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Familial Cancer Oct 2016Multiple endocrine neoplasia type 2A (MEN2A) may be rarely associated with cutaneous lichen amyloidosis (CLA), a skin lesion located in the interescapular region. Here,... (Review)
Review
Multiple endocrine neoplasia type 2A (MEN2A) may be rarely associated with cutaneous lichen amyloidosis (CLA), a skin lesion located in the interescapular region. Here, we describe 3 MEN2A-related CLA kindred and perform a systematic review (SR) of the literature on clinical, biochemical and molecular characteristics of MEN2A-related CLA patients. Thirty-eight patients with MEN2A-related CLA followed at our institution were evaluated. The median age at MEN2A diagnosis in our cohort was 25 (13-41) years, 68 % were women and all harbored codon 634 RET mutations. The literature search resulted in 20 publications that contributed with 25 MEN2A families and 214 individuals. The mean age of MEN2A diagnosis was 31 ± 17 years, with 77 % women. The mean age reported by patients to initial skin lesion suggestive to CLA was 20 ± 13 years. All but two kindred harbored mutations at codon 634: C634R 7 kindred (35 %), C634Y 5 kindred (25 %), C634W 3 kindred (15 %), C634G 1 kindred (5 %), V804M 1 kindred (5 %) and S891A 1 kindred (5 %). Most interesting, the standardized CLA prevalence was higher in women (2.3/1.0, P < 0.005). The overall reported prevalence of medullary thyroid carcinoma, CLA, pheochromocytoma and hyperparathyroidism was 94, 51, 30 and 16 %, respectively. SR of literature indicates that MEN2A-related CLA is more frequent in women and presents a high penetrance, being the second most frequent manifestation of the syndrome, preceded only by MTC.
Topics: Adolescent; Adult; Amyloidosis; Female; Humans; Male; Multiple Endocrine Neoplasia Type 2a; Pedigree; Proto-Oncogene Proteins c-ret; Skin Neoplasms; Young Adult
PubMed: 26920351
DOI: 10.1007/s10689-016-9892-6 -
Journal of Pediatric Surgery Apr 2016A small percentage of pediatric solid cancers arise as a result of clearly identified inherited predisposition syndromes and nongenetic lesions. Evidence supports... (Review)
Review
OBJECTIVE
A small percentage of pediatric solid cancers arise as a result of clearly identified inherited predisposition syndromes and nongenetic lesions. Evidence supports preemptive surgery for children with genetic [multiple endocrine neoplasia type 2 (MEN2), familial adenomatous polyposis syndrome (FAP), hereditary nonpolyposis colorectal cancer (HNPCC), and hereditary diffuse gastric cancer (HDGC) and nongenetic [thyroglossal duct cysts (TGDC), congenital pulmonary airway malformations (CPAM), alimentary tract duplication cysts (ATDC), and congenital choledochal cysts (CCC)] developmental anomalies. Our aim was to explore the utility of risk reduction surgery to treat and prevent cancer in children.
METHODS
A systematic review of the available peer-reviewed literature on PubMed was performed using a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) search strategy, where possible. Search items included "risk reduction surgery", "hereditary cancer predisposition syndrome", "multiple endocrine neoplasia type 2", "familial adenomatous polyposis", "hereditary nonpolyposis colorectal cancer", "hereditary diffuse gastric cancer", "thyroglossal duct cysts", congenital pulmonary airway malformations", "alimentary tract duplication cysts", "malignant transformation", and "guidelines".
RESULTS
We identified 67 articles that met the inclusion criteria describing the indications for prophylactic surgery in surgical oncology. For the genetic predisposition syndromes, 7 studies were related to professional endorsed guidelines, 7 were related to surgery for MEN2, 11 were related to colectomy for FAP, 6 were related to colectomy for HNPCC, and 12 related to gastrectomy for HDGC. Articles for the nongenetic lesions included 5 for techniques related to TGDC resection, 9 for surgery for CPAMs, and 10 for resection of ATDCs. Guidelines and strategies varied significantly especially related to the extent and timing of surgical intervention; the exception was for the timing of thyroidectomy in children with MEN2.
CONCLUSION
Current evidence supporting prophylactic surgery in the management of pediatric cancer predisposition syndromes and nongenetic lesions is best delineated for thyroidectomy to prevent medullary thyroid cancer in children with MEN2 (Strength of Recommendation Grade B/C). Despite the lack of pediatric specific evidence-based recommendations regarding the appropriate extent and timing for risk-reduction surgery for FAP, HNPCC, HDGC and nongenetic anomalies, our review represents an opportunity towards understanding the postgenomic development of these lesions and provides current indications and techniques for preemptive cancer prevention surgery in children.
Topics: Child; Humans; Neoplastic Syndromes, Hereditary; Pediatrics; Prophylactic Surgical Procedures; Surgical Oncology; Treatment Outcome
PubMed: 26898681
DOI: 10.1016/j.jpedsurg.2016.01.004 -
Neurosurgical Focus Feb 2015OBJECT Cushing's disease (CD) can lead to significant morbidity secondary to hormonal sequelae or mass effect from the pituitary tumor. A transsphenoidal approach to... (Review)
Review
OBJECT Cushing's disease (CD) can lead to significant morbidity secondary to hormonal sequelae or mass effect from the pituitary tumor. A transsphenoidal approach to resection of the adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma is the first-line treatment. However, in the setting in which patients are unable to undergo surgery, have acute hypercortisolism, or have recurrent disease, medical therapy can play an important role. The authors performed a systematic review to highlight the efficacy of medical treatment of CD and discuss novel molecular insights that could guide the development of future medical treatments of CD. METHODS A search on current medical therapies for CD was performed. After individual medical therapeutic agents for CD were identified, each agent underwent a formal systematic search. The phrase "(name of agent) and Cushing's" was used as a search term in PubMed for all years up to 2014. The abstract of each article was reviewed for studies that evaluated the efficacy of medical treatment of CD. Only studies that enrolled at least 20 patients were included in the review. RESULTS A total of 11 articles on 6 individual agents were included in this review. Specific medical therapies were categorized based on the level of action: pituitary directed (cabergoline and pasireotide), adrenal/steroidogenesis directed (ketoconazole, metyrapone, and mitotane), and end-tissue directed/cortisol receptors (mifepristone). The studies identified consisted of a mix of retrospective reviews and small clinical trials. Only pasireotide and mifepristone have undergone Phase III clinical trials, from which they garnered FDA approval for the treatment of patients with CD. Overall, agents targeting ACTH secretion and steroidogenesis were found to be quite effective in reducing urine free cortisol (UFC) to levels near normal. A significant reduction in UFC was observed in 45%-100% of patients and a majority of patients gained clinical improvement. Similarly, inhibition at the end-tissue level led to clinical improvement in 87% of patients. However, side-effect rates associated with these drugs are high (up to 88%). Ketoconazole has been shown to enhance tumor appearance on MRI to facilitate pituitary resection. Promising molecular targets have been identified, including epidermal growth factor receptor, retinoic acid receptors, and cyclin dependent kinases. These pathways have been linked to the regulation of pro-opiomelanocortin expression, ACTH secretion, and tumor growth. CONCLUSIONS Despite encouraging Phase III clinical trials leading to FDA approval of 2 agents for treatment of patients with CD, no agent has yet produced results comparable to resection. As a result, the molecular insights gained into CD pathogenesis will need to continue to be expanded until they can lead to the development of medical therapies for CD with a favorable side-effect profile and efficacy comparable to resection. Ideally these agents should also reduce tumor size, which could potentially permit their eventual discontinuation.
Topics: Clinical Trials as Topic; Drug Delivery Systems; Female; Forecasting; Humans; Male; Mitotane; Pituitary ACTH Hypersecretion; Receptors, Retinoic Acid; Retrospective Studies; Somatostatin
PubMed: 25639313
DOI: 10.3171/2014.10.FOCUS14700 -
Pediatric Surgery International Aug 2014The co-occurrence of Hirschsprung's disease (HSCR) and multiple endocrine neoplasia type 2 (MEN2) is a relatively rare event. The basis for this association is the... (Review)
Review
PURPOSE
The co-occurrence of Hirschsprung's disease (HSCR) and multiple endocrine neoplasia type 2 (MEN2) is a relatively rare event. The basis for this association is the presence of a "Janus" mutation in the RET proto-oncogene--a mutation that acts simultaneously as both a gain-in-function and a loss-of-function mutation. To date, four mutations in the exon 10 region of RET that are known to cause MEN2A have been implicated in this association: C620, C618, C611 and C609. We performed a systematic review of the published literature on this association to determine its incidence, the prevalence and phenotype of HSCR associated with the 4 RET mutations mentioned above.
METHODS
A systematic literature-based search for relevant articles was conducted using three online databases. After exclusion of ineligible publications, we recorded data on all patients with a diagnosis of HSCR or MEN2A with a "Janus" RET mutation, as well as those who carried the mutation but were unaffected. Statistical analysis was performed using SPSS.
RESULTS
The literature search yielded 885 publications, of which 36 articles, incorporating data on 341 individuals, were eligible for inclusion in the final analysis. Co-occurrence of HSCR and MEN2A was recorded in 84 cases (24.6 %). HSCR occurred alone in 64 carriers of a "Janus" mutation (18.8 %) and MEN2A occurred in isolation in 173 cases (50.7 %). Twenty individuals (5.9 %) were found to carry a "Janus" mutation after screening on the basis of family history but were unaffected by either MEN2A or HSCR. The most common mutation recorded was the C620 mutation [114 cases (48.1 %)]. There was a relatively high incidence of long-segment aganglionosis (29.3 %) and total colonic aganglionosis (17.3 %) in this cohort. This trend was particularly notable in those with C620 mutations, only 33 % of whom had short-segment disease.
CONCLUSION
While the overall incidence of HSCR co-occurring with MEN2A is low, both conditions occur with a relatively high frequency in families with a RET mutation at exon 10. The proportion of cases of long-segment HSCR and total colonic aganglionosis is higher than that in the general population with HSCR in those with C620 and C618 mutations. These findings reinforce the importance of RET mutation testing in HSCR when a family history of either HSCR or MEN2 is present. In families with MEN2A and known exon 10 RET mutations, the threshold for investigation for HSCR in those with gastrointestinal symptoms should be very low. High-quality prospective longitudinal studies of large HSCR populations are required to shed greater light on this rare but important phenomenon.
Topics: Child; DNA Mutational Analysis; DNA, Neoplasm; Hirschsprung Disease; Humans; Multiple Endocrine Neoplasia Type 2a; Mutation; Pedigree; Phenotype; Proto-Oncogene Mas; Proto-Oncogene Proteins c-ret
PubMed: 24972642
DOI: 10.1007/s00383-014-3538-2