L. Füzesi

Prognostic Significance of Tumor Regression After Preoperative Chemoradiotherapy for Rectal Cancer

PURPOSE We assessed the impact of tumor regression grading (TRG) and its value in correlation to established prognostic factors in a cohort of rectal carcinoma patients treated by preoperative chemoradiotherapy (CRT). PATIENTS AND METHODS TRG was evaluated on surgical specimens of 385 patients treated within the preoperative CRT arm of the CAO/ARO/AIO-94 trial: 50.4 Gy was delivered, fluorouracil was given in the first and fifth week, and surgery was performed 6 weeks thereafter. TRG was determined by the amount of viable tumor versus fibrosis, ranging from TRG 4 when no viable tumor cells were detected, to TRG 0 when fibrosis was completely absent. TRG 3 was defined as regression more than 50% with fibrosis outgrowing the tumor mass, TRG 2 was defined as regression less than 50%, and TRG 1 was defined basically as a morphologically unaltered tumor mass. We performed an initially unplanned, hypothesis-generating analysis with respect to the prognostic value of this TRG system. RESULTS TRG 4, 3, 2, 1, 0 was found in 10.4%, 52.2%, 13.8%, 15.3%, and 8.3% of the resected specimens, respectively. Five-year disease-free survival (DFS) after CRT and curative resection was 86% for TRG 4, 75% for grouped TRG 2 + 3, and 63% for grouped TRG 0 + 1 (P = .006). On multivariate analysis, the pathologic T category and the nodal status after CRT were the most important independent prognostic factors for DFS. CONCLUSION In this exploratory analysis, complete (TRG 4) and intermediate pathologic response (TRG 2 + 3) suggested improved DFS after preoperative CRT. TRG assessment should be implemented in pathologic evaluation and prospectively validated in further studies.

Effectiveness of Gene Expression Profiling for Response Prediction of Rectal Adenocarcinomas to Preoperative Chemoradiotherapy

PURPOSE There is a wide spectrum of tumor responsiveness of rectal adenocarcinomas to preoperative chemoradiotherapy ranging from complete response to complete resistance. This study aimed to investigate whether parallel gene expression profiling of the primary tumor can contribute to stratification of patients into groups of responders or nonresponders. PATIENTS AND METHODS Pretherapeutic biopsies from 30 locally advanced rectal carcinomas were analyzed for gene expression signatures using microarrays. All patients were participants of a phase III clinical trial (CAO/ARO/AIO-94, German Rectal Cancer Trial) and were randomized to receive a preoperative combined-modality therapy including fluorouracil and radiation. Class comparison was used to identify a set of genes that were differentially expressed between responders and nonresponders as measured by T level downsizing and histopathologic tumor regression grading. RESULTS In an initial set of 23 patients, responders and nonresponders showed significantly different expression levels for 54 genes (P < .001). The ability to predict response to therapy using gene expression profiles was rigorously evaluated using leave-one-out cross-validation. Tumor behavior was correctly predicted in 83% of patients (P = .02). Sensitivity (correct prediction of response) was 78%, and specificity (correct prediction of nonresponse) was 86%, with a positive and negative predictive value of 78% and 86%, respectively. CONCLUSION Our results suggest that pretherapeutic gene expression profiling may assist in response prediction of rectal adenocarcinomas to preoperative chemoradiotherapy. The implementation of gene expression profiles for treatment stratification and clinical management of cancer patients requires validation in large, independent studies, which are now warranted.

Prognostic factors influencing surgical management and outcome of gastrointestinal stromal tumours

The purpose of this study was to review surgical experience with gastrointestinal stromal tumours (GISTs) at a single tertiary university hospital, and to identify morphological and genetic prognostic markers of tumour progression.

Surgical cure for early rectal carcinoma and large adenoma: transanal endoscopic microsurgery (using ultrasound or electrosurgery) compared to conventional local and radical resection.

Abstract Background and aims. The minimally invasive technique of transanal endoscopic microsurgery (TEM) combines the benefits of local resections, a low complication rate and high patient comfort, with low recurrence rate and excellent survival rate after radical surgery (RS). The use of an ultrasonically activated scalpel rather than electrosurgery further improves the results of TEM. Patients and methods. A retrospective study was performed of 182 operations on 162 patients with early rectal carcinoma (pT1, G1/2) or adenoma to compare the outcome following four different kinds of surgical resection techniques: RS (anterior or abdominoperineal resection; n=27), conventional transanal resection using Parks retractor (TP; n=76), transanal endoscopic microsurgery (TEM) with electrosurgery (TEM-ES; n=45), and TEM with UltraCision (TEM-UC; n=34). One-third of the patients with RS (33%) received either a colostomy or a protective loop-ileostomy. Results. Operation time with TEM-UC was significantly shorter than with TEM-ES or RS. Hospitalization was significantly longer with RS than for TEM or TP. Complication rate with TEM was significantly lower than with RS. Recurrence rate with RS and TEM was significantly lower than with TP, with a trend to TEM-UC being better than TEM-ES. Mortality rate was 3.7% with RS and 0 with TP and TEM. The 2-year survival rate was 96.3% with RS and 100% each with TP and TEM. Conclusion. TEM using UC seems to be the technique of choice. TP leads to an unacceptable recurrence rate, and RS results in a higher incidence of complication and impairment of life quality.

Collecting duct carcinoma: cytogenetic characterization

Most renal cell carcinomas are assigned to either the papillary or clear cell, non‐papillary type by morphological and cytogenetic criteria. In rare cases, papillary carcinomas of the kidney have been classified as collecting duct carcinoma because of their medullary localization and the associated hyperplastic and dysplastic epithelial lesions of collecting ducts in the vicinity of the tumour. In this first report on the cytogenetics of collecting duct carcinoma, we describe unique and consistent chromosomal aberrations in three cases. Each of the three tumours showed monosomies for chromosomes 1, 6, 14, 15, and 22. This suggests that collecting duct carcinoma is the third type of kidney tumour whose definition is based on morphological as well as on cytogenetic criteria. It appears to be cytogenetically different from the cortical papillary kidney tumour which exhibits trisomy 17 and tri‐ or tetrasomy 7, and from the non‐papillary renal cell carcinoma which characteristically presents deletion of the short arm of chromosome 3.

Surgical Management After Neoadjuvant Imatinib Therapy in Gastrointestinal Stromal Tumours (GISTs) with Respect to Imatinib Resistance Caused by Secondary KIT Mutations

BackgroundIn metastasized GISTs, resistance to imatinib after initial tumour response has been associated with observation of secondary mutations in the activation loop of KIT. The aim of the current study was to evaluate the tumour response and observance of secondary KIT mutations in a case of GIST undergoing neoadjuvant imatinib therapy.MethodsWe report on a case of an initially unresectable gastric GIST with curative resection after 10 months of neoadjuvant imatinib therapy. Mutation analysis of KIT was performed on a pretherapeutic biopsy specimen, as well as on the resected tumour specimen.ResultsThe pretherapeutic biopsy revealed cKit positive tumour cells with mutation of KIT exon 11 Del 560–576. The remaining tumour mass after neoadjuvant imatinib therapy almost exclusively consisted of hypocellular myxohyalinale stroma with rare microfoci of cKit positive tumour cells. Laser microdissection of several tumour microfoci revealed two additional point mutations located in the activation loop of KIT exon 17, C809G and N822Y, each observed separately in a distinct microfocus. Neither of these two point mutations has been reported in a GIST so far.ConclusionsNeoadjuvant imatinib therapy successfully reduces tumour size in GISTs. Since resistance relevant secondary mutations of the activation loop of KIT may be observed after neoadjuvant imatinib therapy, the time elapse with preoperative imatinib therapy should be chosen as short as curative tumour resection or function sparing surgery can be carried out. The determination of the optimal time point for surgery is therefore a critical event and will be discussed.

An oncogenetic tree model in gastrointestinal stromal tumours (GISTs) identifies different pathways of cytogenetic evolution with prognostic implications

To model the cytogenetic evolution in gastrointestinal stromal tumour (GIST), an oncogenetic tree model was reconstructed using comparative genomic hybridization data from 203 primary GISTs (116 gastric and 87 intestinal GISTs, including 151 newly analysed cases), with follow‐up available in 173 cases (mean 40 months; maximum 133 months). The oncogenetic tree model identified three major cytogenetic pathways: one initiated by − 14q, one by − 1p, and another by − 22q. The − 14q pathway mainly characterized gastric tumours with predominantly stable karyotypes and more favourable clinical course. On the other hand, the − 1p pathway was more characteristic of intestinal GISTs, with an increased capacity for cytogenetic complexity and more aggressive clinical course. Loss of 22q, more closely associated with − 1p than − 14q, appeared to initiate the critical transition to an unfavourable cytogenetic subpathway. This − 22q pathway included accumulation of + 8q, − 9p, and − 9q, which could all predict disease‐free survival in addition to tumour site. Thus, insights into the cytogenetic evolution obtained from oncogenetic tree models may eventually help to gain a better understanding of the heterogeneous site‐dependent biological behaviour of GISTs. Copyright

Prognostic role of E2F1 and members of the CDKN2A network in gastrointestinal stromal tumors.

Purpose: The aim of the current study was to examine the prognostic relevance of the CDKN2A tumor suppressor pathway in gastrointestinal stromal tumors (GIST). Experimental Design: We determined the mRNA expression of p1INK4A, p14ARF, CDK4, RB1, MDM2, TP53, and E2F1 by quantitative reverse transcription-PCR in 38 cases of GISTs and correlated the findings with clinicopathologic factors, including mutation analysis of KIT and PDGFRA. Results: The k-means cluster analysis yielded three prognostic subgroups of GISTs with distinct mRNA expression patterns of the CDKN2A pathway. GISTs with low mRNA expression of the CDKN2A transcripts p16INK4A and p14ARF but high mRNA expression of CDK4, RB1, MDM2, TP53, and E2F1 were associated with aggressive clinical behavior and unfavorable prognosis, whereas GISTs with a low mRNA expression of CDK4, RB1, MDM2, TP53, and E2F1 were not. GISTs with a moderate to high mRNA expression of all examined genes also seemed to be associated with unfavorable prognosis. Regarding mutation analysis, we found significant differences in the KIT/PDGFRA genotype among the three clusters. Univariate analysis revealed high expression of E2F1 to be associated with mitotic count, proliferation rate, KIT mutation, and aggressive clinical behavior. These findings on mRNA level could be confirmed by immunohistochemistry. Conclusion: Our findings implicate differential regulation schemes of the CDKN2A tumor suppressor pathway converging to up-regulation of E2F1 as the critical link to increased cell proliferation and adverse prognosis of GISTs.

Use of CpG island microarrays to identify colorectal tumors with a high degree of concurrent methylation.

We provide a comprehensive description of our microarray-based technique for the simultaneous detection of multiple CpG islands in cancer. Amplicons from tumor and control samples were pools of differentially methylated CpG island fragments hybridized to a panel of approximately 8000 CpG island tags. Data analysis identified 694 CpG island loci hypermethylated in a group of 14 colorectal tumors. The Stanford hierarchical cluster algorithm segregated the tumors into two subgroups, one of which exhibited a high level of concurrent hypermethylation while the other had little or no methylation. This is in agreement with previous observations of a CpG island methylation phenotype present in colorectal tumors. The present study demonstrates that this microarray-based technique is useful in classifying tumors according to their methylation profiles.

Peripheral nerve sheath tumors of the gastrointestinal tract: a multicenter study of 58 patients including NF1-associated gastric schwannoma and unusual morphologic variants

The frequency and morphological spectrum of gastrointestinal peripheral nerve sheath tumors (PNSTs) from consecutive case material has not been studied in the c-KIT era. We reviewed all mesenchymal gastrointestinal (GI) lesions at our departments according to current diagnostic criteria. PNSTs formed the third commonest group of mesenchymal GI tumors with a lower frequency (≤5%) compared to gastrointestinal stromal tumors (GISTs; ∼50%) and smooth muscle neoplasms (∼30%). Granular cell tumors (GCTs; n = 31) and schwannomas (n = 22) were the most common types of PNSTs encountered. Rare tumors included neurofibromatosis 1 (NF1)-associated PNSTs (n = 5) and gastric perineurioma (n = 1). Thirteen schwannomas (including also some recent cases) were initially diagnosed as GIST, leiomyoma, or neurofibroma. Unusual histological variants included sigmoid GCT with prominent lipomatous component (n = 1), reticular–microcystic schwannoma of small (n = 1) and large (n = 1) bowel, NF1-associated gastric schwannoma (the first case to date), and psammomatous melanotic colonic schwannoma unrelated to Carney complex (n = 1). PNSTs coexisted with GIST in four patients (three had definite NF1). In conclusion, PNSTs of the GI tract are rare uniformly benign neoplasms that may show schwannian, perineurial, fibroblastic, or mixed differentiation. Most of them (92%) occurred sporadically unassociated with NF1 or NF2. Gastrointestinal PNSTs are still underrecognized by general pathologists. Awareness of their diverse morphology will help to avoid confusing them with smooth muscle neoplasms and GIST that they may closely mimic.