasms/pathology , Female , Humans , Male , Middle Aged , Neoplasm Staging , Retrospective StudiesABSTRACT
We studied metastasis-promoting effect of transmembrane protease TMPRSS4 on mismatch repair (MMR)-deficient colorectal cancer liver metastasis in BALB/c nude mouse model. Histomorphological and histopathological studies showed that the number of liver metastases in the study group were significantly higher than that in the control group (p<0.05). The expression of TMPRSS4 mRNA and protein in the study group were obviously higher than in the control group (p<0.05). These findings suggest that TMPRSS4 possesses a metastasis-promoting effect and its low expression can effectively block the progression of MMR-deficient colon cancer liver metastasis.
Subject(s)
Colonic Neoplasms/pathology , Liver Neoplasms/secondary , Membrane Proteins/physiology , Serine Endopeptidases/physiology , Animals , Brain Neoplasms/complications , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Cell Movement/genetics , Cell Transformation, Neoplastic/genetics , Colonic Neoplasms/genetics , Colorectal Neoplasms/complications , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , DNA Mismatch Repair/genetics , Disease Progression , Female , Gene Expression Regulation, Neoplastic , Humans , Liver Neoplasms/genetics , Membrane Proteins/genetics , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplastic Syndromes, Hereditary/complications , Neoplastic Syndromes, Hereditary/genetics , Neoplastic Syndromes, Hereditary/pathology , Serine Endopeptidases/genetics , Tumor Cells, CulturedABSTRACT
Hamartomatous polyposis syndromes (HPS) are a heterogeneous spectrum of diseases that are characterized by diffuse hamartomatous polyps lining the gastrointestinal (GI) tract together with extra-GI manifestations. Classical HPS includes juvenile polyposis syndrome, Peutz-Jeghers syndrome, PTEN hamartoma tumor syndrome and hereditary mixed polyposis syndrome. Patients with HPS have a higher risk of GI and extra-GI malignancies than the general population, although the underlying mechanisms remain unclear and are obviously different from the carcinogenesis of classical adenocarcinoma and colitis-associated malignancy. In this review we aimed to clarify the risks, possible mechanism and endoscopic surveillance of HPS-associated GI malignancies.
Subject(s)
Hamartoma Syndrome, Multiple , Intestinal Polyposis , Hamartoma Syndrome, Multiple/complications , Hamartoma Syndrome, Multiple/genetics , Humans , Intestinal Polyposis/complications , Intestinal Polyposis/genetics , Intestinal Polyps , Neoplastic Syndromes, Hereditary/complications , Neoplastic Syndromes, Hereditary/genetics , Peutz-Jeghers Syndrome/complications , Peutz-Jeghers Syndrome/geneticsABSTRACT
Beckwith-Wiedemann syndrome (BWS) is a genetic overgrowth and cancer predisposition syndrome that can be associated with a spectrum of clinical features including isolated lateralized overgrowth, macrosomia, macroglossia, organomegaly, omphalocele/umbilical hernia, and distinct facial features. Because of a range of clinical presentations and molecular defects involving Chromosome 11p15, many cases will fall within what is now being defined as the Beckwith-Wiedemann spectrum (BWSp). Cushing syndrome (CS) in infants is a rare neuroendocrinological disease associated with hypercortisolism that has rarely been reported in patients with BWS. Here, we describe the first case of a 5-month-old male with CS secondary to paternal uniparental disomy of Chromosome 11p without additional clinical signs or symptoms of BWS. This case continues to expand the phenotypic spectrum of BWSp.
Subject(s)
Beckwith-Wiedemann Syndrome/pathology , Chromosomes, Human, Pair 11/genetics , Neoplastic Syndromes, Hereditary/pathology , Uniparental Disomy , Beckwith-Wiedemann Syndrome/complications , Beckwith-Wiedemann Syndrome/genetics , Humans , Infant , Male , Neoplastic Syndromes, Hereditary/complications , Neoplastic Syndromes, Hereditary/geneticsABSTRACT
BACKGROUND: The attention on mismatch repair-deficient (dMMR) gastric cancer has increased in this era of anti-PD-1 blockade therapy; however, the prevalence and molecular genetics of patients with dMMR gastric cancer have not been completely investigated. METHODS: Immunohistochemistry of MMR proteins (MLH1, MSH2, MSH6 and PMS2) was performed on formalin-fixed paraffin-embedded sections prepared from resected primary gastric cancers of 513 consecutive patients. Genetic and/or epigenetic alterations of the MMR genes were also investigated. RESULTS: Loss of expression of one or more MMR proteins was observed in 58 patients (11.3%); 54 patients showed loss of MLH1/PMS2, 3 patients showed loss of MLH1/PMS2/MSH6 and 1 patient showed loss of PMS2 alone. Among these 58 patients, 55 showed hypermethylation of the promoter region of MLH1. Genetic testing revealed that the remaining three patients had Lynch syndrome (n = 1) or Lynch-like syndrome (n = 2). A total of 15 patients (25.9% of all patients with dMMR gastric cancer and 2.9% of all patients with gastric cancer), including 11 patients with stage I-III dMMR gastric cancer who had recurrence and 4 patients with stage IV dMMR gastric cancer, are potential candidates for the use of anti-PD-1 blockades. CONCLUSIONS: This is the first study to investigate the frequency and molecular genetic mechanisms of dMMR gastric cancer comprehensively, focusing on the benefit of using PD-1 blockades. Our observations will be beneficial in the clinical practice of metastatic gastric cancer.
Subject(s)
Brain Neoplasms/epidemiology , Brain Neoplasms/genetics , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/genetics , Genetic Testing , Neoplastic Syndromes, Hereditary/epidemiology , Neoplastic Syndromes, Hereditary/genetics , Stomach Neoplasms/epidemiology , Stomach Neoplasms/genetics , Adult , Aged , Aged, 80 and over , Brain Neoplasms/complications , Colorectal Neoplasms/complications , Colorectal Neoplasms, Hereditary Nonpolyposis/epidemiology , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , DNA Mismatch Repair/genetics , Female , Gene Frequency , Hospitalization/statistics & numerical data , Hospitals/statistics & numerical data , Humans , Immunohistochemistry , Japan/epidemiology , Male , Middle Aged , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Neoplastic Syndromes, Hereditary/complications , Prevalence , Retrospective Studies , Stomach Neoplasms/drug therapy , Stomach Neoplasms/pathology , Young AdultABSTRACT
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.
Subject(s)
Carcinoma, Renal Cell/genetics , Citric Acid Cycle , DNA Damage , DNA, Mitochondrial/metabolism , Fumarate Hydratase/genetics , Kidney Neoplasms/genetics , Leiomyomatosis/enzymology , Neoplastic Syndromes, Hereditary/enzymology , Skin Neoplasms/enzymology , Uterine Neoplasms/enzymology , Adult , Aged , Carcinoma, Renal Cell/etiology , Carcinoma, Renal Cell/metabolism , DNA Repair , DNA Replication , Female , Fumarate Hydratase/deficiency , Gene Expression Profiling , Humans , Kidney Neoplasms/etiology , Kidney Neoplasms/metabolism , Leiomyomatosis/complications , Male , Middle Aged , Mitochondria/genetics , Mitochondria/metabolism , Mutation , Neoplastic Syndromes, Hereditary/complications , Skin Neoplasms/complications , Uterine Neoplasms/complications , Young AdultABSTRACT
A 44-yr-old woman with menorrhagia and uterine fibroids underwent total laparoscopic hysterectomy, revealing several submucosal, intramural, and subserosal tan-white nodules in the uterus. Microscopic examination revealed tumors displaying 3 distinct morphologies: 1 tumor with features of conventional leiomyoma; 1 tumor with increased cellularity, staghorn/hemangiopericytoma-like vasculature, and occasional atypical cells with prominent red nucleoli and some perinucleolar halos suggesting a fumarate hydratase (FH)-deficient atypical leiomyoma; and 1 tumor with an admixture of epithelioid and spindled cells with the former arranged around blood vessels suggesting a perivascular epithelioid cell tumor (PEComa). Immunohistochemical studies confirmed these diagnoses by demonstrating loss of FH expression in the atypical leiomyoma and diffuse expression of HMB45 and cathepsin K in the tumor with epithelioid features. Sanger sequencing analysis revealed that the FH-deficient atypical leiomyoma harbored a c.181A>G (p.Lys61Glu) mutation in exon 2 of the FH gene. As this mutation was not present in either the other tumors or peripheral blood, the mutation is somatic and hereditary leiomyomatosis and renal cell cancer syndrome is excluded. This case highlights the importance of thorough examination of uterine mesenchymal tumors with atypical and epithelioid features so that tumors with some potential for recurrence (PEComas) and those that might indicate a hereditary cancer syndrome (FH-deficient atypical leiomyoma) are identified and can trigger appropriate clinical investigation and follow-up.
Subject(s)
Fumarate Hydratase/genetics , Leiomyoma/diagnosis , Neoplastic Syndromes, Hereditary/diagnosis , Perivascular Epithelioid Cell Neoplasms/diagnosis , Uterine Neoplasms/diagnosis , Adult , Amino Acid Substitution , Diagnosis, Differential , Exons/genetics , Female , Fumarate Hydratase/metabolism , Humans , Hysterectomy , Immunohistochemistry , Leiomyoma/complications , Leiomyoma/genetics , Leiomyoma/pathology , Neoplastic Syndromes, Hereditary/complications , Neoplastic Syndromes, Hereditary/genetics , Neoplastic Syndromes, Hereditary/pathology , Perivascular Epithelioid Cell Neoplasms/complications , Perivascular Epithelioid Cell Neoplasms/genetics , Perivascular Epithelioid Cell Neoplasms/pathology , Uterine Neoplasms/complications , Uterine Neoplasms/genetics , Uterine Neoplasms/pathology , Uterus/pathology , Uterus/surgeryABSTRACT
Constitutional mismatch repair deficiency (CMMRD) is an autosomal recessively inherited childhood cancer predisposition syndrome results from biallelic germline mutations affecting the key DNA mismatch repair gene: MLH1, MSH2, MSH6, or PMS2. CMMRD is associated with a high risk of developing early onset of central nervous system tumors, hematologic, and intestinal tract tumors. Clinical manifestations, genetic screening, and cancer prevention strategies are limited. In this report we present a patient with metachronous Wilms tumor, glioblastoma, and acute T-cell lymphoblastic leukemia. He had cutaneous features of neurofibromatosis type 1 (NF1). Molecular testing revealed a novel homozygous mutation in MSH6 (c.2590G>T; p.G864*) that has not been reported previously. CMMRD should be considered in patients with cutaneous features similar to NF1 if tumor is found other than expected tumors in NF, early onset cancer, and strong family history of cancer.
Subject(s)
Brain Neoplasms/complications , Colorectal Neoplasms/complications , DNA-Binding Proteins/genetics , Glioblastoma/pathology , Leukemia, T-Cell/pathology , Mutation , Neoplasms, Second Primary/pathology , Neoplastic Syndromes, Hereditary/complications , Wilms Tumor/pathology , Brain Neoplasms/genetics , Child, Preschool , Colorectal Neoplasms/genetics , Fatal Outcome , Glioblastoma/etiology , Homozygote , Humans , Kidney Neoplasms/etiology , Kidney Neoplasms/pathology , Leukemia, T-Cell/etiology , Male , Neoplasms, Second Primary/etiology , Neoplastic Syndromes, Hereditary/genetics , Wilms Tumor/etiologyABSTRACT
Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) accounts for 0.05-2% of all RCCs. The majority of patients have germline mutations, most frequently in the SDHB gene. People with these mutations are predisposed to developing paragangliomas, phaeochromocytomas and gastrointestinal stromal tumours. Patients should be referred to genetic services for further workup and close surveillance imaging due to the risk of development of further tumours. We present a woman with SDH-deficient RCC and review the literature associated with this uncommon entity.
Subject(s)
Carcinoma, Renal Cell/diagnosis , Genetic Counseling , Kidney Neoplasms/diagnosis , Neoplastic Syndromes, Hereditary/diagnosis , Paraganglioma/diagnosis , Succinate Dehydrogenase/genetics , Adult , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/surgery , Female , Germ-Line Mutation , Humans , Kidney/diagnostic imaging , Kidney/pathology , Kidney/surgery , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Kidney Neoplasms/surgery , Neoplastic Syndromes, Hereditary/complications , Neoplastic Syndromes, Hereditary/genetics , Neoplastic Syndromes, Hereditary/surgery , Nephrectomy , Paraganglioma/genetics , Paraganglioma/surgery , Succinate Dehydrogenase/deficiency , Tomography, X-Ray ComputedABSTRACT
RATIONALE: Juvenile polyposis syndrome (JPS) is a rare genetic gastrointestinal disorder with hidden and variable clinical features. Early detection is crucial for good prognosis. PATIENT CONCERNS: A 20-year-old female went to hospital for fever, and was unexpectedly diagnosed as JPS during treatment. She reported no clinical signs or family history of JPS. DIAGNOSIS: Blood routine examination on hospital admission suggested a moderate anemia. Bone marrow cytology and leukemia fusion gene test were performed to rule out leukemia. Other examinations including ultrasound and computed tomography were also conducted for differential diagnosis. Further electronic colonoscopy identified more than 20 pedicle polyps located at her ileocecum and rectum. Mutation analysis detected a novel de novo pathogenic variant, c.910C>T (p.Gln304Ter) within bone morphogenetic protein receptor type 1A gene, establishing the diagnosis of JPS. INTERVENTIONS: The patient was treated with endoscopic interventions. We also provided a genetic counseling for this family. OUTCOMES: The patient's polyps were removed, some of which already had adenomatous changes. The patient received surveillance of hereditary colorectal cancer according to guidelines. LESSONS: Variable features and lack of family history probably lead to a great underestimation of potential JPS population. It is recommended to perform genetic testing by a multigene panel in individuals who have suspected symptoms of polyposis.