Hanno Spatz

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.

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.

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.

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.

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.

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.

Laparoskopische kolorektale Tumorchirurgie

Das kolorektale Karzinom stellt mit ca. 639 000 krebsbezogenen Todesfällen pro Jahr weltweit eine der häufigsten Todesursachen in der westlichen Hemisphäre dar. Die radikale chirurgische Tumorentfernung ist die entscheidende Behandlungsoption und stellt ein klassisches Betätigungsfeld des Allgemein- und Viszeralchirurgen dar. Resektabilität und an embryologisch-anatomischen Schichten orientierte optimale chirurgische Technik sind entscheidend für das Überleben der Betroffenen. Die minimal invasive Chirurgie scheint nach über 20 Jahre währendem Einsatz eine Alternative zum offenen Vorgehen darzustellen. Ziel der vorliegenden Arbeit war, mithilfe einer Literatursuche in PubMed, DIMDI und EMBASE – ergänzt durch eigene klinische Erfahrungen – den aktuellen Stand, Besonderheiten und neue Entwicklungen der minimal invasiven Chirurgie des kolorektalen Karzinoms darzustellen. Für die onkologische Sicherheit der laparoskopischen Resektionstechnik im Vergleich zum konventionell offenen Vorgehen besteht heute ausreichende Evidenz. Problematisch bleiben die flache Lernkurve und die bei unkritischem Einsatz der Methode und hoher Umsteigeschwelle schlechteren onkologischen Ergebnisse konvertierter Patienten. Unbestritten bringt die Laparoskopie Vorteile für die perioperative Rekonvaleszenz und Kosmetik. Für neue Entwicklungen wie NOTES (natural orifice transluminal endoscopic surgery), «single access»-Strategien (single incision laparoscopic surgery, SILS) wie auch roboterassistierte Techniken fehlen bislang über den Nachweis reiner Machbarkeit hinaus valide Langzeitdaten hinsichtlich der onkologischen Sicherheit. Die Anwendung dieser Techniken sollte daher nur innerhalb kontrollierter Studien stattfinden. In geübter Hand ist die laparoskopische Resektionstechnik nach EBM-Kriterien eine onkologisch sichere Alternative zum Goldstandard des offenen Vorgehens. In keiner Weise darf die minimal invasive Technik jedoch als landesweit flächendeckende Therapieoption angesehen werden und sollte spezialisierten Zentren vorbehalten bleiben.

Sentinel lymph node mapping by colonic tattooing: reply

To the Editors, We feel very grateful and privileged for the visionary discussion of our article by Dr. Cahill and colleagues. In his own recently published study Dr. Cahill provides strong support of the ‘‘in vivo’’ sentinel node concept in early (T1 and T2) colon cancer showing that, under optimal conditions, the negative predictive value of sentinel node biopsy is as high as 97%. In retrospect, the data suggest that localized resection would have been proper treatment for about 75% of patients with T1 cancers [1]. While the mean lymph node harvest in Cahill et al.’s study was 16.8 [standard deviation (SD) 9.5], we speculate that the number of detectable lymph nodes could have been remarkably increased by simple ex vivo Methylene Blue injection into the feeding artery, as we could show for rectal [2] and colon [3] cancers with mean number of retrieved lymph nodes as high as 42 (SD 18) (data not published yet). Since the number of harvested lymph nodes is related to the probability of detecting metastatic nodes [4], sensitivity and negative predictive value might have been altered also. Nevertheless, we totally agree that we are in need of criteria defining the applicability of limited resection of early colon cancer, be it endoscopically, laparoscopically or via access by natural orifice transluminal endoscopic surgery (NOTES) or single-port techniques. Facing accumulating— and vigorously debated—evidence that systemic lymphadenectomy as a surgical treatment option and conditio sine qua non itself may not affect patient survival in a variety of malignant diseases including colon cancer [5], we should be more open-minded regarding new techniques holding the potential to yield the indispensable and undebatable staging information of the N-category without the intrinsic morbidity of systemic lymphadenectomy. In this scenario, in vivo sentinel lymph node mapping indeed seems intriguing despite the well-known pitfalls. In addition to applying new marker substances in the attempt to facilitate in vivo detection of mapped sentinel nodes, concomitant use of other parameters indicating increased risk for lymph node metastasis in early colon cancer such as tumor budding should also be taken into consideration [6]. Moreover, the relevance of lateral lymph nodes in rectal cancer is still unclear. Even though routine lateral lymph node dissection is not established in the Western hemisphere, the investigation of such nodes seems interesting for staging reasons. Therefore, our group is in the process of planning to apply the in vivo sentinel concept in cancers of the lower rectum by use of radioisotope marking of the lesion and gamma-camera scanning of the lateral lymphatic draining pathways and consecutive laparoscopic lymph node biopsy in case of positive sentinel mapping. In conclusion, we strongly support Dr. Cahills and colleagues’ suggestions for further studies concerning the sentinel node concept in early colon cancer. We believe that, by increasing the predictive reliability of the sentinel finding, limited resection and therefore reducing morbidity will turn out to be one way to go in a selected collective of patients. Sincerely, Hanno Spatz and Bruno Märkl