Tumour stage distribution and survival of malignant melanoma in Germany 2002-2011.

BACKGROUND: Over the past two decades, there has been a rising trend in malignant melanoma incidence worldwide. In 2008, Germany introduced a nationwide skin cancer screening program starting at age 35. The aims of this study were to analyse the distribution of malignant melanoma tumour stages over time, as well as demographic and regional differences in stage distribution and survival of melanoma patients. METHODS: Pooled data from 61 895 malignant melanoma patients diagnosed between 2002 and 2011 and documented in 28 German population-based and hospital-based clinical cancer registries were analysed using descriptive methods, joinpoint regression, logistic regression and relative survival. RESULTS: The number of annually documented cases increased by 53.2% between 2002 (N = 4 779) and 2011 (N = 7 320). There was a statistically significant continuous positive trend in the proportion of stage UICC I cases diagnosed between 2002 and 2011, compared to a negative trend for stage UICC II. No trends were found for stages UICC III and IV respectively. Age (OR 0.97, 95% CI 0.97-0.97), sex (OR 1.18, 95% CI 1.11-1.25), date of diagnosis (OR 1.05, 95% CI 1.04-1.06), 'diagnosis during screening' (OR 3.24, 95% CI 2.50-4.19) and place of residence (OR 1.23, 95% CI 1.16-1.30) had a statistically significant influence on the tumour stage at diagnosis. The overall 5-year relative survival for invasive cases was 83.4% (95% CI 82.8-83.9%). CONCLUSIONS: No distinct changes in the distribution of malignant melanoma tumour stages among those aged 35 and older were seen that could be directly attributed to the introduction of skin cancer screening in 2008.

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.

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.

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.

Endoscopic submucosal dissection of early cancers, flat adenomas, and submucosal tumors in the gastrointestinal tract.

BACKGROUND & AIMS: Endoscopic submucosal dissection (ESD) is a promising technique in the treatment of large premalignant and early malignant gastrointestinal lesions. In contrast to Japan and Asian countries, few data are available from Western countries. The objective of this study was to assess the feasibility of ESD in a European center, with special regard for the success rate and learning curve. METHODS: Over a 4-year-period, 82 epithelial or submucosal lesions were referred for ESD. Seventy-one ESDs were performed (51 gastric, 17 rectal, 2 esophageal, and 1 duodenal). Resection rates, procedure times, specimen sizes, complications, and recurrences were noted. The mean follow-up period was 15 months. RESULTS: Specimen size increased significantly (P < .05) and procedural duration decreased significantly (P < .005) over time. En bloc resection rates and R0 en bloc resection rates were 77.1% and 65.7%, respectively, in the first half of the study and increased to 86.1% and 72.2%, respectively, in the second half (P = NS). No recurrence was observed after R0 en bloc resection whereas the recurrence rate was 38.5% after piecemeal resections (P < .001). Two perforations in the first series were treated by surgery; 2 other perforations, 8 minor bleedings, and 2 pyloric stenoses were treated endoscopically. CONCLUSIONS: ESD is technically feasible and shows promising results in this German single-center-study. ESD is time consuming and difficult but shows a learning curve resulting in a decrease of the procedural duration over time. R0 en bloc resection is mostly possible and can avoid the risk of local recurrence.

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.

Injecting methylene blue into the inferior mesenteric artery assures an adequate lymph node harvest and eliminates pathologist variability in nodal staging for rectal cancer.

PURPOSE: The American Joint Committee on Cancer recommends examination of a minimum of 12 lymph nodes in rectal cancer for accurate staging. Despite this, several studies have demonstrated that nodal harvest is highly variable and often inadequate. This study was designed to determine if staining the nodes with methylene blue dye produced a better and more accurate harvest in comparison with standard pathologic lymph node dissection. METHODS: Fifty patients with primary resectable rectal cancer were randomly assigned to undergo a standard nodal harvest or a harvest after ex vivo injection of the inferior mesenteric artery with methylene blue. A fat clearance technique was subsequently used to identify the maximum possible number of lymph nodes and metastasis. RESULTS: The average lymph node harvest was 30 +/- 13.5 in the stained group and 17 +/- 11 in the unstained group (P < 0.001). At least 12 nodes were identified in every case in the stained group. In the unstained group, 7 of 25 cases (28 percent) did not meet the minimum criteria of 12 nodes (P < 0.01). Among the pathologists for the stained group, no difference was found in the harvest (P < 0.05), but variability was detected between the pathologists in the unstained group (P = 0.6). After fat clearance, one case in the unstained group was upstaged, whereas no cases in the stained group were upstaged. CONCLUSIONS: Staining the lymph nodes with methylene blue dye is an accurate staging technique and reliably produces an adequate harvest.

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.

Number of Intratumoral T Lymphocytes Is Associated With Lymph Node Size, Lymph Node Harvest, and Outcome in Node-Negative Colon Cancer.

OBJECTIVES: We postulated that lymph node (LN) harvest and LN size are influenced by immunologic effects. METHODS: To investigate this hypothesis, we performed a retrospective analysis of 170 node-negative colon cancer cases to evaluate the density of intratumoral T lymphocytes (ITLs). CD3- and CD8-positive T cells were counted using a digital system. RESULTS: The ITL density was significantly increased in cases with sufficient LN harvest and high numbers of LNs larger than 5 mm (LN5). High ITL numbers were associated with improved cancer-specific survival. The analysis of the immune score revealed a significantly different cancer-specific outcome (P = .024), with no cancer-related death in the group with the highest score. The immune score and tumor budding were independently prognostic. CONCLUSIONS: ITL density is independently prognostic and associated with LN harvest and LN size. The immune response is very likely the true explanation for the known prognostic effect of the LN harvest in colon cancer.

Combined application of RT-PCR and immunohistochemistry on paraffin embedded sentinel lymph nodes of prostate cancer patients.

The detection of tumor cells in the sentinel lymph node (SLN) is of great importance for the prognosis of cancer patients. At present, immunohistochemistry and RT-PCR for tumor marker expression are the most sensitive techniques available for this analysis. However, so far, most RT-PCR-based analyses of SLNs have been performed on fresh material, excluding a direct comparison with the (immuno)histologic results. In our view, this does not entirely aid routine diagnosis. We established an efficient method for RNA extraction and RT-PCR from paraffin sections of SLNs from prostate cancer patients and compared the results with the (immuno)histologic data of adjacent sections. Amplifiable RNA was obtained from 133 SLNs of 68 prostate cancer patients. Correlation of PSA-specific RT-PCR with (immuno)histologic findings showed a positive and negative predictive value of 83% and 100%, respectively, for the prostate cancer patients investigated. Four of 12 patients with biochemical relapse, but without (immuno)histologically detectable tumor cells were RT-PCR-positive for PSA. We found that single sections of paraffin-embedded SLNs are suitable for routinely performed RT-PCR. Combined with (immuno)histology, PSA-specific RT-PCR is a revealing supplementary technique for the detection of tumor cells in SLNs of prostate cancer patients.

Clinical implications of the EGF receptor/ligand system for tumor progression and survival in gastrointestinal carcinomas: evidence for new therapeutic options.

The epidermal growth factor (EGF) receptor and its various ligands (EGF, TGF-alpha, amphiregulin, heparin-binding (HB)-EGF, heregulin, betacellulin) seem to be involved in the growth regulation of intestinal mucosa and might be related to the development and progression of gastrointestinal tumors. However, few quantitative data investigating the impact of tumor-EGF receptor levels in gastrointestinal carcinomas on tumor stage and prognosis are available. Therefore, EGF receptors were quantitatively determined in colorectal carcinomas in comparison to adjacent normal mucosa by 125I[EGF]-binding studies. EGFR capacity was increased in advanced invasive colorectal carcinomas (T1/2 vs. T3/4 tumors, p<0.001) and advanced UICC stages (UICC I vs. UICC II/III, p<0.001). These findings were confirmed with quantitative 125[I]EGF autoradiography performed on frozen tissue slides and analyzed by laser densitometry (p=0.020). EGF receptor analysis with immunohistochemistry with EGFR antibodies directed against the extracellular domain of the receptor was not correlated with tumor invasion or prognosis. mRNA-expression of EGFR ligands was investigated using semiquantitative RT-PCR amplification using specific primers. RT-PCR transcripts of EGFR ligands (EGF, TGF-alpha, HB-EGF, and amphiregulin) were detected in both carcinomas and normal mucosa, indicating that autocrine growth stimulation of colorectal carcinomas is mediated by coexpression of EGF receptor ligands and upregulation of EGF receptors. Survival of colorectal cancer patients with increased tumor EGF receptor levels was significantly reduced in comparison to patients with low/unchanged tumor EGF receptor levels (mean survival+/-SD, 36.2+/-4.0 vs. 46.8+/-4.3 months; p=0.017). Further studies investigating EGF receptor levels in gastric cancer patients have shown that increased tumor EGF receptor levels were associated with poor prognosis in gastric cancer patients with tumors localized distal from the cardia. Several specific EGF receptor tyrosine kinase inhibitors have recently entered clinical phase I-III studies, with promising antitumor effects in several tumors, including gastrointestinal cancer. Therefore, patients with invasive gastric or colorectal carcinomas might benefit from therapies specifically blocking EGFR-mediated signal transduction.

A very unusual thyroid tumor: a nodule with mature fat papillary hyperplasia and focal atypia.

Fat-containing lesions of the thyroid are rare, encompassing several clinical-pathological conditions such adenolipomas, thyrolipomatosis and lipomotous tissue in case of amyloidosis. Furthermore, cases of papillary thyroid carcinoma have been identified in association with thyrolipomatosis. We report a case of 51 years old man referred to surgery for a multinodular goiter, showing multiple cystic and hemorrhagic nodules of up to 3 cm. One of these lesions showed features of papillary hyperplasia with focal cytological atypia and mature fat. Here, we describe and discuss the histological and immunophenotypical features of this rare lesion.

Prognostic significance of tumor budding in gastrointestinal tumors.

Tumor budding describes the presence of single tumor cells or small tumor cell clusters at the invasion front of carcinomas. It is currently thought to be the result of epithelial-mesenchymal transformation. Tumor budding can be appreciated histologically during routine evaluation of malignant polyps or surgical specimens of malignant tumors. Many studies have been published assessing cancers in all locations from the esophagus to the rectum, almost always reporting similar results. This seems especially remarkable as a generally accepted definition of how budding must be evaluated is still lacking. Regardless of the location, tumor budding generally is associated with nodal metastases and aggressive behavior, and it is mostly independent from other adverse factors. While the prognostic value of tumor budding is evident, especially in stage II colorectal cancers, it still has no therapeutic implications. This is owing to the heterogeneity of the performed studies and the lack of oncological studies, which are urgently needed.

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 (< or =5%) compared to gastrointestinal stromal tumors (GISTs; approximately 50%) and smooth muscle neoplasms ( approximately 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.

Shape is not associated with the origin of pericolonic tumor deposits.

Pericolonic tumor deposits (PTDs) are associated with an adverse outcome in colorectal cancer. According to the International Union Against Cancer they are classified as N1 or V1/V2 depending on their shape. This recommendation, however, is not well supported by the literature. To elucidate the origin of PTDs, we performed a histomorphologic study of 69 PTDs, which were found in 7 of 21 colorectal specimens using the whole-mount step-section technique. Depending on the origin, the nodules were classified as venous invasions, lymphatic invasions, nerve sheath infiltrations, free PTDs, and continuous growth in 18 (26%), 3 (4%), 6 (9%), 34 (49%), and 8 (12%) of 69 PTDs, respectively. Polycyclic and oval-round shapes were identified in all categories. Continuous growth was found only within the inner third of the adhering fat, whereas the other morphologic features were found in all regions. The data of this study do not support PTD classification on the basis of their shape.

Sporadic segmental Interstitial cell of cajal hyperplasia (microscopic GIST) with unusual diffuse longitudinal growth replacing the muscularis propria: differential diagnosis to hereditary GIST syndromes.

Gastrointestinal stromal tumors (GIST) usually form a well-circumscribed mass. However, patients with germline mutations in c-KIT, PDGFRA and NF1 may present with diffuse interstitial cell of Cajal (ICC) hyperplasia along the Auer-bach plexus without forming a discrete mass. To our knowledge, sporadic diffuse ICC hyperplasia replacing the gut wall has not been described previously. We describe herein two such cases. Case 1 was a 59-yr-old woman who presented with signs of ileus and a large mass submitted as Meckel diverticulum. The resection specimen showed a large GIST with diverticulum-like and solid areas. The diverticular component showed a diffuse proliferation of spindle cells extending for several centimetres from the solid tumor replacing the full thickness of the gut wall and lined by intact mucosa. Mutation analysis revealed a combined deletion/insertion in c-KIT exon 11 (V560delEins) in both the solid and the diffuse tumor component. Case 2 was a 66-yr-old man who underwent segmental sigmoid colon resection for adenocarcinoma in a villous adenoma. Random sections from grossly unremarkable colonic wall showed a diffuse proliferation of CD117+/CD34+ spindle cells completely replacing the muscularis propria for a length of 6 mm. Molecular analysis revealed a somatic point mutation/ deletion in exon 11 of c-KIT (Q575L; L576_W582del). Absence of multiple lesions and demonstration of a wild-type sequence for c-KIT in surrounding normal tissue ruled out the possibility of a germline mutation in both cases. This peculiar diffuse form of sporadic ICC hyperplasia results from somatic c-KIT mutations and must be distinguished from syndromic ICC hyperplasia associated with hereditary GIST syndromes.

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.

Perioperative activation of disseminated tumor cells in bone marrow of patients with prostate cancer.

PURPOSE: The outcome of prostate cancer is highly unpredictable. To assess the dynamics of systemic disease and to identify patients at high risk for early relapse we followed the fate of disseminated tumor cells in bone marrow for up to 10 years and genetically analyzed such cells isolated at various stages of disease. PATIENTS AND METHODS: Nine hundred bone marrow aspirates from 384 patients were stained using the monoclonal antibody A45-B/B3 directed against cytokeratins 8, 18, and 19. Log-rank statistics and Cox regression analysis were applied to determine the prognostic impact of positive cells detected before surgery (244 patients) and postoperatively (214 patients). Samples from primary tumors (n = 55) and single disseminated tumor cells (n = 100) were analyzed by comparative genomic hybridization. RESULTS: Detection of cytokeratin-positive cells before surgery was the strongest independent risk factor for metastasis within 48 months (P < .001; relative risk [RR], 5.5; 95% CI, 2.4 to 12.9). In contrast, cytokeratin-positive cells detected 6 months to 10 years after radical prostatectomy were consistently present in bone marrow with a prevalence of approximately 20% but had no influence on disease outcome. Characteristic genotypes of cytokeratin-positive cells were selected at manifestation of metastasis. CONCLUSION: Cytokeratin-positive cells in the bone marrow of prostate cancer patients are only prognostically relevant when detected before surgery. Because we could not identify significant genetic differences between pre- and postoperatively isolated tumor cells before manifestation of metastasis, we postulate the existence of perioperative stimuli that activate disseminated tumor cells. Patients with cytokeratin-positive cells in bone marrow before surgery may therefore benefit from adjuvant therapies.