A. Bembenek

Sentinel lymph node biopsy in colon cancer: A prospective multicenter trial

Introduction:The clinical impact of sentinel lymph node biopsy (SLNB) in colon cancer is still controversial. The purpose of this prospective multicenter trial was to evaluate its clinical value to predict the nodal status and identify factors that influence these results. Methods:Colon cancer patients without prior colorectal surgery or irradiation were eligible. The sentinel lymph node (SLN) was identified intraoperatively by subserosal blue dye injection around the tumor. The SLN underwent step sections and immunohistochemistry (IHC), if classified free of metastases after routine hematoxylin and eosin examination. Results:At least one SLN (median, n = 2) was identified in 268 of 315 enrolled patients (detection rate, 85%). Center experience, lymphovascular invasion, body mass index (BMI), and learning curve were positively associated with the detection rate. The false-negative rate to identify pN+ patients by SLNB was 46% (38 of 82). BMI showed a significant association to the false-negative rate (P < 0.0001), the number of tumor-involved lymph nodes was inversely associated. If only slim patients (BMI ≤24) were investigated in experienced centers (>22 patients enrolled), the sensitivity increased to 88% (14 of 16). Moreover, 21% (30 of 141) of the patients, classified as pN0 by routine histopathology, revealed micrometastases or isolated tumor cells (MM/ITC) in the SLN. Conclusions:The contribution of SLNB to conventional nodal staging of colon cancer patients is still unspecified. Technical problems have to be resolved before a definite conclusion can be drawn in this regard. However, SLNB identifies about one fourth of stage II patients to reveal MM/ITC in lymph nodes. Further studies must clarify the clinical impact of these findings in terms of prognosis and the indication of adjuvant therapy.

Efficacy of Different Technical Procedures for Sentinel Lymph Node Biopsy in Gastric Cancer Staging

BackgroundThe clinical impact of sentinel lymph node biopsy (SLNB) in gastric cancer is controversial. We performed a prospective trial to compare different methods: radiocolloid method (RM), dye method (DM), and both methods simultaneously (dual method, or DUM) for reliability and therapeutic consequences.MethodsRM and DM were applied in 35 gastric cancer patients. After endoscopic peritumoral injection of 99mTc-colloid and Patent Blue V, the positions of all blue sentinel lymph nodes (SLNs) were recorded, and the SLNs microscopically examined by hematoxylin and eosin, step sections, and immunohistochemistry.ResultsRM, DM, and DUM identified the SLNs in 34 (97%) of 35 patients. The sensitivity for the prediction of positive lymph node status for RM was 22 (92%) of 24, for DM 16 (66%) of 24, and for DUM 22 (92%) of 24. In 7 of 17 (RM), 5 of 15 (DM), and 7 of 17 (DUM) patients classified as N0 by routine hematoxylin and eosin staining, micrometastases or isolated tumor cells were found in the SLN (upstaging) after focused examination. If only a limited lymph node dissection of the SLN basins would have been performed in patients, residual lymph node metastases were left in 9 of 24 (RM), in 7 of 34 (DM), and in 5 of 24 (DUM) of patients with node-positive disease.ConclusionsUse of RM was superior. DUM did not further increase the sensitivity. A limited lymph node dissection—i.e., lymphatic basin in patients with SLN-positive disease—is associated with a high risk of residual metastases. Patients with negative SLNs may be selected for a limited surgical procedure if they meet certain criteria.

Detection of Lymph Node Micrometastases and Isolated Tumor Cells in Sentinel and Nonsentinel Lymph Nodes of Colon Cancer Patients

About 20% to 30% of colon cancer patients classified as node negative by routine hematoxylin-eosin (H&E) staining are found to have micrometastases (MM) or isolated tumor cells (ITC) in sentinel lymph nodes (SLNs) if analyzed by step sections and immunohistochemistry (IHC). Whether SLNs are in this respect representative for all lymph nodes was addressed in this study. SLNs were identified using the intraoperative blue dye detection technique. If all lymph nodes (SLNs and non-SLNs) of a patient were negative by routine H&E staining, they were step-sectioned and analyzed by IHC using pancytokeratin antibodies. We identified at least one SLN in 47 of the 55 patients (85%) and examined a median of 26 lymph nodes per patient (range 10–59). By routine H&E staining, 14 of the 47 patients showed lymph node metastases (30%); the remaining 33 were classified as node-negative. In this group (33 patients), 1011 lymph nodes were analyzed by step sections and IHC: 14 of 70 SLNs. (20%) but only 37 of 941 non-SLNs (4%) had MM/ITC (p < 0.001). Furthermore, 13 of the 33 H&E-negative patients were found to have MM/ITC (39%). In 11 of the 13 patients, MM/ITC were identified in both SLNs and non-SLNs in 1 patient in the SLN only, and in 1 patient in a non-SLN only (sensitivity for the identification of MM/ITC: 92%; negative predictive value: 95%). The SLN biopsy is a valid tool to detect, as well as exclude, the presence of MM/ITC in colon cancer patients. Our results may be of prognostic relevance and influence patient stratification for adjuvant therapy trials.

Body Mass Index Does Not Affect Systematic D2 Lymph Node Dissection and Postoperative Morbidity in Gastric Cancer Patients

AbstractBackground: The extent of standard lymph node dissection (D1, D2, or D3) in gastric cancer patients is still controversial. Several prospective European trials attained contradictory results. A generally increased body mass index (BMI) of the European patients was assumed to be one of the major causes for postoperative morbidity. Methods: We evaluated the effect of BMI on the quality of routine D2 lymph node dissection and on postoperative morbidity in patients with gastric cancer who underwent a potentially curative total gastrectomy. A total of 199 consecutive gastric cancer patients who underwent a total gastrectomy and a routine D2 lymph node dissection between 1992 and 2001 were included in the study. According to BMI, they were assigned to three groups: group A, with BMI <25 kg/m2 (normal body weight); group B, with BMI of 25 to 30 kg/m2 (overweight); and group C, with BMI >30 kg/m2 (obesity). Parameters such as complete histopathological staging, intraoperative blood loss, length of operation, and surgical and nonsurgical morbidity were recorded and correlated within the different groups. Results: No significant differences were found with regard to the number of examined lymph nodes, blood loss, length of operation, surgical complications, or length of stay in the intensive care unit. Conclusions:In contrast to comparable Japanese studies, our analysis reveals that even for overweight patients, a standard D2 lymph node dissection is justified without significantly increased morbidity.

Novel Jet-Injection Technology for Nonviral Intratumoral Gene Transfer in Patients with Melanoma and Breast Cancer

Purpose: This phase I clinical trial evaluated safety, feasibility, and efficiency of nonviral intratumoral jet-injection gene transfer in patients with skin metastases from melanoma and breast cancer. Experimental Design: Seventeen patients were enrolled. The patients received five jet injections with a total dose of 0.05 mg β-galactosidase (LacZ)-expressing plasmid DNA (pCMVβ) into a single cutaneous lesion. Clinical and laboratory safety monitoring were done. Systemic plasmid clearance was monitored by quantitative real-time PCR of blood samples throughout the study. All lesions were resected after 2 to 6 days. Intratumoral plasmid DNA load, DNA distribution, and LacZ expression was analyzed by quantitative real-time PCR, quantitative reverse transcription-PCR, Western blot, immunohistochemistry, and 5-bromo-4-chloro-3-indolyl-β-d-galactoside staining. Results: Jet injection of plasmid DNA was safely done in all patients. No serious side effects were observed. Thirty minutes after jet injection, peak plasmid DNA levels were detected in the blood followed by rapid decline and clearance. Plasmid DNA and LacZ mRNA and protein expression were detected in all treated lesions. Quantitative analysis revealed a correlation of plasmid DNA load and LacZ-mRNA expression confirmed by Western blot. Immunohistochemistry and 5-bromo-4-chloro-3-indolyl-β-d-galactoside staining showed LacZ-protein throughout the tumor. Transfected tumor areas were found close and distant to the jet-injection site with varying levels of DNA load and transgene expression. Conclusion: Intratumoral jet injection of plasmid DNA led to efficient LacZ reporter gene expression in all patients. No side effects were experienced, supporting safety and applicability of this novel nonviral approach. A next step with a therapeutic gene product should determine antitumor efficacy of jet-injection gene transfer.

Lymphatic mapping and sentinel lymph node biopsy in epidermoid carcinoma of the anal canal

AIM Although 15-25% of patients with anal cancer present with superficial inguinal lymph node metastases but the routine application of groin irradiation is controversial because of serious side effects. Inguinal sentinel lymph node biopsy (SLNB) can be used to select patients appropriately for inguinal radiation. The study evaluates the efficiency and clinical impact of SLNB. METHODS Forty patients with anal cancer underwent 1 ml Tc(99m)-Nanocolloid injection in four sites around the tumour. Patients with inguinal radio colloid enrichment were selected for sentinel lymph node biopsy (SLNB). Lymph node status was examined by haematoxylin and eosin (H&E) as well as immunohistochemistry-staining. All SLN-positive patients were scheduled for inguinal radiation; SLN-negative patients with T1 and early T2 tumours were not scheduled for inguinal radiation. RESULTS SLN were detected in 36/40 patients. Three common patterns of lymphatic drainage were observed: mesenterial, iliacal and inguinal. Twenty patients with inguinal SLN underwent SLN-biopsy. 6/20 patients were SLN-positive. In 10/20 patients SLNB altered the therapy plan--four patients with T1-tumours and positive SLN had additional groin irradiation, whereas 6 patients with small T2-tumors and tumour-free inguinal SLN did not undergo inguinal irradiation. CONCLUSIONS Inguinal sentinel node biopsy in anal cancer is efficient and could assist in the decision for inguinal radiation. The validity and safety of the proposed therapeutic algorithm has to be proven by a larger, prospective study.

Sentinel lymph node dissection in breast cancer

During the last years, the efficacy and reliability of the sentinel lymph node biopsy (snb) as a minimal invasive diagnostic procedure for the nodal status has been intensively evaluated. After the widespread clinical use in the staging of melanoma patients the snb is currently introduced in the clinical management of breast cancer patients. We present our experience with this method during 3, 5 years and discuss its potential and pitfalls. From 11/95 to 3/99 we performed sentinel node detection in 146 patients with breast cancer stage I to III, consisting of 127 patients with pT1/2-tumors and 19 patients with pT3/4-tumors. We used the radionuclid method including preoperative lymphoscintigraphy and intraoperative gamma-probe detection. The detection rate varied with the tumor size between 94% for tumors with a diameter < 1 cm, 85% (1-3 cm), 70% (3-5 cm) and 63% (> 5 cm). The accuracy of the snb in the prediction of the nodal status changed also with the tumor diameter between 100% for very small tumors (< 1 cm), 97% (1-3 cm), 88% (3-5 cm) and 67% (> 5 cm). In the subgroup of patients restricted to T1-2-tumors (n = 106). 57 patients (53%) showed true negative snb. 38 patients (36%) revealed tumor cells in the H&E-staining and an additional 7 patients (7%) solely in the immunohistochemical staining. 4 (4%) of these patients, all of them from the first half of the study period, underwent false-negative snb, 3 of them showing lymphangiosis carcinomatosa. The presented results show, that snb using the radionuclid method is a reliable method for the evaluation of the nodal status in early breast cancer patients with a tumor size up to ca. 3 cm. Therefore the sn procedure should be restricted to small tumors with clinically uninvolved axillary nodes or patients with a ductal carcinoma in situ (DCIS) to rule out invasiveness.

Lymphatic mapping and sentinel lymph node biopsy in gastric cancer

AbstractIntroduction. Lymphatic mapping and the sentinel lymph node (SLN) concept has been validated in malignant melanoma and breast cancer.However, the application for other solid tumors is still controversial. One of the most promising approaches is selective lymph node staging in gastric cancer.The presented pilot study evaluated the feasibility of the radiocolloid technique in gastric cancer patients and its value in predicting a positive nodal status. Patients and methods. Fifteen patients with gastric cancer (u T1–3) underwent endoscopic submucosal injection of 0.4 ml 60 MBq 99mTc-Nanocis® around the tumor 17 (±3) h prior to surgery.After laparotomy the activity of all 16 (JGCA) lymph node stations was measured by a handheld probe.All patients underwent standard gastrectomy with systematic D2 lymphadenectomy.After resection the site was scanned for residual activity. All sentinel lymph nodes (SLNs) were removed ex vivo from the resected specimen and processed for intensified histopathologic assessment including serial sections and immunohistochemistry. Results. In 14 of 15 patients at least one or more SLNs were obtained (93%), the median number of SLNs was 3 (1–5).Of the 14 patients, 9 revealed lymph node metastases.In eight of the nine patients the sentinel node(s) correctly predicted metastatic lymph node invasion. In five cases the lymph node station with positive sentinel node(s) was the only positive node station resulting in a sensitivity of 8/9 (89%).In one case immunohistochemical staining revealed micrometastases leading to an upstaging in 1/6 of the initially nodal-negative patients. Conclusion. Lymphatic mapping and sentinel node biopsy using the radiocolloid technique is feasible in gastric cancer.Limited results indicate a correct prediction of the nodal status and the potential of upstaging.Further studies seem to be justified to evaluate the clinical impact of the method.ZusammenfassungHintergrund. Das “Lymphatic mapping” und das Sentinel-Lymphknotenkonzept sind beim malignen Melanom und beim Mammakarzinom bereits etabliert.Die Anwendung bei anderen soliden Tumoren ist Gegenstand derzeitiger Untersuchungen und wird kontrovers beurteilt. Als Erfolg versprechender Ansatz bietet sich das selektive Lymphknotenstaging bei Patienten mit einem Magenkarzinom an. Die vorliegende Pilotstudie untersucht die Durchführbarkeit mittels Radiokolloidtechnik und die Genauigkeit bei der Bestimmung des Lymphknotenstatus. Patienten und Methode. Bei 15 Patienten mit einem Magenkarzinom (u T1–3) erfolgte 17 (±3) h präoperativ eine submuköse endoskopische Umspritzung mit 0,4 ml 60 MBq m99Tc-Nanocis® um den Tumor. Unmittelbar nach der Laparotomie wurde die Aktivität der 16 Lymphknotenstationen (JGCA) mit einer Hand-γ-Sonde gemessen. Alle Patienten wurden einer Gastrektomie mit D2-Lymphadenektomie unterzogen.Nach der Resektion wurde der Operationssitus nach verbliebener Aktivität abgescannt. Alle Nuklid speichernden Lymphknoten mit einer 10fachen Aktivität gegenüber dem Grundrauschen wurden als Sentinel-Lymphknoten (SLN) definiert und am Operationspräparat entfernt. Die SLNs wurden gesondert in Serienschnitten und mittels Immunhistochemie aufgearbeitet. Ergebnisse. Bei 14 von 15 Patienten konnte ein SLN detektiert werden (93%). Die mediane Zahl der SLNs betrug 3 (1–5).Von 14 untersuchten Patienten waren 9 nodal positiv. In 8 von diesen 9 Fällen konnte mit dem SLN der positive Lymphknotenstatus vorausgesagt werden,wobei in 5 Fällen die Lymphknotenstation mit dem befallenen SLN die einzige befallene Station war. Damit lag die Sensitivität der Methode bei 89%.In einem Fall zeigte die immunhistochemische Untersuchung des SLN bei einem initial nodal negativen Patienten isolierte Tumorzellen im Randsinus (“Upstaging”). Zusammenfassung. Das “Lymphatic mapping” und die Sentinel-Lymphknotendiagnostik sind beim Magenkarzinom durchführbar.Die ersten Ergebnisse deuten auf eine korrekte Bestimmung des Lymphknotenstatus mit dieser Methode hin.Durch die gezielte histologische Aufarbeitung der SLNs ist zusätzlich ein Upstaging möglich.Weitere zahlenmäßig größere Untersuchungen müssen sich anschließen,um den klinischen Wert der Methode weiter zu klären.

Sentinel lymph node biopsy progress in surgical treatment of cancer

BackgroundForty-three years after the first description of the sentinel lymph node technique in malignant tumours of the parotid by Gould, sentinel lymph node biopsy (SNLB) has become a precious tool in the treatment of solid tumours. MethodsIn the following review we give a synopsis of the fundamentals of the sentinel lymph node concept and then proceed to an overview of recent advances of SNLB in gastrointestinal cancers. ResultsIn some tumour entities, SNLB has been shown to reflect reliably the lymph node status of the tumour-draining lymph node basin. In melanoma and breast cancer, it became a widely accepted element of the routine surgical management of these malignant diseases. In gastrointestinal tumours, the technique is currently under intense investigation. First reports on its application in other solid tumours, such as non-small cell lung cancer, thyroid carcinoma, oropharyngeal carcinoma, vulvar carcinoma, and Merckel cell carcinoma of the skin, were published more recently.ConclusionSNLB has become an important component of diagnosis and treatment of solid tumours. A growing number of publications on SNLB in gastrointestinal cancer documents the interest of many investigators in the application of this technique in this tumour entity. As long as imaging techniques like 18FDG PET or other molecular imaging techniques are limited by their spatial resolution, SNLB remains the technique of choice for lympho-nodal staging.

Refined staging by sentinel lymph node biopsy to individualize therapy in anal cancer

We evaluated the feasibility of the sentinel lymph node technique to refine staging and potentially individualize therapy for anal cancer. Seventeen patients with cancer of the anal canal underwent peritumoral injection of99mTc-colloid, followed 17 hours later by lymphoscintigraphy. A selective lymph node biopsy (SLNB) was attempted in 12 of 13 cases with scintigraphically detected SLNs. Lymph node metastases were present in 5 of 12 cases (42%); in 2 of these 5 cases, micrometastases were detected only by immunohistochemical staining. Hence, SLNB refines the diagnostic workup for anal cancer and provides an accurate basis for individualized therapy.