David Klimstra

Neuroendocrine carcinomas of the colon and rectum.

PURPOSE: This study was designed to review experiencenwith neuroendocrine carcinomas of the colon and rectumnat a single institution, with emphasis on the pathology andnclinical characteristics of this uncommon malignancy.nMETHODS: A study group of patients was identified from anprospective colorectal service database. Pathology was reviewednand neuroendocrine tumors were classified by ansingle pathologist. Medical records were retrospectively reviewed.nRESULTS: From March 1975 to September 1998, 38npatients with neuroendocrine carcinomas were identifiednfrom the colorectal service database comprising 6495 patientsn(0.6 percent). These neuroendocrine carcinomas didnnot include carcinoid tumors. Average patient age was 57nyears (range, 29–86 years). There were 17 males (44.7 percent)nand 21 females (55.3 percent). Tumors were locatednas follows: 17 colon, 14 rectum, 6 anal canal, and 1 appendix.nThe diagnosis of neuroendocrine carcinoma was suggestednpreoperatively from tissue biopsy in 59.3 percentn(16/27) of patients evaluable. Pathology was reviewed andntumors were categorized as small cell carcinoma (n = 22) ornlarge cell neuroendocrine carcinoma (n = 16). Most tumorsn(20/25 evaluable, 80 percent) stained positive by means ofnimmunohistochemistry for neuroendocrine markers, includingnchromogranin (18/19), synaptophysin (10/15),nand/or neuron-specific enolase (14/15). Metastatic diseasenwas detected at the time of diagnosis in 69.4 percent of thenpatients (25/36). Tumors were advanced at the time of diagnosis,nwith American Joint Committee on Cancer (AJCC)nStage I (n = 6), Stage III (n = 7), and Stage IV (n = 25)ntumors. As a group, these tumors had a poor prognosis,nwith a median survival of 10.4 months. One-year, two-year,nand three-year survival was 46 percent, 26 percent, and 13npercent, respectively. There was no significant difference innsurvival based on pathologic subtypes. Median follow-upntime was 9.4 months (range, 0.6–263.7 months). CONCLUSIONS:nNeuroendocrine carcinomas of the colon and rectumnare uncommon, comprising less than 1 percent ofncolon and rectal cancers. Pathologically, these tumors arenpoorly differentiated carcinomas with distinctive cytoarchitecturalnfeatures and are often immunoreactive for markersnof neuroendocrine differentiation. The prognosis for highgradenneuroendocrine carcinomas is poor, as most patientsnhave metastatic disease at the time of diagnosis.

Molecular Markers Help Characterize Neuroendocrine Lung Tumors

BACKGROUNDnThe terms large cell and mixed small-large cell neuroendocrine carcinoma (LCNC, MNC) have been proposed to describe distinct types of high-grade neuroendocrine lung tumors. However, cytologic appearance and neuroendocrine immunohistochemical stains cannot uniformly distinguish these from other neuroendocrine tumors, such as typical and atypical carcinoids or small cell carcinoma, or nonendocrine lung cancers such as large cell undifferentiated carcinoma. This study sought to determine the patterns of expression in LCNC and MNC of several molecular markers often abnormally expressed in lung cancers.nnnMETHODSnPrimary lung tumors with neuroendocrine features operated on between 1984 and 1994 were reviewed and classified as typical carcinoid (TC), atypical carcinoid (AC), LCNC, MNC, and small cell lung cancer (SCLC) based on mitotic rate, extent of necrosis, and cytoarchitectural features. Immunohistochemistry was performed using antibodies MIB-1 for Ki67, pAb1801 for p53, OP-66 for Rb, 31G7 for EGFR. Staining was scored as 0 to 4+ (0 = less than 5%, 1+ = 5% to 20%, 2+ = 20% to 50%, 3+ = 50% to 80%, 4+ = more than 80%) for p53, Ki67, and EGFR; and negative, focal, or positive for Rb. Overall survival was calculated by the Kaplan-Meier method and prognostic factors compared by log rank test.nnnRESULTSnNinety-two tumors were examined: 25 TC, 7 AC, 24 LCNC, 18 MNC, 18 SCLC. The LCNC and MNC presented more frequently as stage II or III tumors (n = 28, 66%) than TC and AC (n = 5, 15%). Median survival for LCNC and MNC was 18.7 months, for SCLC 14.3 months, and has not been reached for TC and AC tumors. TC and AC tumors were uniformly characterized by low proliferative rate, absent p53, and normal Rb staining. LCNC, MNC, and SCLC showed a high proliferative rate, abnormal p53, and absent Rb staining. Overexpression of EGFR was frequent in all five tumor types.nnnCONCLUSIONSn(1) Ki67, p53, and Rb help distinguish LCNC and MNC from TC and AC. (2) Small numbers of patients preclude comparison of survival rates, but LCNC/MNC have a median survival similar to comparable early stage SCLC, and clearly worse than TC/AC. These results justify a sharp separation of high-grade neuroendocrine tumors from carcinoids, and suggest a close relationship between LCNC, MNC, and SCLC.

Colon carcinoma metastatic to the trachea : report of a case and a review of the literature

Tracheal metastases are rarely seen from colorectal carcinoma. We describe the third reported case of colorectal carcinoma metastatic to the trachea and review the current pathogenesis, diagnosis, and management of endotracheal metastases.

Quantitative CT analysis for the preoperative prediction of pathologic grade in pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (PanNETs) account for approximately 5% of all pancreatic tumors, affecting one individual per million each year.1 PanNETs are difficult to treat due to biological variability from benign to highly malignant, indolent to very aggressive. The World Health Organization classifies PanNETs into three categories based on cell proliferative rate, usually detected using the Ki67 index and cell morphology: low-grade (G1), intermediate-grade (G2) and high-grade (G3) tumors. Knowledge of grade prior to treatment would select patients for optimal therapy: G1/G2 tumors respond well to somatostatin analogs and targeted or cytotoxic drugs whereas G3 tumors would be targeted with platinum or alkylating agents.2, 3 Grade assessment is based on the pathologic examination of the surgical specimen, biopsy or ne-needle aspiration; however, heterogeneity in the proliferative index can lead to sampling errors.4 Based on studies relating qualitatively assessed shape and enhancement characteristics on CT imaging to tumor grade in PanNET,5 we propose objective classification of PanNET grade with quantitative analysis of CT images. Fifty-five patients were included in our retrospective analysis. A pathologist graded the tumors. Texture and shape-based features were extracted from CT. Random forest and naive Bayes classifiers were compared for the classification of G1/G2 and G3 PanNETs. The best area under the receiver operating characteristic curve (AUC) of 0:74 and accuracy of 71:64% was achieved with texture features. The shape-based features achieved an AUC of 0:70 and accuracy of 78:73%.

Real-Time Genomic Characterization of Metastatic Pancreatic Neuroendocrine Tumors Has Prognostic Implications and Identifies Potential Germline Actionability

PurposenWe assessed the usefulness of real-time molecular profiling through next-generation sequencing (NGS) in predicting the tumor biology of advanced pancreatic neuroendocrine tumors (panNETs) and in characterizing genomic evolution.nnnMethodsnPatients with metastatic panNETs were recruited in the routine clinical practice setting (between May 2014 and March 2017) for prospective NGS of their tumors as well as for germline analysis using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) sequencing platform. When possible, NGS was performed at multiple time points.nnnResultsnNGS was performed in 96 tumor samples from 80 patients. Somatic alterations were identified in 76 of 80 patients (95%). The most commonly altered genes were MEN1 (56%), DAXX (40%), ATRX (25%), and TSC2 (25%). Alterations could be defined in pathways that included chromatin remodeling factors, histone methyltransferases, and mammalian target of rapamycin pathway genes. Somatic loss of heterozygosity was particularly prevalent (50 of 96 samples [52%]), and the presence of loss of heterozygosity resulted in inferior overall survival (P < .01). Sequencing of pre- and post-treatment samples revealed tumor-grade progression; clonal evolution patterns were also seen (molecular resistance mechanisms and chemotherapy-associated mutagenesis). Germline genetic analysis identified clinically actionable pathogenic or likely pathogenic variants in 14 of 88 patients (16%), including mutations in high-penetrance cancer susceptibility genes (MEN1, TSC2, and VHL).nnnConclusionnA clinical NGS platform reveals pertubations of biologic pathways in metastatic panNETs that may inform prognosis and direct therapies. Repeat sequencing at disease progression reveals increasing tumor grade and genetic evolution, demonstrating that panNETs adopt a more aggressive behavior through time and therapies. In addition to frequent somatic mutations in MEN1 and TSC2, germline mutations in these same genes underlie susceptibility to panNETs and highlight the need to re-evaluate whether germline genetic analysis should be performed for all patients with panNETs.