Bruno Märkl

Endoscopic submucosal dissection in large sessile lesions of the rectosigmoid: learning curve in a European center.

BACKGROUND AND STUDY AIMS Endoscopic submucosal dissection (ESD) in the colorectum is not currently a standard procedure. Few data are available from the Western world. The aim of the present study was to report on the first experiences and the learning curve of colorectal ESD in a European center. PATIENTS AND METHODS A total of 82 rectosigmoid lesions were referred for ESD. Lesion characteristics, resection rates, procedure times, complications, and recurrences were recorded prospectively. Results were compared between three consecutive study periods in order to determine the learning curve. RESULTS Lesions were located in the rectum (86.6 %) and the sigmoid colon (13.4 %). Median diameter was 45.5 mm. Lesions were of Paris type 0-Is with pit pattern type V (n = 8), 0-IIa (n = 33), 0-IIa + Is (n = 36), and 0-IIa + IIc (n = 5). The malignancy rate in these groups was 100 %, 0 %, 14 %, and 20 %, respectively. ESD was possible in 76 lesions (92.7 %). En bloc resection rate and R0 resection rate were 81.6 % and 69.7 %, respectively. Median procedure time was 176 minutes. Between the three consecutive study periods, en bloc resection rate increased (60.0 %, 88.0 %, 96.2 %), R0 resection rate increased (48.0 %, 76.0 %, 84.5 %; P < 0.001), and procedure time decreased (200, 193, 136 minutes; P = 0.027). The perforation and bleeding rates were 1.3 % and 7.9 %, respectively. Recurrence risk was 0 % after R0 en bloc resection and 41.7 % after piecemeal resection (P < 0.05). Median follow-up was 23.6 months. CONCLUSIONS In the European setting, ESD in the distal colon is feasible with acceptable complication risks. Resection rates were not as high as those from Japanese studies; however, a clear learning curve could be shown. Colorectal ESD needs to be further evaluated, particularly in Europe where ESD experience is low.

The Influence of Serial Sections, Immunohistochemistry, and Extension of Pelvic Lymph Node Dissection on the Lymph Node Status in Clinically Localized Prostate Cancer

OBJECTIVES Pelvic lymph node metastases indicate a poor prognosis for patients with clinically localized prostate cancer. The aim of the study was to investigate the value of extended histopathological techniques considering the extent of pelvic lymphadenectomy and preoperative risk factors. METHODS Total of 194 patients with prostate cancer were examined. At first all patients had a sampling of the sentinel lymph nodes (SLN) followed in most cases by a modified or extended pelvic lymphadenectomy. Step sections, serial sections and immunohistochemistry (IHC, pancytokeratin antibody) were analyzed in all SLN and so-called non-SLN of the first 100 patients. Later serial sections and IHC of non-SLN were left out. RESULTS In 26.8% lymphatic metastases were found. The detection rate of lymph node-positive patients depend significantly on the chosen extension of pelvic lymphadenectomy. Limiting the histopathological investigation to the lymph node specimen of the obturator fossa only 44.2% of lymph node-positive cases would have been identified. An additional inclusion of all lymph nodes surrounding the external iliac vessels improves the sensitivity to 65.4% (46.7% and 73.3% for the first 100 patients). Compared to the extension of pelvic lymphadenectomy the diagnostic gain of serial section and IHC (13.8% versus 53.3%) was comparably low. CONCLUSIONS The extension of pelvic lymph node dissection is of outstanding value for the identification of node-positive patients. Limiting the number of lymph nodes to the ones with the highest probability of bearing lymphatic spread (SLN) makes the use of extensive histopathological techniques more feasible.

Early esophageal cancer in Europe: endoscopic treatment by endoscopic submucosal dissection.

BACKGROUND AND STUDY AIMS Endoscopic resection is the standard treatment for superficial esophageal cancer. Data on early adenocarcinoma (EAC) are widely restricted to endoscopic mucosal resection (EMR), whereas large studies have been published on endoscopic submucosal dissection (ESD) for early squamous cell carcinoma (ESCC). ESD has potential advantages regarding en bloc and R0 resection rates, which have been demonstrated for ESCC. However, studies have failed to confirm these advantages in EAC. The aim of this study was to investigate the efficacy of ESD in early esophageal cancer. PATIENTS AND METHODS A total of 111 early esophageal cancers (87 EACs and 24 ESCCs) were resected by ESD at a German tertiary referral center. A total of 60 EACs were resected within Barretts segments ≤ M3. Resection rates, complications, and follow-up data were recorded prospectively. RESULTS En bloc resection rates were 95.4 % for EAC and 100 % for ESCC (P = 0.575), and R0 resection rates were 83.9 % and 91.7 %, respectively (P = 0.515). The R0 resection rate was higher in Barretts ≤ M3 vs. > M3 (90 % vs. 70.4 %; P = 0.029). The curative resection rate was 72.4 % for EAC vs. 45.8 % for ESCC (P = 0.026). Endoluminal recurrence was observed in 2.4 % of EACs (8 % in Barretts > M3, 0 % in Barretts ≤ M3), and 0 % of ESCCs. Complications included strictures (11.7 %) and bleedings (0.9 %), but no perforation. Disease-specific survival was 97.7 % (EAC) and 95.8 % (ESCC), and overall survival was 96.6 % (EAC) and 66.7 % (ESCC) over a mean follow-up period of 24.3 months and 38.0 months, respectively. CONCLUSIONS ESD was shown to be a safe resection method, achieving high R0 resection rates in both EAC and ESCC. Recurrence rates were low. To improve R0 resection within long Barretts segments, diagnosis of the lateral extension of the lesion needs to be improved.

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 (≤5%) compared to gastrointestinal stromal tumors (GISTs; ∼50%) and smooth muscle neoplasms (∼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.

Methylene blue injection into the rectal artery as a simple method to improve lymph node harvest in rectal cancer.

Adequate lymph node assessment in colorectal cancer is crucial for prognosis estimation and further therapy stratification. However, there is still an ongoing debate on required minimum lymph node numbers and the necessity of advanced techniques such as immunohistochemistry or PCR. It has been proven in several studies that lymph node harvest is often inadequate under routine analysis. Lymph nodes smaller than 5 mm are especially concerning as they can carry the majority of metastases. These small, but affected lymph nodes may escape detection in routine analysis. Therefore, fat-clearing protocols and sentinel techniques have been developed to improve accuracy of lymph node staging. We describe a novel and simple method of ex vivo methylene blue injection into the superior rectal artery of rectal cancer specimens, which highlights lymph nodes and makes them easy to detect during manual dissection. Initially, this method was developed for proving accuracy of total mesorectal excision. We performed a retrospective study comparing lymph node recovery of 12 methylene blue stained and an equal number of unstained cases. Lymph node recovery differed significantly with average lymph node numbers of 27±7 and 14±4 (P<0.001) for the methylene blue and the unstained group, respectively. The largest difference was found in size groups between 1 and 4 mm causing a shift in size distribution toward smaller nodes. Metastases were confirmed in 21 and 19 lymph nodes occurring in five and four cases, respectively. Hence, we conclude that methylene blue injection technique improves accuracy of lymph node staging by heightening the lymph node harvest in rectal resections. In our experience, it is a very simple time and cost effective method that can be easily established under routine circumstances.

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.

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.

Sclerosing nodular lesions of the gastrointestinal tract containing large numbers of IgG4 plasma cells

Background: Hyalinised fibrous nodules have been encountered within the gastrointestinal tract (GIT) and been labelled as reactive nodular fibrous tumours. Several have a history of abdominal surgery and/or sepsis that acts as a precipitating cause for the fibrosis. Recently, much attention has been focused on IgG4 related fibrosing lesions that are typically associated with a high population of IgG4 positive plasma cells and tissue fibrosis. There may be attendant elevated serum IgG4 levels and associated autoimmune disease. Methods: We present four patients with well-circumscribed fibrous nodular lesions occurring in the GIT. Tissue was formalin fixed after microwave antigen retrieval and H&E stains and immunohistochemistry were performed. IgG4/IgG ratios were calculated from the three high power fields containing the densest concentration of positive plasma cells. Results: The patients were two females (45 and 56 years) and two males (47 and 60 years) who presented with gastric (2 cases), caecal and sigmoid flexure involvement. One case had four lesions while the other three cases were solitary nodules. Two patients had coexistent autoimmune disease. All lesions were nodular and composed of paucicellular, hyalinised fibrous tissue associated with chronic inflammation. In all lesions the plasma cell population was strongly IgG4 positive. Conclusions: This paper describes unique, well-circumscribed sclerosing nodules containing IgG4 positive plasma cells within the bowel wall that may cause mucosal polypoid lesions. It is possible that these lesions may be related to the spectrum of IgG4 related sclerosing disease or belong to a separate subset of inflammatory reactive conditions that are rich in IgG4 plasma cells.

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.

Tumour budding, uPA and PAI‐1 are associated with aggressive behaviour in colon cancer

The proteases PAI‐1 and uPA play a major role in extracellular matrix degradation, which facilitates tumour progression. Tumour budding is a histomorphological expression of enhanced tumour cell migration.