Paulus G. Schurr

En bloc vascular resection for locally advanced pancreatic malignancies infiltrating major blood vessels: perioperative outcome and long-term survival in 136 patients.

Background:To assess in-hospital complication rates and survival duration after en bloc vascular resection (VR) for infiltration of pancreatic malignancies in major vessels. Methods:Between 1994 and 2005, 585 patients underwent potentially curative pancreatic resection without adjuvant chemotherapy. Four hundred forty-nine patients (77%) underwent standard oncologic resection (VR−), whereas 136 (23%) received VR (VR+). For calculation of in-hospital morbidity and mortality rates, all 136 patients who underwent VR were considered. In contrast, for survival analysis, only pancreatic adenocarcinoma patients (n = 100) were included. Results:One hundred twenty-eight VR+ patients underwent portal or superior mesenteric vein resection and 13 hepatic artery (HA) or superior mesenteric artery (SMA) resection. In 5 patients, synchronous VR addressing both the mesenterico-portal axis and either the HA or SMA was performed. In-hospital morbidity and mortality rates of VR− patients (39.7%/4.0%) nearly equaled that of VR+ patients (40.3%/3.7%). From the 100 patients with pancreatic adenocarcinoma, histopathology confirmed “true” vascular invasion in 77 patients. Twenty-three patients had peritumoral inflammation, mimicking tumor invasion. Median survival was 15 months (11.2–18.8) in patients with histopathologic proven vascular invasion and 16 months (14.0–17.9) in those without (P = 0.86). Two-year survival probabilities were 36% (without) versus 34% (with vascular invasion; P = 0.9). Among VR+ patients with histopathologically evidenced vascular invasion, 19 survived longer than 30 months, and 6 were still alive 5 years after surgery. Multivariate modeling identified nodal involvement (N1) and poor grading (G3) as the only predictors of decreased survival. Evidence of vascular invasion had no adverse impact on survival. Conclusion:Postoperative morbidity and mortality rates after en bloc VR are comparable with “standard” pancreatectomy procedures. Median survival of 15 months in patients with vascular invasion is superior to that of patients who undergo palliative therapy and nearly equals that of patients who are not in need for VR.

Postpancreatectomy Hemorrhage: Diagnosis and Treatment: An Analysis in 1669 Consecutive Pancreatic Resections

Background:To analyze clinical courses and outcome of postpancreatectomy hemorrhage (PPH) after major pancreatic surgery. Summary Background Data:Although PPH is the most life-threatening complication following pancreatic surgery, standardized rules for its management do not exist. Methods:Between 1992 and 2006, 1524 patients operated on for pancreatic diseases were included in a prospective database. A risk stratification of PPH according to the following parameters was performed: severity of PPH classified as mild (drop of hemoglobin concentration <3 g/dL) or severe (>3 g/dL), time of PPH occurrence (early, first to fifth postoperative day; late, after sixth day), coincident pancreatic fistula, intraluminal or extraluminal bleeding manifestation, and presence of “complex” vascular pathologies (erosions, pseudoaneurysms). Success rates of interventional endoscopy and angiography in preventing relaparotomy were analyzed as well as PPH-related overall outcome. Results:Prevalence of PPH was 5.7% (n = 87) distributed almost equally among patients suffering from malignancies, borderline tumors, and focal pancreatitis (n = 47) and from chronic pancreatitis (n = 40). PPH-related overall mortality of 16% (n = 14) was closely associated with 1) the occurrence of pancreatic fistula (13 of 14); 2) vascular pathologies, ie, erosions and pseudoaneurysms (12 of 14); 3) delayed PPH occurrence (14 of 14); and 4) underlying disease with lethal PPH found only in patients with soft texture of the pancreatic remnant, while no patient with chronic pancreatitis died. Conversely, primary severity of PPH (mild vs. severe) and the kind of index operation (Whipple resection, pylorus-preserving partial pancreaticoduodenectomy, organ-preserving procedures) had no influence on outcome of PPH. Endoscopy was successful in 3 from 15 patients (20%), who had intraluminal PPH within the first or second postoperative day. “True,” early extraluminal PPH had uniformly to be treated by relaparotomy. Seventeen patients had “false,” early extraluminal PPH due to primarily intraluminal bleeding site from the pancreaticoenteric anastomosis with secondary disruption of the anastomosis. From 43 patients subjected to angiography, 25 underwent interventional coiling with a success rate of 80% (n = 20). Overall, relaparotomy was performed in 60 patients among whom 33 underwent surgery as first-line treatment, while 27 were relaparotomied as rescue treatment after failure of interventional endoscopy or radiology. Conclusion:Prognosis of PPH depends mainly on the presence of preceding pancreatic fistula. Decision making as to the indication for nonsurgical interventions should consider time of onset, presence of pancreatic fistula, vascular pathologies, and the underlying disease.

Direct Genetic Analysis of Single Disseminated Cancer Cells for Prediction of Outcome and Therapy Selection in Esophageal Cancer

The increasing use of primary tumors as surrogate markers for prognosis and therapeutic decisions neglects evolutionary aspects of cancer progression. To address this problem, we studied the precursor cells of metastases directly for the identification of prognostic and therapeutic markers and prospectively analyzed single disseminated cancer cells from lymph nodes and bone marrow of 107 consecutive esophageal cancer patients. Whole-genome screening revealed that primary tumors and lymphatically and hematogenously disseminated cancer cells diverged for most genetic aberrations. However, we identified chromosome 17q12-21, the region comprising HER2, as the most frequent gain in disseminated tumor cells that were isolated from both ectopic sites. Survival analysis demonstrated that HER2 gain in a single disseminated tumor cell but not in primary tumors conferred high risk for early death.

Frequent homogeneous HER-2 amplification in primary and metastatic adenocarcinoma of the esophagus

HER-2 is the target for antibody based treatment of breast cancer (Herceptin®). In order to evaluate the potential role of such a treatment in esophageal cancers, HER-2 amplification and overexpression was investigated in primary and metastatic cancers of the esophagus. A tissue microarray was constructed from 255 primary esophageal cancers (110 adenocarcinomas and 145 squamous cell carcinomas), 89 nodal and 33 distant metastases. Slides were analyzed by immunohistochemistry (HercepTest™; DAKO) and fluorescence in situ hybridization (FISH; PathVysion™; Vysis-Abbott) for HER-2 amplification and overexpression. Amplification was seen in 16/110 (15%) adenocarcinomas and in 7/145 (5%) squamous cell carcinomas. There was a strong association between HER-2 amplification and overexpression, especially in adenocarcinomas (P<0.0001, log rank). There was a 100% concordance of the HER-2 results in primary tumor and corresponding metastases in 84 analyzed pairs. Amplification was typically high-level with more than 10–15 HER-2 copies per tumor cell. Amplification was unrelated to survival, grading, pT, pN, pM or UICC stage. We conclude that esophageal adenocarcinomas belong to those cancer types with relevant frequency high-level HER-2 gene amplification clinical trials or individual case studies investigating the response of metastatic HER-2-positive esophageal cancers to Herceptin® should be undertaken. The strong concordance of the HER-2 status in primary and metastatic cancers argues for a possible response of metastases from patients with HER-2-positive primary tumors to Herceptin®.

Aggressive surgery improves long-term survival in neuroendocrine pancreatic tumors: an institutional experience.

Objective:To evaluate surgical strategies for neuroendocrine pancreatic tumors (NEPT) in the light of the new WHO classification from 2004 and to draw conclusions for future surgical concepts. Background:The extent of surgical resection in primary and recurrent NEPT is unclear. Methods:Between 1987 and 2004, 62 patients with sporadic NEPT were treated at our institution and sections from biopsy and resection specimen were histopathologically reclassified. Clinical presentation, surgery, metastases, and pattern of recurrence were related to survival. Results:Fifteen well-differentiated tumors (WDT, 24%), 39 low-grade carcinomas (LGC, 63%), and 8 high-grade carcinomas (HGC, 13%) were identified. Median observation time was 30.5 months; 48 of 62 patients (78%) were surgically resected, and in 45 patients R0/R1 status was achieved. Overall 2- and 5-year survival in the latter group was 80% and 64%, respectively. Retrospective WHO classification revealed that organ-preserving segmental resections had been performed in 10 LGC and 1 HGC. These patients showed equal outcome as radically resected counterparts (n = 19). Liver and other organ metastases were present in 19 of 62 patients (31%), and resection was accomplished in 7 of 19 patients, which conferred better overall survival (P = 0.026, log-rank test); 21 of 45 R0/R1-resected patients (47%) suffered from recurrence, and reoperation was accomplished in 9 patients, which resulted in better overall survival (P = 0.066). Conclusion:Organ-preserving resections offer sufficient local control in LGC; therefore, radical resections do not seem to be justified. On the other hand, radical resection is indicated even in metastasized patients or in case of loco-regional recurrence. The silent and slow course of the disease facilitates long-term surgical control.

L1 is associated with micrometastatic spread and poor outcome in colorectal cancer

L1 is a cell adhesion molecule expressed at the invasive front of colorectal tumors with an important role in metastasis. The aim of the present study was to determine L1 protein expression in a large cohort of colorectal cancer patients and its impact on early metastatic spread and survival. A total of 375 patients that underwent surgical treatment for colorectal cancer were chosen retrospectively. A tissue microarray was constructed of 576 tissue samples from these patients and analyzed by immunohistochemistry with a monoclonal antibody against human L1 (UJ127). Lymph node and bone marrow micrometastasis were assessed with monoclonal antibodies Ber-EP4 and pancytokeratin A45-B/B3, respectively. Associations between L1 expression and lymph node, bone marrow micrometastasis and survival were investigated with Fishers, log-rank test and Cox multivariate analysis. All statistical tests were two-sided. L1 was detected in a subset of 48 (13%) of 375 patients examined. Analysis of L1 expression and survival revealed a significantly worse outcome for L1-positive patients by log-rank test (P<0.05). Multivariate Cox regression analysis showed the strongest independent prognostic impact of L1 expression (P<0.05). Fishers test revealed a significant association of L1 expression and presence of disseminated tumor cells in lymph nodes and bone marrow (P<0.05). L1 is a powerful prognostic marker for patients that undergo complete surgical resection. It may have a role in early metastatic spread, as L1 is associated with micrometastases to both the lymph nodes and bone marrow. Thus, L1 should be explored further as a target for adjuvant therapy for micrometastatic disease.

Is it time for a new TNM classification in esophageal carcinoma

Purpose:To investigate the importance of lymph node yield (LNY) and the ratio of afflicted lymph nodes in esophageal carcinoma patients. Patients and Methods:Between 1992 and 2004, 368 patients with esophageal carcinoma underwent surgery. Esophagectomy with curative intent was performed in 255 patients. Subtotal esophagectomy was performed either by thoracoabdominal (104 patients, 40.8%) or by transhiatal approach (151 patients, 59.2%). Results:According to the LNY, patients were grouped into 3 groups. Twenty-six patients had ≤5, 96 had 6 to 18, and 113 had ≥19 dissected lymph nodes. In patients with nodal involvement (pN1), no significant overall survival differences were identified when stratifying subgroups according to the LNY. However, LNY had striking prognostic relevance in pN0 patients. The median overall survival was 23 (≤5 LN), 36 (6–18 LN), and 88 months (≥19). Even for patients with tripled LNY than the proposed minimum by the International Union Against Cancer (UICC) (18 LN), the rate of patients with detected lymph node metastases was only 46%, compared with 61% for patients with a LNY of ≥19 (P = 0.002). In pN1 patients classified according to the ratio of afflicted lymph nodes, median overall survival was 27 months in patients with a ratio <11%, compared with 15 and 13 months in patients with a ratio of 11% to 33% and >33%, respectively (P < 0.001). Multivariate Cox regression modeling identified ratio as the strongest independent prognostic factor for overall survival in pN1 and the LNY in pN0 patients. Conclusions:The minimal regional LNY of 6 lymph nodes as recommended by the UICC for esophageal carcinoma is far too low to appropriately stage the disease. The LNY and the ratio should be reflected in the next version of the UICC classification.

L1 (CD171) is highly expressed in gastrointestinal stromal tumors

The treatment strategy for mesenchymal tumors of the gastrointestinal tract is based upon typing of the tumor. Especially differential diagnosis of gastrointestinal stromal tumors (GISTs) to leiomyomas is crucial for determining radicality of surgery. L1 cell adhesion molecule (CD171) plays an essential role in tumor progression. The aim of this study was to determine expression of L1 in GISTs, smooth muscle tumors, desmoid-type fibromatosis and peripheral nerve sheath tumors (PNSTs). We retrospectively analyzed a total of 129 surgically resected primary tumors or metastases of 72 GISTs, 29 smooth muscle tumors, seven PNSTs and 21 desmoid-type fibromatosis by immunohistochemistry for c-kit, CD34, smooth muscle actin, desmin, vimentin, S-100 and L1 expression. L1 expression was detected in 53 (74%) of 72 GISTs but in none of 29 smooth muscle tumors or 21 desmoid-type fibromatosis (P<0.01 by Fishers test). In all, four (57%) of seven peripheral nerve sheath tumors were L1-positive. Survival analysis of 55 surgically completely resected GISTs presenting without metastasis at initial diagnosis revealed no tumor-specific death among L1-negative patients (P=0.13 by log-rank test; median follow-up time 41 months) and one recurrence was observed (P=0.12). Interestingly high levels of L1 were seen in tumor vascular endothelial cells of smooth muscle tumors and PNSTs, but not in GISTs. Our data show that L1 is highly expressed in GISTs but not in smooth muscle tumors and desmoid-type fibromatosis being important differential diagnoses. The trend towards a reduced survival of L1-positive patients in this study has to be further evaluated in future trials with higher patient numbers.

Mode of Spread in the Early Phase of Lymphatic Metastasis in Pancreatic Ductal Adenocarcinoma: Prognostic Significance of Nodal Microinvolvement

Background:The aim of this study was to assess the prognostic significance of nodal microinvolvement as well as the mode of spread in the early phase of lymphatic metastasis in patients with node-negative pancreatic ductal adenocarcinoma. Methods:Lymph nodes from 48 node-negative patients with R0 resected pancreatic ductal adenocarcinoma were sampled from 3 different compartments: 1) distal hepatoduodenal ligament, 2) superior-anterior compartment, and 3) posterior-inferior. Tissue sections of 148 lymph nodes classified as tumor free by routine histopathology were examined, using a sensitive immunohistochemical assay with the antiepithelial monoclonal antibody Ber-EP4 for tumor cell detection. With regard to histopathologic tumor staging and grading, 26 (54.2%) of the patients were staged as pT1/pT2, 22 (45.8%) as pT3/pT4, while 31 (64.6%) as G1/G2 and 17 (35.4%) patients as G3. Of the 148 “tumor free” lymph nodes, 56 contained Ber-EP4–positive tumor cells. These 56 lymph nodes were from 28 of the 48 patients. The multivariate Cox regression analysis revealed the independent prognostic impact of nodal microinvolvement on relapse-free and overall survival. Analysis by compartment, from which the lymph nodes were collected, revealed that overall survival time (P = 0.006) and time to local recurrence (P = 0.015) depend on the presence of nodal microinvolvement in the superior-anterior compartment. Conclusions:The influence of occult tumor cell dissemination in lymph nodes of patients with histologically proven pancreatic ductal adenocarcinoma supports the need for further tumor staging through immunohistochemistry. This could be a helpful tool in proper selection of patients for adjuvant chemotherapy.

Determination of Microvessel Density by Quantitative Real-time PCR in Esophageal Cancer: Correlation with Histologic Methods, Angiogenic Growth Factor Expression, and Lymph Node Metastasis

Purpose: Angiogenesis and lymphangiogenesis are important steps in tumor growth and dissemination and are of prognostic importance in solid tumors. The determination of microvessel density (MVD) by immunohistology is subject to considerable variability between different laboratories and observers. We compared MVD determination by immunohistology and quantitative real-time PCR and correlated the results with clinical variables. Experimental Design: The expression of endothelial antigens vascular endothelial cadherin (CD144), P1H12 (CD146), tie-2, and VEGFR-2, and lymphatic endothelial markers VEGFR-3, Prox, and LYVE was assessed by quantitative PCR (qPCR) in primary surgical samples. The expression of angiogenetic growth factors VEGF-A, VEGF-C, VEGF-D, angiopoietin-1, and angiopoietin-2 was quantified by PCR and correlated with MVD and clinical variables. Results: The expression of endothelial antigens vascular endothelial cadherin (CD144), P1H12 (CD146), tie-2, and VEGFR-2 correlated with each other in 54 samples of primary esophageal cancer (P < 0.0001 for all comparisons). MVD determined immunohistologically by CD31 staining in a subgroup of 35 patients correlated significantly with the qPCR method. The expression of angiogenetic growth factors VEGF-A, VEGF-C, VEGF-D, angiopoietin-1, and angiopoietin-2 was significantly associated with MVD (P < 0.0001 for all comparisons). Analysis of the expression of lymphendothelial markers VEGFR-3, Prox, and LYVE revealed concordant results, indicating that quantification of lymphendothelial cells is possible by qPCR. The presence of lymph node metastasis on surgical specimens was significantly correlated with MVD (P < 0.003), VEGFR-2 (P < 0.048), and VEGF-C (P < 0.042) expression. Conclusions: These results indicate that quantification of MVD by qPCR in surgical samples of esophageal carcinoma yields similar results with immunohistology. Interestingly, the extent of angiogenesis and lymphangiogenesis was not related in individual tumor samples. Lymph node metastases could be predicted by MVD and VEGF-C expression.