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SUPPLEMENT |
From the Department of Surgery and Surgical Oncology (CU, AB, SG, PMS) and Divisions of Nuclear Medicine (JM), Pathology (US), and Radiotherapy (SK), University Hospital Charité, Campus Buch, Robert Roessle Klinik at the Helios Klinikum, Berlin, Germany.
Correspondence: Address correspondence and reprint requests to: Peter M. Schlag, MD, PhD, Department of Surgery and Surgical Oncology, University Hospital Charite, Campus Buch, Robert-Roessle-Klinik at the Helios Klinikum Berlin, Lindenberger Weg 80, 13125 Berlin, Germany; Fax: 49-30-9417-1404; E-mail: schlag{at}rrk.charite-buch.de
ABSTRACT
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 of 99mTc-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.
Key Words: Anal cancer • Inguinal lymph node biopsy • Lymph node staging • Sentinel lymph node
Carcinomas arising in the anal canal have a distinct clinical and biological behavior.1 Regional lymph node status is crucial for predicting the risk of local failure and overall survival.2-4 The presence of inguinal lymph node metastases in anal cancer reduces the overall survival to 30% to 58%, versus 60% to 76% for patients without lymph node metastases.5-8
In general, lymphatic drainage is based on passive processes like osmotic and hydrostatic pressure and on active muscular contractions and corpuscular transport. Under physiologic conditions, these mechanisms cause centripetal lymph flow.9 The lymph flow of tumors in the anal region is bidirectional, depending on the tumor’s location with respect to the dentate line. Proximal to the dentate line, about two-thirds of the lymph liquid is drained along the inferior rectal artery to the origin of the inferior mesenteric artery. Distal to the dentate line, the main pathway is to the inguinal lymph nodes along the femoral artery.9,10 However, the dentate line is not a strict functional boundary for these metastatic pathways11,12; of all inguinal metastases, about 15% to 35% originate from tumors of the proximal anal canal.
Today the main therapeutic approach to squamous cell carcinoma of the anus is radiochemotherapy, whereas recurrent disease is treated by salvage surgical resection.4,13-16 Because initial treatment is nonsurgical, the true lymph node status of anal canal cancer is not assessable. Reported rates of lymph node metastasis range from 10% to 25%.17-20 Histopathological proof of metastasis may be obtained from clinically suspicious inguinal lymph nodes via core or open biopsy, with subsequent therapy consisting of a specific irradiation boost to the involved groin, combined with inguinal node dissection in selected cases.14-17
Treatment of the clinically uninvolved groin, however, is a more contentious issue. A watch-and-wait policy is advocated in some institutions, whereas elective irradiation is a common practice in many departments.
We initiated a study to assess the feasibility and diagnostic value of SLNB as a minimally invasive and histopathologically confirmed staging approach for anal cancer patients.
PATIENTS AND METHODS
Between April 1999 and March 2003, SLN mapping was performed in 17 patients (11 female and 6 male) with histopathologically proven squamous cell carcinoma of the anal canal. The mean age of the patients was 60.5 years (range, 37 to 83 years). Fourteen patients had squamous cell cancer of the proximal anal canal and three had such cancer in the distal part. Tumor extension (T-stage) was determined by endoscopy and endosonography. Staging was completed by ultrasonography of the abdomen and the groins, radiography of the chest, and computed tomography (CT) of the pelvis, according to the 1997 recommendations of the World Health Organization (WHO) for anal cancer.21 Ten patients had a tumor extension of between 2 and 5 cm (T2), four patients had a tumor extension greater than 5 cm (T3), and one patient had a tumor extension less than 2 cm (T1). Infiltration of the tumor into the vagina (T4) was seen in two cases. The inguinal lymph nodes were clinically and radiologically disease-free in all of these patients.
After informed consent was obtained, 1 mL 99mTc-sulfur colloid (Nanocis, Schering, Berlin, Germany) was injected in four sites submucosally or subdermally around the tumor with a 27-gauge needle and an insulin syringe. Seventeen hours after radiocolloid injection, scintigraphy was recorded with a gamma camera (Fig. 1). Patients with detectable radiocolloid enrichment in a groin underwent SLNB guided by a hand-held gamma probe. Bilateral SLNB was performed in cases of bilateral radiocolloid detection.
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The radiochemotherapy protocol was adjusted according to tumor extension and lymph node status of the groins. Patients with a tumor greater than 2 cm in diameter (T2 to T4) received primary radiochemotherapy with a tumor dose up to 60 Gy and 5-fluorouracil/mitomycin-c chemotherapy. Patients with a tumor less than 2 cm in diameter (T1) underwent local excision. The radiation field included both groins, with a maximum dose of 45 Gy. An elective boost to the groins was administered in patients with T3 and T4 tumors and/or patients with positive SLN(s). No elective groin irradiation was done for node-negative patients with T1 or T2 tumors.
One patient refused further procedures. All others received regular follow-up examinations every 3 months.
RESULTS
SLNs were detected in 13 of 17 patients (76.5%). Eight of these 13 patients had SLNs in only one groin. Twelve patients underwent SLNB, and one patient refused all further procedures.
Metastases were found in the SLN of 5 of 12 biopsied patients (42%); in 2 patients, SLN metastases were detected by serial sectioning or immunohistochemical staining after H&E results were negative for tumor (Table 1).
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The only complication occurred in one patient who had a cutaneous lymphatic fistula diagnosed, which resolved spontaneously after 10 days.
DISCUSSION
Our results show that SLN mapping with a radiocolloid enables precise detection of inguinal metastases in a clinically relevant percentage (42%) of patients. In particular, in two patients, tumor-involved lymph nodes were identified only because of additional histopathologic workup. The incidence of lymph node metastases in our study was twofold higher than stage-adjusted data in the literature.17–20 A negative SLN in our study could not exclude the possibility of missed inguinal metastases, because no elective bilateral inguinal lymph node dissection was performed. However, identification of tumor cells in an SLN is—in contrast to clinical or sonographic findings—unequivocal proof of metastatic disease. Compared with radiological staging with ultrasonography and CT, assessment of the SLN provides more reliable staging of inguinal lymph nodes. Wade et al.24 used a fat-clearing technique to demonstrate that 44% of all lymph node metastases in anal cancer are less than 5 mm in diameter. Modern imaging techniques, such as magnetic resonance imaging or positron emission tomography, are too inaccurate and expensive for routine identification of lymph node metastases.
Although the first-line therapy for squamous cell carcinomas of the anal canal is radiochemotherapy, the optimal radiation dose and field and the most effective chemotherapeutic regimen have not been determined.4,14 Similarly, management of the clinically uninvolved groin remains a contentious issue, with two main strategies: elective inguinal radiation or a watch-and-wait policy. Because the risk of synchronous inguinal metastases increases with tumor size (6.4% in T1 or T2, versus 16% in T3 or T4), some centers prefer management based on T-stage.17,25,26 SLNB is a minimally invasive alternative to predict lymph node metastases. Patients without SLN metastases may be spared unnecessary late side effects from inguinal radiation, such as chronic leg edema, osteonecrosis of the femoral head, or arterial stenosis.
We believe that radiocolloid-guided lymphatic mapping has the potential to detect the lymph nodes at risk for metastases from anal cancer. Subsequent SLNB can reveal a higher percentage of inguinal lymph node metastases than can other, conventional procedures. To evaluate the ultimate clinical relevance of SLNs and SLNB in anal cancer, further studies are warranted.
FOOTNOTES
The sentinel lymph node biopsy technique refines the diagnostic workup for anal cancer and provides an accurate basis for individualized therapy.
Received for publication November 7, 2003. Accepted for publication December 5, 2003.
REFERENCES
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