Article ID: WMC001565 2046-1690

Inguinal Lymph Nodes Management In Squamous Cell Carcinoma Of The Anal Canal

Corresponding Author: Dr. Saleh M Abbas, Surgeon, Surgery - Australia

Submitting Author: Dr. Saleh M Abbas, Surgeon, Surgery - Australia

Article ID: WMC001565 Article Type: Review articles Submitted on:20-Feb-2011, 06:33:08 AM GMT Published on: 22-Feb-2011, 08:50:03 PM GMT Article URL: http://www.webmedcentral.com/article_view/1565 Subject Categories:GENERAL SURGERY Keywords:Carcinoma, Radiotherapy, Inguinal Nodes How to cite the article:Abbas S M. Management In Squamous Cell Carcinoma Of The Anal Canal . WebmedCentral GENERAL SURGERY 2011;2(2):WMC001565

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Inguinal Lymph Nodes Management In Squamous Cell Carcinoma Of The Anal Canal

Author(s): Abbas S M

Abstract Background

Current issues in the management of clinically Although Squamous cell carcinoma (SCC) of the anal negative inguinal lymph nodes in squamous cell canal is an uncommon disease it is the most common carcinoma of the anal canal. Quality of the available malignant tumor of the anal canal accounting for 90% evidence. of malignant tumors at this site. Survival is determined Background essentially by two factors; the size of the tumor and The first line of management of squamous cell spread. Patients with no clinical evidence carcinoma (SCC) of the anal canal is chemo-radiation. of nodal disease have a ten-year survival of 73% The radiation field includes, in addition to the anal compared with 53% in those with nodal disease.1 region and the perirectal nodes, the iliac and both Historically the treatment of SCC of the anal canal was inguinal triangles to target the inguinal nodes. More abdominoperineal resection; this involves wide recently a selective approach has been investigated in dissection of the ischiorectal fossa with clearance of patients with non-palpable inguinal nodes utilizing pararectal lymph nodes with en bloc excision of the sentinel node biopsy and PET scan. posterior vaginal wall in women 2. Methods The current management of SCC of the anal canal is Medline was searched using the keywords, squamous chemoradiotherapy, which includes infusion of cell carcinoma, anal canal, inguinal lymph nodes, 5-flourouracil with or without mitomycin and radiation sentinel node and radiotherapy. fields that include the primary tumor and the pelvic and Relevant articles were reviewed with regard to the inguinal lymph nodes.3, 4, 5, Surgery is reserved for management of inguinal nodes in SCC of the anal patients who have an incomplete response, residual canal. disease and those with later disease recurrence. Results: The lymphatic drainage of tumors of the anal canal is Currently the management of clinically normal inguinal bidirectional and depends on the tumor location in nodes in SCC of the anal canal is prophylactic relation to the dentate line. Above the dentate line radiation of both inguinal areas. Clinically involved most of the lymph drains in a cephalad direction along nodes are included in the radiation field plus a boost of the inferior rectal artery to the origin of the inferior radiation to the groin that harbor involved nodes. The mesenteric artery, also along the territory of the middle radiation is refined recently by intensity modulation rectal artery to the iliac nodes. Below the dentate line it radiotherapy (IMR) to involve the diseased area and drains to the inguinal nodes along the femoral artery. minimize radiation exposure of normal adjacent Hence the lymphatic drainage is to the ipsilateral tissues. Alternatively, more recently, a selective inguinal lymph nodes. The probability of nodal spread approach with utilization of sentinel node biopsy and is relative to the tumor size (T stage). 1 radiation to microscopically involved nodal areas has When the primary tumor is clearly located laterally, the been described. inguinal metastasis nearly always is homolateral to the Conclusion: primary tumor. Midline tumors and locally advanced The treatment of clinically normal inguinal nodes is lesions usually show bilateral inguinal and pararectal currently by prophylactic radiation of both inguinal lymph node involvement. In the Lyon series bilateral regions. It is possible that in the future radiation of involvement was seen only when the primary tumor clinically normal inguinal may become more selective involved the medial part of the anal canal. 6 with an increasing reliance on sentinel node biopsy. Overall, inguinal nodal involvement occurs in 10-25% Further studies are needed in this field to assess the of patients 7, 8,9, 10. Using bipedal lymphangiography efficacy of this approach. in a group of patients with anal cancer Davey et al demonstrated metastasis to external iliac lymph nodes in 7 out of 28 patients (25%).11 CT detected disease in the external iliac nodes in only one of these patients.

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Lymph node involvement is related to the T stage of persistent disease is still amenable to treatment, the tumor with nodal metastases seen in 0-10% of T1 usually by inguinal node dissection, but this event is and 2 lesions and 40- 50% of T3 and 4 disease (table associated with reduced 5 year overall survival of 1).12, 11 At the time of diagnosis local tumor extent is 40-64%.14, 15, 6 T1: 8.5%; T2: 51.1%; T3: 30.4%; T4: 10%.1 Pelvic Molecular studies have failed to show any possible lymph node involvement correlates with increasing risk association between tumor genetics and tumor of pelvic relapse and residual disease after definitive behavior with regard to nodal metastasis or aggressive radio-chemotherapy. Pelvic nodes are routinely behavior and overall survival. Deletion of cancer targeted within the radiation field of the primary tumor suppressor genes such as the p53 and Rb genes has and therefore their involvement or otherwise are no effect on nodal invasion.16 unlikely at this stage to change the approach of In patients with clinically involved inguinal nodes treatment. treated with definitive chemo- radiotherapy there is an However this is not the case for inguinal lymph nodes. increased risk of loco-regional failure in the regional Clinical examination and CT scan are not sensitive for lymph nodes, which translates into a 5-year survival of detecting inguinal node metastases due to the fact that 40% after salvage nodal dissection.17, 18 the size of the lymph node does not accurately predict Options for treatment the likelihood of metastatic disease and 44% of Chemo-radiotherapy involved nodes are less than 5 mm in maximal SCC of the anus is generally considered a slowly diameter.12 growing disease with a low tendency for systemic Currently the treatment of clinically negative inguinal dissemination. Therefore loco-regional control nodes is prophylactic radiation given by inclusion of assumes great importance in improving disease both inguinal regions in the radiation field with a outcome. Before the advent of curative radiation boost if the nodes are clinically involved. chemo-radiation the options for inguinal node More recently a selective approach has been explored treatment depended on clinical circumstances and utilizing staging information obtained from sentinel lymph node dissection was performed only for node biopsy and PET scan. clinically involved nodes.2, 14, 6 The management of We conducted this review to assess the current clinically negative nodes was either wait and watch strategies for dealing with treatment of clinically with node dissection for regional failure that occurs in negative inguinal lymph nodes. 5-25% of cases or elective node dissection at the time of original surgery for the anal canal tumor.18, 10 Methods Currently, chemo-radiotherapy is usually employed as a definitive treatment for anal canal cancer. The radiation field involves the anal canal, perineum, pelvic lymph nodes and bilateral inguinal lymph The literature was searched (Medline and Embase) nodes.3,5,6,14,17,18 Chemo-radiotherapy is the using the keywords, squamous cell carcinoma, anal treatment of choice fordisease in the inguinal nodes canal, inguinal lymph nodes, sentinel node and with a cure rate of 90%4, 21. radiotherapy. The relevant articles were reviewed with The Nigro protocol is widely used. This involves 30 regard to the management of clinically negative Grays of radiotherapy at 2 Gy per day, five days a inguinal nodes in SCC of the anal canal. week for three weeks to the primary tumor and to the Implications of Lymph node involvement for survival pelvic and inguinal lymph nodes with both inguinal The presence of metastatic disease in the inguinal areas involved in the radiation field. Chemotherapy is nodes reflects the local extent of the disease and is a given in the form of 5-fluorouracil intravenous infusions marker for advanced disease (T3 and T4). It is also a (1gm /m2) on days 1-4 of the radiation therapy and marker for the presence of systemic disease at gross repeated on days 29-32 of the treatment regimen. or microscopic level, which is associated with an Mitomycin C is given in the form of an intravenous increased likelihood of incomplete response to bolus (15 mg/m2) on day 1 of the cycle.3 radio-chemotherapy, resulting in loco-regional In a modification of the Nigro protocol Gerard et al 6 recurrence, systemic metastases and reduced overall reported their experience in Lyon, France for 27 survival.2, 13 Inguinal lymph node metastases may patients with clinically involved nodes at the time of occur later in a metachronous manner after curative original presentation. Patients were treated with lymph chemo-radiotherapy in about 8% of patients,and this is node dissection followed by chemo-radiotherapy with also associated with reduced survival. 6 5FU 1gm /m2 for four days of continuous infusion and Treatment failure that manifests as local recurrence or cisplatinum 80 mg/m2 on Day 2 after standard

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hydration. The radiation treatment was initiated 3 Inguinal node dissection is reserved for those who fail weeks after the end of the first cycle of chemotherapy. to respond or relapse after initial response 8. None of The inguinal area was irradiated with a separate direct the available studies had considered the inclusion of field using a mixed beam of telecobalt and electrons. the inguinal region in the field of radiation stratified by The involved inguinal area was irradiated at a dose of the T stage of the disease, given the fact that the 45-50 Gy over 5 weeks through the antero-posterior or higher the T stage the more likely would be a postero-anterior field with an additional electron boost. microscopic disease in the clinically non-palpable This group of patients was followed up for 6 years. At inguinal nodes. the end of the treatment, local control of the inguinal Complications of Radiation area was observed in 25 of the 27 patients (86%). In Radiation therapy to the inguinal region with long-term follow-up, two patients developed concomitant chemotherapy as part of the protocol for contralateral inguinal metastases that were controlled anal canal cancer has proven to be safe and effective by inguinal dissection and irradiation. An incomplete in preventing local recurrence. Death is a rare event response was seen in two patients who had fixed as a complication of chemoradio toxicity and has been inguinal nodes. Other institutions have adopted a reported to occur in approximately 2% of patients.21; similar approach and have achieved similar results.9, but that is not related to inguinal radiation, rather a 18 complication of the whole treatment. With the Another option is inguinal irradiation with concomitant increasing use of intensity modulation radiotherapy chemotherapy using 5- Flourouracil and mitomycin or (IMR), the radiation dose is focused on the target area cisplatinum. Radiation of the involved nodes is given to avoid normal adjacent tissues. Still systemic according to a protocol that involves a large complications of chemotherapy are significant. antero-posterior or postero-anterior field including the However radiotherapy to the inguinal region is not inguinal node areas (45 Gy in 25 fractions over five without its risks. Recognized complications specific to weeks). The clinically involved inguinal fields are inguinal node radiation that have been reported by boosted up to 65 Gy.19-23 various centers are femoral neck fracture, There is no standard recommendation for patients who radionecrosis of the femoral head, iliac artery stenosis present with clinically non-involved inguinal nodes. and inguinal fibrosis leading to lymphedema of the leg. Commonly, such patients receive prophylactic bilateral Cicchini et al reported a single case of penile shaft radiotherapy and elective inguinal dissection is not necrosis following inguinal irradiation due to recommended. Alternatively these patients receive no radiation-induced thrombosis24. These complications treatment for the inguinal nodes and are followed up are rare; usually occur when therapeutic doses given with regular clinical evaluation for inguinal node rather than elective doses, but they can be serious in disease development. Long term follow up studies nature. have shown that 80- 90% of those patients will have The Role of Surgery no inguinal node disease development.1, 6, 23 The role of surgery is controversial. Currently lymph However, there is approximately a 15% chance of node dissection is usually reserved for disease disease recurrence particularly in patients with locally recurrence in the inguinal region.13, 14. Alternatively, advanced disease (T3 and T4) with clinically as noted above, some centers provide elective node non-involved inguinal nodes. In these patients elective dissection for patients with clinically involved nodes at irradiation of non-involved inguinal regions may the time of first presentation 6. minimize the risk of inguinal nodes disease Selective Approach development. Three recent randomized trials have Since it is desirable to avoid irradiation of lymphatic compared, mitomycin-based chemotherapy with fields that are not involved in macroscopic or radiotherapy or radiotherapy without chemotherapy, microscopic disease, a selective approach for the these studies also analyzed elective node radiation management of the inguinal nodes has been versus no radiation in patients with clinically negative evaluated in more recent studies. A selective nodes; and concluded that prophylactic irradiation of approach to management of inguinal lymph nodes in bilateral inguinal regions in normal inguinal nodes anal SCC depends on accurate staging. A number of reduced the development of lymph node disease to methods have been utilized to achieve this. less than 5%.20; however that part of the study was Sentinel Lymph Node Biopsy not randomized and was only a subgroup analysis. For Sentinel node biopsy has been studied by Bobin et al those who develop metachronous metastases, which 25 who evaluated 35 patients with clinically N0 usually happen within six months of initial treatment, disease using a combination of blue dye and Tc99 chemo-radiotherapy is the treatment of first choice. radiocolloid mapping and followed patients for 18

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months. None of the patients, who had a on PET scan and mostly turn out to be reactive pathologically negative sentinel node, had disease hyperplasia. recurrence. Sentinel node biopsy proved to be a sensitive and safe procedure. As noted above it has Conclusions been demonstrated that midline tumors usually have bilateral lymphatic drainage. Perera et al performed the procedure on 12 patients The current treatment options for inguinal lymph nodes and advocated sentinel node biopsy as a safe in patients with SCC of the anal canal vary according technique for detecting metastatic disease in the to local protocols and preferences. The most widely inguinal nodes in patients with anal SCC26. It also used approach is prophylactic bilateral inguinal proved to be useful as a useful technique to detect radiation for those with clinically negative nodes and micrometastatic deposits in clinically normal inguinal for patients with clinically positive nodes a radiation nodes. There are no clinical studies that managed boast of the involved nodes is added. This approach is inguinal nodes with no radiation based on the results associated with good results. Although there is some of the sentinel node biopsy; therefore it is not possible evidence to support the routine irradiation of the to estimate the possibility of nodal recurrence if this clinically negative inguinal lymph nodes, the issue has form of treatment is utilized. not been addressed in the context of the T stage of the Therefore these results suggest that sentinel lymph disease and there are no randomized trials to answer node biopsy may have a role in guiding a more the question. That should be interpreted carefully selective approach for patients with anal cancer taken into consideration the complications of although plainly studies with larger numbers are radiotherapy and the consequence of disease required. 27, 28. The role of sentinel node biopsy role recurrence in the inguinal nodes, which would require is still in its early stages and may play an important further radiotherapy or inguinal nodes dissection. role in the future to manage clinically non-palpable Metachronous metastases are amenable to inguinal nodes. chemo-radiotherapy with good responses in particular PET scanning: when this occurs within six months of the initial PET scanning is an established modality that is useful treatment. Surgical lymph node dissection is reserved in the clinical management of SCC of the head and for primary failure of chemo-radiation (residual disease) neck and esophagus. PET scanning for anal SCC and for recurrent disease. provides accurate staging of disease and may alter It is possible that in the future a selective approach will treatment planning by identifying inguinal node be adopted more often for patients with clinically involvement not apparent on clinical examination.In negative inguinal nodes, particularly in patients with one study with clinically negative nodes at early stage disease. This will likely depend on the presentation 66% of inguinal nodes identified by PET wider application of sentinel node sampling and PET scan were FNA positive for metastatic disease.33 In scanning to detect nodal disease. Such treatment is another study FDG-PET/CT detected abnormal nodes desirable, as patients with negative inguinal nodes can in 20% of groins that were normal by CT, and in 23% avoid potential complications of inguinal node radiation. without abnormality on physical examination. More work is required to prove the efficacy of sentinel Furthermore, 17% of groins negative by both CT and node sampling and PET scan evaluation for selection physical examination showed abnormal uptake on of clinically node negative patients who will benefit FDG-PET/CT. PET upstaged 17% with unsuspected from radiation therapy Meanwhile prophylactic pelvic/inguinal nodal disease 29. Currently PET scan radiation of clinically negative nodes remains widely is effective in monitoring disease response to practiced to prevent inguinal nodes recurrence, which treatment and in detection of recurrence. would require further radiation or surgery. An important pitfall of using PET scan is the false positive detection of inguinal nodes, typically these References nodes turns out to have reactive follicular hyperplasia as confirmed on histopathology of the removed nodes. Since the uptake and retention of 18F-FDG 1. Touboul E, Schlienger M, Buffat L, Lefkopoulos D, (Flourine-18-flourodesoxy-glycose) depends on the Pene F, Parc R, Tiret E, Gallot D, Malafosse M, metabolic activity of the tissue 30. This problem is Laugier A. Epidermoid carcinoma of the anal canal. especially important in assessing patients with HIV Results of curative intent radiation therapy in a series who have generalized lymphadenopathy as part of of 270 patients. Cancer 1994; 6: 1569-79. their HIV infection; such nodes are potentially positive 2. Clark J, Ptrelli N, Mittelman A. Epidermoid

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Illustrations Illustration 1

Table 1

TNM Staging of Squamous Cell Carcinoma of the anal canal

Primary tumor (T)

 T1: Tumor 2 cm or less in greatest dimension

 T2: Tumor more than 2 cm but not more than 5 cm in greatest dimension

 T3: Tumor more than 5 cm in greatest dimension

 T4: Tumor of any size that invades adjacent organ(s),

Regional lymph nodes

 N0: No regional lymph node metastasis

 N1: Metastasis in perirectal lymph node(s)

 N2: Metastasis in unilateral internal iliac and/or inguinal lymph node(s)

 N3: Metastasis in perirectal and inguinal lymph nodes and/or bilateral internal iliac and/or inguinal lymph nodes

Distant metastasis (M)

 M0: No distant metastasis

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