Somatic Testing on Gynecological Cancers Improve the Identification of Lynch Syndrome.

OBJECTIVE: Recent data from the literature indicate gynecological cancers (GCs) as sentinel cancers for a diagnosis of Lynch syndrome (LS). Clinical approaches to identifying LS have low sensitivity, whereas somatic tests on GCs may be a more sensitive and cost-effective strategy. METHODS: A series of 78 GCs belonging to 74 patients sent to the Genetic Counselling Service were investigated using microsatellite instability, immunohistochemical expression of mismatch repair (MMR) genes, and MLH1 promoter methylation. RESULTS: The presence of microsatellite instability was observed in 67.5% of GCs, and the absence of immunohistochemical expression of at least 1 of the 4 MMR proteins was observed in 71.4% of GCs, showing 96.1% concordance between the methods. Methylation analysis using methylation specific multiplex ligation-dependent probe amplification performed on 35 samples revealed MLH1 promoter hypermethylation in 18 cases (54%). Molecular analysis identified 36 LS carriers of MMR variants (27 pathogenetic and 9 variants of uncertain significance), and, interestingly, 3 LS patients had MLH1 methylated GC.With regard to histological features, LS-related GCs included endocervical cancers and also histological types different from the endometrioid cancers. The presence of peritumoral lymphocytes in GCs was statistically associated with LS tumors. CONCLUSIONS: Somatic analysis is a useful strategy to distinguish sporadic from LS GC. Our data allow the identification of a subset of LS patients otherwise unrecognized on the basis of clinical or family history alone. In addition, our results indicate that some clinicopathological features including age of GC diagnosis; presence of peritumoral lymphocytes; isthmic, endocervical sites, and body mass index value could be useful criteria to select patients for genetic counseling.

Identifying factors contributing to reduced breast tumor size: a longitudinal study.

AIM: This study examines the trends and outcomes of breast cancer patients who have undergone surgical procedures at the Department of Surgical Sciences, University of Insubria, Varese, Italy. It also identifies the factors that contributed to the reduction of the breast tumor size over a 13-year period at a tertiary referral center. METHODS: All breast cancer operations performed at the Department of Surgical Sciences, University of Insubria, Varese, Italy, from January 1992 to June 2005 were examined and data from their surgical pathology reports were also analyzed, using a prospective database. A longitudinal study was performed to compare and analyze the pathological data during three consecutive time periods. The periods were from 1992 to 1996, 1997 to 1999, and 2000 to 2005. Surgical and pathological outcomes included age of the patient at the time of the diagnosis, partial breast resections, mastectomies, axillary lymphadenectomies, tumor size, histological type and stage, and lymph node status. RESULTS: The study group was comprised of 3050 patients who underwent breast resection between 1992 and 2005. Quadrantectomy was the preferred surgical approach in 1759 patients (58%). Throughout the longitudinal study, the tumors measuring less than 1cm increased from 13.4% to 15.4%; the number of tumors diagnosed at stage I increased from 44.1% to 56.8%; the most frequent histological type was ductal carcinoma; the number of ductal carcinomas in situ (DCIS) increased from 4% to 6%; and the incidence of lymphadenectomies decreased from 71.6% to 52.5%. Perioperative factors that correlated with the decreased size of the tumor over time were: screening, improvement of diagnostic and therapeutic techniques, and the increased operative use of sentinel lymph node biopsy (SLNB). CONCLUSIONS: There has been an evolving refinement in surgical technique and perioperative management of breast cancer patients undergoing surgical resection at the Department of Surgical Sciences, University of Insubria, Varese, Italy, during the past decades. The present longitudinal study on 3050 surgical breast cancer patients confirmed the progressive reduction of tumor size at the time of the diagnosis. Perioperative factors that correlated with the decreased tumor size over time were mammography screening, improvement of diagnostic and therapeutic techniques, and the use of SLNB. Furthermore, the study showed that the progressive reduced number of useless axillary lymphadenectomies was mainly due to the increased intraoperative use of axillary SLNB.

Two PMS2 mutations in a Turcot syndrome family with small bowel cancers.

We report the clinicopathological, genetic, and immunohistochemical characterization of an atypical Turcot syndrome (TS) family with small bowel cancer. The tumor family history of a patient with cafè-au-lait spots (CALS) and early onset adenomas, duodenal cancer, and glioblastoma was positive for colonic adenoma (mother), jejunal (maternal grandfather), lung (father), and colorectal (paternal uncle) cancers. PMS2 genetic testing identified the nonsense 1951C>T (Q643X) and the missense 161C>T (S46I) mutations. PMS2 expression was absent in the proband's duodenal cancer with high microsatellite instability. The normal cells also displayed no PMS2 expression and some degree of instability. Our findings point out the association between PMS2 and TS, and support the hypothesis that patients with a few polyps, small bowel tumors with a very early onset, glioblastoma, and CALS should be considered as a variant of hereditary nonpolyposis colorectal cancer. A recessive model of inheritance caused by compound heterozygous mutations was consistent with the observed severe clinical phenotype and has important implications for predicting cancer risk in both the proband and his relatives.

Histopathology, hormone products, and clinicopathological profile of endocrine tumors of the upper small intestine: A study of 44 cases.

Forty-two duodenal and 3 upper jejunum tumors from 44 patients were investigated. All tumors were tested immunohistochemically for gastroenteropancreatic hormones and general endocrine cell markers. Twenty-eight of the 45 tumors (62%) proved to be gastrin cell tumors, with (12 cases) or without (16 cases) associated Zollinger-Ellison syndrome. Zollinger-Ellison syndrome was part of type 1 multiple endocrine neoplasia syndrome in 3 cases. Twenty-three of the 28 gastrin cell tumors (82%) were from proximal duodenum, 2 were from the second part of the duodenum, and 3 were from the upper jejunum. Seven cases were somatostatin cell tumors, 6 of which were from the ampullary region; 5 cases were associated with biliary tract disease and 2 with associated cutaneous neurofibromatosis. Four ganglioneuromatous paragangliomas, from the ampullary region or nearby duodenum, showed somatostatin cells, coupled with pancreatic polypeptide cells in 2 cases. Two serotonin-producing argentaffin carcinoids were also identified. In addition to the main cell type, 30 tumors showed one or more, usually minor, cell populations producing somatostatin, serotonin, cholecystokinin, pancreatic polypeptide, insulin, neurotensin, or the alpha chain of human chorionic gonadotropin. Only 3 tumors lacked hormone immunoreactivity. Some correlation has been noted between histological structure and hormone content of tumor cells, with prevalence of broad gyriform trabeculae and vascular pseudorosettes among gastrin cell tumors, tubuloacinar patterns among somatostatin cell tumors, thin parallel trabeculae among PP cell growths, and a solid nest pattern among argentaffin carcinoids. Deep infiltration of the intestinal wall was observed in 22 tumors, 6 of which also had metastases to local lymph nodes. All metastatic cases were among ZES tumors or ampullary somatostatin cell tumors. Ganglioneuromatous paragangliomas and nonfunctioning gastrin cell tumors had essentially benign behavior, even when involving deep strata of the intestinal wall. Post operative follow-up study of 36 cases, including all metastatic tumors, showed no evidence of tumor-related death or progressive tumor disease.