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Original Article |
1 Colorectal, Pathology and Nuclear Medicine Divisions, Aristides Maltez Cancer Hospital, Av. D. João VI, 332, Brotas, 40285-001, Salvador, Bahia, Brazil
2 Pelvic Surgery Department, Hospital do Cancer A.C. Camargo, São Paulo, Brazil
3 Surgical Clinic Post-Graduation Program, School of Medicine, University of São Paulo, São Paulo, Brazil
Correspondence: Address correspondence and reprint requests to: Claudio Almeida Quadros, MD; E-mail: caquadros{at}gmail.com
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Methods: Thirty rectal adenocarcinoma patients were submitted to RLPL, with RLPN mapping using technetium (Tc 99 m) and patent blue, having nodes examined histopathologically and immunohistochemically.
Results: Eight hundred and two nodes were analyzed, mean of 26.7 per patient; RLPL was responsible for 41% (330) of the examined nodes, mean of 11 per patient. Metastatic RLPN have occurred in 20% of the patients; the RLPN were metastatic in only 6.7% of the patients; RLPL upstaged 13.3%. For identification of metastatic RLPN with technetium, sensitivity was 33%, specificity 79%, positive predictor value (PPV) 29%, negative predictor value (NPV) 83% and false negative (FN) rate 67%. For patent blue and technetium metastatic RLPN identification, sensitivity was 17%, specificity 92%, PPV 33%, NPV 82% and FN 83%.
Conclusions: Preliminary results have pointed out technetium and blue dye low accuracy to identify metastatic RLPN; no metastatic RLPN were reported in the patients submitted to preoperative chemoradiation and important upstaging with RLPL. Considering no increase in morbi-mortality rates with RLPL, definitive conclusions will be obtained as the study carries on.
Key Words: Rectal cancer • Retroperitonial and lateral pelvic lymphadenectomy • Lateral node dissection • Lymph node mapping • Rectal adenocarcinoma staging
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Actually, there is a controversy concerning the best surgical approach for local and regional treatment of rectal adenocarcinoma. Some groups support the total mesorectal excision (TME),7 combined with neoadjuvant or adjuvant radiotherapy as the standard choice, with 5-year survival rate of 61.5% for stage II, according to the American Joint Committee on Cancer (AJCC) Tumor, Node and Metastasis (TNM) and 41.5% for stage III.8 Other groups, led by Japanese surgeons, have been supporting TME associated with a radical (extended) upper retroperitoneal and lateral pelvic lymphadenectomy (RLPL), with a more restricted indication for postoperative radiotherapy, which has a 5-year survival rates of 79.8% for TNM stage II and 64.7% for stage III.9 All scholars agree with chemotherapy as an adjuvant treatment.
The purpose of this ongoing study is to evaluate the presence of positive cancer cells in retroperitoneal and lateral pelvic lymph nodes (RLPN), its eventual upstaging impact and to define the accuracy of dye and probe search in the detection of positive cancer cells nodes resected by extended lymphadenectomy (RLPL). All rectal adenocarcinoma patients without distant metastasis were preoperatively injected with patent blue and technetium, submitted to standard TME procedure and, after specimen removal, RLPL was performed. Blue dye or radiation detected RLPN were evaluated histopathologically and when they were negative for cancer cells, immunohistochemical (IHC) techniques were held.
The results of this study will answer some questions: the first one is if a more extended lymphadenectomy will lead to patient upstaging; second, if the search and presence of radioactive and blue positive RLPN can indicate a need for an extended lymphadenectomy; and third, if there is any preoperative indication for extended lymphadenectomy based on the occurrence of metastatic RLPN.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Physical examination, including digital rectal assessment, abdominal and pelvic computed tomographic scan (CT scan), chest radiography and serum carcinoembryonic antigen (CEA) levels have been used for preoperative evaluation. All patients have had resectable primary tumors and no distant metastases. Preoperative chemoradiotherapy has been indicated in patients with T4 lesions, fixed tumors and CT scan suggesting positive pelvic lymph nodes. Neoadjuvant treatment has consisted of a 5.040 cGy dose of radiotherapy delivered in 180 cGy fractions per day, associated with daily chemotherapy regimen of 5-fluorouracil (375 mg/m2 of body surface), and leucovorin (30 mg/m2 of body surface) has been delivered in a 5-day cycle, one at the first and another on the third week of radiotherapy.
Operations for primary tumors have included anterior rectal resection (AR), abdominoperineal rectal resection (APR), APR plus anterior vaginal wall resection, and total pelvic exenteration (TPE). All patients have been treated with a curative intent, including TME followed by RLPL, at the Division of Colorectal Tumors of the Hospital Aristides Maltez, by the first author that had been trained to perform RLPL in an o3cial fellowship program of Surgical Oncology at the National Cancer Institute—Brazil—INCA. All surgical specimens have been accessed by a single pathologist, the third author. The standardized protocol has included lymphoscintigraphy and blue dye technique to evaluate RLPN after standard TME surgery.
After anesthetic induction, a solution containing 0.1 mCi of 99 m-technetium-labeled phytate diluted in 0.2 ml of saline solution has been injected around the tumor using a tuberculin syringe, followed immediately by injection of 01 ml of a 2.5% patent blue solution. In patients with tumors in the peritoneal reflection, the radiotracer and the dye have been subserosally injected in a circumferential manner around the tumor. In middle and low rectal cancer patients, it has been injected with a proctoscope, into the submucosal and muscular layer using the transanal route. TME has been performed and, after specimen extraction, search for retroperitoneal and lateral pelvic (RLPN) radioactive and blue nodes has been done with a handheld gamma probe device (Europrobe
, CaTe detector). Radioactive nodes have been defined if their counts had been at least three times greater than the background counts, away from the site of the 99 m-technetium phytate injection; blue nodes have been identified by visual inspection. The radioactive or blue nodes, once identified and isolated, have been sent for pathological analyses. RLPL has been performed in all cases, following the Japanese radical lymph node dissection (J-LND) standards.10
The lymph nodes have been separately sent for pathological analysis according to the group definition of the Japanese Colorectal Cancer Society.3 Group 1 has been composed by the lymph nodes in the TME specimen with high ligation of the inferior mesenteric artery.3 Other lymph nodes groups have been dissected with the RLPL procedure. The lymph nodes between the internal iliac arteries and veins have been classified as group 2.3 The nodes resected at the root of the inferior mesenteric artery, common iliac arteries, between the internal and external iliac arteries and those of the obturator space have constituted the group 3.3 Group 4 consisted of the para aortic lymph nodes inferior to the left renal vein or duodenum and of those lateral to the common iliac arteries.3
The criteria that has been used for definition of lymph node positivity in radiation or blue detected RLPN has been detection of metastatic cancer cells, initially in histopathological exam with hematoxylin–eosin staining. When these RLPN result negative, IHQ tests with antibody against cytokeratin were done. The presence of IHQ cytokeratin detected cells turns the node into positive. For TME dissected nodes and not radioactive or blue detected RLPN, the criteria has been identification of metastatic cancer cells through routine hematoxylin–eosin staining.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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As far as lymph node number was concerned, histopathological examination has been performed in 802, with a mean of 26.7 nodes dissected per patient. In terms of surgical approach, TME has been responsible for the dissection of a total of 472 lymph nodes (group1), with mean value of 15.7 nodes per patient. The extended RLPL procedure has added 330 lymph nodes (41% of the examined nodes), with mean of 11 nodes per patient.
In the surgical specimens obtained with the classical TME procedure, 53 metastatic lymph nodes have been found in 14 patients. The RLPL procedure has been responsible for the detection of 13 metastatic lymph nodes in six patients (20%). In two cases (6.7%) all the TME nodes have been negative and the only metastatic lymph node has been obtained with the RLPL. All patients with metastatic RLPN had not been submitted to neoadjuvant chemoradiotherapy.
In terms of group distribution of the RLPN,3 group 2 has had eight metastatic nodes, group 3 has had five and, no metastatic nodes have been found in group 4. The most frequent location of metastatic RLPN has been between the internal iliac arteries (group 2), with eight metastatic lymph nodes. The other two sites of metastatic RLPL nodes have been in group 3, at the obturator space with three metastatic nodes and at the root of the inferior mesenteric artery with two metastatic nodes. In 6.7% of the patients (2/30), metastatic cells were only present in their RLPN, with only one metastatic lymph node in each patient in group 3, adjacent to the aorta, at the root of the inferior mesenteric artery.
It has occurred TNM upstaging with the RLPL procedure in four cases (13.3%). Two patients (6.7%) have had their node classification modified from N1 to N2, changing from stage IIIb to IIIc. One patient has had a T4 tumor with one metastatic node out of 19 TME lymph nodes, and it has been found four more metastatic nodes out of 17 RLPN, becoming T4N2M0, stage IIIc. Other case has had three metastatic nodes out of 24 of the TME specimen, and had three more metastatic ones out of 24 RLPN, staging T3N2M0, IIIc. Two other patients (6.7%) have had their only metastatic lymph node in the RLPN. Both cases have been considered T3N0M0, stage II, at the TME procedure, becoming T3N1N0, stage III after RLPL. The number of dissected negative nodes with TME in these cases has been 12 and 20. RLPL has obtained, respectively, 20 and 18 nodes, with only one metastatic in each patient, changing TNM stage from II to III.
Technetium radioactive lymph nodes have been obtained in the RLPN of seven patients, giving an identification rate of 23.3% (7/30). Eleven radioactive nodes has been detected, with average number of 1.6 detected nodes per patient. As far as a predictor of metastatic involvement, concerning radioactive nodes accuracy, the values obtained were sensitivity 33%, specificity 79%, positive predictor value (PPV) 29%, negative predictor value (NPV) 83% and false negative (FN) rate 67%.
Investigation of dye labeling in RLPN has identified blue nodes in three cases, with an identification rate of 10% (3/30) and mean of 2.0 blue nodes per patient. All blue nodes have also been radioactive. In one patient, the only positive node for cancer cells obtained out of 38 lymph nodes of the TME and RLPL procedures has been a radioactive and blue node. Sensitivity was 17%, specificity 92%, PPV 33%, NPV 82%, and FN 83%.
If only patients not submitted to preoperative radiotherapy had been considered, RLPN would have been metastatic in 35.3% (6/17) of the cases. This would have raised up to 11.8% the proportion of patients with metastatic nodes only in the RLPN. Upstaging, according to TNM, would have increased to 23.5%.
When patients not submitted to preoperative radiotherapy had been evaluated, the identification rate of radioactive nodes has been 35.3%. In terms of accuracy, for the technetium nodes sensitivity was 33 %, specificity 64%, PPV 33%, NPV 64% and FN 67%. For the blue and technetium nodes, sensitivity was 17%, specificity 88%, PPV 33%, NPV 75% and FN percentage values 83%.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The needed major extension of dissection to perform RLPL has not increased morbidity or mortality. This fact has made possible the maintenance of the current study as it has been designed aiming to answer the three above-mentioned questions.
The first one has been if RLPL could cause patient upstaging. These preliminary results have shown an overall 13.3% patient upstaging, defining stage III in 6.7% of the patients that have had all their TME lymph nodes without metastasis. When only patients not submitted to preoperative radiotherapy have been included, patient upstaging has increased to 35.3%, with a specific stage III migration in 11.8%.
Adjuvant radio-chemotherapy has been currently established for stage III rectal cancer since the 1990 National Institutes of Health Conference. The increase in 3-year survival rate of chemotherapy in stage III patients has ranged from 17 to 30%.11–13 If RLPL had not been performed, 6.7% of the patients would not had the benefits of adjuvant chemotherapy, and 20% of the patients would have had metastatic nodes left behind, with a mean of 2.2 not resected metastatic nodes per patient. Metastatic pelvic and retroperitoneal nodes left behind in a supposed curative surgery and not performing indicated adjuvant chemoradiation treatment would have certainly led to pelvic or systemic recurrence. Adjuvant radiotherapy would have not been initiated in 11.8% of patients not submitted to neoadjuvant treatment, which have had metastatic RLPN.
Concerning the second question: if the search and presence of positive radioactive and blue RLPN would have indicated the need for an extended lymphadenectomy, in this preliminary report, the accuracy of the dye and radioactive mapping has not been satisfactory. Low sensitivity and high false negative values have shown no benefit of the method as an indicator for RLPL. But higher number of patients will be necessary in order to have an authoritative statement. The unfavorable results could be explained by surgeries performed in large size tumors with massive nodal involvement, in patients undergoing neoadjuvant chemoradiation treatment. The mean tumor diameter has been 5.32 cm, ranging from 2.5 to 15.8 cm. Eight patients (26.7%) have presented tumors invading adjacent organs (T4). Seven (43.7%) of the 16 stage III patients have been N2. Twelve patients (43.3%) had been treated with neoadjuvant chemoradiation. Studies aiming the accuracy of sentinel lymph node technique for colorectal cancer have shown worse results in rectal,14–16 large tumors,17,18 with extensive nodal metastases,14,17,19,20 tumors invading adjacent organs21 and patients submitted to preoperative chemoradiation.21
Taking into account if it has occurred a preoperative indication for the need of an extended lymphadenectomy based on the occurrence of metastatic RLPN, in these 30 patients, only those with metastatic RLPN have been the ones that had not been submitted to preoperative radiotherapy. The study shall be continued and more detailed analyses must be done primarily, concerning the occurrence of metastatic RLPN in patients that had not been submitted to preoperative radiotherapy. This might bring up a need for a more accurate definition of preoperative radiotherapy indication. Follow-up can show the impact of performing RLPL on survival and on tumor recurrence.
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ACKNOWLEDGMENTS |
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Received for publication May 21, 2006. Accepted for publication May 23, 2006.
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