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. Inguinal Lymph Nodes 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
negative inguinal lymph nodes in squamous cell
carcinoma of the anal canal. Quality of the available
evidence.
Background
The first line of management of squamous cell
carcinoma (SCC) of the anal canal is chemo-radiation.
The radiation field includes, in addition to the anal
region and the perirectal nodes, the iliac and both
inguinal triangles to target the inguinal nodes. More
recently a selective approach has been investigated in
patients with non-palpable inguinal nodes utilizing
sentinel node biopsy and PET scan.
Methods
Medline was searched using the keywords, squamous
cell carcinoma, anal canal, inguinal lymph nodes,
sentinel node and radiotherapy.
Relevant articles were reviewed with regard to the
management of inguinal nodes in SCC of the anal
canal.
Results:
Currently the management of clinically normal inguinal
nodes in SCC of the anal canal is prophylactic
radiation of both inguinal areas. Clinically involved
nodes are included in the radiation field plus a boost of
radiation to the groin that harbor involved nodes. The
radiation is refined recently by intensity modulation
radiotherapy (IMR) to involve the diseased area and
minimize radiation exposure of normal adjacent
tissues. Alternatively, more recently, a selective
approach with utilization of sentinel node biopsy and
radiation to microscopically involved nodal areas has
been described.
Conclusion:
The treatment of clinically normal inguinal nodes is
currently by prophylactic radiation of both inguinal
regions. It is possible that in the future radiation of
clinically normal inguinal may become more selective
with an increasing reliance on sentinel node biopsy.
Further studies are needed in this field to assess the
efficacy of this approach.
Although Squamous cell carcinoma (SCC) of the anal
canal is an uncommon disease it is the most common
malignant tumor of the anal canal accounting for 90%
of malignant tumors at this site. Survival is determined
essentially by two factors; the size of the tumor and
lymph node spread. Patients with no clinical evidence
of nodal disease have a ten-year survival of 73%
compared with 53% in those with nodal disease.1
Historically the treatment of SCC of the anal canal was
abdominoperineal resection; this involves wide
dissection of the ischiorectal fossa with clearance of
pararectal lymph nodes with en bloc excision of the
posterior vaginal wall in women 2.
The current management of SCC of the anal canal is
chemoradiotherapy, which includes infusion of
5-flourouracil with or without mitomycin and radiation
fields that include the primary tumor and the pelvic and
inguinal lymph nodes.3, 4, 5, Surgery is reserved for
patients who have an incomplete response, residual
disease and those with later disease recurrence.
The lymphatic drainage of tumors of the anal canal is
bidirectional and depends on the tumor location in
relation to the dentate line. Above the dentate line
most of the lymph drains in a cephalad direction along
the inferior rectal artery to the origin of the inferior
mesenteric artery, also along the territory of the middle
rectal artery to the iliac nodes. Below the dentate line it
drains to the inguinal nodes along the femoral artery.
Hence the lymphatic drainage is to the ipsilateral
inguinal lymph nodes. The probability of nodal spread
is relative to the tumor size (T stage). 1
When the primary tumor is clearly located laterally, the
inguinal metastasis nearly always is homolateral to the
primary tumor. Midline tumors and locally advanced
lesions usually show bilateral inguinal and pararectal
lymph node involvement. In the Lyon series bilateral
involvement was seen only when the primary tumor
involved the medial part of the anal canal. 6
Overall, inguinal nodal involvement occurs in 10-25%
of patients 7, 8,9, 10. Using bipedal lymphangiography
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
the tumor with nodal metastases seen in 0-10% of T1
and 2 lesions and 40- 50% of T3 and 4 disease (table
1).12, 11 At the time of diagnosis local tumor extent is
T1: 8.5%; T2: 51.1%; T3: 30.4%; T4: 10%.1 Pelvic
lymph node involvement correlates with increasing risk
of pelvic relapse and residual disease after definitive
radio-chemotherapy. Pelvic nodes are routinely
targeted within the radiation field of the primary tumor
and therefore their involvement or otherwise are
unlikely at this stage to change the approach of
treatment.
However this is not the case for inguinal lymph nodes.
Clinical examination and CT scan are not sensitive for
detecting inguinal node metastases due to the fact that
the size of the lymph node does not accurately predict
the likelihood of metastatic disease and 44% of
involved nodes are less than 5 mm in maximal
diameter.12
Currently the treatment of clinically negative inguinal
nodes is prophylactic radiation given by inclusion of
both inguinal regions in the radiation field with a
radiation boost if the nodes are clinically involved.
More recently a selective approach has been explored
utilizing staging information obtained from sentinel
node biopsy and PET scan.
We conducted this review to assess the current
strategies for dealing with treatment of clinically
negative inguinal lymph nodes.
Methods
The literature was searched (Medline and Embase)
using the keywords, squamous cell carcinoma, anal
canal, inguinal lymph nodes, sentinel node and
radiotherapy. The relevant articles were reviewed with
regard to the management of clinically negative
inguinal nodes in SCC of the anal canal.
Implications of Lymph node involvement for survival
The presence of metastatic disease in the inguinal
nodes reflects the local extent of the disease and is a
marker for advanced disease (T3 and T4). It is also a
marker for the presence of systemic disease at gross
or microscopic level, which is associated with an
increased likelihood of incomplete response to
radio-chemotherapy, resulting in loco-regional
recurrence, systemic metastases and reduced overall
survival.2, 13 Inguinal lymph node metastases may
occur later in a metachronous manner after curative
chemo-radiotherapy in about 8% of patients,and this is
also associated with reduced survival. 6
Treatment failure that manifests as local recurrence or
WebmedCentral > Review articles
persistent disease is still amenable to treatment,
usually by inguinal node dissection, but this event is
associated with reduced 5 year overall survival of
40-64%.14, 15, 6
Molecular studies have failed to show any possible
association between tumor genetics and tumor
behavior with regard to nodal metastasis or aggressive
behavior and overall survival. Deletion of cancer
suppressor genes such as the p53 and Rb genes has
no effect on nodal invasion.16
In patients with clinically involved inguinal nodes
treated with definitive chemo- radiotherapy there is an
increased risk of loco-regional failure in the regional
lymph nodes, which translates into a 5-year survival of
40% after salvage nodal dissection.17, 18
Options for treatment
Chemo-radiotherapy
SCC of the anus is generally considered a slowly
growing disease with a low tendency for systemic
dissemination. Therefore loco-regional control
assumes great importance in improving disease
outcome. Before the advent of curative
chemo-radiation the options for inguinal node
treatment depended on clinical circumstances and
lymph node dissection was performed only for
clinically involved nodes.2, 14, 6 The management of
clinically negative nodes was either wait and watch
with node dissection for regional failure that occurs in
5-25% of cases or elective node dissection at the time
of original surgery for the anal canal tumor.18, 10
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
nodes.3,5,6,14,17,18 Chemo-radiotherapy is the
treatment of choice fordisease in the inguinal nodes
with a cure rate of 90%4, 21.
The Nigro protocol is widely used. This involves 30
Grays of radiotherapy at 2 Gy per day, five days a
week for three weeks to the primary tumor and to the
pelvic and inguinal lymph nodes with both inguinal
areas involved in the radiation field. Chemotherapy is
given in the form of 5-fluorouracil intravenous infusions
(1gm /m2) on days 1-4 of the radiation therapy and
repeated on days 29-32 of the treatment regimen.
Mitomycin C is given in the form of an intravenous
bolus (15 mg/m2) on day 1 of the cycle.3
In a modification of the Nigro protocol Gerard et al 6
reported their experience in Lyon, France for 27
patients with clinically involved nodes at the time of
original presentation. Patients were treated with lymph
node dissection followed by chemo-radiotherapy with
5FU 1gm /m2 for four days of continuous infusion and
cisplatinum 80 mg/m2 on Day 2 after standard
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hydration. The radiation treatment was initiated 3
weeks after the end of the first cycle of chemotherapy.
The inguinal area was irradiated with a separate direct
field using a mixed beam of telecobalt and electrons.
The involved inguinal area was irradiated at a dose of
45-50 Gy over 5 weeks through the antero-posterior or
postero-anterior field with an additional electron boost.
This group of patients was followed up for 6 years. At
the end of the treatment, local control of the inguinal
area was observed in 25 of the 27 patients (86%). In
long-term follow-up, two patients developed
contralateral inguinal metastases that were controlled
by inguinal dissection and irradiation. An incomplete
response was seen in two patients who had fixed
inguinal nodes. Other institutions have adopted a
similar approach and have achieved similar results.9,
18
Another option is inguinal irradiation with concomitant
chemotherapy using 5- Flourouracil and mitomycin or
cisplatinum. Radiation of the involved nodes is given
according to a protocol that involves a large
antero-posterior or postero-anterior field including the
inguinal node areas (45 Gy in 25 fractions over five
weeks). The clinically involved inguinal fields are
boosted up to 65 Gy.19-23
There is no standard recommendation for patients who
present with clinically non-involved inguinal nodes.
Commonly, such patients receive prophylactic bilateral
radiotherapy and elective inguinal dissection is not
recommended. Alternatively these patients receive no
treatment for the inguinal nodes and are followed up
with regular clinical evaluation for inguinal node
disease development. Long term follow up studies
have shown that 80- 90% of those patients will have
no inguinal node disease development.1, 6, 23
However, there is approximately a 15% chance of
disease recurrence particularly in patients with locally
advanced disease (T3 and T4) with clinically
non-involved inguinal nodes. In these patients elective
irradiation of non-involved inguinal regions may
minimize the risk of inguinal nodes disease
development. Three recent randomized trials have
compared, mitomycin-based chemotherapy with
radiotherapy or radiotherapy without chemotherapy,
these studies also analyzed elective node radiation
versus no radiation in patients with clinically negative
nodes; and concluded that prophylactic irradiation of
bilateral inguinal regions in normal inguinal nodes
reduced the development of lymph node disease to
less than 5%.20; however that part of the study was
not randomized and was only a subgroup analysis. For
those who develop metachronous metastases, which
usually happen within six months of initial treatment,
chemo-radiotherapy is the treatment of first choice.
WebmedCentral > Review articles
Inguinal node dissection is reserved for those who fail
to respond or relapse after initial response 8. None of
the available studies had considered the inclusion of
the inguinal region in the field of radiation stratified by
the T stage of the disease, given the fact that the
higher the T stage the more likely would be a
microscopic disease in the clinically non-palpable
inguinal nodes.
Complications of Radiation
Radiation therapy to the inguinal region with
concomitant chemotherapy as part of the protocol for
anal canal cancer has proven to be safe and effective
in preventing local recurrence. Death is a rare event
as a complication of chemoradio toxicity and has been
reported to occur in approximately 2% of patients.21;
but that is not related to inguinal radiation, rather a
complication of the whole treatment. With the
increasing use of intensity modulation radiotherapy
(IMR), the radiation dose is focused on the target area
to avoid normal adjacent tissues. Still systemic
complications of chemotherapy are significant.
However radiotherapy to the inguinal region is not
without its risks. Recognized complications specific to
inguinal node radiation that have been reported by
various centers are femoral neck fracture,
radionecrosis of the femoral head, iliac artery stenosis
and inguinal fibrosis leading to lymphedema of the leg.
Cicchini et al reported a single case of penile shaft
necrosis following inguinal irradiation due to
radiation-induced thrombosis24. These complications
are rare; usually occur when therapeutic doses given
rather than elective doses, but they can be serious in
nature.
The Role of Surgery
The role of surgery is controversial. Currently lymph
node dissection is usually reserved for disease
recurrence in the inguinal region.13, 14. Alternatively,
as noted above, some centers provide elective node
dissection for patients with clinically involved nodes at
the time of first presentation 6.
Selective Approach
Since it is desirable to avoid irradiation of lymphatic
fields that are not involved in macroscopic or
microscopic disease, a selective approach for the
management of the inguinal nodes has been
evaluated in more recent studies. A selective
approach to management of inguinal lymph nodes in
anal SCC depends on accurate staging. A number of
methods have been utilized to achieve this.
Sentinel Lymph Node Biopsy
Sentinel node biopsy has been studied by Bobin et al
25 who evaluated 35 patients with clinically N0
disease using a combination of blue dye and Tc99
radiocolloid mapping and followed patients for 18
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months. None of the patients, who had a
pathologically negative sentinel node, had disease
recurrence. Sentinel node biopsy proved to be a
sensitive and safe procedure. As noted above it has
been demonstrated that midline tumors usually have
bilateral lymphatic drainage.
Perera et al performed the procedure on 12 patients
and advocated sentinel node biopsy as a safe
technique for detecting metastatic disease in the
inguinal nodes in patients with anal SCC26. It also
proved to be useful as a useful technique to detect
micrometastatic deposits in clinically normal inguinal
nodes. There are no clinical studies that managed
inguinal nodes with no radiation based on the results
of the sentinel node biopsy; therefore it is not possible
to estimate the possibility of nodal recurrence if this
form of treatment is utilized.
Therefore these results suggest that sentinel lymph
node biopsy may have a role in guiding a more
selective approach for patients with anal cancer
although plainly studies with larger numbers are
required. 27, 28. The role of sentinel node biopsy role
is still in its early stages and may play an important
role in the future to manage clinically non-palpable
inguinal nodes.
PET scanning:
PET scanning is an established modality that is useful
in the clinical management of SCC of the head and
neck and esophagus. PET scanning for anal SCC
provides accurate staging of disease and may alter
treatment planning by identifying inguinal node
involvement not apparent on clinical examination.In
one study with clinically negative nodes at
presentation 66% of inguinal nodes identified by PET
scan were FNA positive for metastatic disease.33 In
another study FDG-PET/CT detected abnormal nodes
in 20% of groins that were normal by CT, and in 23%
without abnormality on physical examination.
Furthermore, 17% of groins negative by both CT and
physical examination showed abnormal uptake on
FDG-PET/CT. PET upstaged 17% with unsuspected
pelvic/inguinal nodal disease 29. Currently PET scan
is effective in monitoring disease response to
treatment and in detection of recurrence.
An important pitfall of using PET scan is the false
positive detection of inguinal nodes, typically these
nodes turns out to have reactive follicular hyperplasia
as confirmed on histopathology of the removed nodes.
Since the uptake and retention of 18F-FDG
(Flourine-18-flourodesoxy-glycose) depends on the
metabolic activity of the tissue 30. This problem is
especially important in assessing patients with HIV
who have generalized lymphadenopathy as part of
their HIV infection; such nodes are potentially positive
WebmedCentral > Review articles
on PET scan and mostly turn out to be reactive
hyperplasia.
Conclusions
The current treatment options for inguinal lymph nodes
in patients with SCC of the anal canal vary according
to local protocols and preferences. The most widely
used approach is prophylactic bilateral inguinal
radiation for those with clinically negative nodes and
for patients with clinically positive nodes a radiation
boast of the involved nodes is added. This approach is
associated with good results. Although there is some
evidence to support the routine irradiation of the
clinically negative inguinal lymph nodes, the issue has
not been addressed in the context of the T stage of the
disease and there are no randomized trials to answer
the question. That should be interpreted carefully
taken into consideration the complications of
radiotherapy and the consequence of disease
recurrence in the inguinal nodes, which would require
further radiotherapy or inguinal nodes dissection.
Metachronous metastases are amenable to
chemo-radiotherapy with good responses in particular
when this occurs within six months of the initial
treatment. Surgical lymph node dissection is reserved
for primary failure of chemo-radiation (residual disease)
and for recurrent disease.
It is possible that in the future a selective approach will
be adopted more often for patients with clinically
negative inguinal nodes, particularly in patients with
early stage disease. This will likely depend on the
wider application of sentinel node sampling and PET
scanning to detect nodal disease. Such treatment is
desirable, as patients with negative inguinal nodes can
avoid potential complications of inguinal node radiation.
More work is required to prove the efficacy of sentinel
node sampling and PET scan evaluation for selection
of clinically node negative patients who will benefit
from radiation therapy Meanwhile prophylactic
radiation of clinically negative nodes remains widely
practiced to prevent inguinal nodes recurrence, which
would require further radiation or surgery.
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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
 M1: Distant
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