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1.
Pathologe ; 41(Suppl 1): 1-8, 2020 Jun.
Article in English | MEDLINE | ID: mdl-31273418

ABSTRACT

Poorly differentiated thyroid carcinomas (PDTCs) are a rare subtype of thyroid carcinomas that are biologically situated between well-differentiated papillary/follicular thyroid carcinomas and anaplastic thyroid carcinomas (ATCs).The diagnosis of conventional as well as oncocytic poorly differentiated thyroid carcinoma is difficult and often missed in daily routine. The current WHO criteria to allow the diagnosis of PDTCs are based on the results of a consensus meeting held in Turin in 2006. Even a minor poorly differentiated component of only 10%of a given carcinoma significantly affects patient prognosis and the oncocytic subtype may even have a worse outcome. Immunohistochemistry is not much help and is mostly used to exclude a medullary thyroid carcinoma with calcitonin and to establish a follicular cell of origin via thyroglobulin staining.Due to the concept of stepwise dedifferentiation, there is a vast overlap of different molecular alterations like BRAF, RAS, CTNNB1, TP53 and others between different thyroid carcinoma subtypes. A distinctive molecular tumor profile is therefore currently not available.PDTCs have a unique miRNA signature, which separates them from other thyroid carcinomas. The average relapse free survival is less than one year and about 50% of patients die of the disease. Modern tyrosine kinase inhibitors offer in conjunction with powerful molecular diagnostic new chances in these difficult to treat carcinomas.


Subject(s)
Carcinoma/pathology , Thyroid Neoplasms/pathology , Humans , Missed Diagnosis , Undiagnosed Diseases
2.
Pathologe ; 40(4): 467-492, 2019 Jul.
Article in German | MEDLINE | ID: mdl-31250089

ABSTRACT

Nodular hyperplasias and adenomas are by far the most frequently resected tumors of the adrenal cortex followed by pheochromocytomas, which are either discovered incidentally or become conspicuous due to hormonal hypersecretions. Cortical nodes and adenomas are easy to diagnose using simple staining methods. Uncertain cortical carcinomas, pheochromocytomas and other tumors of the adrenal region require additional immunohistochemical staining methods. Determination of the dignity of tumors of the adrenal cortex necessitates at least the Weiss score (possibly in its modified form), for oncocytic tumors the Bisceglia score and for pediatric tumors the Wieneke score. The Ki-67 index must also be taken into consideration. For pheochromocytomas the PASS and the GAPP systeme are used.


Subject(s)
Adrenal Gland Neoplasms , Adrenocortical Carcinoma , Pheochromocytoma , Adenoma , Adrenal Cortex Neoplasms/pathology , Adrenal Gland Neoplasms/pathology , Adrenal Glands/pathology , Child , Humans , Pheochromocytoma/pathology
3.
Pathologe ; 40(3): 227-234, 2019 May.
Article in German | MEDLINE | ID: mdl-31093689

ABSTRACT

Poorly differentiated thyroid carcinomas (PDTCs) are a rare subtype of thyroid carcinomas that are biologically situated between well-differentiated papillary/follicular thyroid carcinomas and anaplastic thyroid carcinomas (ATCs).The diagnosis of conventional as well as oncocytic poorly differentiated thyroid carcinoma is difficult and often missed in daily routine. The current WHO criteria to allow the diagnosis of PDTCs are based on the results of a consensus meeting held in Turin in 2006. Even a minor poorly differentiated component of only 10% of a given carcinoma significantly affects patient prognosis and the oncocytic subtype may even have a worse outcome. Immunohistochemistry is not much help and is mostly used to exclude a medullary thyroid carcinoma with calcitonin and to establish a follicular cell of origin via thyroglobulin staining.Due to the concept of stepwise dedifferentiation, there is a vast overlap of different molecular alterations like BRAF, RAS, CTNNB1, TP53 and others between different thyroid carcinoma subtypes. A distinctive molecular tumor profile is therefore currently not available.PDTCs have a unique miRNA signature, which separates them from other thyroid carcinomas.The average relapse free survival is less than one year and about 50% of patients die of the disease. Modern tyrosine kinase inhibitors offer in conjunction with powerful molecular diagnostic new chances in these difficult to treat carcinomas.


Subject(s)
Adenocarcinoma/pathology , Thyroglobulin/physiology , Thyroid Neoplasms , Humans , Neoplasm Recurrence, Local , Prognosis , Thyroid Neoplasms/pathology
5.
Pathologe ; 37(4): 304-13, 2016 Jul.
Article in German | MEDLINE | ID: mdl-27379621

ABSTRACT

The current WHO classification of neuroendocrine tumors (NET) differentiates between typical carcinoids (low grade NET), atypical carcinoids (intermediate grade NET) and small cell and large cell carcinomas (high grade NET) according to the prognosis. Neuroendocrine neoplasms (NEN) of the gastrointestinal tract and the pancreas are graded in an identical way. Together with the TNM system this enables a preoperative estimation of the prognosis in biopsies and fine needle aspirates. Well-differentiated tumors are graded into G1 tumors by the number of mitoses, <2 per 10 high-power fields (HPF) and the Ki-67 (index <3 %) and G2 tumors (2-20 mitoses/10 HPF, Ki-67 3-20 %). Discrepancies between the number of mitoses and the Ki-67 index are not uncommon and in these cases the higher value of the two should be applied. The more differentiated tumors of the G3 type have to be differentiated from undifferentiated carcinomas of the small cell type and large cell type with a much poorer prognosis. Prognosis relevant grading of thyroid cancers is achieved by special subtyping so that the G1-G3 system is not applicable. The rare cancers of the parathyroid gland and of the pituitary gland are not graded. Adrenal tumors also have no grading system. The prognosis is dependent on the Ki-67 index and with some reservations on the established scoring systems.


Subject(s)
Lung Neoplasms/pathology , Neuroendocrine Tumors/pathology , Adrenal Gland Neoplasms/classification , Adrenal Gland Neoplasms/pathology , Adrenal Gland Neoplasms/therapy , Biomarkers, Tumor/analysis , Cell Proliferation/physiology , Gastrointestinal Neoplasms/classification , Gastrointestinal Neoplasms/pathology , Gastrointestinal Neoplasms/therapy , Humans , Ki-67 Antigen/analysis , Lung Neoplasms/classification , Lung Neoplasms/therapy , Mitotic Index , Neoplasm Grading , Neoplasm Staging , Neuroendocrine Tumors/classification , Neuroendocrine Tumors/therapy , Pancreatic Neoplasms/classification , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/therapy , Parathyroid Neoplasms/classification , Parathyroid Neoplasms/pathology , Parathyroid Neoplasms/therapy , Pituitary Neoplasms/classification , Pituitary Neoplasms/pathology , Pituitary Neoplasms/therapy , Thymus Neoplasms/classification , Thymus Neoplasms/pathology , Thymus Neoplasms/therapy , Thyroid Neoplasms/classification , Thyroid Neoplasms/pathology , Thyroid Neoplasms/therapy , World Health Organization
6.
Pathologe ; 37(3): 253-7, 2016 May.
Article in German | MEDLINE | ID: mdl-27099223

ABSTRACT

Polyglandular autoimmune syndromes (PGAS), also known as autoimmune polyendocrinopathy syndromes (APS), are a heterogeneous group of rare, genetically caused diseases of the immune system which lead to inflammatory damage of various endocrine glands resulting in malfunctions. In addition, autoimmune diseases of non-endocrine organs may also be found. Early diagnosis of PGAS is often overlooked because of heterogeneous symptoms and the progressive occurrence of the individual diseases. The two most important forms of PGAS are the juvenile and adult types. The juvenile type (PGAS type 1) is caused by mutations in the autoimmune regulator (AIRE) gene on chromosome 21, exhibits geographic variations in incidence and is defined by the combination of mucocutaneous candidiasis, Addison's disease and hypoparathyroidism. In addition, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome and other autoimmune diseases can also occur. The adult form of PGAS (PGAS type 2) is a multigenetic disorder associated with some HLA haplotypes, is more common than the juvenile type, shows female predominance and exhibits the combination of type 1 diabetes, autoimmune thyroid disease, Addison's disease and other autoimmune disorders. The histological alterations in affected organs of PGAS patients are similar to findings in sporadically occurring autoimmune diseases of these organs but there are no pathognomic fine tissue findings. If patients exhibit autoimmune changes in two different endocrine glands or if there are indications of several autoimmune disorders from the patient history, it is important to consider PGAS and inform the clinicians of this suspicion.


Subject(s)
Polyendocrinopathies, Autoimmune/immunology , Polyendocrinopathies, Autoimmune/pathology , Adult , Child , Chromosomes, Human, Pair 21/genetics , DNA Mutational Analysis , Diagnosis, Differential , Early Diagnosis , Endocrine Glands/immunology , Endocrine Glands/pathology , Female , Humans , Male , Multigene Family/genetics , Polyendocrinopathies, Autoimmune/diagnosis , Polyendocrinopathies, Autoimmune/genetics , Transcription Factors/genetics , AIRE Protein
7.
Pathologe ; 36(3): 220-8, 2015 May.
Article in German | MEDLINE | ID: mdl-25941099

ABSTRACT

The diagnostics of pancreatic neuroendocrine tumors (PanNEN) have changed in recent years especially concerning the World Health Organization (WHO) classification, TNM staging and grading. Furthermore, some new prognostic and predictive immunohistochemical markers have been introduced. Most progress, however, has been made in the molecular pathogenesis of these neoplasms. Using next generation sequencing techniques, the mammalian target of rapamycin (mTOR) pathway, hypoxia and epigenetic changes were identified as key players in tumorigenesis. In this article the most important developments of morphological as well as immunohistochemical diagnostics together with the molecular background of PanNEN are summarized.


Subject(s)
Neuroendocrine Tumors/pathology , Pancreatic Neoplasms/pathology , Biomarkers, Tumor/analysis , Biomarkers, Tumor/genetics , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology , Humans , Immunohistochemistry , Neoplasm Grading , Neoplasm Staging , Neuroendocrine Tumors/genetics , Pancreas/pathology , Pancreatic Neoplasms/genetics , Prognosis , TOR Serine-Threonine Kinases/genetics
8.
Pathologe ; 35(3): 283-93; quiz 294, 2014 May.
Article in German | MEDLINE | ID: mdl-24671468

ABSTRACT

Neuroendocrine neoplasms (NEN) of the distal jejunum and ileum derive from serotonin-producing enterochromaffin (EC) cells. Due to their low proliferation rate and their infiltrative growth, they are often discovered at an advanced disease stage when metastasis has already occurred. The biology of these tumours is different from other NEN of the digestive tract. In order to standardise and improve diagnosis and therapy, the guidelines for the diagnosis and clinical management of jejuno-ileal NEN as well as for the management of patients with liver and other distant metastases from NEN were revised by the European Neuroendocrine Tumour Society (ENETS) in 2012. This review focuses on aspects relevant for surgical pathology.


Subject(s)
Ileal Neoplasms/pathology , Jejunal Neoplasms/pathology , Neuroendocrine Tumors/pathology , Cell Proliferation , Diagnosis, Differential , Disease Progression , Enterochromaffin Cells/pathology , Humans , Ileal Neoplasms/surgery , Ileum/pathology , Ileum/surgery , Jejunal Neoplasms/surgery , Jejunum/pathology , Jejunum/surgery , Neuroendocrine Tumors/surgery , Practice Guidelines as Topic , Receptors, Somatostatin/analysis
9.
J Natl Cancer Inst ; 104(10): 764-77, 2012 May 16.
Article in English | MEDLINE | ID: mdl-22525418

ABSTRACT

BACKGROUND: Both the European Neuroendocrine Tumor Society (ENETS) and the International Union for Cancer Control/American Joint Cancer Committee/World Health Organization (UICC/AJCC/WHO) have proposed TNM staging systems for pancreatic neuroendocrine neoplasms. This study aims to identify the most accurate and useful TNM system for pancreatic neuroendocrine neoplasms. METHODS: The study included 1072 patients who had undergone previous surgery for their cancer and for which at least 2 years of follow-up from 1990 to 2007 was available. Data on 28 variables were collected, and the performance of the two TNM staging systems was compared by Cox regression analysis and multivariable analyses. All statistical tests were two-sided. RESULTS: Differences in distribution of sex and age were observed for the ENETS TNM staging system. At Cox regression analysis, only the ENETS TNM staging system perfectly allocated patients into four statistically significantly different and equally populated risk groups (with stage I as the reference; stage II hazard ratio [HR] of death = 16.23, 95% confidence interval [CI] = 2.14 to 123, P = .007; stage III HR of death = 51.81, 95% CI = 7.11 to 377, P < .001; and stage IV HR of death = 160, 95% CI = 22.30 to 1143, P < .001). However, the UICC/AJCC/WHO 2010 TNM staging system compressed the disease into three differently populated classes, with most patients in stage I, and with the patients being equally distributed into stages II-III (statistically similar) and IV (with stage I as the reference; stage II HR of death = 9.57, 95% CI = 4.62 to 19.88, P < .001; stage III HR of death = 9.32, 95% CI = 3.69 to 23.53, P = .94; and stage IV HR of death = 30.84, 95% CI = 15.62 to 60.87, P < .001). Multivariable modeling indicated curative surgery, TNM staging, and grading were effective predictors of death, and grading was the second most effective independent predictor of survival in the absence of staging information. Though both TNM staging systems were independent predictors of survival, the UICC/AJCC/WHO 2010 TNM stages showed very large 95% confidence intervals for each stage, indicating an inaccurate predictive ability. CONCLUSION: Our data suggest the ENETS TNM staging system is superior to the UICC/AJCC/WHO 2010 TNM staging system and supports its use in clinical practice.


Subject(s)
Neuroendocrine Tumors/epidemiology , Neuroendocrine Tumors/pathology , Pancreatic Neoplasms/epidemiology , Pancreatic Neoplasms/pathology , Adult , Age Distribution , Aged , Cohort Studies , Confounding Factors, Epidemiologic , Europe/epidemiology , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Multivariate Analysis , Neoplasm Staging , Neuroendocrine Tumors/mortality , Observer Variation , Odds Ratio , Pancreatic Neoplasms/mortality , Predictive Value of Tests , Proportional Hazards Models , Retrospective Studies , Sex Distribution , United States/epidemiology
11.
Internist (Berl) ; 51(9): 1185-9, 2010 Sep.
Article in German | MEDLINE | ID: mdl-20848268

ABSTRACT

The right-sided heart valves are affected in about 10% of patients with infective endocarditis. However, the tricuspid valve is the most frequently involved valve in intravenous drug users with infective endocarditis. When treated with antibiotics, the prognosis is considered favorable. Reported here is the case of a drug-addicted patient with polymicrobial (Staphylococcus aureus and Streptococcus pneumoniae) infective endocarditis of the tricuspid valve and a lethal outcome due to multiple organ failure. The indications and options to perform cardiac surgery in patients with infective endocarditis of the tricuspid valve are discussed.


Subject(s)
Endocarditis, Bacterial/diagnosis , Endocarditis, Bacterial/pathology , Enterobacter cloacae , Illicit Drugs , Pneumococcal Infections/diagnosis , Staphylococcal Infections/diagnosis , Substance Abuse, Intravenous/complications , Tricuspid Valve , Adult , Alcoholism/complications , Anti-Bacterial Agents/therapeutic use , Diagnosis, Differential , Echocardiography , Endocarditis, Bacterial/drug therapy , Enterobacteriaceae Infections/diagnosis , Enterobacteriaceae Infections/drug therapy , Enterobacteriaceae Infections/pathology , Fatal Outcome , Humans , Male , Multiple Organ Failure/diagnosis , Multiple Organ Failure/drug therapy , Pneumococcal Infections/drug therapy , Pneumococcal Infections/pathology , Smoking/adverse effects , Staphylococcal Infections/drug therapy , Staphylococcal Infections/pathology , Substance Abuse, Intravenous/pathology , Tricuspid Valve/pathology , Tricuspid Valve Insufficiency/diagnosis , Tricuspid Valve Insufficiency/drug therapy , Tricuspid Valve Insufficiency/pathology , Video Recording
12.
Endocr Relat Cancer ; 16(4): 1219-27, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19690016

ABSTRACT

A small subset of familial pancreatic endocrine tumors (PET) arises in patients with von Hippel-Lindau syndrome and these tumors may have an adverse outcome compared to other familial PET. Sporadic PET rarely harbors somatic VHL mutations, but the chromosomal location of the VHL gene is frequently deleted in sporadic PET. A subset of sporadic PET shows active hypoxia signals on mRNA and protein level. To identify the frequency of functionally relevant VHL inactivation in sporadic PET and to examine a possible prognostic significance we correlated epigenetic and genetic VHL alterations with hypoxia signals. VHL mutations were absent in all 37 PETs examined. In 2 out of 35 informative PET (6%) methylation of the VHL promoter region was detected and VHL deletion by fluorescence in situ hybridization was found in 14 out of 79 PET (18%). Hypoxia inducible factor 1alpha (HIF1-alpha), carbonic anhydrase 9 (CA-9), and glucose transporter 1 (GLUT-1) protein was expressed in 19, 27, and 30% of the 152 PETs examined. Protein expression of the HIF1-alpha downstream target CA-9 correlated significantly with the expression of CA-9 RNA (P<0.001), VHL RNA (P<0.05), and VHL deletion (P<0.001) as well as with HIF1-alpha (P<0.005) and GLUT-1 immunohistochemistry (P<0.001). These PET with VHL alterations and signs of hypoxia signalling were characterized by a significantly shortened disease-free survival. We conclude that VHL gene impairment by promoter methylation and VHL deletion in nearly 25% of PET leads to the activation of the HIF-pathway. Our data suggest that VHL inactivation and consecutive hypoxia signals may be a mechanism for the development of sporadic PET with an adverse outcome.


Subject(s)
DNA Methylation , Endocrine Gland Neoplasms/genetics , Gene Deletion , Mutation/genetics , Pancreatic Neoplasms/genetics , Von Hippel-Lindau Tumor Suppressor Protein/genetics , Antigens, Neoplasm/genetics , Antigens, Neoplasm/metabolism , Carbonic Anhydrase IX , Carbonic Anhydrases/genetics , Carbonic Anhydrases/metabolism , Endocrine Gland Neoplasms/metabolism , Endocrine Gland Neoplasms/pathology , Glucose Transporter Type 1/genetics , Glucose Transporter Type 1/metabolism , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Immunoenzyme Techniques , In Situ Hybridization, Fluorescence , Pancreas/metabolism , Pancreas/pathology , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Prognosis , Promoter Regions, Genetic , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Survival Rate , Von Hippel-Lindau Tumor Suppressor Protein/antagonists & inhibitors , Von Hippel-Lindau Tumor Suppressor Protein/metabolism
13.
Radiologe ; 49(3): 198-205, 2009 Mar.
Article in German | MEDLINE | ID: mdl-19224191

ABSTRACT

Tumors of the disseminated/diffuse neuroendocrine system (NET) are characterized by a common phenotype. However, the biology varies according to histomorphology, endocrine symptoms and organ of origin. The WHO classification takes these differences into account and uses a common framework, where the parameters size and extent of invasion vary according to the organ of origin. In order to achieve a further standardization of reporting the European Neuroendocrine Tumor Society (ENETS) recently proposed a tumor-node-metastasis (TNM) staging and grading system for gastro-entero-pancreatic NET.


Subject(s)
Diagnostic Imaging , Digestive System Neoplasms/classification , Neuroendocrine Tumors/classification , Cell Transformation, Neoplastic/pathology , Digestive System Neoplasms/diagnosis , Digestive System Neoplasms/pathology , Disease Progression , Humans , Neoplasm Invasiveness , Neoplasm Staging , Neuroendocrine Tumors/diagnosis , Neuroendocrine Tumors/pathology , Prognosis , Terminology as Topic
14.
Virchows Arch ; 451(4): 757-62, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17674042

ABSTRACT

Criteria for the staging and grading of neuroendocrine tumors (NETs) of midgut and hindgut origin were established at the second Consensus Conference in Frascati (Rome) organized by the European Neuroendocrine Tumor Society (ENETS). The proposed tumor-node-metastasis (TNM) classifications are based on the recently published ENETS Guidelines for the Diagnosis and Treatment of gastroenteropancreatic NETs and follow our previous proposal for foregut tumors. The new TNM classifications for NETs of the ileum, appendix, colon, and rectum, and the grading system were designed, discussed, and consensually approved by all conference participants. These proposals need to be validated and are meant to help clinicians in the stratification, treatment and follow-up of patients.


Subject(s)
Appendiceal Neoplasms/pathology , Carcinoma, Neuroendocrine/pathology , Colonic Neoplasms/pathology , Ileal Neoplasms/pathology , Neoplasm Staging/methods , Rectal Neoplasms/pathology , Appendiceal Neoplasms/diagnosis , Carcinoma, Neuroendocrine/diagnosis , Cell Proliferation , Colonic Neoplasms/diagnosis , Europe , Guidelines as Topic , Humans , Ileal Neoplasms/diagnosis , Lymph Nodes/pathology , Lymphatic Metastasis , Rectal Neoplasms/diagnosis
15.
Praxis (Bern 1994) ; 96(21): 859-63, 2007 May 23.
Article in German | MEDLINE | ID: mdl-17569438

ABSTRACT

We report the preoperative imaging findings of a 75 year old man with a large tumor of the lower abdomen. Computed tomography showed a large intraabdominal mass. In the differential diagnosis a gastrointestinal stromal tumor (GIST) or a metastasis of an unknown primary neoplasia were considered. Histology confirmed the diagnosis of a gastrointestinal stromal tumor (GIST).


Subject(s)
Gastrointestinal Stromal Tumors/diagnosis , Intestinal Neoplasms/diagnosis , Jejunal Neoplasms/diagnosis , Magnetic Resonance Imaging , Tomography, X-Ray Computed , Ultrasonography , Aged , Gastrointestinal Stromal Tumors/pathology , Gastrointestinal Stromal Tumors/secondary , Gastrointestinal Stromal Tumors/surgery , Hepatectomy , Humans , Intestinal Neoplasms/pathology , Intestinal Neoplasms/surgery , Jejunal Neoplasms/pathology , Jejunal Neoplasms/surgery , Jejunum/pathology , Jejunum/surgery , Liver/pathology , Liver Neoplasms/diagnosis , Liver Neoplasms/pathology , Liver Neoplasms/secondary , Liver Neoplasms/surgery , Male
16.
Gut ; 56(5): 637-44, 2007 May.
Article in English | MEDLINE | ID: mdl-17135306

ABSTRACT

BACKGROUND: Patients with a multiple endocrine neoplasia type 1 (MEN1)-associated Zollinger-Ellison syndrome (ZES) show multifocal duodenal gastrinomas and precursor lesions. AIMS: To test these lesions for loss of heterozygosity (LOH) of the MEN1 gene locus on chromosome 11q13, and to investigate whether the MEN1-related endocrine cell changes also involved somatostatin cells. MATERIAL AND METHODS: Tissue specimens from six patients with MEN1 and ZES were analysed by immunohistochemistry and immunofluorescence. LOH analysis was performed by fluorescence in situ hybridisation (FISH), using probes containing the MEN1 gene locus and the centromere 11 (C11) region. For simultaneous analysis of hormones and allelic deletions, a combined FISH/immunofluorescence protocol was established. RESULTS: 28 of a total of 33 duodenal neuroendocrine tumours (NETs) were gastrin-producing tumours; 13/28 (46.4%) revealed LOH on 11q13 and/or C11. Five of the NETs were somatostatin-expressing tumours, two revealing LOH. Allelic loss was detected in tumours as small as 300 microm (gastrin) and 400 microm (somatostatin) in diameter. The gastrin-producing tumours showed different deletion/retention patterns. Hyperplastic somatostatin cell lesions, similar to those of the gastrin cells, were present in all patients. The hyperplastic lesions of both cell lines consistently retained both 11q13 alleles. CONCLUSIONS: Allelic deletion of the MEN1 gene may reflect a pivotal event in the development of multifocal gastrin and somatostatin cell neoplasms in the duodenum of patients with MEN1. The observation of distinct deletion patterns in small synchronous tumours supports the concept that each gastrin-producing tumour in an individual MEN1 patient arises from an independent cell clone.


Subject(s)
Duodenal Neoplasms/genetics , Gastrinoma/genetics , Loss of Heterozygosity , Multiple Endocrine Neoplasia Type 1/genetics , Proto-Oncogene Proteins/genetics , Adult , Chromosomes, Human, Pair 11/genetics , Duodenal Neoplasms/pathology , Female , Gastrinoma/pathology , Humans , Hyperplasia/genetics , In Situ Hybridization, Fluorescence , Male , Middle Aged , Multiple Endocrine Neoplasia Type 1/pathology , Precancerous Conditions/genetics , Precancerous Conditions/pathology , Zollinger-Ellison Syndrome/genetics , Zollinger-Ellison Syndrome/pathology
17.
Ann N Y Acad Sci ; 1073: 138-48, 2006 Aug.
Article in English | MEDLINE | ID: mdl-17102080

ABSTRACT

Pheochromocytomas (PCCs) are neuroendocrine tumors of chromaffin tissue that produce catecholamines. They are usually located in the adrenal medulla, although in about 10% the tumors arise from extra-adrenal chromaffin tissue. The majority of PCCs arise sporadically, but PCCs occur also in the context of hereditary cancer syndromes. Familial PCC is inherited as an autosomal dominant trait alone or as a component of the multiple endocrine neoplasia Type 2 (MEN2) syndrome (RET gene), Von Hippel-Lindau (VHL) disease (VHL gene), neurofibromatosis Type 1 (NF1 gene), or familial pheochromocytoma-paraganglioma (PCC-PGL) syndrome (SDHD/B and C genes). It has been reported that 24% of apparently sporadic PCCs patients harbor germline mutations in these PCC-causing genes. We investigated the contribution of the inherited PCC-causing genes in a partly retrospectively and partly prospectively obtained series of 213 apparently sporadic PCCs. Mutation analysis was performed for RET (56 cases), VHL (136 cases), and SDHD (126 cases) and SDHB (47 cases). No germline RET mutations, six (4.4%) germline VHL mutations, two (1.5%) germline SDHD mutations, and one germline (1.6%) SDHB mutation were found. In total we found germline mutations in about 7.5% of the investigated apparently sporadic PCCs. Although 7.5% germline mutations in a series of apparently sporadic PCCs are far less than the more than 20% reported in the literature, the figure is significant enough to consider germline mutation testing for each patient with PCC.


Subject(s)
Adrenal Gland Neoplasms/genetics , Pheochromocytoma/genetics , Genetic Predisposition to Disease , Germ-Line Mutation , Humans , Polymerase Chain Reaction , Proto-Oncogene Proteins c-ret/genetics , Succinate Dehydrogenase/genetics , Von Hippel-Lindau Tumor Suppressor Protein/genetics
18.
Virchows Arch ; 449(4): 395-401, 2006 Oct.
Article in English | MEDLINE | ID: mdl-16967267

ABSTRACT

The need for standards in the management of patients with endocrine tumors of the digestive system prompted the European Neuroendocrine Tumor Society (ENETS) to organize a first Consensus Conference, which was held in Frascati (Rome) and was based on the recently published ENETS guidelines on the diagnosis and treatment of digestive neuroendocrine tumors (NET). Here, we report the tumor-node-metastasis proposal for foregut NETs of the stomach, duodenum, and pancreas that was designed, discussed, and consensually approved at this conference. In addition, we report the proposal for a working formulation for the grading of digestive NETs based on mitotic count and Ki-67 index. This proposal, which needs to be validated, is meant to help clinicians in the stratification, treatment, and follow-up of patients.


Subject(s)
Digestive System Neoplasms/diagnosis , Neoplasm Staging/methods , Neuroendocrine Tumors/diagnosis , Biomarkers, Tumor/analysis , Digestive System Neoplasms/chemistry , Digestive System Neoplasms/classification , Humans , Lymph Nodes/chemistry , Lymph Nodes/pathology , Mitotic Index , Neoplasm Metastasis/diagnosis , Neoplasm Staging/standards , Neuroendocrine Tumors/chemistry , Neuroendocrine Tumors/classification
19.
Histopathology ; 49(3): 298-307, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16918977

ABSTRACT

AIMS: The differentiation of adrenocortical carcinomas from adenomas may be difficult based on morphology alone. Differential expression of insulin-like growth factor (IGF) II and cyclin-dependent kinase (CDK) 4 has recently been described in these tumours. The aim of this study was to investigate the diagnostic usefulness of these markers immunohistochemically. METHODS AND RESULTS: We examined 22 benign and 17 malignant adrenocortical tumours and compared IGFII and CDK4 expression with known immunohistochemical as well as morphological criteria of malignancy. Thirteen of 17 carcinomas showed immunohistochemical reactivity for IGFII, whereas all adenomas but one were negative. Intense CDK4 expression was detected in 11 of 17 carcinomas but was present in only three of 22 adenomas. The MIB1 index was >5% in 14 of 16 carcinomas and was <5% in all adenomas but one. The combination of IGFII immunohistochemistry with MIB1 index led to high sensitivity and specificity in detecting adrenocortical carcinomas. CONCLUSIONS: IGFII and MIB1 are helpful immunohistochemical markers to predict malignancy in adrenocortical neoplasms. These markers can be used in addition to clinical, gross and morphological features to establish a diagnosis in difficult cases.


Subject(s)
Adrenal Cortex Neoplasms/diagnosis , Adrenocortical Adenoma/diagnosis , Adrenocortical Carcinoma/diagnosis , Insulin-Like Growth Factor Binding Protein 2/biosynthesis , Ki-67 Antigen/biosynthesis , Adrenal Cortex Neoplasms/metabolism , Adrenocortical Adenoma/metabolism , Adrenocortical Carcinoma/metabolism , Adult , Aged , Biomarkers, Tumor/analysis , Cyclin-Dependent Kinase 4/biosynthesis , Diagnosis, Differential , Golgi Apparatus/metabolism , Humans , Immunohistochemistry , Middle Aged , Sensitivity and Specificity , Tumor Suppressor Protein p53/biosynthesis
20.
J Pathol ; 209(2): 274-80, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16538614

ABSTRACT

Mutations of the 'phosphatase and tensin homologue deleted on chromosome 10' (PTEN/MMAC1) gene have been associated with a variety of human cancers, including prostate cancer, glioblastoma, and melanoma. The gene is thought to be one of the most frequently mutated tumour suppressor genes and inactivation of PTEN is associated with disease progression and angiogenesis. High vascularization and resistance to chemo- and radio-therapy are two well-established features of phaeochromocytomas (PCCs). Furthermore, benign and malignant PCCs are found in several PTEN knockout mouse models. This study therefore evaluated whether inactivation of PTEN may be involved in the tumourigenesis of PCC in man and whether PTEN abnormalities may help to define the malignant potential of these tumours. Tumour and germline DNA was analysed from 31 patients with apparently sporadic PCC, including 14 clinically benign and 17 malignant tumours, for loss of the PTEN gene locus, mutations in the PTEN gene, and for PTEN protein expression by immunohistochemistry. Loss of heterozygosity (LOH) analysis showed loss of PTEN in four malignant tumours (40%) and in one benign tumour (14%). However, no mutations of PTEN were observed. Immunohistochemistry showed no correlation with clinical behaviour and/or LOH status. The results indicate that inactivation of the PTEN/MMAC1 gene may play a minor role in the development of malignant phaeochromocytomas.


Subject(s)
Adrenal Gland Neoplasms/genetics , Genes, Tumor Suppressor/physiology , Neoplasm Proteins/genetics , PTEN Phosphohydrolase/genetics , Pheochromocytoma/genetics , Adolescent , Adult , Aged , DNA Mutational Analysis/methods , DNA, Neoplasm/genetics , Female , Gene Silencing/physiology , Humans , Immunohistochemistry/methods , Loss of Heterozygosity/genetics , Male , Middle Aged , Polymorphism, Single-Stranded Conformational
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