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350
Internal iliac
nal iliac
Exter
node
A. L. Lightner et al.
nodes
Superior rectal nodes
nal iliac
s
Inguinal nodes
Fig. 20.2 Lymph node description. Mesorectal. Inguinal:
supercial, deep. Superior rectal (hemorrhoidal). External
iliac. Internal iliac (hypogastric). All other nodal groups
represent sites of distant metastasis
Exter
nodes
Mesorectal
nodes
presence of a palpable lesion. HRA may reveal a
distinct vascular pattern within the acetowhitened
mucosa. These vessel changes are characteristic
of HSIL regardless of the underlying tissue
type—distal rectal mucosa or anus. Additionally,
examination of the inguinal nodes should be
performed to exclude involvement, which may be
present in the setting of ASCC (Fig.20.2).
Ultimately, the diagnosis of LSIL and HSIL
requires histopathology. A biopsy is diagnosed
as LSIL when 20–25% of the epithelium is
replaced by abnormal basaloid cells, characterized
by an increased nuclear to cytoplasmic ratio.
LSIL is characterized by the presence of
koilocytes, enlarged cells with a cytoplasmic halo
surrounding the nucleus that is indicative of HPV
replication. HSIL is diagnosed when abnormal
basaloid cells replace more than 50% of the
epithelium.
Treatment
The goal of treating HSIL is the prevention of
ASCC while maintaining anal function,
continence of stool and gas. Several therapies are
available for the treatment of HSIL including
surgical excision, electrocautery, topical
imiquimod, and topical uoruracil (5-FU).
Unfortunately, data regarding the efcacy of
treatment is largely limited to case series. Only
one randomized control trial has been conducted
comparing treatment options, and only one
clinical trial is currently listed looking at efcacy
of observation versus treatment.
Historically, surgery was a dominant player in
the treatment options for HSIL.In fact, in 2000, a
survey of 663 members of the ASCRS found that
87% of respondents chose surgical excision with
margins as the optimal treatment for HSIL [25].
However, a number of subsequent studies suggested surgery may not be the optimal treatment
approach. Brown etal reported 34 patients with
HSIL treated surgically in the UK. Within
41 months, 14 of 34 patients had macroscopic
recurrences and 25% of patients had anal function defects postoperatively [26]. Scholeeld
etal reported on 35 patients who underwent limited excision for HSIL and were followed
63months. Three of 35 (9%) had progression to
ASCC [2]. Watson et al. reported their experiences of 72 patients treated surgically, of which
nine patients developed incontinence, and four of
these required colostomy. Despite their aggressive surgical approach, 8 patients (11%) progressed to invasive ASCC [3]. These investigations
suggested surgical excision is not ideal for HSIL
due to incomplete excisions, frequent recurrences, and complications including stenosis and
incontinence. They argued further that because
chemoradiation for small invasive anal carcinoma is effective, a less radical approach may be
warranted because early surgical intervention
with the associated complications may compromise later denitive treatment.
Results from subsequent investigations suggest that HRA may be the optimal treatment
approach. The use of HRA allows targeted
destruction of suspicious lesions with the lowest
reported rates of progression to cancer with
simultaneous preservation of anorectal function.
HRA is used to identify dysplastic epithelium
under the magnication of a standard colposcope
or operating microscope (Fig.20.3). The technical application of HRA itself is discussed in more
ab
cd
20 Anal Intraepitheial Neoplasia
351
Fig. 20.3 High resolution anoscopy images of LSIL and
HSIL after the application of acetic acid. Biopsies of visualized lesions conrmed HRA appearances and region
biopsied is indicated with arrows in images (b, d). (a, b)
Demonstrate anal LSIL in the distal rectal mucosa with
subtle punctate vessel changes. The geography of the
lesion is emphasized in the left frame with a black border.
detail in the section regarding our treatment
approach, but, briey, HRA can be used with
either targeted infrared coagulation (IRC) or
electrocautery (EC). Both procedures are outpatient with only enemas given in preparation. IRC
coagulates lesions using 1.6 s pulses until the
entire surface and an approximately 3 mm surrounding border are coagulated. The coagulated
tissue may then scraped off with a small cotton
Q-tip or debrided with biopsy forceps. This is
repeated until the submucosal vessels are identied and coagulated. HRA EC, unlike IRC, uses
bipolar cautery creating a smoke plume that
requires a smoke evacuator to prevent transmission of HPV. Across the four listed studies
(Table 20.1) regarding HRA targeted IRC for
(c, d) Distal rectal mucosa where HSIL is visible. The left
image has the lesion highlighted with a black border
focusing the reader on the serpiginous, cerebriform vessels and the outline of the entire lesion. The right image
demonstrates the mosaic pattern created by blood vessels
in an aceto-white background. With permission from [48]
© 2011 Springer
HSIL, there was no reported anal function compromise, 10–38% had recurrence of HSIL, and
none had progression to ASCC [27–30].
Similarly, in the two listed studies regarding
HRA targeted EC, there was no reported anal
function compromise, 17–31% had recurrence of
HSIL, and 0.4% had progression to anal squamous cell carcinoma [31, 32]. Of note, recurrence of HSIL was higher in HIV patients and
patients with higher burden of disease.
The use of topical uorouracil (5-FU) and
imiquimod have the advantages of treating AIN
by the patient themselves without compromising
anorectal function. However, topical treatments
have the disadvantage of extended treatment
courses and signicant side effects including
352
Table 20.1 Results from published studies regarding HRA targeted IRC for HSIL
Study ID Patients
Surgery
Excision
Watson etal. [3] 10/62
immunocompromised
Scholeeld etal. [2] 6/35
immunocompromised
Devaraj and Cosman [12] 40 HIV + MSM 3 Not reported 8
Brown etal. [26] 34M and F 15 Not reported 0
Marchesa etal. [42] 16 M, 31 F 0 38% 6
HRA-targeted IRC
Goldstone etal. [28] 52 HIV-MSM/44 HIV
+ MSM
Weis etal. [30] 99M/25F all HIV+ 0 Treated 13%;
Stier etal. [29] 16 M/2 F all HIV+ 0 38% 0
Cranston etal. [27] 68 HIV + MSM 0 36% 0
HRA-targeted EC
Marks and Goldstone [31] 132 HIV + MSM; 100
HIV-MSM
HRA-targeted EC f/u IRC or TCA
Pineda etal. [37] 194/246
immunocompromised
Topical medical therapy
5-FU
Snyder etal. [43] 11 HIV + MSM 0 72% 0
Richel etal. [38] 46 HIV + MSM 0 30% 0
Graham etal. [33] 1/9 HIV+ 0 13% 13 (n=1)
Imiquimod
Wieland etal. [44] 28 HIV + MSM 0 9% 0
Kreuter etal. [45] 10 HIV + MSM 0 Not reported 0
Fox etal. [34] 64 HIV + MSM 0 39% 3
Van der Snoek etal. [46] 44 HIV + MSM Not reported 34% Not reported
TCA
Singh etal. [47] 54 MSM; 35 HIV+ 0 39% 0
Cranston etal. [27] 72 HIV + MSM Not reported 20% Not reported
RCT
Richel etal. [35] 246 HIV+MSM 0 At 72weeks: 71%
Anal function
compromised (%) HSIL at last f/u (%)
13 Not reported 11
0 Not reported 9
0 HIV+18%;
HIV-10%
untreated 93%
0 HIV+31%;
HIV-17%
0.8 22% 1.2
imiquimod; 58%
5-FU; 68% EC
A. L. Lightner et al.
Developed
ASCC (%)
0
0
0.4
1.2% (n=3)
perianal pain and irritation that result in
non-compliance. Treatment with 5-FU is not
standardized with variable frequency and
amounts reported. Despite several treatment
interruptions due to side effects and variable
protocols administered, there was very little
progression to ASCC.Only one patient among
the three studies listed in Table 20.1 had
progression to ASCC [33]. Similarly the use of
topical imiquimod 5% cream applied three times
daily has very little progression to ASCC, with
only one series reporting 2 patients with
progression (3%) [34]. When topical medical
treatments are prescribed the patients should be
told that symptoms of itching, burning, and pain
are evidence that imiquimod is working and is
not a sign that treatment should be discontinued.
Additionally, imiquimod may cause transient u
20 Anal Intraepitheial Neoplasia
353
like symptoms the day following treatment. If no
signs of erythema or erosions develop while on
imiquimod the frequency can be increased
throughout the treatment course. Unfortunately,
the low adherence rate and typical treatment
interruptions with the use of topical imiquimod
for treatment of HSIL may be prohibitive to
recommending this agent as an optimal treatment.
Randomized controlled trials have begun
to compare the aforementioned treatment
approaches. One looking at 246 HIV-positive
MSM found that electrocautery had signicantly
increased rates of complete resolution compared
to both topical imiquimod and topical uorouracil,
and therefore concluded EC was the superior
treatment option [35]. However, it is important to
note that recurrence rates of HSIL were still high
in all treatment groups, underscoring the need for
frequent surveillance and follow up. At week 24,
48 and 72, 22%, 46%, and 67% of patients had
recurrence respectively. Specically, recurrence
at 72 weeks was found in 71% (n = 10/14) of
patients treated with imiquimod, 58% (n=7/12)
of patients treated with 5-FU, and 68% (n=13/19)
of patients treated with EC. Treatment sideeffects, most commonly pain, bleeding and itching were signicantly more common in the
imiquimod and 5-FU group at 43% and 27%
respectively, than the noted 18% in the
electrocautery group.
Expectant Management
Due to the efcacy of chemoradiation for ASCC,
there has been the suggestion that expectant
management, which has no immediate associated
costs or side effects, may be effective for HSIL
rather than treatment. A trial addressing this point
was conducted at a university and VA practice.
Forty 40 HIV infected patients were followed for a
mean of 32 months [12]. Patients had a clinical
exam every 6 months, and biopsies of new
macroscopic or symptomatic disease. Of the 40
patients, 28 had HSIL. Three of the 28 patients
developed ASCC at 10, 16 and 84 months, all of
whom had a cancer less than 2.5cm in diameter.
This trial suggested that very few patients
progressed to cancer, and, if cancer developed they
were diagnosed at an early stage. To better
understand this question, the ANCHOR trial, a
large ongoing randomized phase III trial comparing
topical or ablative treatment with active monitoring
in HIV-positive patients with HSIL is currently
ongoing. The primary measure is time to anal
cancer. The study is estimated to be completed in
2022 (clinicaltrials.gov NCT02135419) and may
provide additional answers regarding active
monitoring versus treatment in a high-risk group
with HSIL.Unfortunately, no trials are currently
underway for low risk patient cohort with HSIL,
likely because there are so few patients, and even
fewer who progress to ASCC.
Practical Application oftheData
Several limitations exist when interpreting the
aforementioned data. Studies of HSIL screening
and treatment practices are largely comprised of
immunosuppressed patients. The only RCT to
date includes only high risk HIV+ MSM,
limiting the applicability of their results to other
patient cohorts. Treatments reported for HSIL
are not standardized, and reports of treatment
outcome are mainly in the form of case series
and open-label studies, with the only one aforementioned RCT.
Despite these limitations, there is strong evidence that HSIL, left untreated, can and does
progress to ASCC [1]. Once diagnosed with
ASCC, unless the lesion is less than 2cm in size
and can be locally excised with clear margins,
these patients require chemotherapy with radiation, and possible surgical intervention, all with
associated morbidity and mortality, which is 80%
for even the earliest lesions. Thus, since several
treatment options do exist for HSIL, and some
with nearly zero progression to ASCC [36–38]
with one RCT demonstrating EC as the superior
choice [35] patients with HSIL should be actively
treated to prevent progression to ASCC.
Therapy with HRA targeted EC may be an
outpatient ofce based procedure without need
for anorectal preparation or narcotics upon dismissal if the lesions are above the dentate line or
354
A. L. Lightner et al.
quite limited in the anal mucosa or perianal skin.
Alternatively, for extensive disease below the
dentate line involving anal mucosa and or perianal skin, the patients may be treated on an outpatient basis and discharged with instructions for
Sitz baths, topical analgesics (5% Lidocaine
Cream—Recticare (Ferndale labs) preferred, and
either Ultram, Tylenol with codeine, NSAIDS or
Tylenol. HRA targeted destruction is technically
easy and can be performed by colorectal surgeons, family practitioners, gynecologists and
advanced practice providers, to name a few.
As a practicing colorectal surgeon, most
patients will be referred for colorectal evaluation
with a chief complaint, or reason for referral, of
hemorrhoids. In those in whom hemorrhoids are
clearly not the actual need being met by our
evaluation, a detailed history should be performed
to document risk factors for anal dysplasia
including HPV infection (anal-genital warts),
history of receptive anal intercourse or sexually
transmitted disease, a history of cervical vulvar
or vaginal cancer, immunosuppression after solid
organ transplant or HIV infection, hematologic
malignancies, certain autoimmune disorders
including Crohn’s disease [39] and smoking.
Physical exam is focused with perianal inspection,
digital rectal exam, and anoscopy with inspection
of other involved areas as indicated. We prefer
the operating room for the initial examination
and treatment, and for needed re-treatment of
extensive disease or disease complicated by
benign disease (e.g. overlying hermorrhoidal
tissue or complicating stulous disease). HRA is
preferred for our initial evaluation and treatment
because we feel we get the best exposure with the
sphincters completely relaxed with an anal block
which allows for attening of the hemorrhoidal
complexes and clear visualization of the tissues
that might otherwise hide at the base of a large
hemorrhoidal complex if visualized with a plastic
anoscope in the ofce.
In the operating room, the patient is positioned
prone jack knife with the buttocks taped apart.
Anesthesia with MAC local and 0.25% Marcaine
inthe subcutaneous tissues and 0.5% in the sphincters for the anal block are administered. A thorough examination looking for hyperpigmentation,
erythema, elevation, or scaling is performed. The
distal rectal mucosa, anal mucosa, and perianal skin
is then treated with 3% acetic acid by placing one
acetic acid soaked raytec in the anal canal and distal
rectum, and one over the anus/perianus. We use an
operating microscope for magnication. We
look for a distinct vascular pattern within the
acetowhitened rectal and anal mucosa or perianal
skin that is characteristic of HSIL regardless of the
underlying tissue type. Any concerning lesions are
biopsied and then treated with needle tip cautery
[32]. A deep burn is avoided by quickly moving
supercially across the surface of the tissue, sparing
the surrounding normal mucosa. Our experience is
we can limit the depth of injury to less than that with
excision which may contribute signicantly to our
low observed rate of complications [37]. This is safe
and effective in both HIV (+) and HIV (−) men and
women [36].
Ongoing Surveillance
How to follow “low-risk” patients with LSIL
remains unclear as patients with condyloma acuminatum (low-grade intraepithelial neoplasia
LSIL, AIN-1) have a very low potential for
malignancy [23]. Treatment should probably
only be offered to symptomatic patients or those
who simply want to have the lesions removed
(the vast majority). This is where routine typing
of HPV may be benecial in triaging follow up.
For “high-risk” patients with LSIL, LSIL can be
a marker for the presence of HSIL and therefore
annual surveillance with digital anal rectal exam,
anal cytology and HRA may be benecial for
early detection of HSIL.For patients who have
been treated for HSIL, a one and six month follow up exam with anoscopy is reasonable. If the
patient is not involved in high risk behavior then
annual exam with digital anal examination and
anal cytology is sufcient. If involved in high risk
behavior, HRA should be added to this algorithm
annually. If immunosuppressed, or if the patient
has “high risk disease”, this interval may be
shortened to 3–6months on a case by case basis.
If a recurrence is found, the patient should be
treated in the ofce with trichloracetic acid, IRC
20 Anal Intraepitheial Neoplasia
355
or hyfercation unless complex as noted above.
With this approach there is excellent control of
HSIL and minimal progression to cancer [28, 32,
37, 39, 40]; even in the setting of recurrent dis-
ease, HSIL can be cleared in approximately 80%
of patients [37, 40].
Limitations toTreatment
There are several limitations to the treatment of
HSIL.The rst, as already mentioned, is the lack
of consistency in denitions and anatomy.
Second, there is paucity of randomized controlled
trials looking at surveillance versus treatment or
the comparison of treatment practices. Thus,
many argue they are not sure which lesions will
progress to cancer. However, this is not substantiated by the literature. Third, HRA has been
shown to have low reimbursement rates with a
lack of billing codes, and many surgeons report it
is a painful procedure [41]. Thus, there has been
a lack of widespread adoption of HRA to ofce
based practice among colon and rectal surgeons.
Summary
Ultimately, the goals of treating patients with
HSIL are preventing morbidity associated with
the treatment of anal cancer and mortality from
anal cancer itself without causing disturbances of
anal function, i.e., continence of stools and atus.
Fortunately, there are low cost, outpatient tools to
treat HSIL, and evidence to support their effectiveness in preventing ASCC.Although there is
an ongoing trial looking at surveillance rather
than treatment for HSIL, at this time, treatment
should be endorsed especially given its ease to
perform. Ultimately, prevention, screening, and
treatment of anal HSIL should be as widespread
as that for cervical dysplasia. But to achieve this
goal, clinicians need to be educated and dedicated to the eradication of this disease; that
includes learning HRA and willingness to follow
patients longitudinally. Hopefully, in the future,
rates of ASCC will be minimized with the use of
HPV vaccine and screening for HSIL.
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Rectal Carcinoma: Imaging for Staging
MitDattani andGinaBrown
21
Introduction
In the modern day multimodality management of
rectal cancer, a growing number of treatment
options are available, the choice of which is largely
determined by tumour related factors. An accurate
and reproducible staging system is therefore
invaluable for rectal cancer multidisciplinary
teams, which rely increasingly on radiological
prognostication to individualise treatment plans.
This information is equally important for
counselling patients, who will need to make
informed decisions by weighing the oncological
merits of a radical resection, against the impact on
quality of life ensuing from the multimodality
management of their cancer.
Indeed, pre-operative rectal cancer assessment has evolved beyond the determination of
conventional prognostic features such as depth
of tumour invasion, nodal involvement and
metastatic spread. Tumour threatened resection
margins which require neo-adjuvant treatment,
or involved anal sphincters for which extensive
surgery offers the best chance of cure are just as
important in guiding treatment decisions, if not
M. Dattani
Pelican Cancer Foundation,
Basingstoke, Hampshire, UK
G. Brown (*)
The Royal Marsden NHS Foundation Trust and
Imperial College of London, London, UK
e-mail: gina.brown@rmh.nhs.uk
more, as the absolute TNM stage. Moreover,
additional prognostic determinants such as
extramural vascular invasion, which were until
now only evaluable in the post-resection specimen, are being diagnosed on pre-operative imaging. In this regard, advances in imaging
technology, largely driven by magnetic resonance imaging (MRI) over the last two decades,
have enabled the selection of appropriate treatment strategies, which optimise the balance
between oncological and functional outcome.
More recently, imaging has found a novel role in
assessing the response after neo-adjuvant treatment, which in selected cases mitigates the need
for surgery with the detection of a complete
response following (chemo)radiotherapy. The
current imaging modalities available to stage
rectal cancer include endorectal ultrasound scan
(ERUS), MRI, computed tomography (CT) and
positron emission tomography (PET). These
techniques have their own strengths and limitations, and often play a complementary role in
what is a challenging aspect of rectal cancer
management. This chapter summarises the evidence base and the utility of the different imaging modalities that underpin the current standards
of care in rectal cancer management.
© Springer International Publishing AG, part of Springer Nature 2019
D. E. Beck et al. (eds.), Fundamentals of Anorectal Surgery,
https://doi.org/10.1007/978-3-319-65966-4_21
359
360
M. Dattani and G. Brown
Imaging Modalities
Endorectal Ultrasound
History andTechnique
The clinical application for ultrasound was rst
developed by Wild and Reid in 1952, who used a
linear B-mode transducer in the diagnosis of breast
lesions, “with a view to future applications at other
sites” [1]. But it was not until 1983 that an advanced
version of their ‘echoendo probe’ was utilised by
Dragsted and Gammelgaard to evaluate the depth
of invasion in rectal cancer. They assessed 13
patients with rectal cancer using a 4.5MHz rotating transducer probe, and correctly identied the
depth of mural inltration in 11 of the patients
when compared to subsequent histopathology [2].
In the two remaining patients, the technique was
limited owing to the presence of a stricturing tumor,
which the probe could not access. These initial
ndings were conrmed in 1985 by Hilderbrandt
and Feifel in a slightly larger series comprising 25
patients [3]. More importantly, they objectively
dened the reporting criteria for depth of rectal
wall invasion based on the TNM classication system, which is still universally used. Denoted by the
prex ‘u’ to indicate evaluation by endorectal ultrasound (ERUS), the depth of tumour invasion is
staged according to the level of disruption of the
ve distinct anatomical layers of the rectal wall
(Fig.21.1a, b) by the tumour, which appears as a
hypoechoic irregular lesion. Beynon etal. [4] rst
proposed the ve layer model following their careful study comparing ultrasonographic appearances
of the rectal wall with that of sequentially dissected
out histological layers in the normal rectum. The
differential acoustic impedance across the rectal
wall gives the appearance of a concentric ring of
alternating hyper- and hypoechoic layers as shown
in Fig.21.1c, and described below:
Mucosa: Hyperechoic layer
Muscularis mucosae: Hypoechoic layer
Submucosa: Hyperechoic layer
Muscularis propria: Hypoechoic layer
Serosa/perirectal fat: Hyperechoic layer
Despite vast advances in the ERUS equipment
over the years, the basic principles of imaging
remain unchanged. The procedure is not labour
intensive, and is simple enough to be performed by
a colorectal surgeon in a clinic setting with the
consent of the patient. Sedation is seldom required,
although it is usually necessary to give the patient
an enema to avoid image distortion because faeces
in the rectum. The patient is normally positioned in
the left lateral decubitus position, following which
a digital rectal examination and a proctosigmoidoscopy is performed to clinically assess the size,
xity and position of the lesion being investigated.
Any rectal residue should be suctioned to provide
an optimal image. A rigid or exible endorectal
probe is then inserted into the rectal cavity. The tip
has a rotating transducer covered by a balloon,
which is lled with a variable volume of degassed
water after insertion. This ensures coupling
between the transducer and the rectal wall without
any acoustic interference from air within the rectum. Imaging is normally carried out starting from
the proximal end, gradually withdrawing the probe
distally whilst meticulously assessing the preservation or loss of the normal anatomical layers of
the rectal wall. The adjacent perirectal tissue is
also scanned to evaluate any potentially involved
mesorectal lymph nodes. Real time images are
acquired and transmitted to a screen for image capture and interpretation in a clockwise manner.
A range of probes with varying frequencies are
available, depending on the intended aim of
ERUS and bearing in mind that the focal length is
inversely related to the frequency. As an example,
a high frequency probe will give higher resolution
images, but at a lower depth of penetration. This
may be useful in assessing the depth of invasion,
whereas a lower frequency may be more relevant
in imaging the deeper perirectal tissues, albeit at
the expense of image resolution. Frequencies of
between 7 and 10MHz will provide a focal length
of 1–5cm and are usually sufcient for the purpose of staging rectal neoplasms.
Primary Rectal Cancer Staging:
TheRole ofERUS
Depth ofInvasion
The precise assessment of tumour depth into the
rectal wall is of particular importance, given the
possibility of a local transanal excision in selected
cases of early rectal cancer, thus avoiding major
resectional surgery and its associated morbidity.