Small cell cervical cancer

Study objectives: The objective of this study was to evaluate the feasibility of the sentinel lymph node (SLN) biopsy in peripheral clinically stage I or II non-small cell lung cancer (NSCLC) using [sup.99m]Tc colloid and a hand-held gamma detection probe, associated with a blue dye technique.

Design: Prospective study.

Setting: Royal Brompton Hospital, London, UK; and Hopital Nord, Saint Etienne, France.

Methods: After thoracotomy, a total of 2 mL patent blue dye mixed with 1,600 [mu]Ci [sup.99m]Tc-albumin or [sup.99m]Tc-colloid was injected into each quadrant of lung tissue immediately surrounding the tumor. Routine lymphadenectomy was carried out. The first lymph nodes to stain blue or radioactive, if any, were considered SLNs.

Results: Twenty-four patients were evaluated. We successfully identified 17 SLNs in 13 patients (detection rate, 54.2%). Mean time from injection to identification of SLNs was 18 min (range, 5 to 30 min). In nine cases, the SLN was blue and radioactive, in six cases only blue, and in two eases only radioactive. The pathologic status of the SLN reflected the pathologic status of other nodes of the routine lymphadenectomy except one case of false-negative SLN (14%). Four SLNs were in N2 stations (23.5%).

Conclusions: The sentinel node mapping in NSCLC with blue dye and radioisotopic techniques is feasible, but the detection rate has to be improved. This technique is an accurate method of identifying the first node draining a tumor, although it is not yet sufficiently sensitive to have a role in reducing the extent of nodal dissection.

Key words: intraoperative detection; lung cancer; sentinel lymph node

Abbreviations: LLL = left lower lobe; LUL = left upper lobe; NSCLC = non-small cell lung cancer; RLL = right lower lobe; RUL = right upper lobe; SLN = sentinel lymph node

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In developed countries, non-small cell lung cancer (NSCLC) remains the leading cause of cancer mortality. (1) Early stages of disease enjoy favorable survival rates following surgery: 5-year actuarial survival is from 50 to 80% for stage I, from 24 to 45% for stage II, and 22 to 50% for T3N0. (2-5) However, the ranges for 5-year survival are wide, which may in part be explained by variations in the manner and extent of nodal dissection. (6) It is known that adequate surgical dissection of the regional lymphatics improves treatment results, but how far this lymph node dissection is directly therapeutic is a source of controversy. (7-9) Our knowledge of the mechanisms and pathway of lymphatic tumor spread is rather limited and based on statistical evaluation. Different teams have described the percentage of stations involved depending of the location of the primary tumor, (10-12) but what the thoracic surgeon wants to know during the operation is the individual risk of lymphatic spread in order to achieve selective lymphadenectomy. Three potential reasons could explain the high rate of recurrence for T1N0 NSCLC (20 to 50%): first, an inadequacy of the lymphadenectomy, in other words the lymph nodes draining the tumor are either not or incompletely removed; second, a pathologic failure in that the appropriate lymph nodes were removed, but routine histologic evaluation failed to unveil microscopic disease; finally, there may be hematologic or pleural dissemination. The sentinel lymph node (SLN) is the first node draining a tumor. As shown for early stage in malignant melanoma and breast cancer, (13-17) the SLN is the first site affected in eases of metastatic dissemination. Verification of the SLN concept in melanoma has allowed the identification of patients who may benefit from lymphadenectomy, and prevented unnecessary lymphadenectomy in those with no affected SLN. Moreover, when the pathologist focused on a single node, up to 8.4% of the patients had a SLN containing micrometastasis. (15) In future, the SLN technique may be the solution for adequate surgical resection and pathologic evaluation in NSCLC. The intraoperative knowledge of tumor lymphatic drainage could help the surgeon to perform a better lymphadenectomy. Moreover, SLN biopsy allows the pathologist to perform a focused analysis of one or a few lymph nodes with multiple sectioning and, if required, immunohistochemical staining, and this may improve the accuracy of nodal staging. The objective of this prospective study is therefore to evaluate the feasibility of SLN mapping in NSCLC using Tc colloid and a handheld gamma detection probe, associated with blue dye technique.

MATERIALS AND METHODS

The protocol was approved by the Ethics Committee of the Royal Brompton & Harefield NHS Trust/National Heart & Lung Institute, London, UK; and by the Consultative Committee for the Protection of Persons Assisting in Biomedical Research of the Rhone-Alpes-Loire region, France. Twenty-six patients were enrolled in this prospective study after informed and signed consent from October 1, 1999, through April 31, 2002. Inclusion criteria were as follows: > 18 years of age, peripheral NSCLC (without bronchoscopic evidence of invasion and more distal than the lobar bronchus), clinical stage I or II, and surgically operable and resectable. Exclusion criteria were as follows: legal minority, pregnancy, patient refusal, previous ipsilateral thoracic surgery, and multiple synchronous or metachronous carcinomas of the lung.

Routine preoperative staging was performed, including clinical examination, chest radiography, CT scans of the chest and the upper abdomen, and cervical mediastinoscopy in case of mediastinal enlarged node (> 1 cm in the short axis). Two patients required mediastinoscopy for enlarged node in homolateral stations 2 and 4.

At thoracotomy, if necessary, a frozen section of the tumor was undertaken to ensure diagnosis, and then a total of 2 mL Patent Blue Dye-V (Laboratoire Guerbet; Roissy, France), mixed with 1,600 [mu]Ci [sup.99m]Tc-albumin ([sup.99m]Tc Nano-colloid; Mallinckrodt; Bicester, UK) or of [sup.99m]Tc-sulfur colloid (Nanocis; CIS Bio International; Nancy, France; reduced heating time protocol and filter) was injected in four divided doses into each quadrant of lung tissue immediately surrounding the tumor in a collapsed lung. The first two patients had only patent blue dye injected. The systematic nodal dissection before lung resection as described by Graham et al (7) was carried out immediately after injection. In a previous study (14) in melanoma, preoperative dynamic lymphoscintigraphy correctly identified 90% of the SLNs in < 1.5 min after a peritumoral injection. Dissection was carried out just alter the injection because prolonged anesthesia remained a concern to us. SLN mapping by visual and handheld gamma probe guidance (Navigator intraoperative gamma probe; Tyco; Gosport, UK; or Neoprobe 2000; Ethicon Endo-surgery; Issy les Moulineaux, France) was performed every 5 min or 10 min or at each step of the lymphadenectomy. The first lymph nodes to stain blue or radioactive (three times the background) were considered to be the sentinel nodes. The exact station according the lymph node classification of Naruke et al (10) was recorded. Each blue node, if any, was checked with the gamma probe, and the count per second was recorded after removal. We then verified the absence of residual radioactivity; a probe count < 1% of the most radioactive lymph node was regarded as background radiation. The SLNs were sent separately for pathologic examination. In the absence of blue coloration, this was recorded and the probe alone was used to detect the SLN, and vice versa. The planned intervention then continued according to standard practice. On the specimen, all lymph nodes (stations 11, 12, 13, and 14) were dissected from the surrounding parenchyma and connective tissue and checked for blue staining with the gamma probe.

The nodes were processed in their entirety, and sections were stained with hematoxylin-eosin. If required, sections of SLN were stained immunohistochemically using epithelial markers: MNFll6 (1/80 dilution; Dako; Cambridge, UK) and Ber-EP4 (1/30 dilution: Dako) to confirm or refute involvement by tumor. Tissues obtained during radioguided SLN biopsy contained low residual radioactivity, and pathologic examination was delayed by 48 h. (18)