Health-related quality of life after Ivor Lewis esophagectomy.

PURPOSE: Transthoracic Ivor Lewis esophagectomy is a surgical standard therapy for esophageal carcinoma. The aim of this study was to assess health-related quality of life (HRQL) in mid- and long-term survivors. METHODS: Patients with cancer-free survival of at least 12 months after esophageal resection for cancer were identified from a prospectively maintained database. EORTC questionnaires were sent out to assess health-related general (QLQ-C30) and esophageal cancer-specific (QLQ-OES18) quality of life (QOL). A numeric score was calculated in each conceptual area and compared with reference data. RESULTS: One hundred forty-seven patients completed the self-rated questionnaires. They were 121 men and 26 women with a mean age of 63.4 (21-83) years; median FU was 39 (12-139) months. Global health status, functional scales, and symptom scores were significantly reduced compared with healthy reference populations. Also, there was no significant impact of tumor histology, neoadjuvant treatment, minimally invasive approach, or duration of follow-up on HRQL. However, more than half of the patients reported a HRQL similar to that of the healthy reference population. CONCLUSIONS: Despite the major psychosocial and physiological impacts of the disease, more than 50 % of mid- and long-term survivors of the Ivor Lewis procedure for esophageal cancer have a HRQL similar to that of the healthy reference population.

Impact of duct-to-mucosa pancreaticojejunostomy with external drainage of the pancreatic duct after pancreaticoduodenectomy.

BACKGROUND: A variety of different techniques are established for the management of the pancreatic remnant after partial pancreaticoduodenectomy. Although pancreaticojejunostomy is one of the most favored methods, technical details are still under discussion. We report about a series of duct-to-mucosa pancreaticojejunostomies with total external drainage of the pancreatic duct. PATIENTS AND METHODS: Between 1998 and 2007 257 patients underwent surgical therapy for malignant disease of the pancreas and the periampullary region and for chronic pancreatitis. Of these, 153 partial pancreaticoduodenectomies (85 pylorus preserving resections and 68 Whipple's procedures) were performed. In all of these cases, the pancreatic remnant was drained by a duct-to-mucosa pancreaticojejunostomy with external drainage of the pancreatic duct. Presence of postoperative pancreatic fistula (PPF) was defined according to the International Study Group on Pancreatic Fistula (ISGPF). RESULTS: Postoperative mortality was 1.9%. The incidence of postoperative pancreatic fistula (PPF) was 19.6% according to the ISGPF criteria. Only one patient required re-laparotomy for complications caused by PPF. Patients with PPF had a significantly longer operation time (7.3 h versus 6.6 h; P=0.041). Incidence of PPF was not influenced by histology. In all cases the fistulas resolved under conservative treatment. CONCLUSION: Duct-to-mucosa PJ with external drainage is a safe procedure to enteralize the pancreatic stump after partial pancreaticoduodenectomy.

Strong impact of micrometastatic tumor cell load in patients with esophageal carcinoma.

BACKGROUND: To assess the role of immunohistochemically detectable nodal microinvolvement of patients with "curatively" resected esophageal carcinoma. METHODS: In 73 patients with resectable esophageal carcinoma [squamous cell carcinoma (SCC), n = 45 (61.6%); adenocarcinoma (AC), n = 28 (38.4%)] a total of 2174 lymph nodes (LN) were removed. In each of the 1958 LN classified as negative on conventional histopathology, immunohistochemistry was performed using the anticytokeratin antibody AE1/AE3. To determine the role of the amount of residual tumor load, the patients were grouped according to the percentage of LN affected with micrometastasis (0%, <11%, and > or =11%). RESULTS: Tumor cells were immunohistochemically detected in 47 LN (2.4%) from 25 (34.2%) patients. Five-year overall survival probability (5-YSP) of 30% in pN(0 )patients with detected occult tumor cells in LN was significantly worse than that in those without nodal microinvolvement (76%, P = 0.021), hereby resembling that of pN1-patients (24%, P = 0.84). Median overall survival in patients with no (0%), low (<11%), and high (>11%) micrometastatic tumor load was 43, 27, and 11 months, respectively. Substratification according to histological type showed that, in patients with AC, the presence of nodal microinvolvement had a significant impact on 5-YSP (0% versus 65%; P = 0.03), whereas in patients with SCC, differences of 5-YSP were only of borderline significance (24% versus 53%; P = 0.081). CONCLUSION: Minimal tumor cell load as assessed by the ratio of micrometastatically affected LN is a complementary tool for better risk stratification of patients with esophageal carcinoma.

Significant overexpression of SPARC/osteonectin mRNA in pancreatic cancer compared to cancer of the papilla of Vater.

Cancer of the papilla of Vater (CPV) has a significantly better outcome compared to pancreatic cancer (PC) after curative resection. Increasing evidence suggests that prognostic differences are influenced by a different tumor biology. Secreted protein acidic and rich in cystein (SPARC)/osteonectin is a multifunctional matricellular protein involved in cell-matrix interactions and might be involved in tumor pathogenesis and progression. We examined quantitative SPARC mRNA expression in CPV and PC to evaluate if varying expression might contribute to the different biologic behaviour of these entities. Quantitative real-time reverse transcription-PCR was performed to analyze expression of SPARC mRNA in a series of 31 PC and 8 CPV specimens and corresponding uninvolved pancreatic tissues. Relative mRNA levels (ratio tumor/normal) were calculated as (SPARC/beta-actin in tumor)/(SPARC/beta-actin in paired normal tissue). SPARC expression levels were associated with clinical and histopathological parameters. SPARC mRNA expression was detected in all tumor and normal tissues of the pancreas and papilla of Vater. In pancreatic cancer, 15/31 (48.4%) patients showed overexpression of SPARC (ratio tumor/normal >1) whereas in CPV only 1/8 (12.5%) exhibited SPARC overexpression and this difference was statistically significant (p<0.05, Mann-Whitney test). No associations were detected with T- and N-categories, grading or prognosis. In conclusion, SPARC mRNA overexpression is significantly more frequent in CP than CPV and adds further evidence that CP and CPV are biologically different tumor entities.

Differential c-erbB-1 and c-erbB-2 mRNA expression in cancer of the pancreas compared with cancer of the papilla of Vater.

AIM: We examined quantitative mRNA expression of growth factor receptors (c-erbB-1, c-erbB-2) and the anti-apoptosis gene survivin known to be regulated in pancreatic adenocarcinomas and compared the expression pattern with that in carcinomas of the papilla of Vater. METHODS: Quantitative real-time reverse transcriptase-PCR (QRT-PCR, Taqman) was performed to analyze mRNA expression levels of c-erbB-1, c-erbB-2 and survivin in normal and corresponding tumor samples of 31 pancreatic adenocarcinomas and 8 cancers of the papilla of Vater. RESULTS: The overall median mRNA expression of survivin was significantly increased in both adenocarcinoma of the pancreas (P<0.01) and papilla of Vater (P<0.008) compared with uninvolved normal control tissue. In pancreatic cancer, expression of c-erbB-1 was significantly decreased compared with the normal pancreatic tissue (P<0.03), whereas in the cancer of the papilla of Vater expression of c-erbB-2 was significantly downregulated (P<0.05) compared with the paired normal samples. Gene expression was not associated with tumor stage, differentiation or prognosis. CONCLUSION: The common anti-apoptosis gene survivin is overexpressed both in the cancer of the papilla of Vater and pancreas. In contrast, the growth factor receptor genes c-erbB-1 and c-erbB-2 are differentially regulated in both tumor entities adding further evidence that pancreatic cancer is biologically different from the cancer of papilla of Vater.

Molecular markers predicting lymph node metastasis in early esophageal cancer.

AIMS: The aim of this study was to identify molecular markers predicting depth of tumor infiltration and presence of lymph node metastasis in early esophageal cancer. METHODS: Between 1996 and 2004, 67 patients with pT1 esophagus cancer underwent esophagectomy. Resected tumors and lymph nodes were analyzed by immunohistochemistry for tissue infiltration, lymph node metastasis (LNM), micrometastasis and extracapsular lymph node infiltration (ELNI). We focused on MMP-2 (matrix-metalloproteinase-2), TIMP-2 (tissue inhibitor of metalloproteinase-2), PIM-1 and survivin as the most promising marker candidates. The data was correlated with the patients' long term follow-up (median follow-up time 11.4 years). RESULTS: We found 22 pT1a and 45 pT1b carcinomas. None of the mucosal carcinomas, but 58% (26 patients) of the submucosal carcinomas showed lymph node metastasis or micrometastasis. The rate of LNM positively correlated with the depth of tumor infiltration (23% LNM in sm1 tumors and 82% LNM in sm3 tumors). Low grade PIM-1 expression (<30%) was significantly associated with occurrence of LNM (p=0.034) while high expression TIMP-2 (>70%) were detected in submucosal tumors. Logistic regression analysis revealed PIM-1 and Grading G3 as independent risk factors for LNM (p<0.001). Survival of patients with micrometastasis was comparable to those with LNM (median survival: 5.05 years versus 5.52 years). Patients with ELNI had the worst prognosis (median survival: 1.7 years). CONCLUSIONS: PIM-1 is a promising marker for prediction of lymph node metastasis in early esophagus cancer. Extracapsular lymph node infiltration has an independent worse prognostic impact.

Lymph node size and metastatic infiltration in non-small cell lung cancer.

BACKGROUND: Preoperative lymph node staging of lung cancer by CT relies on the premise that malignant lymph nodes are larger than benign ones. Lymph nodes > 1 cm in size are regarded as metastatic nodes. The surgical approach and potential application of neoadjuvant therapy regimens are dependent on this evaluation. PATIENTS AND METHODS: In a morphometric study, hilar and mediastinal lymph nodes from 256 patients with non-small cell lung cancer (NSCLC) were analyzed. The lymph nodes were counted, the largest diameter of each lymph node was measured, and each lymph node was analyzed for metastatic involvement by histopathologic examination. The frequency of metastatic involvement was calculated and correlated with lymph node size. Preoperative CT scans of 80 patients were retrospectively analyzed by a staff radiologist. Lymph node size was measured, and lymph nodes were evaluated due to radiologic criteria. The radiologic evaluation was compared to the histopathologic diagnosis. RESULTS: A total of 2,891 lymph nodes were present in the 256 specimens examined for this study. One hundred thirty-nine patients had a pN0 status, whereas 117 patients had lymph nodes that were positive for cancer. Two thousand four hundred eighty-six lymph nodes (86%) were tumor-free, while 405 (14%) showed metastatic involvement on histopathologic examination. The mean (+/- SD) diameter of the nonmetastatic lymph nodes was 7.05 +/- 3.75 mm, whereas infiltrated nodes had a diameter of 10.7 +/- 4.7 mm (p = 0.005). One thousand nine hundred fifty-three of the tumor-free lymph nodes (79%) and 170 of the metastatic lymph nodes (44%) were < 10 mm in diameter. Of 139 patients with no metastatic lymph node involvement, 101 (77%) had at least one lymph node that was > 10 mm in diameter. Of 127 patients with metastatic lymph node involvement, 12% had no lymph node that was < 10 mm. The independent radiologic evaluation of the CT scans of 80 patients yielded a sensitivity of 57.1% and a specificity of 80.6%. CONCLUSION: Lymph node size is not a reliable parameter for the evaluation of metastatic involvement in patients with NSCLC.

Extracapsular lymph node spread as a negative prognostic factor of adenocarcinoma of the pancreas and cancer of the papilla of vater.

OBJECTIVE: The aim of this study was to analyze the incidence and impact of extracapsular lymph node spread (ELNS) in pancreatic cancer (PC) and cancer of the papilla of Vater (CPV). METHODS: Between 2004 and 2009, 148 patients underwent surgical therapy for PC (n = 112) and CPV (n = 36). The resected lymph nodes (LNs) were further analyzed for ELNS. RESULTS: In 95 (64.2%) patients, LN metastasis was present. In 45 (47.3%) of these patients, an ELNS was present on histopathology. The patients' survival was negatively affected by ELNS. For PC, the 5-year survival rate was 37% for patients with no LN metastasis compared with 4% and 0% for patients with LN metastasis (pN1) but without extracapsular LN involvement and patients with pN1 disease with extracapsular LN involvement of at least 1 LN, respectively (P < 0.001). In patients with CPV, the 5-year survival rate was 56% for patients with no LN metastasis and 44% and 0% for patients with pN1 disease but without extracapsular LN involvement and patients with pN1 disease with extracapsular LN involvement of at least 1 LN, respectively (P = 0.006). Multivariate analysis revealed ELNS as an independent prognostic factor of survival for both tumor types. CONCLUSIONS: Extracapsular LN spread is an independent negative prognostic factor in PC and CPV. In future staging systems, ELNS should be included.

Effect of aging on esophageal motility in patients with and without GERD.

BACKGROUND/AIMS: The impact of aging on esophageal motility is not completely understood. This study aims at assessing 1) whether degeneration of esophageal body motility occurs with age and 2) whether this development is influenced by gastroesophageal reflux disease (GERD). METHODS: 326 consecutive patients with symptoms of GERD underwent a diagnostic work-up including a water-perfused esophageal manometry. Patients were divided by age: 17-39 years (group 1, n=75), 40-49 years (group 2, n=79), 50-59 years (group 3, n=64), 60-69 years (group 4, n=74), and >70 years (group 5, n=34). GERD was diagnosed if patients had erosive esophagitis at endoscopy, a positive pH-metry, or both. The amplitude of esophageal contraction waves 3 cm and 8 cm above the lower esophageal sphincter and the percentage of peristaltic contraction waves of the tubular esophagus were analyzed and correlated to GERD. RESULTS: A normal esophageal manometry was found in 86.7%, 73.4%, 67.2%, 58.1%, and 55.9% (p<0.01) in groups 1-5, respectively. Esophageal contraction wave amplitudes were affected by age in patients positive for GERD only (p<0.01). Esophageal body peristalsis was affected by age (p<0.01) independent of the diagnosis of GERD. CONCLUSION: Aging is correlated to esophageal motor abnormalities. GERD has a significant impact on esophageal contraction wave amplitude, but not on peristalsis.

Prognostic relevance of skip metastases in esophageal cancer.

BACKGROUND: Presence of nodal skip metastasis is an established prognostic factor for patients with non-small cell lung cancer. Little is known about this form of lymphatic spread in esophageal cancer. The aim of this study was to assess nodal skip metastasis and its clinical importance for patients with cancer of the esophagus. METHODS: Resected lymph nodes of 128 patients with esophageal cancer and pN1 status (adenocarcinoma, n = 67; squamous cell cancer, n = 61) were mapped according to the Japanese lymph-node classification for esophageal cancer. Skip metastases were defined as tumor-free N1 lymph nodes, whereas N2 through N4 lymph nodes harbor metastases. RESULTS: Skip metastases were present in 26 of 128 (20%) patients. There was a higher rate of skip metastasis in early tumors (39% versus 23% versus 14% for T1, T2, and T3 tumors; p = 0.032) and tumors in the middle and upper third of the esophagus (37% versus 15% for upper- and middle-third and lower-third tumors; p = 0.022). Patients with skip metastasis had a significantly better 5-year survival rate than patients with continuous metastasis (53% versus 15%; p < 0.0001). Multivariate analysis revealed skip metastasis as an independent prognostic factor. CONCLUSIONS: Skip metastasis is a common form of lymphatic spread in esophageal cancer, which is associated with a favorable prognosis.

Preoperative survivin mRNA detection in peripheral blood is an independent predictor of outcome in esophageal carcinoma.

AIMS: Survivin (SVV) mRNA expression levels in peripheral blood of patients with gastrointestinal malignancies change significantly during the course of treatment. We wanted to scrutinize these findings in patients with esophageal carcinoma and furthermore evaluate whether the detection of mRNA and the change in detecting ability have an association with overall survival. MATERIALS & METHODS: Whole blood was drawn 1 day pre- and 10 days post-operatively from 62 patients with esophageal carcinoma. Tumor cells were enriched from whole blood by density-gradient centrifugation prior to extraction of total cellular RNA and subsequent direct quantitative reverse transcriptase-PCR assays. RESULTS: SVV was detectable in 48 out of 62 patients (77%). Stepwise multivariate Cox linear regression models demonstrated a significant and independent association of measured SVV with overall survival (6.6 exp[b]; 95% CI: 1.97-22.12; p = 0.002). Increased SVV levels after the operation were linked to shorter overall survival (p = 0.04). CONCLUSION: Preoperative SVV expression levels appear to be associated with overall survival in patients with esophageal cancers. Increasing levels could potentially indicate a higher risk for shorter overall survival and therefore demand adapted treatment modalities.

Variable 18F-fluorodeoxyglucose uptake in gastric cancer is associated with different levels of GLUT-1 expression.

OBJECTIVES: Detection rates of gastric cancer in F-fluorodeoxyglucose (FDG)-PET depend on the histopathological characteristics of the primary tumor. To clarify this observation, FDG uptake in gastric carcinoma was analyzed by focusing on histopathology and on the expression of the glucose transporter (GLUT-1) in the primary tumor. METHODS: Thirty-five patients with the diagnosis of gastric cancer underwent FDG-PET with visual image analysis and measurement of maximum standardized uptake value (SUV(max)) before surgical treatment. Resected tumor samples were categorized according to Union internationale contre le cancer, WHO, and Laurén classification and tumor differentiation. GLUT-1 expression was graded semiquantitatively by immunohistochemistry. Statistical analysis was done for the correlation of histology, different classifications, and tumor grading with SUV(max) and GLUT-1 expression. RESULTS: SUV(max) significantly correlated with histopathological classifications according to the WHO (P=0.009) and Laurén classification (P=0.034). Signet-ring cell carcinoma had a median SUV(max) of only 3.0 (range, 1.0-11.5). Median SUV(max) for papillary and tubular carcinoma was 7.8 (range, 1.8-14.4). In 21 (60%) cases, GLUT-1 expression in the primary tumor was positive. GLUT-1 expression correlated significantly with tumor differentiation (P=0.018) and the classification according to Laurén (P=0.023) and WHO (P<0.001). Thirteen (76%) of 17 signet-ring cell carcinoma cases did not show any GLUT-1 expression. SUV(max) in relation to GLUT-1 expression showed a significant correlation (P=0.002). For cases with detectable GLUT-1 expression the median SUV(max) was 6.9 (range, 2.3-14.1) versus a median of 3.1 (range, 1-8.8) for cases without GLUT-1 expression. CONCLUSION: FDG uptake in gastric cancer depends on GLUT-1 expression. One major reason for low FDG uptake in signet-ring cell carcinoma is the low GLUT-1 expression in this histological subtype of gastric cancer.

Significant down-regulation of the plasminogen activator inhibitor 1 mRNA in pancreatic cancer.

OBJECTIVES: We examined mRNA expression of the urokinase-type plasminogen activator (uPA), its receptor (uPAR), and the plasminogen activator inhibitor 1 (PAI-1) in a panel of adenocarcinomas of the pancreas (PC) and cancers of the papilla of Vater (CPV). Expression profiles were compared with paired uninvolved normal tissues to define a possible differential role of these genes in tumorigenesis of both tumor types. METHODS: Urokinase-type plasminogen activator, uPAR, and PAI-1 mRNA expression was analyzed by real-time quantitative reverse-transcriptase polymerase chain reaction (TaqMan) in 25 PC, 7 CPV, and in the paired uninvolved normal tissues. RESULTS: Uninvolved normal tissue probes from PC and CPV showed similar mRNA expression profiles of uPA, uPAR, and PAI-1. Whereas expression levels of uPA (P = 0.81) and uPAR (P = 0.75) were not statistically significant different between tumor and paired normal tissues, PAI-1 levels were significantly down-regulated in tumor compared with paired normal tissue samples (Wilcoxon test; P < 0.006). No differences in mRNA expression of uPA, uPAR, and PAI-1 between PC and CPV were observed. Expression levels of the 3 genes were not associated with tumor stage, grading, or survival. CONCLUSIONS: Increased mRNA expression of uPA and uPAR could not be detected in PC and CPV; however, PAI-1 mRNA expression levels are significantly down-regulated in PC, which might lead to higher activity levels of uPA components. Our data are merely hypothesis generating and should be validated in larger translational studies.

High expression of heparanase is significantly associated with dedifferentiation and lymph node metastasis in patients with pancreatic ductal adenocarcinomas and correlated to PDGFA and via HIF1a to HB-EGF and bFGF.

BACKGROUND: Pancreatic cancer still has one of the worst prognoses of all cancers with a 5-year survival rate of 5%, making it necessary to find markers or gene sets that would further classify patients into different risk categories and thus allow more individually adapted multimodality treatment regimens. Especially heparanase (HPSE) has recently been discussed as a key factor in pancreatic cancer. MATERIALS AND METHODS: Paraffin-embedded tissue samples were obtained from 41 patients with pancreatic adenocarcinoma who were scheduled for primary surgical resection. Direct quantitative real-time reverse transcriptase polymerase chain reaction (TaqMan) assays were performed in triplicates to determine HPSE, hypoxia inducible factor-1 alpha (HIF1a), platelet-derived growth factor alpha (PDGFA), heparin-binding EGF-like growth factor (HB-EGF), and basic fibroblast growth factor (bFGF) gene expression levels. RESULTS: HPSE was significantly correlated to PDGFA (p = 0.04) and HIF1a (p = 0.04). The correlation of HIF1a to bFGF and HB-EGF was significant (p = 0.04, p = 0.02). Stepwise multiple linear regression models showed a significant independent association of HPSE with lymph node metastasis (p = 0.025) and with dedifferentiation (p = 0.042). CONCLUSIONS: Heparanase seems to be significantly associated with lymph node metastasis (p = 0.025) as well as dedifferentiation (p = 0.042). We assume that HPSE plays a crucial role for the aggressiveness of pancreatic cancer. Larger studies including more patients seem to be warranted.

High expression of HIF1a is a predictor of clinical outcome in patients with pancreatic ductal adenocarcinomas and correlated to PDGFA, VEGF, and bFGF.

PURPOSE: Pancreatic cancer still has one of the worst prognoses in gastrointestinal cancers with a 5-year survival rate of 5%, making it necessary to find markers or gene sets that would further classify patients into different risk categories and thus allow more individually adapted multimodality treatment regimens. In this study, we investigated the prognostic values of HIF1a, bFGF, VEGF, and PDGFA gene expressions as well as their interrelationships. EXPERIMENTAL DESIGN: Formalin-fixed paraffin-embedded tissue samples were obtained from 41 patients with pancreatic adenocarcinoma (age, 65; range, 34-85 years). After laser capture microdissection, direct quantitative real-time reverse transcription-polymerase chain reaction assays were performed in triplicates to determine HIF1a, PDGFA, VEGF, and bFGF gene expression levels. Multivariate Cox proportional hazards regression analysis was used to assess the impact of HIF1a gene expression on prognosis. RESULTS: HIF1a was significantly correlated to every gene we tested: bFGF (P = .04), VEGF (P = .02), and PDGFA (P = .03). Tumor size, P = .04, and high HIF1a mRNA expression (cutoff, 75th percentile) had a significant impact on survival, P = .009 (overall model fit, P = .02). High HIF1a expression had a sensitivity of 87.1% and a specificity of 55.6% for the diagnosis short (<6 months) versus long (6-60 months) survival. CONCLUSIONS: Measuring PDGFA, bFGF, and HIF1a expression may contribute to a better understanding of the prognosis of patients with pancreatic cancer and may even play a crucial role for the distribution of patients to multimodal therapeutic regimens. Larger studies including patients treated with actual chemotherapeutics seem to be warranted.

Reduced incidence of nodal micrometastasis after major response to neoadjuvant chemoradiation in locally advanced esophageal cancer.

BACKGROUND: Neoadjuvant treatment modalities for esophageal cancer were developed to improve local tumor control as well as to reduce lymph node metastases and distant metastases in patients with locally advanced esophageal cancer. The influence on nodal micrometastasis has not yet been evaluated. METHODS: This study includes 52 patients with localized (cT2-4, Nx, M0) esophageal cancers (21 adenocarcinomas, 31 squamous cell cancers) who received neoadjuvant chemoradiation (36Gy, 5-FU, cisplatin) followed by transthoracic en bloc esophagectomy with two field lymphadenectomy. The extent of histomorphologic regression was categorized into major (< 10%) and minor response (>10% vital residual tumor cells) as recently reported. A total of 1186 lymph nodes were diagnosed as negative for metastases by routine histopathological analysis and were further examined for the presence of isolated tumor cells with the monoclonal anti-epithelial antibody AE1/AE3. RESULTS: Twenty-two tumors (42.3%) showed a major histopathologic response whereas in 30 tumors (57.7%) only a minor response was present. Of 32 patients with a pN0 category, major response was present in 19 (59.4%) tumors, whereas 13 (40.6%) tumors showed minor response. Nine (69%) out of 13 patients with minor response had AE1/AE3-positive cells in their lymph nodes, whereas only four (21%) out of 19 pN0-patients with major response showed nodal micrometastasis (P = 0.013, chi(2)-test). CONCLUSIONS: If tumors show a major histomorphologic response following neoadjuvant chemoradiation, the presence of nodal micrometastasis is significantly reduced compared to those with minor response.

Role of skip metastasis to mediastinal lymph nodes in non-small cell lung cancer.

BACKGROUND: Skip metastasis to mediastinal lymph nodes is a well-known phenomenon in non-small cell lung cancer (NSCLC). Little is reported in the literature about its clinical importance. It is still under discussion whether any prognostic differences exist between resected NSCLC with either skip metastases or continuous mediastinal lymph node metastases (N2). PATIENTS AND METHODS: We analyzed retrospectively the data of 45 patients with a pN2-stage, who underwent resection for NSCLC. Seventeen of these patients (37.8%), showing no metastatic involvement of hilar (N1) lymph nodes, were compared to the remaining 28 patients with infiltration of hilar nodes (N1) as well as N2 nodes. RESULTS: Multivariate analysis showed no statistically significant difference between the skip metastasis and the continuous N2 group regarding sex, age, histology, T- or M-status. The frequency of skip metastasis was higher in patients with a primary tumor in the upper lobe (n = 12, 71%) compared to the lower lobe (n = 5, 29%). This difference was not statistically significant. In patients with a non-continuous lymph node spread, 29 out of 119 resected mediastinal lymph nodes were infiltrated (1.7 per patient, range: 1-10). Compared to 83 metastatic involved lymph nodes out of 198 resected mediastinal nodes (three per patient, range: 1-10) in patients with involvement of N1 and N2 nodes (P = 0.034, Mann-Whitney test). The 5-year survival rate of pN2 patients with skip metastasis was 41% compared to 14% in patients with involvement of N1 and N2 nodes (P = 0.019). CONCLUSIONS: pN2 patients with mediastinal lymph node skip metastasis have a more favorable prognosis compared to pN2 patients with continuous infiltration of the regional lymph nodes. Patients with a continuous lymph node involvement show an increased number of infiltrated mediastinal lymph nodes per patient compared to patients with a non-continuous spread. Skip metastasis is an independent prognostic factor of survival. The presence of skip metastasis seems to be a unique subgroup of pN2 disease in NSCLC.

Skip metastasis in nonsmall cell lung carcinoma: predictive markers and isolated tumor cells in N1 lymph nodes.

BACKGROUND: Skip metastasis to mediastinal lymph nodes is a prognostic factor for patients with nonsmall cell lung carcinoma (NSCLC). Little is known about the biologic behavior of tumors with noncontinuous spread to the mediastinal lymph nodes. In patients with pN2 skip metastases, micrometastases to N1 lymph nodes, which only mimic skip metastases, have not been investigated. METHODS: In a retrospective study, the authors analyzed the primary tumor specimens from 45 patients with pN2 NSCLC (18 patients had squamous cell carcinomas, 23 had adenocarcinomas, and 4 had large cell carcinomas). They immunohistochemically evaluated the expression of p21, p53, MUC-1, Bcl-2, c-ErbB-2, and E-cadherin. Survival rates and biomarker expression levels were compared between patients with pN2 disease and infiltration of N1 lymph nodes (without skip metastasis [n = 28]) and patients with pN2 disease without N1 infiltration (with skip metastasis [n = 17]). To evaluate micrometastasis in the pN1 lymph nodes of 17 patients with skip metastases, lymph nodes were stained using the anticytokeratin antibody, AE1/AE3. RESULTS: The 5-year survival rate of patients with skip metastases was 41%, compared with 14% for patients without skip metastases (P = 0.019). In a multivariate analysis, the incidence of skip metastases did not vary significantly according to gender, age, histology, pT status, or cM status. Three skip-positive patients (17.6%) had micrometastatic tumor involvement of pN1 lymph nodes. After adding these patients to the group of patients without skip metastases, there was still a significant difference in survival between the two groups. p53, MUC-1, c-ErbB-2, and E-cadherin expression levels in primary tumor specimens were not significantly different in patients with continuous metastasis and patients with skip metastases. Patients with skip metastases expressed lower levels of p21 (P = 0.026), whereas Bcl-2 expression levels were considerably higher (P = 0.019) compared with the corresponding levels in patients without skip metastases. CONCLUSIONS: Patients with NSCLC and pN2 skip metastases have a more favorable prognosis than do patients with pN2 disease without skip metastases. Tumor specimens from these patients exhibit elevated expression of the antiapoptosis gene BCL2 and lower expression levels of p21 relative to patients with pN2 disease without skip metastases. Micrometastases occurred in 3 of 17 (17.6%) patients with pN2 disease and skip metastases diagnosed by routine histopathology.