Anne Marie McNicol

TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system

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.

Consensus guidelines for the management of patients with liver metastases from digestive (neuro)endocrine tumors: Foregut, midgut, hindgut, and unknown primary

a DRK Kliniken Westend, Berlin , Germany; b UFR Bichat-Beaujon-Louis Mourier, Service de Chirurgie Digestive, Hopital Louis Mourier, Colombes , France; c Medicine and Surgery, General Surgery Section, MED/18 – General Surgery and d Department of Pathology, University of Verona, Verona , Italy; e Netherlands Cancer Centre, Amsterdam , and f Department of Nuclear Medicine, Erasmus University Medical Center, Rotterdam , The Netherlands;

ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Towards a Standardized Approach to the Diagnosis of Gastroenteropancreatic Neuroendocrine Tumors and Their Prognostic Stratification

ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors : towards a standardized approach to the diagnosis of gastroenteropancreatic neuroendocrine tumors and their prognostic stratification

Elevated luteinizing hormone induces expression of its receptor and promotes steroidogenesis in the adrenal cortex

Transgenic (TG) female mice expressing bLHbeta-CTP (a chimeric protein derived from the beta-subunit of bovine luteinizing hormone [LH] and a fragment of the beta-subunit of human chorionic gonadotropin [hCG]) exhibit elevated serum LH, infertility, polycystic ovaries, and ovarian tumors. In humans, increased LH secretion also occurs in infertility and polycystic ovarian syndrome, often concomitant with adrenocortical dysfunction. We therefore investigated adrenal function in LH overexpressing bLHbeta-CTP female mice. The size of their adrenals was increased by 80% with histological signs of cortical stimulation. Furthermore, adrenal steroid production was increased, with up to 14-fold elevated serum corticosterone. Primary adrenal cells from TG and control females responded similarly to ACTH stimulation, but, surprisingly, the TG adrenals responded to hCG with significantly increased cAMP, progesterone, and corticosterone production. LH receptor (LHR) expression and activity were also elevated in adrenals from female TG mice, but gonadectomized TG females showed no increase in corticosterone, suggesting that the dysfunctional ovaries of the intact TG females promote adrenocortical hyperfunction. We suggest that, in intact TG females, enhanced ovarian estrogen synthesis causes increased secretion of prolactin (PRL), which elevates LHR expression. Chronically elevated serum LH, augmented by enhanced PRL production, induces functional LHR expression in mouse adrenal cortex, leading to elevated, LH-dependent, corticosterone production. Thus, besides polycystic ovaries, the bLHbeta-CTP mice provide a useful model for studying human disorders related to elevated LH secretion and adrenocortical hyperfunction.

Overexpression of HER2/neu in solid tumours: an immunohistochemical survey

Using a standardized immunohistochemical assay we have evaluated 575 primary neoplasms of different histogenesis to determine the incidence of HER2 overexpression in some of the most common categories of human solid neoplasms. This study addresses the variable incidence of HER2 overexpression previously published for some tumour types.

ENETS consensus guidelines for the standards of care in neuroendocrine tumors: Somatostatin receptor imaging with IIIIn-pentetreotide

ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors : Somatostatin Receptor Imaging with In-111-Pentetreotide

Poorly differentiated carcinomas of the foregut (gastric, duodenal and pancreatic)

a Department of Pathology, Gothenburg University, Gothenburg , Sweden; b Department of Gastroenterology, Gasthuisberg University, Leuven , Belgium; c Department of Gastroenterology, Ospedale S. Andrea, Rome , Italy; d Department of Oncology, University of Texas, Houston, Tex. , USA; e Department of Endocrinology, Erlangen University, Erlangen , Germany; f Department of Oncology and Pathology, Royal Infirmary Hospital, Glasgow , UK; g Department of Oncology, Virgen de la Victoria Hospital, Malaga , Spain; h Department of Nuclear Medicine, Medizinische Hochschule Hannover, Hannover , Germany; i Department of Endocrinology, Erciyes University, Kayseri , Turkey; j Department of Surgery, Beaujon Hospital, Clichy , France; k Department of Nuclear Medicine, Catholique de Louvain University, Brussels , Belgium; l Department of Nuclear Medicine, Erasmus MC University, Rotterdam , The Netherlands; m Department of Gastroenterology, Royal Free Hospital, London , UK

Hypermethylation of thep16/CDKN2A/MTS1 gene and loss of protein expression is associated with nonfunctional pituitary adenomas but not somatotrophinomas

The cyclin‐dependent kinase inhibitor 2A/multiple tumor suppressor gene 1 (CDKN2A/MTS1/p16) plays an important role in the control of progression from G1 to S‐phase of the cell cycle through the inhibition of CDK4‐mediated RB1 phosphorylation. In this study we investigated 46 nonfunctional pituitary tumors and 21 somatotrophinomas for aberrant methylation of the CpG island contained within the CDKN2A gene as an alternative mechanism of gene silencing. We demonstrate methylation in 32/46 (70%) of nonfunctioning tumors, in contrast to 2/21 (9.5%) somatotrophinomas and 0/15 histologically normal postmortem pituitaries. Methylation in noninvasive and invasive nonfunctional tumors was approximately equal at 15/20 (75%) and 17/26 (65%), respectively. Immunohistochemical analysis showed an absence of CDKN2A protein in 25/32 (78%) methylated nonfunctioning tumors, demonstrating a highly significant overall correlation (P = 0.00007) between hypermethylation of the gene and absence of the p16 protein. The association between hypermethylation and absence of CDKN2A protein remained when the cohort of nonfunctional tumors was further subdivided into noninvasive 12/15 (80%; P = 0.004) and invasive 13/17 (76%; P = 0.01), suggesting this to be an early event in pituitary tumorigenesis. In contrast, a single invasive methylated somatotrophinoma failed to express the CDKN2A protein. These data show that hypermethylation of the CpG island within exon 1, but not exon 2, of the CDKN2A gene is frequently associated with loss of protein expression in nonfunctional pituitary tumors, but not somatotrophinomas, suggesting different tumorigenic pathways. Genes Chromosomes Cancer 24:328–336, 1999.

Consensus guidelines for the management of patients with digestive neuroendocrine tumours: Well-differentiated colon and rectum tumour/carcinoma

a Department of Gastroenterology, North Hampshire Hospital, Basingstoke , UK; b Stadtisches Klinikum Neuss, Lukaskrankenhaus, Chirurgische Klinik I, Neuss , Germany; c Istituto di Radiologia, Policlinco GB Rossi, Verona , Italy; d Institute for Pathology, Kantonsspital, Baden , Switzerland; e Departments of Internal Medicine and Endocrinological and Metabolic Sciences, University of Genoa, Genoa , Italy; f II. Internal Medical Department, University Hospital Martin, Martin , Slovakia; g G. Genimatas Hospital, Athens , Greece; h Erciyes University Medical School, Department of Endocrinology and Metabolism, Kayseri , Turkey; i H. Lee Moffitt Cancer Center/ University of South Florida, Tampa, Fla. , USA; j Anatomie Pathologique, Hopital Edouard Herriot, Lyon , France;

ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Follow-Up and Documentation

Summary of follow-up recommendations in patients with benign and malignant neuroendocrine tumorsFollow-upyes/no endoscopy US/CT/MRI Octreoscan CgABenign insulinoma noType 1 gastric carcinoid yes yearlyRectal carcinoid no (if completely resected)Appendiceal carcinoid T1 noAppendiceal carcinoid T2 ? (see text)Resectable tumor (uncertain behavior)G1 every 6–12 months yes(gastric carc.)yes every 2 years 2 yes 1 Resectable malignant tumor with/without nodal involvementG1 every 6–12 months yes every 2 years 2 yes 1 G2 every 6 months yes yearly 2 yes 1 G3 every 3 months yes yearly 2 yes 3 Non-resectable malignant tumor with/without nodal involvement and/or liver and other metastasesG1 every 6–12 months yes every 2 years 2 yesG2 every 6 months yes yearly 2 yesG3 every 3 months yes yearly 2 yes 31 Only in the presence of a visible tumor. 2 Recommendations regarding the time frames of Octreoscan should be adjusted to the individual situation. 3 In poorly differentiated tumors and negative CgA NSE may act as a suitable marker.