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The tumor-node-metastasis (TNM) classification describes the anatomic extent of cancer. The ability to separately classify the individual T, N, and M elements and then group them into stages differs from other cancer staging classifications, which are primarily concerned with summarized groups. The objectives of the TNM system are to aid clinicians and investigators in planning treatment, assessing prognosis, stratifying patients for therapeutic studies, evaluating the results of treatment, and facilitating communication. The most important challenge facing TNM is how to interface the current taxonomy with the numerous nonanatomic prognostic factors currently in use or under study. As nonanatomic prognostic factors become widely used, TNM will remain a solid foundation on which to build prognostic classifications. There is, however, a risk that this system will be corrupted by a variety of irrelevant prognostic data. An anatomic extent of disease classification is needed to provide a standard against which to measure the importance of nonanatomic factors. Methods are needed to express overall prognosis without losing the vital anatomic content of TNM. These methods should be able to integrate multiple prognostic factors, including TNM, yet permit TNM to remain intact and distinct. [PUBLICATION ABSTRACT]

The inflammatory fibroid polyp is a rare benign lesion occurring throughout the digestive tract. It usually forms a solitary mass, characterized by a proliferation of fibrovascular tissue infiltrated by a variable number of inflammatory cells. The etiology of this lesion is unknown and conflicting histogenetic theories have been proposed. Recently, mutations in platelet-derived growth factor receptor ( PDGFRA ) and PDGFRA expression were reported in gastric inflammatory fibroid polyps. In this study, PDGFRA exons 12, 14, and 18 were screened for activating mutations in 60 small intestinal inflammatory fibroid polyps. In addition, the PDGFRA expression was evaluated immunohistochemically. Mutations in PDGFRA were identified in 33 of 60 (55%) cases, whereas 95% expressed PDGFRA. There were 26 deletions, three deletion–insertions, duplication, and single nucleotide substitution in exon 12, and a single nucleotide substitution and deletion in exon 18. The majority ( n =23) of exon 12 deletions were 1837_1851del leading to S566_E571delinsR. However, 1835_1852delinsCGC leading to the same S566_E571delinsR, were found in two tumors. Three inflammatory fibroid polyps had 1836_1850del leading to S566_E571delinsK. A complex deletion–insertion affecting a similar region (1837_1856delinsGATTGATGATC) and leading to S566_I573delinsRIDDL was identified once. In addition, duplication and single nucleotide substitution were found 5′ to the common inflammatory fibroid polyp mutational ‘hot spot’. These mutations consist of 1808_1828dup leading to I557_E563dup, and 1821T>A resulting in 561V>D substitution. A 2664A>T and 2663_2674del leading to 842D>V and D842_H845del, respectively, were identified in exon 18. Similar gain-of-function PDGFRA mutations reported in gastrointestinal stromal tumors have been considered to be a driving pathogenetic force. This study showed consistent expression and common mutational activation of PDGFRA in small intestinal inflammatory fibroid polyps as in their gastric counterparts, and these lesions should be considered PDGFRA-driven benign neoplasms. We also suggest that these polyps may develop from earlier described PDGFRA-positive mesenchymal cells distributed along the villus membrane after oncogenic PDGFRA activation.

Gastrointestinal stromal tumors (GISTs) are KIT expressing spindle cell, epithelioid and rarely pleomorphic mesenchymal tumors. The majority of GISTs show gain-of-function KIT mutations. However, GISTs without KIT mutations and GISTs with weak or lack of immunohistochemical KIT expression have also been reported. Recently, gain-of-function mutations in exon 18 (activation loop) and exon 12 (juxtamembrane domain) of the PDGFRA were identified in such tumors. The purpose of this study was to test the hypothesis that PDGFRA mutation may define a specific clinicopathologic subgroup of GISTs. A total of 447 KIT exon 11 (juxtamembrane domain) mutation-negative GISTs were studied. DNA samples were obtained from formaldehyde-fixed paraffin-embedded tissues. Genomic sequences of PDGFRA exons 18 and 12 were evaluated for the mutations by PCR amplification and direct sequencing. PDGFRA exon 18 mutations were identified in 122 of 346 (35.3%) gastric GISTs and two of 75 (2.7%) intestinal GISTs. A great majority of these mutations represented simple T to A missense mutation at the codon 842 leading to substitution of the valine for aspartic acid (D842 V). However, in-frame deletions and deletions with point mutations clustering between codons 841–847 were found in approximately 23% of all exon 18 mutations. Mutations in PDGFRA exon 12 were found only in 10 of 170 (5.8%) gastric and one of 54 (1.9%) intestinal GISTs negative for KIT exon 11 and PDGFRA exon 18 mutations. There were seven substitutions of aspartic acid for valine at codon 561 (V561D) and four in-frame deletions with point mutations clustering between codons 566 and 571. The majority of GISTs with PDGFRA mutations had pure or predominant epithelioid morphology. Low mitotic activity, ≤5 mitoses/50HPF was detected in 81% of analyzed GISTs including larger, >5 cm tumors. Based on long-term follow-up (average 135 months), a majority (83.5%) of GISTs with PDGFRA mutations followed a benign course.

Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract, typically express the KIT protein. Activating mutations in the juxtamembrane domain (exon 11) of the c-kit gene have been shown in a subset of GISTs. These mutations lead into ligand-independent activation of the tyrosine kinase of c-kit, and have a transforming effect in vitro. Several groups have studied the clinical implication of the c-kit mutation status of exon 11 in GISTs and a possible relationship between c-kit mutations and malignant behavior has been established. Recently, a 1530ins6 mutation in exon 9 and missense mutations, 1945A>G in exon 13 of the c-kit gene were reported. The frequency and clinical importance of these findings are unknown. In this study we evaluated 200 GISTs for the presence of mutations in exons 9 and 13 of c-kit. Six cases revealed 1530ins6 mutation in exon 9 and two cases 1945A>G mutation in exon 13. All tumors with mutations in exon 9 and 13 lacked mutations in exon 11 of c-kit. None of the analyzed tumors had more than one type of c-kit mutation. All but one of the eight tumors with mutations in exon 9 or 13 of the c-kit gene were histologically and clinically malignant. All four of six cases with exon 9 mutation of which location of primary tumor was known, were small intestinal, suggesting that this type of mutation could preferentially occur in small intestinal tumors. Exon 9 and 13 mutations seem to be rare, and they cover only a small portion (8%) of the balance of GISTs that do not have mutations in exon 11 of c-kit. This finding indicates that other genetic alterations may activate c-kit in GISTs, or that KIT is not activated by mutations in all cases.

As a result of major recent advances in understanding the biology of gastrointestinal stromal tumors (GIST), specifically recognition of the central role of activating KIT mutations and associated KIT protein expression in these lesions, and thedevelop-ment of novel and effective therapy for GISTs using thereceptor tyrosine kinase in hibitor STI-571, these tumors have become the focus of considerable attention among pathologists, clinicians, and patients. Stromal/mesenchymal tumors of the gastrointestinal tract have long been a sourceof confusion and controversy with regard to classification, line(s) of differentiation, and prognostication. Characterization of the KIT pathway and its phenotypic implications has helped to resolve some but not all of these issues. Given the now critical role of accurate and reproducible pathologic diagnosis in ensuring appropriate treatment for patients with GIST, the National Institutes of Health (NIH) convened a GIST workshop in April 2001 with the goal of developing a consensus approach to diagnosis and morphologic prognostication. Key elements of the consensus, as described herein, are the defining role of KIT immunopositivity indiagnosis and a proposed scheme for estimating metastatic riskin these lesions, based on tumor size and mitotic count, recognizing that it is probably unwise to use the definitive term benign for any GIST, at least at the present time.

Most mesenchymal tumors of the gastrointestinal tract are currently classified as specific gastrointestinal stromal tumors. However, true leiomyomas are more common in the esophagus, and they have been occasionally noted in the colon and rectum, but the small number of reported cases does not allow for clinicopathologic profiling. This study was undertaken to characterize 88 tumors of the muscularis mucosae of the colon and rectum. Seventy tumors were obtained form the files of AFIP and 18 cases from the Department of Pathology of the Haartman Institute of the University of Helsinki. The lesions, except one, were removed by snare polypectomy as incidental lesions at cancer or polyp surveillance; one small tumor was an incidental finding in the rectal resection specimen. The tumors had a significant male predominance in both institutions (overall 2.4:1). They occurred in age range of 38 to 85 years (median 62 years). The lesions were typically small (range 1 to 22 mm, median 4 mm) and located predominantly in the rectum and sigmoid (72%). All tumors were composed of well-differentiated, eosinophilic smooth muscle cells that were seen immediately beneath the mucosa obliterating the muscularis mucosae layer and merging with it. Two tumors had significant atypia (“symplastic leiomyoma”); mitotic activity was seen in one of these tumors, but not in others. The lesional cells were uniformly positive for smooth muscle actin and desmin and negative for CD34, CD117 and S100-protein, based on immunohistochemical studies on 20 to 24 cases with each marker. No gastrointestinal stromal tumors were identified among the tumors of muscularis mucosae, and no CD117-positive cells, except mast cells, were seen in the muscularis mucosae layer. None of the patients had morbidity related to the tumor. Based on follow-up data on 29 patients, leiomyomas of muscularis mucosae are benign. They should be separated from gastrointestinal stromal tumors that have a clinicopathologic spectrum including frequent disease-related mortality. Snare polypectomy is an adequate treatment, but ensuring the complete removal and follow-up are necessary precautions for tumors with any atypia or mitotic activity.

The aim of our study was to evaluate the quality of histo- and cytomorphological features of PAXgene-fixed specimens and their suitability for histomorphological classification in comparison to standard formalin fixation. Fifteen colon cancer tissues were collected, divided into two mirrored samples and either formalin fixed (FFPE) or PAXgene fixed (PFPE) before paraffin embedding. HE- and PAS-stained sections were scanned and evaluated in a blinded, randomised ring trial by 20 pathologists from Europe and the USA using virtual microscopy. The pathologists evaluated histological grading, histological subtype, presence of adenoma, presence of lymphovascular invasion, quality of histomorphology and quality of nuclear features. Statistical analysis revealed that the reproducibility with regard to grading between both fixation methods was rather satisfactory (weighted kappa statistic ( k w ) = 0.73 (95 % confidence interval (CI), 0.41–0.94)), with a higher agreement between the reference evaluation and the PFPE samples ( k w  = 0.86 (95 % CI, 0.67–1.00)). Independent from preservation method, inter-observer reproducibility was not completely satisfactory ( k w  = 0.60). Histomorphological quality parameters were scored equal or better for PFPE than for FFPE samples. For example, overall quality and nuclear features, especially the detection of mitosis, were judged significantly better for PFPE cases. By contrast, significant retraction artefacts were observed more frequently in PFPE samples. In conclusion, our findings suggest that the PAXgene Tissue System leads to excellent preservation of histomorphology and nuclear features of colon cancer tissue and allows routine morphological diagnosis.

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of disease. Samples of different body regions from hundreds of human donors are used to study how genetic variation influences gene expression levels in 44 disease-relevant tissues. Genetic effects on gene expression across human tissues The GTEx (Genotype-Tissue Expression) Consortium has established a reference catalogue and associated tissue biobank for gene-expression levels across individuals for diverse tissues of the human body, with a broad sampling of normal, non-diseased human tissues from postmortem donors. The consortium now presents the deepest survey of gene expression across multiple tissues and individuals to date, encompassing 7,051 samples from 449 donors across 44 human tissues. Barbara Engelhardt and colleagues characterize the relationship between genetic variation and gene expression, and find that most genes are regulated by genetic variation near to the affected gene. In accompanying GTEx studies, Alexis Battle, Stephen Montgomery and colleagues examine the effect of rare genetic variation on gene expression across human tissues, Daniel MacArthur and colleagues systematically survey the landscape of X chromosome inactivation in human tissues, and Jin Billy Li and colleagues provide a comprehensive cross-species analysis of adenosine-to-inosine RNA editing in mammals. In an accompanying News & Views, Michelle Ward and Yoav Gilad put the latest results in context and discuss how these findings are helping to crack the regulatory code of the human genome.

A significant percentage of conventional schwannomas, whether sporadic or associated with neurofibromatosis 2 (NF2), show loss of heterozygosity (LOH) at NF2 and/or NF2 inactivating mutations. Similarly, a significant percentage of neurofibromas show LOH at NF1 and/or NF1 inactivating mutations. There are no molecular genetic data on gastrointestinal (GI) nerve sheath tumors traditionally diagnosed as benign schwannomas, rare neoplasms possibly derived from the schwannian elements dispersed between the smooth muscle fibers. In this study, we analyzed 1 esophageal, 16 gastric, 1 small intestinal, and 2 colonic tumors of such type. Histologically, all were spindle cell neoplasms positive for S-100 protein, vimentin, and glial fibrillary acidic protein, and negative for smooth muscle markers, KIT, CD34, neurofilament proteins, and HMB45. Focal or extensive lymphoid cuffs, often containing germinal centers, were present in most cases. None of the patients had NF2 or NF1. Chromosomes 22 and 17, particularly NF2 and NF1 loci, were analyzed for LOH in all GI tumors and for comparative purposes in 10 conventional schwannomas. LOH on 22q was seen in 40% of conventional schwannomas but in only 5% (1 of 20) of GI schwannomas. PCR amplification followed by direct sequencing of PCR products failed to identify mutations in NF2 coding sequences (exons 1-15) in 13 cases, including a case with LOH on 22q. Losses on 17q involving NF1 were seen in both GI and conventional schwannomas in 50% and 33% of analyzed tumors, respectively. LOH at NF1 might be one of the genetic features seen in peripheral nerve sheath tumors from different locations and should be interpreted with caution. However, lack of NF2 alterations strongly supports the hypothesis that GI schwannomas represent a morphologically and genetically distinct group of peripheral nerve sheath tumors that are different from conventional schwannomas.