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Comparison of Positron Emission Tomography Scanning and Sentinel Node Biopsy in the Detection of Inguinal Node Metastases in Patients With Anal Cancer
Int. J. Radiation Oncology Biol. Phys., Vol. 77, No. 1, pp. 73–78, 2010 Copyright Ó 2010 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/10/$–see front matter
doi:10.1016/j.ijrobp.2009.04.020
CLINICAL INVESTIGATION
Anus
COMPARISON OF POSITRON EMISSION TOMOGRAPHY SCANNING AND SENTINEL NODE BIOPSY IN THE DETECTION OF INGUINAL NODE METASTASES IN PATIENTS WITH ANAL CANCER MASSIMILIANO MISTRANGELO, PH.D., M.D.,*k ETTORE PELOSI, M.D.,y MARILENA BELLO`, M.D.,y ISABELLA CASTELLANO, M.D.,z PAOLA CASSONI, PH.D., M.D.,z UMBERTO RICARDI, M.D.,x FERNANDO MUNOZ, M.D.,x PATRIZIA RACCA, M.D.,** VIVIANA CONTU, M.D.,** GIANCARLO BELTRAMO, M.D.,x MARIO MORINO, M.D.,* AND ANTONIO MUSSA, M.D.{ * Departments of Surgery, y Nuclear Medicine, z Anatomo-Pathology, and x Radiotherapy, the { Surgical and Oncological Department, the kCentre of Minimally Invasive Surgery, and the ** Oncological Centre for Gastrointestinal Neoplasms, University of Turin, Italy; and the PET Center IRMET, Turin, Italy Background: Inguinal lymph node metastases in patients with anal cancer are an independent prognostic factor for local failure and overall mortality. Inguinal lymph node status can be adequately assessed with sentinel node biopsy, and the radiotherapy strategy can subsequently be changed. We compared this technique vs. dedicated 18F-fluorodeoxyglucose positron emission tomography (PET) to determine which was the better tool for staging inguinal lymph nodes. Methods and Materials: In our department, 27 patients (9 men and 18 women) underwent both inguinal sentinel node biopsy and PET-CT. PET-CT was performed before treatment and then at 1 and 3 months after treatment. Results: PET-CT scans detected no inguinal metastases in 20 of 27 patients and metastases in the remaining 7. Histologic analysis of the sentinel lymph node detected metastases in only three patients (four PET-CT false positives). HIV status was not found to influence the results. None of the patients negative at sentinel node biopsy developed metastases during the follow-up period. PET-CT had a sensitivity of 100%, with a negative predictive value of 100%. Owing to the high number of false positives, PET-CT specificity was 83%, and positive predictive value was 43%. Conclusions: In this series of patients with anal cancer, inguinal sentinel node biopsy was superior to PET-CT for staging inguinal lymph nodes. Ó 2010 Elsevier Inc. Anal cancer, Squamous cancer, Lymph node metastases, Sentinel lymph node metastases, PET-CT.
Anal cancer is a rare disease. An estimated 5,070 new cases (2,020 men and 3,050 women) of anal cancer (involving the anus, the anal canal, or the anorectum) were expected to occur in the United States in 2008, accounting for approximately 1.85% of digestive system cancers. It was estimated that 680 deaths from anal cancer would occur in the United States in 2008 (1). Surveillance Epidemiology and End Results (SEER) data from 1975 to 2003 suggest that its incidence is rising (2). Human papilloma virus infection, cervical dysplasia or cancer, HIV seropositivity, low CD4 count, cigarette smoking, anoreceptive intercourse, and
immunosuppression following solid organ transplant are known risk factors for anal cancer. Before the mid-1980s, the treatment of choice for anal cancer was abdominoperineal resection (APR). The 5-year survival rate after APR for anal cancer was 40%–70%, with worse outcomes for those with larger tumors and nodal metastases. In the 1920s and 1930s, inguinal node dissection was included in the surgical management of these patients, and it was generally reserved for those patients with clinically enlarged (although not necessarily involved) inguinal nodes (3). By the 1950s, it had became clear that the morbidity associated with lymph node dissection was much greater
Reprint requests to: Massimiliano Mistrangelo, M.D., Department of Surgery and Centre of Minimal Invasive Surgery, Molinette Hospital, University of Turin, Corso A. M. Dogliotti 14, 10126 Turin, Italy. Tel: (+39) 011-6313149; Fax: (+39) 011-6336725; E-mail: [email protected]; mmistrangelo3@molinette. piemonte.it The study was presented at the Third Annual Meeting of the European Society of Coloproctology, September 24–27, 2008, Nantes, France.
Conflict of interest: none. Acknowledgments—We thank Dr. Vincenzo Arena and Dr. Angela Cistaro (PET Center IRMET, Turin, Italy) and Dr. Enrica Milanesi (Oncological Centre for Gastrointestinal Neoplasms, University of Turin, Italy) for their active participation and work. We thank Dr. Marco Pizzio (Department of Surgery and Centre of Minimal Invasive Surgery, University of Turin) for statistical analyses. Received Feb 3, 2009, and in revised form April 15, 2009. Accepted for publication April 15, 2009.
INTRODUCTION
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than any survival benefit, so the procedure was gradually abandoned (4). In 1974, Nigro et al. (5) proposed a multimodality treatment combining radiation and chemotherapy, which has since become the standard treatment. Local control rates of 60%–90% over all stages are achievable, with sphincter preservation in approximately 65% of cases. The prognosis after combined radiochemotherapy for anal cancer may be influenced by several factors: high tumor stage and regional nodal involvement, tumor site in the anal canal, and inguinal lymph node involvement in anal canal carcinoma. Synchronous inguinal metastases have been reported in 10%–25% of patients and metachronous metastases in 5%–25% (6). An array of tools for assessing inguinal metastasis have been proposed, including clinical examination, endosonography, computed tomography (CT), and magnetic resonance imaging (MRI); however, they are unable to detect nodal involvement in all cases. Furthermore, only histologic study can confirm metastasis in a enlarged node or a micrometastasis in a normal-sized node. In recent years, sentinel node biopsy (SNB) has proven to be a safe and effective technique for sampling inguinal sentinel lymph nodes (7, 8). Since 2001, SNB in patients with anal cancer has improved the accuracy of inguinal staging and planning of radiotherapy treatment, obviating the need for inguinal radiotherapy and eliminating its related morbidity in patients without metastasis at SLN biopsy. In their recent review of the literature, Damin et al. (7) evaluated 84 patients by SLN sampling: the detection rate was between 66% and 100%, and metastases were found in 7.1%–42.0% of cases. No major complications were reported. After this review and our recent report, Gretschel et al. (9) described their experience with 40 patients. In contrast to their previous reports, they observed a detection rate of 56% in inguinal lymph nodes (76% in a previous series), with 30% of inguinal node metastases (42% previously). They suggested that SLN biopsy in anal cancer can be used to appropriately select patients for inguinal irradiation, especially in T1 and T2 tumors. These patients receive either additional treatment or are spared unnecessary radiation. In their opinion, SLN biopsy is not currently recommended for larger (T3/T4) tumors or in patients with prior surgical manipulation of the anal or inguinal region (9). Recently, the use of fluorodeoxyglucose (FDG) positron emission tomography (PET) has also gained an important place in this setting. Trautmann and Zuger (10) presented a brief report evaluating PET both during staging and after completion of therapy. PET identified disease not documented by CT in 24% of patients, resulting in a change of stage in 10%. In a study of 41 consecutive patients with anal cancer, Cotter et al. (11) reported that PET seemed to detect more inguinal disease, with abnormal nodes noted in 29% of all groins vs. 16% at CT. The incidence of PETpositive inguinal nodes was found be higher (44% vs. 16%) in HIV-positive patients. The report also suggested that FDG-PET might offer better sensitivity in identifying nodal disease and so could be used to upstage the disease
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and modify the treatment plan to include radiotherapy boost to the groins. In this connection, Anderson et al. (12) suggested that PET-CT can change the management of anorectal tumors by early detection of metastatic disease or disease outside standard radiation fields (12). Nguyen et al. (13) recently found that PET upstages disease in 17% of patients and changes radiotherapy planning in 19%. Prospective studies are necessary to determine the extent to which PET can aid in anal cancer staging and identification of residual disease and recurrent or metastatic disease. In this study, we compared FDG-PET CT with biopsy of the inguinal sentinel node to determine whether PET-CT could upstage the disease, but not overstage it, in patients with inguinal metastases who could potentially benefit from inguinal radiotherapy. METHODS AND MATERIALS Between October 2004 and December 2007, 27 patients with anal cancer were studied in our department (General Surgical Departmente and Centre of Minimally Invasive Surgery, University of Turin, Turin, Italy). All patients presented for bleeding on defecation, sometimes associated with anal pain or the sensation of an anal mass. Proctological examination and anoscopy revealed an anal neoplasm. At biopsy, 27 of these tumours were diagnosed as squamous cell carcinomas, 11 of which displayed basaloid features according to the most recent World Health Organization classification. Clinical workup included digital rectal examination, anoscopy, rigid proctoscopy, total colonoscopy (possible in 16 patients), CT, endosonography (possible in 14 patients), and tumor marker assay. Tumor sites were the anal canal in 16 patients and the anal margin in 11 patients. TNM staging was T1 in 2 patients, T2 in 13, T3 in 9, and T4 in 3 (Table 1). Five patients (18.5%) presented with palpable lymph nodes on clinical examination. Three of these patients were HIV positive, a condition that usually presents with palpable lymph nodes. Table 1. Patients characteristics Characteristic Sex Male Female Race White Age Median Range HIV positive Histological subtype Squamous Basaloid Localization Anal canal Anal margin T T1 T2 T3 T4
No. of patients (%) 9 (33.33) 18 (66.66) 27 (100) 58 years 32–75 years 7 (25.9) 16 (59.2) 11 (40.7) 16 (59.2) 11 (40.7) 2 (7.4) 13 (48.1) 9 (33.33) 3 (14.1)
PET-CT vs. SNB in the detection of inguinal metastased in anal cancer d M. MISTRANGELO et al.
All patients underwent FDG-PET CT for adequate pretreatment staging of the disease. Patients gave written informed consent. All PET-CT studies were acquired using the same combined tomographs (Discovery ST, General Electric Medical Systems, Waukesha, WI). Patients were asked to refrain from food intake for at least 6 hours before scanning; at the time of tracer injection, all patients presented with a blood glucose value <160 mg/dL. Whole-body emission scans were acquired beginning 60 min after the intravenous injection of FDG (dose range, 222–370 MBq). No adverse events after administration of 18F-FDG were observed. The acquisition protocol started with a scout view, then a CT was performed (140 kV; tube current 60 mA/s) from the proximal femur to the base of the skull. The scan lasted approximately 1 min and was used for both anatomic localization and attenuation correction of the PET emission data. At the end of CT scanning, the bed position was moved into the PET field of view (FOV) for the emission study. PET data of the whole-body distribution of the tracer were acquired in three-dimensional (3D) mode from the pelvis to the neck. Coronal, sagittal, and transverse data sets were reconstructed. Images were reconstructed as a 3D reconstruction algorithm FOREiterative. Coregistered images were visualized using dedicate software (Advantage 4.2, GE Healthcare, Chalfont St. Giles, United Kingdom). All lymph nodes $2 cm in diameter with a 18F-FDG uptake lower than or equal to that of mediastinal blood pool structures were considered negative for the presence of tumor metastases. A mild degree of 18F-FDG uptake can be related to an inflammatory reaction. In contrast, lymph nodes with uptakes exceeding the activity of mediastinal blood pool structures were considered positives. Any increased uptake above the surrounding background in lymph nodes less than 2 cm in diameter was considered positive. Sentinel node biopsy (SNB), as previously described (8), was the final examination in the assessment of inguinal lymph node metastases. All patients gave written informed consent after being informed about the risks and benefits of the procedure. All patients were submitted to radiochemotherapy as reported by Nigro et al. (5). Chemotherapy was performed with the following schedule: fluorouracil (5-FU) 1,000 mg/m2 on Days 1, 4, 28, and 31, with mitomycin C (MMC) 10 mg/m2 at Days 1 and 28. With regard to radiotherapy (RT), all patients were treated with megavoltage therapy units. In 24 cases, 3D conformal RT was performed, and in 3 cases, intensity-modulated RT was performed. Patients received 45.0–59.4 Gy (average, 56.4 Gy). In two cases, further treatment with brachytherapy with 15 and 18 Gy, respectively, was indicated to treat a minimal recurrence. Follow-up FDG-PET CT at 1 and 3 months after RT and chemotherapy was performed to evaluate treatment outcome.
Statistical analysis Midpoints for sensitivity, specificity, and positive and negative predictive value were estimated. The 95% confidence intervals were calculated according to the efficient-score method (corrected for continuity). A sensitivity-specificity evaluation was performed for PET-CT with inguinal node biopsy as the reference standard (Table 2).
RESULTS PET-CT confirmed the presence of anal neoplastic disease in 26 of 27 patients (96.2%). A false-negative result in the remaining case concerned a patient who had undergone surgical excision of an anal canal mass diagnosed as a squamous
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Table 2. PET-CT performance vs. SNB: estimated midpoints and 95% CI PET-CT Sensitivity (95% CI) Specificity (95% CI) Positive predictive values (95% CI) Negative predictive values (95% CI)
100 (30–100) 83 (62–94) 43 (12–80) 100 (80–100)
Abbreviations: CI = confidence interval; PET-CT = positron emission tomography–computed tomography; SNB = sentinel node biopsy.
cancer with tumoral involvement of the lateral margins. In this case, PET-CT was unable to detect residual disease. PET-CT revealed inguinal lymph node metastases in seven patients (25.9%, bilateral in one case), perirectal nodes in two patients (7.4%), and mediastinic lymph node metastases in one patient (3.7%). In the SNB procedure, preoperative lymphoscintigraphy evidenced bilateral migration of Nanocoll in 13 patients and monolateral migration in 14. No intraoperative complications were observed. Postoperative complications occurred in 14 patients (51.8%): inguinal lymphorrhea in 13 patients, which required ambulatorial suction to evacuate the lymph in some cases; lymphocele in 1 case was resolved surgically. No major or other complications occurred. In total, 123 lymph nodes were excised (median, 4.55; range, 2–10). The average diameter of sentinel lymph nodes was 1.16 cm (range, 0.8–2.0 cm). Two patients had lymph nodes 2 cm in diameter, one of whom was an obese patient (170 kg), and thus the lymph node was not palpable. Considering size of positive and negative lymph nodes, there was not a statistical difference between the two groups (1.19 vs. 1.16 cm). The detection rate was 100%. Histologic analysis detected metastases in three patients (11.11%), which were bilateral in 1 patient. The metastasis rate was lower than the 20% reported in our previous study (8). Inguinal lymph node metastases were found in two patients with a squamous cancers (T2 and T4) and in one patient with a basaloid neoplasm (T3) (Table 3). A comparison of the two techniques showed that SNB confirmed inguinal lymph node metastases in only three cases with four false-positive nodes (Table 4). Bilateral metastases at SNB corresponded to bilateral metastases at PET-CT. The diameter of metastatic lymph nodes were 1.5, 1.2, 2.3, and 2.4 cm respectively (the last two nodes refer to bilateral inguinal metastases). As stated earlier, lymph nodes >2 cm in diameter were considered positive when FDG uptake exceeded the activity of mediastinal blood pool structures, whereas for lymph nodes <2 cm in diameter, an increased uptake above the surrounding background was sufficient to consider them positive. The patient with mediastinic lymph node metastases on PET-CT subsequently underwent thoracoscopic biopsy; histological analysis revealed a chronic lung fibrosis. In this series, seven patients were HIV positive, two of whom had positive results for metastases on PET-CT (one
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Table 3. PET-CT an SNB: localization and tumor characteristics Anal canal Squamous T1N0 T2N0 T2N2 T3N0 T3N0 T3N1 T4N2 Basaloid T1N0 T2N0 T2N0 T3N0 T3N0 T3N2 T4N1 T4N0 Total
Anal margin
PET-CT*
Table 5. PET-CT and HIV serostatus False positive
True positive
True negative
0
4 (14.8%)
3 (11.1%)
20 (74.1%)
0 0
1 (14.3%) 3 (15%)
1 (14.3%) 2 (10%)
5 (71.4%) 15 (75%)
SNB*
1 1 1 3 1 1 0
0 6 0 1 0 0 1
Anus Anus Anus + inguinal LFN Anus Anus + inguinal LFN Anus + perirectal LFN Anus + inguinal LFN
NEG NEG POS NEG NEG NEG POS
0 3 1 1 0 1 1
1 1 0 0 1 0 0
NEG NEG NEG NEG NEG POS NEG
1 16
0 11
Anus + inguinal LFN 4 anus Anus + inguinal LFN Anus Anus + inguinal LFN Anus + inguinal LFN Anus + perirectal LFN + mediastinic LFN Anus
NEG
Abbreviations: PET-CT = positron emission tomography–computed tomography; SNB = sentinel node biopsy. * Anus = Anal localization on PET-CT; inguinal LFN: inguinal metastases on PET-CT; SNB POS = inguinal metastases on SNB; SNB NEG: hyperplasia on SNB.
false positive), and only one patient at SNB (14% of all HIVpositive patients and 3.7% of all patients). PET-CT detected inguinal metastases in two HIV-positive and in five HIV-negative patients; false-positive results occurred in three HIVnegative patients and in 1 HIV+ patient (Table 5). All patients found negative for inguinal lymph node metastases at PET-CT were also negative at SNB. No false-negative results were observed. The median duration of the follow-up period was 24.8 months (range, 2–39 months). During this period, no cases of inguinal lymph node metastases were observed in the patients who had tested negative at SNB. These patients did not receive inguinal radiotherapy, thus reducing RT-related morbidity and confirming that the sentinel node technique in staging inguinal lymph nodes was accurate. PET-CT was performed at 1 and 3 months after the end of RT and chemotherapy; all patients were negative for inguinal Table 4. Number and percent (%) of inguinal metastases: Comparison of PET-CT and SNB
Inguinal metastases No inguinal metastases False positive True positive False negative True negative
False negative
PET-CT (n = 27)
SNB (n = 27)
7 (25.9) 20 (74.1) 4 (14.8%) 3 (11.1%) 0 20 (74.1%)
3 (11.1) 24 (88.8) 0 3 (11.1%) 0 24 (88.9%)
Abbreviations: PET-CT = positron emission tomography–computed tomography; SNB = sentinel node biopsy.
Total no. of patients HIV+ HIV–
Abbreviation: PET-CT = positron emission tomography– computed tomography.
disease. Follow-up assessment included clinical examination, neoplastic marker assay, and CT scan or inguinal endosonography if necessary. All patients testing negative for inguinal metastases at the histologic analysis of the sentinel node were negative for disease during follow-up. DISCUSSION Anal cancer is a rare neoplasm, accounting for approximately 1.7% of digestive system cancers. Histological regional lymph node evaluation is the most important prognostic factor in the locoregional staging of malignant tumors. According to a multivariate analysis in the Phase III European Organization for Research and Treatment of Cancer trial, synchronous inguinal lymph node metastasis is an independent prognostic factor for local failure and overall mortality (14), whereas the presence of a concomitant perirectal lymph node does not significantly affect prognosis. Published studies describe various approaches to the treatment of inguinal lymph node metastases in patients with anal cancer. Elective irradiation is a common practice in many departments, but the doses may differ considerably. Inguinal dissection is a common practice, although not widely used, and a watchful waiting policy is advocated at some institutions. Groin dissection has a key role in the management of patients with penile, vulvar, anal, and cutaneous malignancy, and approximately 500 procedures are performed in the United Kingdom every year (15). However, the procedure has often been associated with high morbidity and prolonged hospital stay. Tonouchi et al. (16) reported an overall wound infection rate of 24% and an incidence of moderate to severe infection of 16%. Compared with straight incisions, an S-shaped cutaneous incision seems to influence the incidence of volume of drain discharge. Two other factors that contribute to wound complications are obesity and aging. Leg edema occurs in 40% of patients; pulmonary embolism has been reported in 0.6%–1.0% (16). Inguinal RT also carries has a high rate of morbidity. In a study of 223 patients treated with chemoradiation sparing inguinal fields, Papillon et al. (17) found metachronous inguinal metastases in only 7.4% of cases over a follow-up period of more than 3 years (17). In a more recent study of 270 patients treated without elective inguinal irradiation, late inguinal metastases were diagnosed in 7.8% of patients (6). In light of these results, it might be concluded that the vast majority of patients (92%) submitted to routine inguinal
PET-CT vs. SNB in the detection of inguinal metastased in anal cancer d M. MISTRANGELO et al.
irradiation is being overtreated (7). Systematic irradiation of the groins has proved to demand a larger volume of radiotherapy, which increases toxicity, especially when associated with chemotherapy. Acute toxicity-related deaths occurred in 2.0%–2.7% of cases (14), and the late toxicity related to primary treatment, such a small bowel injury, soft tissue injury, and neurogenic bladder, was reported to be as high as 33%, with 15% of patients requiring major medical or surgical intervention (18). Following on these considerations, Sapienza et al. (19) suggested that the low incidence of metachronous metastases and the high morbidity after inguinal lymphadenectomy and RT do not advocate the choice of preventive treatment. In an earlier study, Wade et al. (20) at the Roswell Park Cancer Institute used a ‘‘clearing technique’’; they found that 44% of perianal, perirectal, and pericolonic lymph node metastases were <5 mm in diameter. An adequate technique to detect early inguinal node metastases is therefore needed. In this regard, SNB in patients with anal cancer has produced good results and allows selection of eligible patients and a choice of RT plans (7–9). Many recent studies have demonstrated that PET-CT may improve the staging of anal cancer and is useful in the followup of these patients after RT and chemotherapy. Nguyen et al. (13) reported that staging of anal cancer can be improved with PET scanning, since the procedure identifies nodal and distant disease involvement, resulting in upstaging in up to one fifth of cases (13). Other published studies, although not comparable because of variations in timing of PET-CT execution, suggested advantages in this technique over CT in the staging of anal cancer. Schwarz et al. (21) reported that the complete metabolic response identified on the posttherapy FDG-PET/CT scan is associated with significantly improved clinical outcomes (21). Anderson et al. (12) confirmed that PET can change the management of anorectal tumors by early detection of metastatic disease or disease
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outside standard radiation fields. Trautmann and Zuger (10) and Cotter et al. (11) reported that PET-CT detects the primary tumor more often than CT and detects substantially more abnormal inguinal lymph nodes than are identified by standard clinical staging with CT and physical examination. We compared SNB with PET-CT to assess their value in the detection of inguinal lymph node metastases. To the best of our knowledge, this is the first study to compare the two techniques in patients with anal cancer. In our study, SNB was superior to PET-CT in staging inguinal lymph nodes and yielded no false-positive results. In anal cancer, correct detection of inguinal node involvement is essential to reserve inguinal RT only for patients with metastases so that irradiation-associated morbidity in N0 and N1 patients can be avoided. HIV status may be a confounding factor in analyzing treatment outcome. Cotter et al. (11) found a higher rate of PET-CT scans positive for inguinal metastases in HIVpositive patients (44% vs. 16%), whereas we observed inguinal metastases in 28.5% of HIV-positive vs. 25% in HIV-negative patients. The difference was not statistically significant, and HIV status did not appear to influence PET-CT results (Table 5), although HIV-positive patients often present with multiple lymphadenopathies related to the infection. In our study, PET-CT had a sensitivity of 100% and a negative predictive value of 100%. When the high number of false-positive results is considered, the specificity and the positive predictive value were low (83% and 43%, respectively). No false negatives were observed with either technique (Table 2). In conclusion, we suggest that SNB of inguinal lymph nodes may offer the technique of choice in staging inguinal metastases from anal cancer, and it likely should be used in all patients with anal cancer. A multicenter study is necessary to confirm these results, with adequate follow-up to determine how inguinal metastases compare in nonirradiated patients.
REFERENCES 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008;58:71–96. 2. Ries LAG, Harkins D, Krapcho M, et al., editors. SEER Cancer Statistics Review, 1975–2003. Baltimore, MD: National Cancer Institute; 2005. p. 1–103. 3. Stearns MW, Urmacher C, Sternberg SS. Cancer of the anal canal. Cur Probl Cancer 1980;4:1–44. 4. Golden GT, Horsley JS. Surgical management of epidermoid carcinoma of the anus. Am J Surg 1976;131:275–280. 5. Nigro ND, Vaitkeicus VK, Basil Considine B. Combined therapy for cancer of the anal canal: A preliminary report. Dis Colon Rectum 1974;17:354–356. 6. Gerard J-P, Chapet O, Samiei F, et al. Management of inguinal lymph node metastases in patients with carcinoma of the anal canal. Experience in a series of 270 patients treated in Lyon and review of the literature. Cancer 2001;92:77–84. 7. Damin DC, Rosito MA, Schwartsmann G. Sentinel lymph node in carcinoma of the anal canal: A review. EJSO 2006;32:247–252. 8. Mistrangelo M, Bello` M, Mobiglia A, et al. Feasibility of the sentinel node biopsy in anal cancer. Q J Nucl Med Mol Imaging 2009;53:3–8.
9. Gretschel S, Warnick P, Bembenek A, et al. Lymphatic mapping and sentinel lymph node biopsy in epidermoid carcinoma of the anal canal. Eur J Surg Oncol 2008;34:890–894. 10. Trautmann TG, Zuger JH. Positron emission tomography for pre-treatment staging and posttreatment evaluation in cancer of the anal canal. Mol Imaging Biol 2005;7:309–313. 11. Cotter SE, Grigsby PW, Siegel BA, et al. FDG-PET/CT in the evaluation of anal carcinoma. Int J Radiat Oncol Biol Phys 2006;65:720–725. 12. Anderson C, Koshy M, Staley C, et al. PET-CT fusion in radiation management of patients with anorectal tumors. Int J Radiat Oncol Biol Phys 2007;69:155–162. 13. Nguyen BT, Joon DL, Khoo V, et al. Assessing the impact of FDG-PET in the management of anal cancer. Radiother Oncol 2008;87:376–382. 14. Bartelink H, Roelofsen F, Eschwege F, et al. Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: Results of a Phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups. J Clin Oncol 1997;15:2040–2049.
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15. Swan MC, Furniss D, Cassell OCS. Surgical management of metastatic inguinal lymphadenopathy. BMJ 2004;329:1272–1276. 16. Tonouchi H, Ohmori Y, Kobayashi M, et al. Operative morbidity associated with groin dissections. Surg Today 2004;34:413–418. 17. Papillon J, Montbarbon JF. Epidermoid carcinoma of the anal canal: A series of 276 cases. Dis Colon Rectum 1987;30:324–333. 18. Myerson RJ, Kong F, Birnbaum EH, et al. Radiation therapy for epidermoid carcinoma of the anal canal, clinical and treatment factors associate with outcome. Radiother Oncol 2001;61: 15–22.
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19. Sapienza P, Mingoli A, Nicolanti V, et al. Massive metachronous inguinal metastases from cancer of anal margin. A clinical case report. Minerva Chir 1992;47:1207–1210. 20. Wade DS, Herrera L, Castillo NB, Petrelli NJ. Metastases to the lymph nodes in epidermoid carcinoma of the anal canal studied by a clearing technique. Surg Gynecol Obstet 1989;169: 238–242. 21. Schwarz JK, Siegel BA, Dehdashti F, et al. Tumor response and survival predicted by post therapy FDG-PET/CT in anal cancer. Int J Radiation Oncol Biol Phys 2008;71:180–186.
doi:10.1016/j.ijrobp.2009.04.020
CLINICAL INVESTIGATION
Anus
COMPARISON OF POSITRON EMISSION TOMOGRAPHY SCANNING AND SENTINEL NODE BIOPSY IN THE DETECTION OF INGUINAL NODE METASTASES IN PATIENTS WITH ANAL CANCER MASSIMILIANO MISTRANGELO, PH.D., M.D.,*k ETTORE PELOSI, M.D.,y MARILENA BELLO`, M.D.,y ISABELLA CASTELLANO, M.D.,z PAOLA CASSONI, PH.D., M.D.,z UMBERTO RICARDI, M.D.,x FERNANDO MUNOZ, M.D.,x PATRIZIA RACCA, M.D.,** VIVIANA CONTU, M.D.,** GIANCARLO BELTRAMO, M.D.,x MARIO MORINO, M.D.,* AND ANTONIO MUSSA, M.D.{ * Departments of Surgery, y Nuclear Medicine, z Anatomo-Pathology, and x Radiotherapy, the { Surgical and Oncological Department, the kCentre of Minimally Invasive Surgery, and the ** Oncological Centre for Gastrointestinal Neoplasms, University of Turin, Italy; and the PET Center IRMET, Turin, Italy Background: Inguinal lymph node metastases in patients with anal cancer are an independent prognostic factor for local failure and overall mortality. Inguinal lymph node status can be adequately assessed with sentinel node biopsy, and the radiotherapy strategy can subsequently be changed. We compared this technique vs. dedicated 18F-fluorodeoxyglucose positron emission tomography (PET) to determine which was the better tool for staging inguinal lymph nodes. Methods and Materials: In our department, 27 patients (9 men and 18 women) underwent both inguinal sentinel node biopsy and PET-CT. PET-CT was performed before treatment and then at 1 and 3 months after treatment. Results: PET-CT scans detected no inguinal metastases in 20 of 27 patients and metastases in the remaining 7. Histologic analysis of the sentinel lymph node detected metastases in only three patients (four PET-CT false positives). HIV status was not found to influence the results. None of the patients negative at sentinel node biopsy developed metastases during the follow-up period. PET-CT had a sensitivity of 100%, with a negative predictive value of 100%. Owing to the high number of false positives, PET-CT specificity was 83%, and positive predictive value was 43%. Conclusions: In this series of patients with anal cancer, inguinal sentinel node biopsy was superior to PET-CT for staging inguinal lymph nodes. Ó 2010 Elsevier Inc. Anal cancer, Squamous cancer, Lymph node metastases, Sentinel lymph node metastases, PET-CT.
Anal cancer is a rare disease. An estimated 5,070 new cases (2,020 men and 3,050 women) of anal cancer (involving the anus, the anal canal, or the anorectum) were expected to occur in the United States in 2008, accounting for approximately 1.85% of digestive system cancers. It was estimated that 680 deaths from anal cancer would occur in the United States in 2008 (1). Surveillance Epidemiology and End Results (SEER) data from 1975 to 2003 suggest that its incidence is rising (2). Human papilloma virus infection, cervical dysplasia or cancer, HIV seropositivity, low CD4 count, cigarette smoking, anoreceptive intercourse, and
immunosuppression following solid organ transplant are known risk factors for anal cancer. Before the mid-1980s, the treatment of choice for anal cancer was abdominoperineal resection (APR). The 5-year survival rate after APR for anal cancer was 40%–70%, with worse outcomes for those with larger tumors and nodal metastases. In the 1920s and 1930s, inguinal node dissection was included in the surgical management of these patients, and it was generally reserved for those patients with clinically enlarged (although not necessarily involved) inguinal nodes (3). By the 1950s, it had became clear that the morbidity associated with lymph node dissection was much greater
Reprint requests to: Massimiliano Mistrangelo, M.D., Department of Surgery and Centre of Minimal Invasive Surgery, Molinette Hospital, University of Turin, Corso A. M. Dogliotti 14, 10126 Turin, Italy. Tel: (+39) 011-6313149; Fax: (+39) 011-6336725; E-mail: [email protected]; mmistrangelo3@molinette. piemonte.it The study was presented at the Third Annual Meeting of the European Society of Coloproctology, September 24–27, 2008, Nantes, France.
Conflict of interest: none. Acknowledgments—We thank Dr. Vincenzo Arena and Dr. Angela Cistaro (PET Center IRMET, Turin, Italy) and Dr. Enrica Milanesi (Oncological Centre for Gastrointestinal Neoplasms, University of Turin, Italy) for their active participation and work. We thank Dr. Marco Pizzio (Department of Surgery and Centre of Minimal Invasive Surgery, University of Turin) for statistical analyses. Received Feb 3, 2009, and in revised form April 15, 2009. Accepted for publication April 15, 2009.
INTRODUCTION
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than any survival benefit, so the procedure was gradually abandoned (4). In 1974, Nigro et al. (5) proposed a multimodality treatment combining radiation and chemotherapy, which has since become the standard treatment. Local control rates of 60%–90% over all stages are achievable, with sphincter preservation in approximately 65% of cases. The prognosis after combined radiochemotherapy for anal cancer may be influenced by several factors: high tumor stage and regional nodal involvement, tumor site in the anal canal, and inguinal lymph node involvement in anal canal carcinoma. Synchronous inguinal metastases have been reported in 10%–25% of patients and metachronous metastases in 5%–25% (6). An array of tools for assessing inguinal metastasis have been proposed, including clinical examination, endosonography, computed tomography (CT), and magnetic resonance imaging (MRI); however, they are unable to detect nodal involvement in all cases. Furthermore, only histologic study can confirm metastasis in a enlarged node or a micrometastasis in a normal-sized node. In recent years, sentinel node biopsy (SNB) has proven to be a safe and effective technique for sampling inguinal sentinel lymph nodes (7, 8). Since 2001, SNB in patients with anal cancer has improved the accuracy of inguinal staging and planning of radiotherapy treatment, obviating the need for inguinal radiotherapy and eliminating its related morbidity in patients without metastasis at SLN biopsy. In their recent review of the literature, Damin et al. (7) evaluated 84 patients by SLN sampling: the detection rate was between 66% and 100%, and metastases were found in 7.1%–42.0% of cases. No major complications were reported. After this review and our recent report, Gretschel et al. (9) described their experience with 40 patients. In contrast to their previous reports, they observed a detection rate of 56% in inguinal lymph nodes (76% in a previous series), with 30% of inguinal node metastases (42% previously). They suggested that SLN biopsy in anal cancer can be used to appropriately select patients for inguinal irradiation, especially in T1 and T2 tumors. These patients receive either additional treatment or are spared unnecessary radiation. In their opinion, SLN biopsy is not currently recommended for larger (T3/T4) tumors or in patients with prior surgical manipulation of the anal or inguinal region (9). Recently, the use of fluorodeoxyglucose (FDG) positron emission tomography (PET) has also gained an important place in this setting. Trautmann and Zuger (10) presented a brief report evaluating PET both during staging and after completion of therapy. PET identified disease not documented by CT in 24% of patients, resulting in a change of stage in 10%. In a study of 41 consecutive patients with anal cancer, Cotter et al. (11) reported that PET seemed to detect more inguinal disease, with abnormal nodes noted in 29% of all groins vs. 16% at CT. The incidence of PETpositive inguinal nodes was found be higher (44% vs. 16%) in HIV-positive patients. The report also suggested that FDG-PET might offer better sensitivity in identifying nodal disease and so could be used to upstage the disease
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and modify the treatment plan to include radiotherapy boost to the groins. In this connection, Anderson et al. (12) suggested that PET-CT can change the management of anorectal tumors by early detection of metastatic disease or disease outside standard radiation fields (12). Nguyen et al. (13) recently found that PET upstages disease in 17% of patients and changes radiotherapy planning in 19%. Prospective studies are necessary to determine the extent to which PET can aid in anal cancer staging and identification of residual disease and recurrent or metastatic disease. In this study, we compared FDG-PET CT with biopsy of the inguinal sentinel node to determine whether PET-CT could upstage the disease, but not overstage it, in patients with inguinal metastases who could potentially benefit from inguinal radiotherapy. METHODS AND MATERIALS Between October 2004 and December 2007, 27 patients with anal cancer were studied in our department (General Surgical Departmente and Centre of Minimally Invasive Surgery, University of Turin, Turin, Italy). All patients presented for bleeding on defecation, sometimes associated with anal pain or the sensation of an anal mass. Proctological examination and anoscopy revealed an anal neoplasm. At biopsy, 27 of these tumours were diagnosed as squamous cell carcinomas, 11 of which displayed basaloid features according to the most recent World Health Organization classification. Clinical workup included digital rectal examination, anoscopy, rigid proctoscopy, total colonoscopy (possible in 16 patients), CT, endosonography (possible in 14 patients), and tumor marker assay. Tumor sites were the anal canal in 16 patients and the anal margin in 11 patients. TNM staging was T1 in 2 patients, T2 in 13, T3 in 9, and T4 in 3 (Table 1). Five patients (18.5%) presented with palpable lymph nodes on clinical examination. Three of these patients were HIV positive, a condition that usually presents with palpable lymph nodes. Table 1. Patients characteristics Characteristic Sex Male Female Race White Age Median Range HIV positive Histological subtype Squamous Basaloid Localization Anal canal Anal margin T T1 T2 T3 T4
No. of patients (%) 9 (33.33) 18 (66.66) 27 (100) 58 years 32–75 years 7 (25.9) 16 (59.2) 11 (40.7) 16 (59.2) 11 (40.7) 2 (7.4) 13 (48.1) 9 (33.33) 3 (14.1)
PET-CT vs. SNB in the detection of inguinal metastased in anal cancer d M. MISTRANGELO et al.
All patients underwent FDG-PET CT for adequate pretreatment staging of the disease. Patients gave written informed consent. All PET-CT studies were acquired using the same combined tomographs (Discovery ST, General Electric Medical Systems, Waukesha, WI). Patients were asked to refrain from food intake for at least 6 hours before scanning; at the time of tracer injection, all patients presented with a blood glucose value <160 mg/dL. Whole-body emission scans were acquired beginning 60 min after the intravenous injection of FDG (dose range, 222–370 MBq). No adverse events after administration of 18F-FDG were observed. The acquisition protocol started with a scout view, then a CT was performed (140 kV; tube current 60 mA/s) from the proximal femur to the base of the skull. The scan lasted approximately 1 min and was used for both anatomic localization and attenuation correction of the PET emission data. At the end of CT scanning, the bed position was moved into the PET field of view (FOV) for the emission study. PET data of the whole-body distribution of the tracer were acquired in three-dimensional (3D) mode from the pelvis to the neck. Coronal, sagittal, and transverse data sets were reconstructed. Images were reconstructed as a 3D reconstruction algorithm FOREiterative. Coregistered images were visualized using dedicate software (Advantage 4.2, GE Healthcare, Chalfont St. Giles, United Kingdom). All lymph nodes $2 cm in diameter with a 18F-FDG uptake lower than or equal to that of mediastinal blood pool structures were considered negative for the presence of tumor metastases. A mild degree of 18F-FDG uptake can be related to an inflammatory reaction. In contrast, lymph nodes with uptakes exceeding the activity of mediastinal blood pool structures were considered positives. Any increased uptake above the surrounding background in lymph nodes less than 2 cm in diameter was considered positive. Sentinel node biopsy (SNB), as previously described (8), was the final examination in the assessment of inguinal lymph node metastases. All patients gave written informed consent after being informed about the risks and benefits of the procedure. All patients were submitted to radiochemotherapy as reported by Nigro et al. (5). Chemotherapy was performed with the following schedule: fluorouracil (5-FU) 1,000 mg/m2 on Days 1, 4, 28, and 31, with mitomycin C (MMC) 10 mg/m2 at Days 1 and 28. With regard to radiotherapy (RT), all patients were treated with megavoltage therapy units. In 24 cases, 3D conformal RT was performed, and in 3 cases, intensity-modulated RT was performed. Patients received 45.0–59.4 Gy (average, 56.4 Gy). In two cases, further treatment with brachytherapy with 15 and 18 Gy, respectively, was indicated to treat a minimal recurrence. Follow-up FDG-PET CT at 1 and 3 months after RT and chemotherapy was performed to evaluate treatment outcome.
Statistical analysis Midpoints for sensitivity, specificity, and positive and negative predictive value were estimated. The 95% confidence intervals were calculated according to the efficient-score method (corrected for continuity). A sensitivity-specificity evaluation was performed for PET-CT with inguinal node biopsy as the reference standard (Table 2).
RESULTS PET-CT confirmed the presence of anal neoplastic disease in 26 of 27 patients (96.2%). A false-negative result in the remaining case concerned a patient who had undergone surgical excision of an anal canal mass diagnosed as a squamous
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Table 2. PET-CT performance vs. SNB: estimated midpoints and 95% CI PET-CT Sensitivity (95% CI) Specificity (95% CI) Positive predictive values (95% CI) Negative predictive values (95% CI)
100 (30–100) 83 (62–94) 43 (12–80) 100 (80–100)
Abbreviations: CI = confidence interval; PET-CT = positron emission tomography–computed tomography; SNB = sentinel node biopsy.
cancer with tumoral involvement of the lateral margins. In this case, PET-CT was unable to detect residual disease. PET-CT revealed inguinal lymph node metastases in seven patients (25.9%, bilateral in one case), perirectal nodes in two patients (7.4%), and mediastinic lymph node metastases in one patient (3.7%). In the SNB procedure, preoperative lymphoscintigraphy evidenced bilateral migration of Nanocoll in 13 patients and monolateral migration in 14. No intraoperative complications were observed. Postoperative complications occurred in 14 patients (51.8%): inguinal lymphorrhea in 13 patients, which required ambulatorial suction to evacuate the lymph in some cases; lymphocele in 1 case was resolved surgically. No major or other complications occurred. In total, 123 lymph nodes were excised (median, 4.55; range, 2–10). The average diameter of sentinel lymph nodes was 1.16 cm (range, 0.8–2.0 cm). Two patients had lymph nodes 2 cm in diameter, one of whom was an obese patient (170 kg), and thus the lymph node was not palpable. Considering size of positive and negative lymph nodes, there was not a statistical difference between the two groups (1.19 vs. 1.16 cm). The detection rate was 100%. Histologic analysis detected metastases in three patients (11.11%), which were bilateral in 1 patient. The metastasis rate was lower than the 20% reported in our previous study (8). Inguinal lymph node metastases were found in two patients with a squamous cancers (T2 and T4) and in one patient with a basaloid neoplasm (T3) (Table 3). A comparison of the two techniques showed that SNB confirmed inguinal lymph node metastases in only three cases with four false-positive nodes (Table 4). Bilateral metastases at SNB corresponded to bilateral metastases at PET-CT. The diameter of metastatic lymph nodes were 1.5, 1.2, 2.3, and 2.4 cm respectively (the last two nodes refer to bilateral inguinal metastases). As stated earlier, lymph nodes >2 cm in diameter were considered positive when FDG uptake exceeded the activity of mediastinal blood pool structures, whereas for lymph nodes <2 cm in diameter, an increased uptake above the surrounding background was sufficient to consider them positive. The patient with mediastinic lymph node metastases on PET-CT subsequently underwent thoracoscopic biopsy; histological analysis revealed a chronic lung fibrosis. In this series, seven patients were HIV positive, two of whom had positive results for metastases on PET-CT (one
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Table 3. PET-CT an SNB: localization and tumor characteristics Anal canal Squamous T1N0 T2N0 T2N2 T3N0 T3N0 T3N1 T4N2 Basaloid T1N0 T2N0 T2N0 T3N0 T3N0 T3N2 T4N1 T4N0 Total
Anal margin
PET-CT*
Table 5. PET-CT and HIV serostatus False positive
True positive
True negative
0
4 (14.8%)
3 (11.1%)
20 (74.1%)
0 0
1 (14.3%) 3 (15%)
1 (14.3%) 2 (10%)
5 (71.4%) 15 (75%)
SNB*
1 1 1 3 1 1 0
0 6 0 1 0 0 1
Anus Anus Anus + inguinal LFN Anus Anus + inguinal LFN Anus + perirectal LFN Anus + inguinal LFN
NEG NEG POS NEG NEG NEG POS
0 3 1 1 0 1 1
1 1 0 0 1 0 0
NEG NEG NEG NEG NEG POS NEG
1 16
0 11
Anus + inguinal LFN 4 anus Anus + inguinal LFN Anus Anus + inguinal LFN Anus + inguinal LFN Anus + perirectal LFN + mediastinic LFN Anus
NEG
Abbreviations: PET-CT = positron emission tomography–computed tomography; SNB = sentinel node biopsy. * Anus = Anal localization on PET-CT; inguinal LFN: inguinal metastases on PET-CT; SNB POS = inguinal metastases on SNB; SNB NEG: hyperplasia on SNB.
false positive), and only one patient at SNB (14% of all HIVpositive patients and 3.7% of all patients). PET-CT detected inguinal metastases in two HIV-positive and in five HIV-negative patients; false-positive results occurred in three HIVnegative patients and in 1 HIV+ patient (Table 5). All patients found negative for inguinal lymph node metastases at PET-CT were also negative at SNB. No false-negative results were observed. The median duration of the follow-up period was 24.8 months (range, 2–39 months). During this period, no cases of inguinal lymph node metastases were observed in the patients who had tested negative at SNB. These patients did not receive inguinal radiotherapy, thus reducing RT-related morbidity and confirming that the sentinel node technique in staging inguinal lymph nodes was accurate. PET-CT was performed at 1 and 3 months after the end of RT and chemotherapy; all patients were negative for inguinal Table 4. Number and percent (%) of inguinal metastases: Comparison of PET-CT and SNB
Inguinal metastases No inguinal metastases False positive True positive False negative True negative
False negative
PET-CT (n = 27)
SNB (n = 27)
7 (25.9) 20 (74.1) 4 (14.8%) 3 (11.1%) 0 20 (74.1%)
3 (11.1) 24 (88.8) 0 3 (11.1%) 0 24 (88.9%)
Abbreviations: PET-CT = positron emission tomography–computed tomography; SNB = sentinel node biopsy.
Total no. of patients HIV+ HIV–
Abbreviation: PET-CT = positron emission tomography– computed tomography.
disease. Follow-up assessment included clinical examination, neoplastic marker assay, and CT scan or inguinal endosonography if necessary. All patients testing negative for inguinal metastases at the histologic analysis of the sentinel node were negative for disease during follow-up. DISCUSSION Anal cancer is a rare neoplasm, accounting for approximately 1.7% of digestive system cancers. Histological regional lymph node evaluation is the most important prognostic factor in the locoregional staging of malignant tumors. According to a multivariate analysis in the Phase III European Organization for Research and Treatment of Cancer trial, synchronous inguinal lymph node metastasis is an independent prognostic factor for local failure and overall mortality (14), whereas the presence of a concomitant perirectal lymph node does not significantly affect prognosis. Published studies describe various approaches to the treatment of inguinal lymph node metastases in patients with anal cancer. Elective irradiation is a common practice in many departments, but the doses may differ considerably. Inguinal dissection is a common practice, although not widely used, and a watchful waiting policy is advocated at some institutions. Groin dissection has a key role in the management of patients with penile, vulvar, anal, and cutaneous malignancy, and approximately 500 procedures are performed in the United Kingdom every year (15). However, the procedure has often been associated with high morbidity and prolonged hospital stay. Tonouchi et al. (16) reported an overall wound infection rate of 24% and an incidence of moderate to severe infection of 16%. Compared with straight incisions, an S-shaped cutaneous incision seems to influence the incidence of volume of drain discharge. Two other factors that contribute to wound complications are obesity and aging. Leg edema occurs in 40% of patients; pulmonary embolism has been reported in 0.6%–1.0% (16). Inguinal RT also carries has a high rate of morbidity. In a study of 223 patients treated with chemoradiation sparing inguinal fields, Papillon et al. (17) found metachronous inguinal metastases in only 7.4% of cases over a follow-up period of more than 3 years (17). In a more recent study of 270 patients treated without elective inguinal irradiation, late inguinal metastases were diagnosed in 7.8% of patients (6). In light of these results, it might be concluded that the vast majority of patients (92%) submitted to routine inguinal
PET-CT vs. SNB in the detection of inguinal metastased in anal cancer d M. MISTRANGELO et al.
irradiation is being overtreated (7). Systematic irradiation of the groins has proved to demand a larger volume of radiotherapy, which increases toxicity, especially when associated with chemotherapy. Acute toxicity-related deaths occurred in 2.0%–2.7% of cases (14), and the late toxicity related to primary treatment, such a small bowel injury, soft tissue injury, and neurogenic bladder, was reported to be as high as 33%, with 15% of patients requiring major medical or surgical intervention (18). Following on these considerations, Sapienza et al. (19) suggested that the low incidence of metachronous metastases and the high morbidity after inguinal lymphadenectomy and RT do not advocate the choice of preventive treatment. In an earlier study, Wade et al. (20) at the Roswell Park Cancer Institute used a ‘‘clearing technique’’; they found that 44% of perianal, perirectal, and pericolonic lymph node metastases were <5 mm in diameter. An adequate technique to detect early inguinal node metastases is therefore needed. In this regard, SNB in patients with anal cancer has produced good results and allows selection of eligible patients and a choice of RT plans (7–9). Many recent studies have demonstrated that PET-CT may improve the staging of anal cancer and is useful in the followup of these patients after RT and chemotherapy. Nguyen et al. (13) reported that staging of anal cancer can be improved with PET scanning, since the procedure identifies nodal and distant disease involvement, resulting in upstaging in up to one fifth of cases (13). Other published studies, although not comparable because of variations in timing of PET-CT execution, suggested advantages in this technique over CT in the staging of anal cancer. Schwarz et al. (21) reported that the complete metabolic response identified on the posttherapy FDG-PET/CT scan is associated with significantly improved clinical outcomes (21). Anderson et al. (12) confirmed that PET can change the management of anorectal tumors by early detection of metastatic disease or disease
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outside standard radiation fields. Trautmann and Zuger (10) and Cotter et al. (11) reported that PET-CT detects the primary tumor more often than CT and detects substantially more abnormal inguinal lymph nodes than are identified by standard clinical staging with CT and physical examination. We compared SNB with PET-CT to assess their value in the detection of inguinal lymph node metastases. To the best of our knowledge, this is the first study to compare the two techniques in patients with anal cancer. In our study, SNB was superior to PET-CT in staging inguinal lymph nodes and yielded no false-positive results. In anal cancer, correct detection of inguinal node involvement is essential to reserve inguinal RT only for patients with metastases so that irradiation-associated morbidity in N0 and N1 patients can be avoided. HIV status may be a confounding factor in analyzing treatment outcome. Cotter et al. (11) found a higher rate of PET-CT scans positive for inguinal metastases in HIVpositive patients (44% vs. 16%), whereas we observed inguinal metastases in 28.5% of HIV-positive vs. 25% in HIV-negative patients. The difference was not statistically significant, and HIV status did not appear to influence PET-CT results (Table 5), although HIV-positive patients often present with multiple lymphadenopathies related to the infection. In our study, PET-CT had a sensitivity of 100% and a negative predictive value of 100%. When the high number of false-positive results is considered, the specificity and the positive predictive value were low (83% and 43%, respectively). No false negatives were observed with either technique (Table 2). In conclusion, we suggest that SNB of inguinal lymph nodes may offer the technique of choice in staging inguinal metastases from anal cancer, and it likely should be used in all patients with anal cancer. A multicenter study is necessary to confirm these results, with adequate follow-up to determine how inguinal metastases compare in nonirradiated patients.
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15. Swan MC, Furniss D, Cassell OCS. Surgical management of metastatic inguinal lymphadenopathy. BMJ 2004;329:1272–1276. 16. Tonouchi H, Ohmori Y, Kobayashi M, et al. Operative morbidity associated with groin dissections. Surg Today 2004;34:413–418. 17. Papillon J, Montbarbon JF. Epidermoid carcinoma of the anal canal: A series of 276 cases. Dis Colon Rectum 1987;30:324–333. 18. Myerson RJ, Kong F, Birnbaum EH, et al. Radiation therapy for epidermoid carcinoma of the anal canal, clinical and treatment factors associate with outcome. Radiother Oncol 2001;61: 15–22.
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19. Sapienza P, Mingoli A, Nicolanti V, et al. Massive metachronous inguinal metastases from cancer of anal margin. A clinical case report. Minerva Chir 1992;47:1207–1210. 20. Wade DS, Herrera L, Castillo NB, Petrelli NJ. Metastases to the lymph nodes in epidermoid carcinoma of the anal canal studied by a clearing technique. Surg Gynecol Obstet 1989;169: 238–242. 21. Schwarz JK, Siegel BA, Dehdashti F, et al. Tumor response and survival predicted by post therapy FDG-PET/CT in anal cancer. Int J Radiation Oncol Biol Phys 2008;71:180–186.