Impact of age and gender on tumor related prognosis in gastrointestinal stromal tumors (GIST).

BACKGROUND: Risk classification and prediction of prognosis in GIST is still a matter of debate. Data on the impact of age and gender as potential confounding factors are limited. Therefore we comprehensively investigated age and gender as independent risk factors for GIST. METHODS: Two independent patient cohorts (cohort I, n = 87 [<50 years]; cohort II, n = 125 [≥50 years]) were extracted from the multicentre Ulmer GIST registry including a total of 659 GIST patients retrospectively collected in 18 collaborative German oncological centers. Based on demographic and clinicopathological parameters and a median follow-up time of 4.3 years (range 0.56; 21.33) disease-specific-survival (DSS), disease-free-survival (DFS) and overall survival (OS) were calculated. RESULTS: GIST patients older than fifty years showed significantly worse DSS compared to younger patients (p = 0.021; HR = 0.307, 95% CI [0.113; 0.834]). DSS was significantly more favorable in younger female GIST patients compared with elderly females (p = 0.008). Female gender resulted again in better prognosis in younger patients (p = 0.033). CONCLUSIONS: Patient age (<50 years) and female gender were significantly associated with a more favourable prognosis in GIST. Extended studies are warranted to confirm our clinical results and to elucidate underlying pathophysiological mechanisms.

Frequency and clinicopathological features of fibroelastotic changes in the gastrointestinal tract.

Fibroelastotic changes (FEC) and especially elastotic polyps of the gastrointestinal (GI) tract are considered rare benign lesions. They consist of accumulations of elastic fibers within the mucosal, submucosal, or muscular layer, occurring in all parts of the GI tract and often appearing as polyps, but also as diffuse non-polyp-forming deposits. They have been the subject of only a few studies. To explore the clinical and histopathological features of FEC in the GI tract, a series of 162 elastotic lesions was collected within a 2-year period. The clinical data and endoscopic findings were correlated. FEC appeared as polyp-forming lesions of the large intestine in 23 samples (14 %), all other samples concerning histological findings without an identifiable gross mass. Frequently related findings were postinterventional status (9 %), previous irradiation (7 %), and history of GI lymphoma (4 %). Eight samples (5 %) presented endoscopically with lesions justifying surgical intervention. We identified three different histological patterns of FEC, which we have called fibroelastosis, angioelastosis, and elastofibroma. Consistent with previous studies, CD34 immunohistochemical staining (performed on 38 polypoid FEC specimens) showed an increase of CD34-positive mesenchymal cells in 95 % of immunostained samples, suggesting a potential role for CD34-positive mesenchymal cells in the accumulation of elastic fibers. In conclusion, FEC are more common in the GI tract than previously recognized. They often present as a benign polyp. Many accompany other diseases like ulcers and atrophic gastritis or represent a residual finding after an intervention.

Methylene blue-assisted lymph node dissection technique is not associated with an increased detection of lymph node metastases in colorectal cancer.

Lymph node staging is of paramount importance for prognosis estimation and therapy stratification in colorectal cancer. A high number of harvested lymph nodes is associated with an improved outcome. Methylene blue-assisted lymph node dissection effectively improves the lymph node harvest and ensures sufficient staging. Now, the effect on node positivity rate and stage-related outcome was investigated. The study cohort with advanced lymph node dissection consisted of 669 colorectal cancer cases of all stages, which were collected between 2007 and 2012. A historical collection of 663 cases investigated with conventional techniques between 2002 and 2004 served as control. Lymph node harvest was dramatically improved in the study group with mean lymph node numbers of 34 ± 17 vs 13 ± 5 (P<0.001) and sufficient staging rates of 98% vs 62% (P<0.001). However, neither the rate of nodal positive cases (37% vs 37%; P = 0.98) nor the rate of N2 cases differed between the two groups (14% vs 13%; P = 0.80). Furthermore, no differences were found concerning the outcome in both groups. The advanced lymph node dissection technique guarantees adequate histopathological lymph node staging in virtually all cases of colorectal cancer and is therefore extremely helpful. The hypothesis that it also provides a higher sensitivity in detecting metastases, however, could be not proved.

The clinical significance of lymph node size in colon cancer.

To date, the clinical value of lymph node size in colon cancer has been investigated only in a few studies. Only in radiological diagnosis is lymph node size routinely recognized, and nodes ≥10 mm in diameter are considered pathologic. However, the few studies regarding this topic suggest that lymph node size is not a reliable indicator of metastatic disease. Moreover, we hypothesized that increasing lymph node size is associated with favorable outcome. By performing a morphometric study, we investigated the clinical significance of lymph node size in colon cancer in terms of metastatic disease and prognosis. A cohort of 237 cases with excellent lymph node harvest (mean lymph node count: 33±17) was used. The size distribution in node-positive and -negative cases was almost identical. In all, 151 out of the 305 metastases detected (49.5%) were found in lymph nodes with diameters ≤5 mm. Only 25% of lymph nodes >10 mm showed metastases. Minute lymph nodes ≤1 mm were involved only very rarely (2 of 81 cases). In 67% of the cases, the largest positive lymph node was <10 mm. The prognostic relevance of lymph node size was investigated in a subset of 115 stage I/II cases. The occurrence of ≥7 lymph nodes that were >5 mm in diameter was significantly associated with better overall survival. Our data show that lymph node size is not a suitable factor for preoperative lymph node staging. Minute lymph nodes have virtually no role in correct histopathological lymph node staging. Finally, large lymph nodes in stage I/II disease might indicate a favorable outcome.

Combination of ex vivo sentinel lymph node mapping and methylene blue-assisted lymph node dissection in gastric cancer: a prospective and randomized study.

BACKGROUND: Exact lymph node (LN) staging is crucial for prognosis estimation and treatment stratification in gastric cancer. Recently, a new concept for improving LN harvest and the accuracy of LN staging was introduced. It combines methylene blue-assisted lymph node dissection (MBLND) with a new ex vivo sentinel lymph node (evSLN) mapping technique. The purpose of this study was to investigate these techniques in a prospective and randomized manner. METHODS: A total of 50 patients with proven or suspicious gastric cancer were enrolled. Twenty-five patients each were randomized to the conventional technique (Unstained) or MBLND (Methylene). In 46 cases, additional evSLN mapping with black ink as a marker dye was performed. RESULTS: Methylene blue-assisted lymph node dissection was associated with a highly significantly improved LN harvest (36 ± 10 vs. 21 ± 10; P < 0.001). The biggest differences were seen in LNs ≤ 6 mm. In contrast to the conventional technique, neither partial gastrectomy nor preoperative chemotherapy influenced LN harvest in the methylene group. The evSLN detection rate, sensitivity, and accuracy were 87, 81, and 93%, respectively. Isolated tumor cells were detected after immunohistochemical staining in 3 of 17 cases (18%). The probability of carrying a metastasis was two times higher in evSLNs compared to non-evSLNs (44 vs. 23%; P < 0.001). CONCLUSIONS: Methylene blue-assisted lymph node dissection is a highly effective method of improving the LN harvest in gastric cancer. Further application of evSLN mapping is feasible and has the potential to heighten the sensitivity of metastasis detection.

Cyclin H expression is increased in GIST with very-high risk of malignancy.

BACKGROUND: Risk estimation of gastrointestinal stromal tumours (GIST) is based on tumour size and mitotic rate according to the National Institutes of Health consensus classification. The indication for adjuvant treatment of patients with high risk GIST after R0 resection with small molecule inhibitors is still a controversial issue, since these patients represent a highly heterogeneous population. Therefore, additional prognostic indicators are needed. Here, we evaluated the prognostic value of cyclin H expression in GIST. METHODS: In order to identify prognostic factors of GIST we evaluated a single centre cohort of ninety-five GIST patients. First, GISTs were classified with regard to tumour size, mitotic rate and localisation according to the NIH consensus and to three additional suggested risk classifications. Second, Cyclin H expression was analysed. RESULTS: Of ninety-five patients with GIST (53 female/42 male; median age: 66.78a; range 17-94a) risk classification revealed: 42% high risk, 20% intermediate risk, 23% low risk and 15% very low risk GIST. In patients with high risk GIST, the expression of cyclin H was highly predictive for reduced disease-specific survival (p = 0.038). A combination of cyclin H expression level and high risk classification yielded the strongest prognostic indicator for disease-specific and disease-free survival (p < or = 0.001). Moreover, in patients with tumour recurrence and/or metastases, cyclin H positivity was significantly associated with reduced disease-specific survival (p = 0.016) regardless of risk-classification. CONCLUSION: Our data suggest that, in addition to high risk classification, cyclin H expression might be an indicator for "very-high risk" GIST.

A new concept for the role of ex vivo sentinel lymph nodes in node-negative colorectal cancer.

BACKGROUND: We recently introduced ex vivo, intra-arterial methylene blue injection as a simple method to improve the lymph node (LN) harvest in gastrointestinal cancer. We now combined it with a novel ex vivo sentinel lymph node (evSLN) mapping technique. METHODS: evSLN mapping was performed by subserosal (n = 20) or submucosal (n = 30) India ink injection. Subsequently, methylene blue was injected intra-arterially to enhance visibility of all LNs to improve the overall LN harvest. Manual LN dissection was carried out after fixing overnight. evSLNs nodes were identified by detecting carbon particles during histological examination. In primary node-negative cases, all detected LNs were step sectioned and immunohistochemically stained for pan-cytokeratin. RESULTS: India ink injection was easy to perform. Methylene blue injection failed in 1 case. The mean lymph node harvest was 42 ± 18 LNs, and the SLN detection rate was 78%. The sensitivity for detecting metastases was 75%. The mean SLN number was 3 ± 1. LN metastases were found in 20 of 47 malignant cases (43%). Skip metastases occurred in 4 cases. Of these cases, 3 showed involvement of at least 1 entire LN. True upstaging (N0 â†’ N1mi) was found in 1 of 23 cases (4%) within a SLN after advanced evaluation. CONCLUSIONS: Combination of methylene blue technique and ex vivo sentinel mapping is feasible, easy to perform, and cost effective. It guarantees an optimal LN harvest and has the potential to heighten the sensitivity of metastasis detection.

Shift from cytoplasmic to nuclear maspin expression correlates with shorter overall survival in node-negative colorectal cancer.

Maspin has been characterized as a potent tumor suppressor in many in vitro and in vivo studies. In contrast, in stage III colon cancer, an association with shorter overall survival as well as sensitivity to chemotherapy was found for cases with nuclear maspin expression. Because 20% of node-negative colorectal cancer cases show a fatal clinical course, we hypothesized that immunohistochemical maspin expression could be of help to identify higher-risk cases. Therefore, we analyzed survival in a study employing 156 cases of stage I/II colorectal cases. Immunohistochemical cytoplasmic and/or nuclear maspin expression was found in 72% and 48% of the cases, respectively. Significant correlations between cytoplasmic expression and high tumor grade (P < .01) and between nuclear expression and tumor budding (P < .001) were shown. No differences concerning overall survival and immunohistochemical maspin expression were found when the complete collective was analyzed. However, evaluation of the pT3 cases revealed a highly significant worse mean overall survival of cases with a combination of nuclear expression and cytoplasmic loss of maspin compared to cases with the opposite expression pattern nuclear loss and cytoplasmic expression (mean overall survival 40 versus 63 months, respectively; P < .001). The other possible combinations (complete positive and complete negative) showed intermediate mean overall survival times with 54 and 49 months, respectively. Our findings suggest a compartment-dependent function of maspin in colorectal cancer, which can be useful in identifying stage II cases with a higher risk for fatal outcome with a possible benefit from adjuvant chemotherapy.

Sentinel lymph node mapping as a side-effect of colonoscopic tattooing.

BACKGROUND: Correct tumor localization is crucial for proper surgical therapy in colorectal cancer. Intraoperative visualization of the lesion is facilitated by preoperative colonoscopic tattooing, regardless of whether an open or laparoscopic approach is employed. OBJECTIVE: This pilot study tests the hypothesis that colonoscopic tattooing can serve the additional role of sentinel lymph node (SLN) mapping. METHODS: We collected 5 prospective and 16 retrospective cases, in which colonoscopic tattooing was applied and surgery was performed. Nineteen of these cases showed colorectal cancer. High-grade intraepithelial neoplasia was found in two cases. All lymph nodes (LNs) were histologically assessed for metastasis and carbon particles, and those that tested positive were registered as carbon-containing lymph nodes (CcLNs). Subsequently, additional step sections were cut and immunohistochemistry was performed on all lymph nodes of the malignant cases. RESULTS: A total number of 311 lymph nodes were investigated. CcLNs could be identified in 17 of 21 cases (detection rate: 81%). The histomorphology of CcLNs was identical to that known from carbon as a sentinel marker dye. The mean CcLN number was 2 +/- 2 (range 1-6). After primary evaluation, one metastasis was detected in a case where a CcLN was not observed. All other cases showed no positive LNs. After step sectioning and immunohistochemical staining, one additional micrometastasis was found in a CcLN, resulting in upstaging from N0 to N1 (mi). CONCLUSION: Our findings support the thesis that colonoscopic tattooing holds the potential for SLN mapping. Therefore, a prospective study with an appropriate case number should follow this pilot study to clarify the clinical value of this finding.

Methylene blue-assisted lymph node dissection in combination with ex vivo sentinel lymph node mapping in gastric cancer.

AIMS: Lymph node (LN) stage is still the strongest prognostic marker in potentially curable gastric cancer. Accuracy of histopathological lymph node assessment depends on the number of investigated LNs and detection rate of metastases and micrometastases. The aim was to perform a feasibility study employing intra-arterial methylene blue injection - a novel method to improve LN harvest - and ex vivo sentinel LN mapping. METHODS AND RESULTS: A total of 33 cases were enrolled, including 14 retrospective cases that served as a control group. The methylene group showed a highly significant improved mean LN harvest compared with unstained cases, with 38 +/- 14 versus 21 +/- 10 LNs (P < 0.001), respectively. The detection rate of ex vivo sentinel mapping was 88%. No skip metastases occurred. CONCLUSION: Both techniques have the potential to improve the accuracy of histopathological LN staging and can be combined successfully.

Methylene blue-assisted lymph node dissection in colon specimens: a prospective, randomized study.

Recently, we introduced ex vivo intra-arterial methylene blue injection into the inferior mesenteric artery as a novel method to improve lymph node (LN) harvest in rectal cancer. We have now adapted this method to the other segments of the colon. A total of 60 cases were enrolled. Primary LN dissection was followed by fat clearance and a secondary dissection. The mean +/- SD primary LN harvest differed highly significantly with 35 +/- 18 and 17 +/- 10 LNs in the methylene blue-stained and unstained groups, respectively. Primary insufficient LN harvest occurred in 8 cases of the unstained group and in only 1 case of the methylene blue-stained group (P = .0226). After secondary dissection, upstaging was seen exclusively in the unstained group. The time/LN ratio differed significantly with 0.9 and 0.6 min/LN in the unstained and methylene blue-stained groups, respectively. Intraarterial methylene blue injection is recommended as a routine technique in the histopathologic study of colon cancer.

Elastosis of the colon and the ileum as polyp causing lesions: a study of six cases and review of the literature.

Benign lesions in the gastrointestinal tract characterized by an increase of elastic fibers in the submucosal and mucosal layer are termed elastoma, elastosis, elastofibroma or elastofibromatous change, and present mostly as polyps. Twenty-seven such cases are published in the English and French literature. Some lesions are similar to alterations which are well-known from elastofibroma dorsi of the scapular region. The morphology is highly suggestive of amyloid, but the results of Congo red staining are consistently negative. The etiology of these alterations remains unclear. Some authors consider elastoma a reactive process due to an injury, others speculate about a link to a systemic disease. We present six cases including a right and a left hemicolectomy specimen that presented as polypoid alterations of the ileum and the colon, respectively. Histologically, we found an impressive increase in fine fibrillar elastic fibers that showed a clear association to submucosal vessels. We did not observe elastofibroma-like alterations. After comparing literature cases, we conclude that elastofibromatous change consists either of two different stages, or even more likely, of two different entities. We propose the term angioelastosis for cases we describe in our study to emphasize the involvement of submucosal vessels.

Minimal residual disease in gastric cancer.

In curatively resected gastric cancer, the incidence of distant relapse is as high as 30%. Although the most important factor contributing to the local control of the tumor is the microscopic tumor-free margin of the surgical resection, the occurrence of distant metastases is in many cases due to preoperative or perioperative tumor cell dissemination. In addition to the established TNM staging system, disseminated tumor cells may serve as independent prognostic factors influencing patient outcome after curative surgery. Basically, in gastric cancer three compartments have been identified in which single tumor cells may be shed: lymph nodes, peritoneal cavity, and bone marrow. Assessment of resected regional lymph nodes with monoclonal antibodies directed against cytokeratin antigens leads to an upstaging in comparison with conventional histology. Nodal micrometastases detected by immunohistochemistry result in an upstaging of up to 36% of patients. However, their prognostic significance remains controversial. Local dissemination of tumor cells in the peritoneal cavity determines the outcome in advanced gastric cancer and diffuse-type carcinoma. Patients with negative peritoneal washings seem to have a more favorable prognosis. Moreover, with the use of these diagnostic tools, patient subpopulations may be identified which profit from intraperitoneal therapy regimens. Diffuse hematogenous tumor cell dissemination into the bone marrow has been shown to be a prognostic factor in several studies. In our own population of 180 gastric cancer patients, bone marrow cells were screened immunohistochemically with a monoclonal antibody directed against cytokeratin 18 (CK18). In 95 patients (53%), CK2-posititve cells were detected. In a multivariate analysis, the independence of the presence of three or more disseminated tumor cells per 10(6) mononuclear cells was proven to be a prognostic factor in patients with intestinal-type tumors, pT1/2 status, and pN0 status. In conclusion, the TNM status only partially reflects the actual extent of systemic disease in patients with resected gastric cancer. The assessment of minimal residual disease is valuable in estimating the prognosis in many patients. In the future, staging systems will have to not only include TNM data but also provide specific information on biological properties of residual cancer cells in order to establish more exact prognostic estimates and provide patients with an individually tailored multimodal treatment.