Friedrich Prall

Tumour budding in colorectal carcinoma

The term tumour budding denotes that at the invasion front of colorectal adenocarcinomas tumour cells, singly or in small aggregates, become detached from the neoplastic glands. This morphological feature is increasingly being recognized as a strong and robust adverse prognostic factor. Biologically, tumour budding is closely related to the epithelial–mesenchymal transition. In this review the morphological features of tumour budding are discussed, as observed by the surgical pathologist reporting colorectal carcinoma resection specimens. The morphological features are put into context with the rapidly expanding knowledge of the epithelial–mesenchymal transition in general, and the molecular pathology of colorectal carcinoma in particular. Finally, a systematic analysis of the relevant published clinicopathological studies emphasizes the potential of tumour budding as a prognostic factor for routine surgical pathology.

Tumour budding as prognostic factor in stage I/II colorectal carcinoma

Aims : The term tumour ‘budding’ has been coined for the detachment of tumour cells from the neoplastic glands of adenocarcinomas and is presumed to be an early step in the metastatic process. A limited number of studies have shown budding to be an adverse prognostic factor.

Postoperative Chemotherapy May Not Be Necessary for Patients With ypN0-Category After Neoadjuvant Chemoradiotherapy of Rectal Cancer

PurposeAfter neoadjuvant radiochemotherapy and surgery, there is no general agreement about whether postoperative chemotherapy is necessary. With the help of clinical and pathohistologic data, prognostic factors were determined as a basis for the decision to spare a patient additional chemotherapy or to urgently recommend it.ResultsNinety-five patients treated with neoadjuvant 5-fluorouracil-based radiochemotherapy (November 4, 1997 and June 15, 2004) without distant metastases and an R0 (microscopically complete) resection were evaluated. Adjuvant chemotherapy (5-fluorouracil or 5-fluorouracil/folinic acid) was given to 65 of 95 patients (68.4 percent). The disease-free survival rate after 36 months was chosen as the target parameter (median follow-up, 36 months).MethodsThe five-year survival rate for all patients was 80.3 ± 5.6 percent; the five-year disease-free survival was 78.1 ± 5.1 percent; the five-year local control rate was 94.2 ± 5.1 percent. In the univariate and multivariate analysis of the disease-free survival, the pathohistologic lymph node status after radiochemotherapy (ypN) was the only significant prognostic parameter. Disease-free survival (36 months) for patients without lymph node metastases (ypN0) was excellent, independent of whether they had received postoperative chemotherapy (n = 43; 87.5 ± 6.0 percent) or not (n = 29; 87.7 ± 6.7 percent). Patients with ypN2 status have, despite chemotherapy, a poor disease-free survival at 30 ± 17.6 percent after 36 months.ConclusionsThese retrospective data suggest that, for some patients, postoperative chemotherapy can be spared. For patients with ypN2 status, an intensification of the postoperative chemotherapy should be considered. Further evaluation in prospective studies is urgently recommended.

R1 resection in pancreatic cancer has significant impact on long-term outcome in standardized pathology modified for routine use

BACKGROUND The quality of a histopathologic workup after oncologic resection of pancreatic malignancies has changed the central role of surgery substantially for radical tumor clearance over the past years. The development of standardized protocols for pathologic workup increased the rate of R1 resections from around 20% up to 80%. In the present study, we investigated the incidence of R1 and its impact on survival after oncologic pancreatic resections using a standardized pathologic routine protocol. PATIENTS AND METHODS We performed 265 pancreatic resections from September 2003 to September 2010. Among 128 patients with malignant neoplasms, histology revealed ductal pancreatic adenocarcinoma in 97, ampullary cancer in 10, and distal bile duct cancer in 21 patients. Resected specimens were analyzed according to this improved standardized pathology protocol introduced in 2000. Follow-up data on overall and cancer-related survival, presence and site of tumor recurrence, and chemotherapy were obtained from 120 patients. RESULTS Pancreatic resection comprised a pylorus-preserving or classical pancreaticoduodenectomy in 112, a distal pancreatectomy in 8, and a total pancreatectomy in 7 patients. In the overall series, 56 (44%) were classified R1 resections and 68 (43%) R0 resections, 3 patients with R2 resections were excluded, leaving 125 patients for analysis. In pancreatic adenocarcinoma, the rate of R1 was 51% (48/94). R1 resection involved most frequently the circumferential margin in 86% (48/125) of the total group and in 92% (44/48) in pancreatic cancer. Follow-up was performed after a median of 17 months (range, 1-85) postoperatively. Cancer-related death rate in R0 and R1-resected patients was 60% and 83% (P < .02) in all cancers (n = 117) and 66% and 80% in patients with pancreatic adenocarcinoma (n = 88). Median tumor-related survival in R0 and R1 resections was 22 (range, 4-85) vs 14 months (range, 2-48) in all cancers (P < .002), and 19 (range, 4-85) vs 14 months (range, 2-48) in pancreatic adenocarcinoma (P < .04). Kaplan-Meier survival analysis revealed a survival benefit after R0 resection in both all cancers (P = .002) and pancreatic adenocarcinoma (P < .02). The pattern of tumor recurrence had a greater rate of regional metastases in the R1 group (P < .05). CONCLUSION Our 51% rate of R1 resections in ductal pancreatic carcinoma indicates a high quality standard of pathologic evaluation. The vast majority of R1 margins are located at the retroperitoneal dissection surface. Standardization of histopathologic analysis has a clinically relevant impact on survival after oncologic resection of pancreatic cancer and can be achieved by less extensive protocols.

Microvessel densities and microvascular architecture in colorectal carcinomas and their liver metastases: significant correlation of high microvessel densities with better survival.

Aims:  Microvessel densities in cancers have been shown to be a prognostic factor for some types of cancer. For colorectal cancer, however, the situation is far from clear.

Expression of Connexin26 in Islets of Langerhans Is Associated With Impaired Glucose Tolerance in Patients With Pancreatic Adenocarcinoma

Objectives: Impairment of glucose tolerance is one of the leading clinical presentations in patients with pancreatic carcinoma. The mechanism of disturbed glucose metabolism, however, is still under debate. Using microarray technology, key mechanisms of deregulated molecular functions of cancer cell–specific mRNAs and tumor-induced mRNAs in peritumorous tissue should be identified in pancreatic ductal adenocarcinoma (PDAC) by comparison to chronic pancreatitis and normal pancreas. Methods: Forty-three mRNAs were abundant in tissue specimens of patients operated due to pancreatic carcinoma but absent or of low abundance in chronic pancreatitis and normal pancreas. One of these mRNAs encodes the gap junction protein connexin26, known as a tumor suppressor, which was 10.8- and 6.9-fold more abundant in pancreatic carcinoma than in normal pancreas and chronic pancreatitis, respectively. Quantitative RT-PCR was performed for connexin26, with mRNA being expressed 26.7- and 2.9-fold more than in normal pancreas (n = 6), in pancreatic carcinoma (n = 7), and chronic pancreatitis (n = 8), respectively. Results: By immunohistochemistry, connexin26 was predominantly localized to the islets in the vicinity of the pancreatic carcinoma tissue. Control sections of tissue with chronic pancreatitis and normal pancreas show connexin26 expression in the islets as well. Interestingly, the level of mRNA abundance (fold over normal pancreas) in RT-PCR correlates (r = 0.62) with the 2h value of the pre-operative oral glucose tolerance test of these patients. Conclusion: Whether overexpressed connexin26 in pancreatic cancer is a cause of impaired glucose tolerance remains to be elucidated in further experimental studies.

Hemophagocytic lymphohistiocytosis and Kawasaki disease: Combined manifestation and differential diagnosis

Both hemophagocytic lymphohistiocytosis (HLH) and Kawasaki disease (KD) are diagnosed in patients with prolonged resistant fever by using a scoring system. Concurrent manifestation of both conditions has been reported previously. We describe an infant of 7 weeks whose condition fulfilled the criteria of HLH, but who, after clinical response to treatment, suddenly died from a myocardial infarction at 11 weeks. Post‐mortem examination revealed a previously unknown coronary arteritis typical for KD. Since it is difficult to distinguish between KD and HLH, both diseases should be considered in young children with overlapping symptoms. Repeated echocardiograms may be helpful in these cases. Pediatr Blood Cancer 2009;53:493–495.

Expression profiling of colorectal carcinomas using tissue microarrays: cell cycle regulatory proteins p21, p27, and p53 as immunohistochemical prognostic markers in univariate and multivariate analysis.

With the rapidly growing understanding of tumor biology, molecular staging of cancer is expected to improve prognostication. This would be particularly important for cancers amenable to adjuvant treatment, such as colorectal carcinomas. To generate data for this, the tissue microarray technique may prove useful. Tissue microarrays were constructed with triplicate cores (0.6 mm diameter) from the invasive margins of a consecutive single-institution series of 184 colorectal carcinomas. Immunostaining for p53, p21, p27, E-cadherin, and β-catenin was scored. Tumor cell proliferation was assessed by mitotic indices and Ki-67 labeling, apoptosis by quantification of apoptotic bodies. Reduced nuclear immunostaining for p21 (<10%) and p27 (≤50%) and reduced membranous expression of E-cadherin were significantly associated with a poorer clinical course by univariate analysis. β-catenin immunostaining had no prognostic impact. Mitotic and apoptotic indices as well as Ki-67 labeling below the median were indicators of poor prognosis. Complete absence of p53 nuclear staining was a significant adverse prognostic factor. By Cox regression, p53 = 0%, p53 = 0%, in combination with p27 ≤50%, the mitotic index and the combined mitotic and apoptotic index added prognostic information to UICC stage. The authors found that growth pattern, lymphohistiocytic response, lymphatic permeation, and venous spread, too, each was a strong prognosticator in addition to UICC stage. The results support that tissue microarrays are a useful tool for screening immunohistochemical markers for prognostic use. An immunopanel of p21, p27, and p53 could be useful for prognostication in colorectal carcinoma in addition to UICC stage.

PHENOTYPES OF INVASION IN SPORADIC COLORECTAL CARCINOMAS RELATED TO ABERRATIONS OF THE ADENOMATOUS POLYPOSIS COLI (APC ) GENE

Aims:  To determine whether the dissociation of tumour cells from neoplastic glands in colorectal carcinomas is caused by disruption of the wnt‐signalling pathway and whether the adenomatous polyposis coli (APC) protein is implicated in this.

Ex-vivo Clonally Expanded B Lymphocytes Infiltrating Colorectal Carcinoma Are of Mature Immunophenotype and Produce Functional IgG

Background Tumor infiltrating B cells (TiBc) have not yet been investigated in detail. This may at least in part be due to technical difficulties. Here we describe a straightforward and reproducible method to isolate and culture TiBc from primary colorectal carcinomas (CRC). Methods/Results TiBc cultures were generated by Epstein-Barr virus (EBV) immortalization. With this method, monoclonal TiBc cultures were obtained for 14/19 CRCs. As assessed by flow cytometry and ELISA, TiBc showed an activated immunophenotype (CD23+, CD80+) and produced immunoglobulin (Ig; IgG secretion in 55% of the cultures). In functional in vitro analysis, most of the IgGs specifically bound to allogeneic CRC target cells. These data suggest that TiBc are antigen-experienced and thus may exhibit functionality in situ. Additionally, mini-cultures generated from 12 further CRCs revealed TiBc outgrowth exclusively in the presence of EBV. Conclusion In summary, this simple method provides a cellular tool and our data set the stage for analysing the bivalent role of TiBc; being antigen-presenting cells on the one hand and tumor-specific antibody producers on the other. Additionally, the generation of long-term TiBc cultures and their monoclonal Ig may serve to identify novel tumor-specific antigens.