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Open access

David C Llewellyn, Rajaventhan Srirajaskanthan, Royce P Vincent, Catherine Guy, Eftychia E Drakou, Simon J B Aylwin, Ashley B Grossman, John K Ramage, and Georgios K Dimitriadis

Calcitonin-secreting neuroendocrine neoplasms of the lung are rare, with few cases reported in the literature. Differentiating between medullary thyroid carcinoma and an ectopic source of calcitonin secretion can represent a complex diagnostic conundrum for managing physicians, with cases of unnecessary thyroidectomy reported in the literature. This manuscript reports a case of ectopic hypercalcitonaemia from a metastatic neuroendocrine neoplasm of the lung with concurrent thyroid pathology and summarises the results of a systematic review of the literature. Medical Literature Analysis and Retrieval System Online, Excerpta Medica, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov and SCOPUS databases were systematically and critically appraised for all peer reviewed manuscripts that suitably fulfilled the inclusion criteria established a priori. The protocol for this systematic review was developed according to the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols, and followed methods outlined in The Cochrane Handbook for Systematic Reviews of Interventions. This systematic review is registered with PROSPERO. It is vital to consider diagnoses other than medullary thyroid carcinoma when presented with a patient with raised calcitonin, as it is not pathognomonic of medullary thyroid carcinoma. Lung neuroendocrine neoplasms can appear similar to medullary thyroid carcinoma histologically, they can secrete calcitonin and metastasize to the thyroid. Patients with medullary thyroid carcinoma may show stimulated calcitonin values over two or more times above the basal values, whereas calcitonin-secreting neuroendocrine neoplasms may or may not show response to stimulation tests. The present review summarises existing evidence from cases of ectopic hypercalcitonaemia to lung neuroendocrine neoplasms.

Open access

Kjell Oberg, Eric Krenning, Anders Sundin, Lisa Bodei, Mark Kidd, Margot Tesselaar, Valentina Ambrosini, Richard P Baum, Matthew Kulke, Marianne Pavel, Jaroslaw Cwikla, Ignat Drozdov, Massimo Falconi, Nicola Fazio, Andrea Frilling, Robert Jensen, Klaus Koopmans, Tiny Korse, Dik Kwekkeboom, Helmut Maecke, Giovanni Paganelli, Ramon Salazar, Stefano Severi, Jonathan Strosberg, Vikas Prasad, Aldo Scarpa, Ashley Grossman, Annemeik Walenkamp, Mauro Cives, Irene Virgolini, Andreas Kjaer, and Irvin M Modlin

The complexity of the clinical management of neuroendocrine neoplasia (NEN) is exacerbated by limitations in imaging modalities and a paucity of clinically useful biomarkers. Limitations in currently available imaging modalities reflect difficulties in measuring an intrinsically indolent disease, resolution inadequacies and inter-/intra-facility device variability and that RECIST (Response Evaluation Criteria in Solid Tumors) criteria are not optimal for NEN. Limitations of currently used biomarkers are that they are secretory biomarkers (chromogranin A, serotonin, neuron-specific enolase and pancreastatin); monoanalyte measurements; and lack sensitivity, specificity and predictive capacity. None of them meet the NIH metrics for clinical usage. A multinational, multidisciplinary Delphi consensus meeting of NEN experts (n = 33) assessed current imaging strategies and biomarkers in NEN management. Consensus (>75%) was achieved for 78% of the 142 questions. The panel concluded that morphological imaging has a diagnostic value. However, both imaging and current single-analyte biomarkers exhibit substantial limitations in measuring the disease status and predicting the therapeutic efficacy. RECIST remains suboptimal as a metric. A critical unmet need is the development of a clinico-biological tool to provide enhanced information regarding precise disease status and treatment response. The group considered that circulating RNA was better than current general NEN biomarkers and preliminary clinical data were considered promising. It was resolved that circulating multianalyte mRNA (NETest) had clinical utility in both diagnosis and monitoring disease status and therapeutic efficacy. Overall, it was concluded that a combination of tumor spatial and functional imaging with circulating transcripts (mRNA) would represent the future strategy for real-time monitoring of disease progress and therapeutic efficacy.

Open access

Thomas Couronne, Paul Girot, Julien Hadoux, Thierry Lecomte, Alice Durand, Caroline Fine, Katia Vandevoorde, Catherine Lombard-Bohas, and Thomas Walter

Objective

First-line chemotherapy in metastatic neuroendocrine carcinomas (NECs) is based on etoposide and platinum. However, there is no standard concerning second-line treatment. The objective of this study was to evaluate efficacy and tolerance of dacarbazine or temozolomide in metastatic digestive NEC as post first-line treatment.

Material and methods

This study included patients with a metastatic NEC of digestive or unknown primary site. All patients received platinum-etoposide as first-line chemotherapy. Primary endpoint was progression-free survival (PFS). Secondary endpoints were clinical/morphological responses, toxicity, and overall survival (OS).

Results

Twenty-seven patients were included: 17 received dacarbazine and 10 temozolomide as post-first line treatments. Median PFS was 3.0 (95%CI (2.2;3.7)) months. There was no significant difference between dacarbazine and temozolomide on PFS. Clinical and morphological responses were found in 12 and 9 patients, respectively. Median OS was 7.2 (95%CI (2.2;12.2)) months. The toxicity profile was that expected with such treatments.

Conclusion

LV5FU2-dacarbazine or temozolomide-capecitabine chemotherapies allow a temporary clinical response for almost half of patients and/or a morphological response for a third of patients.

Open access

Luigia Cinque, Angelo Sparaneo, Antonio S Salcuni, Danilo de Martino, Claudia Battista, Francesco Logoluso, Orazio Palumbo, Roberto Cocchi, Evaristo Maiello, Paolo Graziano, Geoffrey N Hendy, David E C Cole, Alfredo Scillitani, and Vito Guarnieri

Background

The occurrence of parathyroid carcinoma in multiple endocrine neoplasia type I (MENI) is rare and the 15 cases of malignant parathyroid tumor reported so far have been associated with MENI in individuals and not with multiple members within a family.

Methods

We report on a 61-year-old male, operated for a 7.3 cm parathyroid carcinoma infiltrating the esophagus. In his brother, a 4.6 cm parathyroid carcinoma was diagnosed histologically, while in the daughter, neck ultrasonography revealed 2 extrathyroidal nodules, yet to be excised.

Results

Screening of the MEN1 gene identified a known germline heterozygous missense mutation (c.1252G>A; p.D418N) in exon 9, in all affected subjects.

Conclusions

The occurrence of parathyroid carcinoma in more than one affected member of a single MEN1 family represents the first reported familial case. This suggests that additional constitutional genetic mutations may contribute to the variation in malignant potential and clinical behavior of parathyroid tumors in MEN1.

Open access

Weixi Wang, Rulai Han, Lei Ye, Jing Xie, Bei Tao, Fukang Sun, Ran Zhuo, Xi Chen, Xiaxing Deng, Cong Ye, Hongyan Zhao, and Shu Wang

Objective

Up to 40% of multiple endocrine neoplasia type 1 (MEN1) patients may have adrenal cortical tumors. However, adrenocortical carcinoma (ACC) is rare. The clinical manifestations, prevalence, inheritance and prognosis of ACC associated with MEN1 remain unclear. Here we report the clinical manifestations and prevalence of ACC in patients with MEN1.

Design and methods

A retrospective analysis of ACC associated with MEN1 patients at a single tertiary care center from December 2001 to June 2017. Genetic analysis of MEN1 and other ACC associated genes, loss of heterozygosity (LOH) of MEN1 locus, immunohistochemistry staining of menin, P53 and β-catenin in ACC tissue were performed.

Results

Two related patients had ACC associated with MEN1. The father had ENSAT stage IV tumor with excessive production of cortisol; the daughter had nonfunctional ENSAT stage I tumor. Both patients carried novel germline heterozygous mutation (c.400_401insC) of MEN1. The wild-type MEN1 allele was lost in the resected ACC tissue from the daughter with no menin staining. The ACC tissue had nuclear β-catenin staining, with heterozygous CTNNB1 mutation of 357del24 and P53 staining in only 20% cells.

Conclusions

ACC associated with MEN1 is rare and may occur in familial aggregates.

Open access

Rui M B Maciel, Cleber P Camacho, Lígia V M Assumpção, Natassia E Bufalo, André L Carvalho, Gisah A de Carvalho, Luciana A Castroneves, Francisco M de Castro Jr, Lucieli Ceolin, Janete M Cerutti, Rossana Corbo, Tânia M B L Ferraz, Carla V Ferreira, M Inez C França, Henrique C R Galvão, Fausto Germano-Neto, Hans Graf, Alexander A L Jorge, Ilda S Kunii, Márcio W Lauria, Vera L G Leal, Susan C Lindsey, Delmar M Lourenço Jr, Léa M Z Maciel, Patrícia K R Magalhães, João R M Martins, M Cecília Martins-Costa, Gláucia M F S Mazeto, Anelise I Impellizzeri, Célia R Nogueira, Edenir I Palmero, Cencita H C N Pessoa, Bibiana Prada, Débora R Siqueira, Maria Sharmila A Sousa, Rodrigo A Toledo, Flávia O F Valente, Fernanda Vaisman, Laura S Ward, Shana S Weber, Rita V Weiss, Ji H Yang, Magnus R Dias-da-Silva, Ana O Hoff, Sergio P A Toledo, and Ana L Maia

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant genetic disease caused by RET gene germline mutations that is characterized by medullary thyroid carcinoma (MTC) associated with other endocrine tumors. Several reports have demonstrated that the RET mutation profile may vary according to the geographical area. In this study, we collected clinical and molecular data from 554 patients with surgically confirmed MTC from 176 families with MEN2 in 18 different Brazilian centers to compare the type and prevalence of RET mutations with those from other countries. The most frequent mutations, classified by the number of families affected, occur in codon 634, exon 11 (76 families), followed by codon 918, exon 16 (34 families: 26 with M918T and 8 with M918V) and codon 804, exon 14 (22 families: 15 with V804M and 7 with V804L). When compared with other major published series from Europe, there are several similarities and some differences. While the mutations in codons C618, C620, C630, E768 and S891 present a similar prevalence, some mutations have a lower prevalence in Brazil, and others are found mainly in Brazil (G533C and M918V). These results reflect the singular proportion of European, Amerindian and African ancestries in the Brazilian mosaic genome.

Open access

Dirk-Jan van Beek, Rachel S van Leeuwaarde, Carolina R C Pieterman, Menno R Vriens, Gerlof D Valk, and the DutchMEN Study Group

Rare diseases pose specific challenges in the field of medical research to provide physicians with evidence-based guidelines derived from studies with sufficient quality. An example of these rare diseases is multiple endocrine neoplasia type 1 (MEN1), which is an autosomal dominant endocrine tumor syndrome with an estimated occurrence rate of 2–3 per 100,000. For this complex disease, characterized by multiple endocrine tumors, it proves difficult to perform both adequate and feasible studies. The opinion of patients themselves is of utmost importance to identify the gaps in the evidence-based medicine regarding clinical care. In the search for scientific answers to clinical research questions, the aim for best available evidence is obvious. Observational studies within patient cohorts, although prone to bias, seem the most feasible study design regarding the disease prevalence. Knowledge and adaptation to all types of bias is demanded in the strive for answers. Guided by our research on MEN1 patients, we elaborate on strategies to identify sufficient patients, to maximize and maintain patient enrolment and to standardize the data collection process. Preferably, data collection is performed prospectively, however, under certain conditions, data storage in a longitudinal retrospective database with a disease-specific framework is suitable. Considering the global challenges on observational research on rare diseases, we propose a stepwise approach from clinical research questions to scientific answers.

Open access

Xu Han, Xuefeng Xu, Hongyun Ma, Yuan Ji, Dansong Wang, Tiantao Kuang, Wenchuan Wu, Bin Song, Gang Li, Gang Jin, and Wenhui Lou

Purpose

Emerging evidence suggests G3 pancreatic neuroendocrine neoplasms (pNENs) present heterogeneous morphology and biology. The 2017 WHO classification has introduced a new category of well-differentiated pancreatic neuroendocrine tumors (WD-pNETs) G3, compared with poorly differentiated pancreatic neuroendocrine carcinomas (PD-pNECs) G3. We aim to analysis the demographics and outcomes of patients with resectable 2017 WHO G3 pNENs to facilitate the distinction between two entities.

Methods

The multi-institutional retrospective cohort involving 57 surgically treated patients affected by 2017 WHO G3 pNENs were morphologically identified and clinically analyzed. Patients having WD-pNETs G3 and those having PD-pNECs G3 were compared.

Results

Thirty patients had WD-pNETs and 27 patients had PD-pNECs. The distributions of Ki-67 and mitotic count in patients with PD-pNECs or WD-pNETs showed remarkable disparities. ROC indicated cut-off value of Ki-67 was 45. PD-pNECs were more common in patients with elevated Ki-67 and mitotic count, advanced AJCC TNM stage, vascular invasion, regional lymph-node metastases, elevated NSE and decreased CgA levels compared with WD-pNETs (P < 0.05). The association between 2017 WHO G3 grade and TTR was statistically significant (P < 0.05). Univariate analysis indicated OS rates were associated with morphologic differentiation (WD-pNETs vs PD-pNECs), Ki-67, TNM staging, synchronous distant metastases, initial treatments, vascular invasion, regional lymph nodes metastases, mitotic count and age (P < 0.05). Multivariate analyses illustrated Ki-67, differentiation, TNM staging and vascular invasion were independent predictors (P < 0.05).

Conclusions

PD-pNECs G3 presented malignant biological behavior and dismal outcome compared with WD-pNETs G3. These findings challenge 2010 WHO classification and suggest the categorization can be improved by refined tumor grading.

Open access

Elizaveta Mamedova, Natalya Mokrysheva, Evgeny Vasilyev, Vasily Petrov, Ekaterina Pigarova, Sergey Kuznetsov, Nikolay Kuznetsov, Liudmila Rozhinskaya, Galina Melnichenko, Ivan Dedov, and Anatoly Tiulpakov

Background

Primary hyperparathyroidism (PHPT) is a relatively rare disorder among children, adolescents and young adults. Its development at an early age is suspicious for hereditary causes, though the need for routine genetic testing remains controversial.

Objective

To identify and describe hereditary forms of PHPT in patients with manifestation of the disease under 40 years of age.

Design

We enrolled 65 patients with PHPT diagnosed before 40 years of age. Ten of them had MEN1 mutation, and PHPT in them was the first manifestation of multiple endocrine neoplasia type 1 syndrome.

Methods

The other fifty-five patients underwent next-generation sequencing (NGS) of a custom-designed panel of genes, associated with PHPT (MEN1, CASR, CDC73, CDKN1A, CDKN1B, CDKN1C, CDKN2A, CDKN2C, CDKN2D). In cases suspicious for gross CDC73 deletions multiplex ligation-dependent probe amplification was performed.

Results

NGS revealed six pathogenic or likely pathogenic germline sequence variants: four in CDC73 c.271C>T (p.Arg91*), c.496C>T (p.Gln166*), c.685A>T (p.Arg229*) and c.787C>T (p.Arg263Cys); one in CASR c.3145G>T (p.Glu1049*) and one in MEN1 c.784-9G>A. In two patients, MLPA confirmed gross CDC73 deletions. In total, 44 sporadic and 21 hereditary PHPT cases were identified. Parathyroid carcinomas and atypical parathyroid adenomas were present in 8/65 of young patients, in whom CDC73 mutations were found in 5/8.

Conclusions

Hereditary forms of PHPT can be identified in up to 1/3 of young patients with manifestation of the disease at <40 years of age. Parathyroid carcinomas or atypical parathyroid adenomas in young patients are frequently associated with CDC73 mutations.

Open access

Sara Storvall, Helena Leijon, Eeva Ryhänen, Johanna Louhimo, Caj Haglund, Camilla Schalin-Jäntti, and Johanna Arola

Introduction

Parathyroid carcinoma represents a rare cause of primary hyperparathyroidism. Distinguishing carcinoma from the benign tumors underlying primary hyperparathyroidism remains challenging. The diagnostic criteria for parathyroid carcinoma are local and/or metastatic spreading. Atypical parathyroid adenomas share other histological features with carcinomas but lack invasive growth. Somatostatin receptors are commonly expressed in different neuroendocrine tumors, but whether this also holds for parathyroid tumors remains unknown.

Aim

Our aim is to examine the immunohistochemical expression of somatostatin receptor 1–5 in parathyroid typical adenomas, atypical adenomas and carcinomas.

Methods

We used a tissue microarray construct from a nationwide cohort of parathyroid carcinomas (n = 32), age- and gender-matched typical parathyroid adenomas (n = 72) and atypical parathyroid adenomas (n = 27) for immunohistochemistry of somatostatin receptor subtypes 1–5. We separately assessed cytoplasmic, membrane and nuclear expression and also investigated the associations with histological, biochemical and clinical characteristics.

Results

All parathyroid tumor subgroups expressed somatostatin receptors, although membrane expression appeared negligible. Except for somatostatin receptor 1, expression patterns differed between the three tumor types. Adenomas exhibited the weakest and carcinomas the strongest expression of somatostatin receptor 2, 3, 4 and 5. We observed the largest difference for cytoplasmic somatostatin receptor 5 expression.

Conclusions

Parathyroid adenomas, atypical adenomas and carcinomas all express somatostatin receptor subtypes 1–5. Somatostatin receptor 5 may serve as a potential tumor marker for malignancy. Studies exploring the role of somatostatin receptor imaging and receptor-specific therapies in patients with parathyroid carcinomas are needed.