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The Journal of Clinical Endocrinology... Jun 2024Primary Pigmented Nodular Adrenocortical Disease (PPNAD) and Bilateral Macronodular Adrenocortical Disease (BMAD) are two forms of Adrenocortical Nodular Diseases...
Primary Pigmented Nodular Adrenocortical Disease (PPNAD) and Bilateral Macronodular Adrenocortical Disease (BMAD) are two forms of Adrenocortical Nodular Diseases causing Cushing's syndrome, but are two very distinct conditions. PPNAD, affecting mostly young patients with an almost constant severe Cushing's syndrome, is characterized by pigmented micronodules, usually less than 1 cm, not always visible on imaging. On the contrary, BMAD is predominantly diagnosed in the fifth and sixth decades, with highly variable degrees of cortisol excess, from mild autonomous cortisol secretion to overt Cushing's syndrome. BMAD presents as large bilateral adrenal macronodules, easily observed on imaging. Both diseases are often genetically determined: frequently PPNAD is observed in a multiple neoplasia syndrome, Carney complex (CNC), and a germline genetic defect is identified in around 80% of index cases, always affecting key actors of the cAMP/PKA pathway: mostly PRKAR1A, encoding the PKA 1-alpha regulatory subunit. On the other hand, BMAD appears mostly isolated, and two predisposing genes are known at present: ARMC5, accounting for around 20% of index cases, and the recently identified KDM1A, causing the rare presentation with food-dependent Cushing's syndrome, mediated by the ectopic expression of the Glucose-dependent Insulinotropic Polypeptide receptor (GIPR) in adrenal nodules. GIPR was the first demonstrated receptor to illegitimately regulate cortisol secretion in nodular adrenocortical diseases, and a myriad of other receptors and paracrine signals were discovered afterward. The last 30 years were pivotal in the understanding of the genetics and pathophysiology of Bilateral Adrenocortical Nodular Diseases, leading to a personalized approach of these fascinating conditions.
PubMed: 38888184
DOI: 10.1210/clinem/dgae419 -
Clinical Case Reports Jun 2024Acute chest pain can be the first manifestation of multiple endocrine neoplasia type 1(MEN1)-associated thymic neuroendocrine neoplasms (NEN). Comprehensive treatment...
KEY CLINICAL MESSAGE
Acute chest pain can be the first manifestation of multiple endocrine neoplasia type 1(MEN1)-associated thymic neuroendocrine neoplasms (NEN). Comprehensive treatment may be an effective strategy for MEN1-associated NEN.
ABSTRACT
Multiple endocrine neoplasia type 1(MEN1)-associated thymic neuroendocrine neoplasms (NEN) is caused by the mutation of tumor suppressor gene. Patients with MEN1-associated NEN initially presenting with acute chest pain are very rare. In the manuscript, we reported a case of a 45-year-old man who developed MEN1-associated NEN with acute chest pain as initial symptom. Thoracoscopic thymotomy was performed and thymic NEN was successfully removed. Genetic test showed a germline mutation of gene in this patient. Immunohistochemical staining exhibited Syn(+), CgA(+), INSM1(+), CD56(+) and Ki67-positive cells (2%) in MEN1-associated NEN. Further evaluation unveiled MEN1-associated benign tumors including digestive NEN and pituitary gland adenoma. The 99mTc-HYNIC-TOC scintigraphy showed that focally increased radioactivity in the mid-upper abdomen. This patient was administered with 50Gy/25F of radiation dose to treat the postoperative lesions. Subsequently, sandostatin LAR (30 mg per week) was used as systemic therapy. He had no recurrence or metastasis for 6-month follow-up. Thus, acute chest pain can be the first manifestation of MEN1-associated NEN, and comprehensive treatment including surgery, radiation and systemic treatment may be an effective strategy for MEN1-associated NEN.
PubMed: 38883224
DOI: 10.1002/ccr3.9031 -
Annales D'endocrinologie Jun 2024Lipomatoses are benign proliferation of adipose tissue. Lipomas (benign fat tumors) are the most common component of lipomatosis. They may be unique or multiple,... (Review)
Review
Lipomatoses are benign proliferation of adipose tissue. Lipomas (benign fat tumors) are the most common component of lipomatosis. They may be unique or multiple, encapsulated or not, subcutaneous or sometimes visceral. In some cases, they form large areas of non-encapsulated fat hypertrophy, with a variable degree of fibrosis. They can develop despite the absence of obesity. They may be familial or acquired. At difference with lipodystrophy syndromes, they are not associated with lipoatrophy areas, except in some rare cases such as type 2 familial partial lipodystrophy syndromes (FPLD2). Their metabolic impact is variable in part depending on associated obesity. They may have functional or aesthetic consequences. Lipomatosis may be isolated, be part of a syndrome, or may be visceral. Isolated lipomatoses include multiple symmetrical lipomatosis (Madelung disease or Launois-Bensaude syndrome), familial multiple lipomatosis, the painful Dercum's disease also called Adiposis Dolorosa or Ander syndrome, mesosomatic lipomatosis also called Roch-Leri lipomatosis, familial angiolipomatosis, lipedema and hibernomas. Syndromic lipomatoses include PIK3CA-related disorders, Cowden/PTEN hamartomas-tumor syndrome, some lipodystrophy syndromes, and mitochondrial diseases, especially MERRF, multiple endocrine neoplasia type 1, neurofibromatosis type 1, Wilson disease, Pai or Haberland syndromes. Finally, visceral lipomatoses have been reported in numerous organs and sites: pancreatic, adrenal, abdominal, epidural, mediastinal, epicardial… The aim of this review is to present the main types of lipomatosis and their physiopathological component, when it is known.
Topics: Humans; Lipomatosis; Lipoma; Lipomatosis, Multiple Symmetrical; Lipodystrophy; Adipose Tissue; Adiposis Dolorosa
PubMed: 38871514
DOI: 10.1016/j.ando.2024.05.003 -
Molecular and Cellular Endocrinology Jun 2024Medullary thyroid carcinoma (MTC) is a rare primary neuroendocrine thyroid carcinoma that is distinct from other thyroid or neuroendocrine cancers. Most cases of MTC are...
Medullary thyroid carcinoma (MTC) is a rare primary neuroendocrine thyroid carcinoma that is distinct from other thyroid or neuroendocrine cancers. Most cases of MTC are sporadic, although MTC exhibits a high degree of heritability as part of the multiple endocrine neoplasia syndromes. REarranged during Transfection (RET) mutations are the primary oncogenic drivers and advances in molecular profiling have revealed that MTC is enriched in druggable alterations. Surgery at an early stage is the only chance for cure, but many patients present with or develop metastases. C-cell-specific calcitonin trajectory and structural doubling times are critical biomarkers to inform prognosis, extent of surgery, likelihood of residual disease, and need for additional therapy. Recent advances in the role of active surveillance, regionally directed therapies for localized disease, and systemic therapy with multi-kinase and RET-specific inhibitors for progressive/metastatic disease have significantly improved outcomes for patients with MTC.
PubMed: 38871174
DOI: 10.1016/j.mce.2024.112295 -
Frontiers in Endocrinology 2024Well-differentiated pancreatic neuroendocrine tumors (PNETs) can be non-functional or functional, e.g. insulinoma and glucagonoma. The majority of PNETs are sporadic,... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Well-differentiated pancreatic neuroendocrine tumors (PNETs) can be non-functional or functional, e.g. insulinoma and glucagonoma. The majority of PNETs are sporadic, but PNETs also occur in hereditary syndromes, primarily multiple endocrine neoplasia type 1 (MEN1). The Knudson hypothesis stated a second, somatic hit in as the cause of PNETs of MEN1 syndrome. In the recent years, reports on genetic somatic events in both sporadic and hereditary PNETs have emerged, providing a basis for a more detailed molecular understanding of the pathophysiology. In this systematic review and meta-analysis, we made a collation and statistical analysis of aggregated frequent genetic alterations and potential driver events in human grade G1/G2 PNETs.
METHODS
A systematic search was performed in concordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) reporting guidelines of 2020. A search in Pubmed for published studies using whole exome, whole genome, or targeted gene panel (+400 genes) sequencing of human G1/G2 PNETs was conducted at the 25 of September 2023. Fourteen datasets from published studies were included with data on 221 patients and 225 G1/G2 PNETs, which were divided into sporadic tumors, and hereditary tumors with pre-disposing germline variants, and tumors with unknown germline status. Further, non-functioning and functioning PNETs were distinguished into two groups for pathway evaluation. The collated genetical analyses were conducted using the 'maftools' R-package.
RESULTS
Sporadic PNETs accounted 72.0% (162/225), hereditary PNETs 13.3% (30/225), unknown germline status 14.7% (33/225). The most frequently altered gene was , with somatic variants and copy number variations in overall 42% (95/225); hereditary PNETs (germline variations in , , , , , , and/or ) 57% (16/30); sporadic PNETs 36% (58/162); unknown germline status 64% (21/33). The point mutations/indels were distributed throughout . Overall, (16%, 37/225) and -variants (12%, 27/225) were also abundant with missense mutations clustered in mutational hotspots associated with histone binding, and translocase activity, respectively. mutations occurred more frequently in PNETs with mutations, p<0.05. While functioning PNETs shared few variated genes, non-functioning PNETs had more recurrent variations in genes associated with the Phosphoinositide 3-kinase, Wnt, NOTCH, and Receptor Tyrosine Kinase-Ras signaling onco-pathways.
DISCUSSION
The somatic genetic alterations in G1/G2 PNETs are diverse, but with distinct differences between sporadic vs. hereditary, and functional vs. non-functional PNETs. Increased understanding of the genetic alterations may lead to identification of more drivers and driver hotspots in the tumorigenesis in well-differentiated PNETs, potentially giving a basis for the identification of new drug targets. (Funded by Novo Nordisk Foundation, grant number NNF19OC0057915).
Topics: Humans; Pancreatic Neoplasms; Neuroendocrine Tumors; Sequence Analysis, DNA; Mutation
PubMed: 38868744
DOI: 10.3389/fendo.2024.1351624 -
Endocrinologia, Diabetes Y Nutricion May 2024
Topics: Humans; Multiple Endocrine Neoplasia Type 1; Multiplex Polymerase Chain Reaction; Female; Male
PubMed: 38849252
DOI: 10.1016/j.endien.2024.02.004 -
Langenbeck's Archives of Surgery Jun 2024Middle segment-preserving pancreatectomy (MSPP) is a relatively new parenchymal-sparing surgery that has been introduced as an alternative to total pancreatectomy (TP)... (Review)
Review
PURPOSE
Middle segment-preserving pancreatectomy (MSPP) is a relatively new parenchymal-sparing surgery that has been introduced as an alternative to total pancreatectomy (TP) for multicentric benign and borderline pancreatic diseases. To date, only 36 cases have been reported in English.
METHODS
We reviewed 22 published articles on MSPP and reported an additional case.
RESULTS
Our patient was a 49-year-old Japanese man diagnosed with Zollinger-Elison syndrome (ZES) caused by duodenal and pancreatic gastrinoma associated with multiple endocrine neoplasia syndrome type 1. We avoided TP and chose MSPP as the operative technique due to his relatively young age. The patient developed a grade B postoperative pancreatic fistula (POPF), which improved with conservative treatment. He was discharged without further treatment. To date, no tumor has recurred, and pancreatic function seems to be maintained. According to a literature review, the morbidity rate of MSPP is as high as 54%, mainly due to the high incidence of POPF (32%). In contrast, there was no perioperative mortality, and postoperative pancreatic function was comparable to that after conventional pancreatectomy.
CONCLUSIONS
Despite the high incidence of POPF, MSPP appears to be safe, with low perioperative mortality and good postoperative pancreatic sufficiency.
Topics: Humans; Pancreatectomy; Male; Middle Aged; Pancreatic Neoplasms; Zollinger-Ellison Syndrome; Gastrinoma; Postoperative Complications; Organ Sparing Treatments; Multiple Endocrine Neoplasia Type 1
PubMed: 38847851
DOI: 10.1007/s00423-024-03370-4 -
GE Portuguese Journal of... Jun 2024Pancreatic neuroendocrine neoplasms (panNENs) have been historically regarded as rare, but their incidence has raised more than 6-fold over the last 3 decades, mostly... (Review)
Review
Portuguese Pancreatic Club Perspectives on Pancreatic Neuroendocrine Neoplasms: Diagnosis and Staging, Associated Genetic Syndromes and Particularities of Their Clinical Approach.
Pancreatic neuroendocrine neoplasms (panNENs) have been historically regarded as rare, but their incidence has raised more than 6-fold over the last 3 decades, mostly owing to improvement in the detection of small asymptomatic tumours with imaging. Early detection and proper classification and staging are essential for the prognosis and management of panNENs. Histological evaluation is mandatory in all patients for the diagnosis of panNEN. Regarding localization and staging, multiphasic contrast-enhanced computer tomography is considered the imaging study of choice. Nevertheless, several other diagnostic modalities might present complementary information that can help in diagnosis and staging optimization: magnetic resonance imaging, somatostatin receptor imaging using positron emission tomography in combination with computed tomography (PET/CT), PET/CT with fluorodeoxyglucose (F-FDG), and endoscopic ultrasound. Approximately 10% of panNENs are due to an inherited syndrome, which includes multiple endocrine neoplasia type 1, von Hippel-Lindau disease, neurofibromatosis type 1 (NF-1), tuberous sclerosis complex, and Mahvash disease. In this review, the Portuguese Pancreatic Club summarizes the classification, diagnosis, and staging of panNENs, with a focus on imaging studies. It also summarizes the characteristics and particularities of panNENs associated with inherited syndromes.
PubMed: 38836119
DOI: 10.1159/000534641 -
Hormones (Athens, Greece) May 2024Somatic mutations in ubiquitin-specific protease-8 (USP8), encoding a deubiquinating protein, are found in approximately 30% of corticotroph-derived pituitary adenomas...
INTRODUCTION
Somatic mutations in ubiquitin-specific protease-8 (USP8), encoding a deubiquinating protein, are found in approximately 30% of corticotroph-derived pituitary adenomas (CPAs). Stratifin, a protein encoded by SFN, inhibits USP8 catalytic activity. USP8 has immunomodulating properties that have been demonstrated in non-tumoral diseases.
METHODS
We assessed the influence of USP8 on the immune landscape of CPA and validated this effect and its dependency on stratifin in large cohorts of non-pituitary tumors. We analyzed data of CPA samples (n = 20) and additional non-pituitary tumors from the TCGA database, using transcriptome signature-recognition algorithms. Immune tumor microenvironment (iTME) was compared both by USP8 and SFN expression levels (n = 843) and by USP8 mutation status and SFN expression (n = 12,389).
RESULTS
CPA with activating USP8 mutations was associated with "cold" iTME compared with wild-type USP8 CPA, as reflected by lower fractions of immune cells, including B cells, CD4, regulatory and gamma/delta T cells, natural killer cells, M0 and M1 macrophages, dendritic cells, and eosinophils (p < 0.05 for all comparisons). Pathways altered by the presence of USP8 mutation, based on the most differentially expressed genes (3061 genes), included microglia pathogen phagocytosis and multiple toll-like receptor signaling pathways (p < 0.0001). In a validation analysis based on large cohorts of non-pituitary tumors, high expression of USP8 was associated with a suppressed iTME effect that was augmented by a low SFN expression.
CONCLUSIONS
Our data demonstrate for the first time, to our knowledge, a distinct immune landscape of tumors based on USP8 status and expression and the dependency of this immunological effect on SFN expression.
PubMed: 38819743
DOI: 10.1007/s42000-024-00569-4 -
World Journal of Clinical Cases May 2024Multiple endocrine neoplasia type 2 (MEN2) is a rare, autosomal dominant endocrine disease. Currently, the proto-oncogene is the only gene implicated in MEN2A...
BACKGROUND
Multiple endocrine neoplasia type 2 (MEN2) is a rare, autosomal dominant endocrine disease. Currently, the proto-oncogene is the only gene implicated in MEN2A pathogenesis. Once an carrier is detected, family members should be screened to enable early detection of medullary thyroid carcinoma, pheochromocytoma, and hyperparatitity. Among these, medullary thyroid carcinoma is the main factor responsible for patient mortality. Accordingly, delineating strategies to inform clinical follow-up and treatment plans based on genes is paramount for clinical practitioners.
CASE SUMMARY
Herein, we present proto-oncogene mutations, clinical characteristics, and treatment strategies in a family with MEN2A. A family study was conducted on patients diagnosed with MEN2A. DNA was extracted from the peripheral blood of family members, and first-generation exon sequencing of the proto-oncogene was conducted. The mutation was identified in three family members spanning three generations. Two patients were sequentially diagnosed with pheochromocytomas and bilateral medullary thyroid carcinomas. A 9-year-old child harboring the gene mutation was diagnosed with medullary thyroid carcinoma. Surgical resection of the tumors was performed. All family members were advised to undergo complete genetic testing related to the mutation, and the corresponding treatments administered based on test results and associated clinical guidelines.
CONCLUSION
Advancements in MEN2A research are important for familial management, assessment of medullary thyroid cancer invasive risk, and deciding surgical timing.
PubMed: 38817239
DOI: 10.12998/wjcc.v12.i15.2627