Tina Schaller

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.

Endoscopic submucosal dissection for early rectal neoplasia: experience from a European center.

Background and study aims Endoscopic resection is a curative treatment option for large nonpedunculated colorectal polyps (LNPCPs). Endoscopic submucosal dissection (ESD) allows en bloc resection but ESD experience is still limited outside Asia. The aim of our study was to evaluate the role of ESD in the treatment of early rectal neoplasia in a European center. Patients and methods 330 patients referred for endoscopic resection of rectal LNPCPs were included prospectively. Results ESD was performed for 302 LNPCPs (median diameter 40 mm). Submucosal invasive cancer (SMIC) was present in 17.2 % (n = 52). SMIC was associated with Paris type (54.5 % among type 0-Is lesions, 100 % of 0-Is-IIc type, 0 % of 0-IIa, 14.9 % of 0-IIa-Is, and 59.3 % of 0-IIa-IIc type; P < 0.001) and with surface pattern (71.4 % among nongranular plus mixed surface lesions, 17.9 % of lesions with granular surface and nodule ≥ 10 mm). For SMICs, resection rates were en bloc 81.4 %, R0 65.1 %, and curative 30.2 %. Curative resection rate improved from 13.6 % to 47.6 % over the study period (P = 0.036). The reason for 83.3 % (25/30) of noncurative resections was submucosal invasion exceeding 1000 µm. For benign lesions (n = 250, 82.8 %), the R0 resection increased from 55.2 % to 84.8 % over the study period (P < 0.001). Recurrence rate was 4.8 %, bleeding rate 5.2 %, and perforation rate 0.8 % (all complications managed conservatively). Median follow-up was 35 months. Conclusions The majority of rectal LNPCPs are benign lesions. ESD offers high R0 resection and low recurrence rates but EMR may be appropriate. In lesions with a risk for SMIC, ESD should be offered to achieve R0 resection. Despite high rates of R0 resection the curative resection rate of ESD for rectal SMIC is < 50 %. Pretherapeutic lesion selection needs improvement.

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.

Endoscopic submucosal dissection for early gastric cancer: are expanded resection criteria safe for Western patients?

Background and study aims Endoscopic submucosal dissection (ESD) is the standard treatment for early gastric cancer (EGC) fulfilling guideline resection criteria or the expanded resection criteria in Asia. It is unclear whether the expanded criteria can be transferred to European patients, and long-term follow-up data are lacking. The aim of this study was to evaluate long-term follow-up data after ESD of EGCs in Europe. Patients and methods Patients with EGC who underwent ESD were included in this single-center study at a German referral center. Patient and lesion characteristics, procedure characteristics, and follow-up data were recorded prospectively. Results A total of 179 patients with 191 EGCs were included over a period of 141 months, with 29.6 % of lesions meeting guideline criteria and 48.6 % meeting expanded criteria. The en bloc resection rate was 98.4 % for guideline criteria and 89.0 % for expanded criteria lesions (P = 0.09), and the R0 resection rate was 90.2 % and 73.6 %, respectively (P = 0.02). The main reason for the expanded criteria was a lesion diameter > 20 mm (81.6 %). COMPLICATIONS perforation 1 %, delayed bleeding 6.3 %, stricture 2.1 %, procedure-related mortality 1.1 %. Local recurrence rate was 0 % for guideline criteria and 4.8 % for expanded criteria lesions (P = 0.06), and the rate of metachronous neoplasia was 15.1 % and 7.1 %, respectively (median follow-up 51 and 56 months, respectively); 92.9 % of metachronous neoplasia were treated curatively with repeat ESD. One patient developed lymph node metastasis after ESD of a submucosal invasive expanded criteria lesion. Long-term-survival was comparable between the two criteria (P = 0.58). No gastric cancer-related death was observed in either group. Conclusions ESD can achieve high rates of long-term curative treatment using the expanded criteria in EGCs in Western countries. We recommend ESD as treatment of choice not only for guideline criteria EGCs but also for intramucosal nonulcerated EGCs regardless of their diameter.

‘Neuroendocrine’ middle ear adenomas: consistent expression of the transcription factor ISL1 further supports their neuroendocrine derivation

Neuroendocrine middle ear adenoma (MEA) is a rare epithelial neoplasm of uncertain histogenesis that frequently shows neuroendocrine features. To date, <120 cases have been reported. The aims of the current study were to describe our experience with neuroendocrine MEA, to assess the frequency of specific neuroendocrine differentiation, and to test these lesions for transcription factors known to be expressed in a variety of other neuroendocrine tumours.

The role of lymph node size and FOXP3+ regulatory T cells in node-negative colon cancer

Recently, we demonstrated that the intratumoural density of CD3+ and CD8+ T cells is independently prognostic and associated with lymph node (LN) harvest and LN size in node-negative colon cancer. We assumed that FOXP3+ T cells (Tregs) could be inversely associated with these LN features. Therefore, we performed a retrospective immunohistochemical analysis using an already well-characterised collection of stage I/II colon cancer cases. Receiver operating characteristic analysis revealed the optimal cut-off for predicting cancer-related death to be 70 FOXP3+ Tregs/mm2 at the invasion front. Other than T-stage, none of the relevant histopathological parameters were associated with the density of FOXP3+ cells. In particular, no relation to LN size and count were found. Cancer-specific survival was significantly improved in cases with high densities (115 vs 86 months; p=0.026) in univariable but not in multivariable analysis. In contrast to other cancers, FOXP3+ T cells are associated with a favourable outcome.

Tumor Budding, uPA, and PAI-1 in Colorectal Cancer: Update of a Prospective Study

Aims. The prognostic role of the proteases uPA and PAI-1, as well as tumor budding, in colon cancer, has been investigated previously. Methods. We provide 6-year follow-up data and results of the validation set. The initial test set and validation set consisted of 55 colon cancers and 68 colorectal cancers, respectively. Tissue samples were analyzed for uPA and PAI-1 using a commercially available Enzyme-Linked Immunosorbent Assay (ELISA). Tumor budding was analyzed on cytokeratin-stained slides. Survival analyses were performed using cut-offs that were determined previously. Results. uPA was not prognostic for outcome. PAI-1 showed a trend towards reduced cancer specific survival in PAI-1 high-grade cases (68 versus 83 months; P = 0.091). The combination of high-grade PAI-1 and tumor budding was associated with significantly reduced cancer specific survival (60 versus 83 months; P = 0.021). After pooling the data from both sets, multivariate analyses revealed that the factors pN-stage, V-stage, and a combination of tumor budding and PAI-1 were independently prognostic for the association with distant metastases. Conclusions. A synergistic adverse effect of PAI-1 and tumor budding in uni- and multivariable analyses was found. PAI-1 could serve as a target for anticancer therapy.

Specific immunohistochemical pattern of carbonic anhydrase IX is helpful for the diagnosis of CNS hemangioblastoma.

Hemangioblastomas are rare capillary-rich tumors predominantly found in the CNS. The histological appearance of these tumors varies across a broad spectrum. Several entities show considerable histomorphological similarities to hemangioblastomas. Therefore, morphological evaluation can be challenging. In this study, we evaluated the diagnostic utility of immunohistochemistry using antibodies against carbonic anhydrase IX and cytokeratin staining. Within our files, we identified 20 hemangioblastomas. A collection of 46 other tumors relevant to the differential diagnosis (12 pilocytic astrocytomas, 11 meningiomas, one pleomorphic xanthoastrocytoma, one angiomatous fibrous histiocytoma, 14 carcinoma metastases and seven gliomas grades II-IX) served as control. The pattern of strong, diffuse expression of carbonic anhydrase IX with membranous accentuation in combination with keratin negativity was considered diagnostic for hemangioblastomas. It was found in 18 out of 20 (90%) hemangioblastomas and in none of the control cases (P < 0.001). This resulted in a sensitivity of 90% and a specificity of 100%. The positive and negative predictive values were 100% and 96%, respectively. Carbonic anhydrase IX with cytokeratin is thus a highly sensitive and specific marker combination for hemangioblastomas. It is therefore very helpful in the diagnosis of these tumors and in their discrimination from other entities.

Interobserver variability in the H&E-based assessment of tumor budding in pT3/4 colon cancer: does it affect the prognostic relevance?

Tumor budding is a mostly accepted adverse prognostic factor in colorectal carcinoma. It is on the cusp of a widespread use after agreement was reached recently on uniform assessment criteria. We investigated whether the interobserver variability has a direct influence on the prognostic relevance in pT3/4 colon cancer in the background of different levels of experience of the investigators. In total, six investigators with different levels of experience evaluated tumor budding on H&E slides in 244 cases with primary diagnosed (2002–2011) colon carcinoma (pT3/4, N+/−, M0). High-grade tumor budding/budding grade 3 (defined as majority assessment among the investigators) was significantly associated with an adverse outcome (overall survival p = 0.03, cancer-specific survival p = 0.08) and the occurrence of distant metastasis (p = 0.009). However, a detailed analysis of the rating results of the individual investigators revealed that only ratings of one investigator (advanced resident) were associated with an adverse outcome (p = 0.01 cancer-specific survival, overall survival p = 0.09, distant metastasis p = 0.002). The results of another investigator (consultant) were significantly associated with distant metastasis (p = 0.007). The kappa values among the investigators have a range between 0.077 and 0.357 (median 0.166). Total agreement of all investigators existed in 109 cases (44.7%). Our results demonstrate that the evaluation of tumor budding on H&E slides in pT3/4 colon cancer goes along with a considerable interobserver variability among investigators of different levels of experience. Furthermore, our results reveal that these findings directly influence the prognostic value.

Value of histomorphometric tumour thickness and smoothelin for conventional m-classification in early oesophageal adenocarcinoma

AIM To test the validity of tumour thickness measurement in distinguishing between the different infiltration depths, especially when the duplication of muscularis mucosae cannot be demarcated clearly. METHODS We re-evaluated 100 completely embedded Barrett’s adenocarcinomas regarding m-classification, maximum tumour thickness, and muscularis mucosae duplication. For validation, smoothelin staining was performed on a subset of cases. RESULTS The m1-, m2- and m3-classified adenocarcinomas showed a significant lower tumour thickness compared to the m4- and sm1-classified lesions (P < 0.001). Smoothelin staining determined a clear muscularis mucosae duplication in 64% of the tested samples and enabled the differentiation of the two layers in diffuse and merged splits. CONCLUSION Tumour thickness in early oesophageal adenocarcinoma significantly correlates with the depth of infiltration and demonstrates its worth as an accurate pT classification in non-polypoid lesions. We created a new algorithm, which combines histomorphology with morphometric analyses. It is noteworthy that it facilitates the assessment of mucosal vs submucosal infiltration depth. The smoothelin staining strengthened our results of the tumour thickness evaluation and can be used in cases of doubt.