carcinoma anal canal

1. Dr. Naina Kumar Agarwal
Surgical Oncology
SMS Hospital, Jaipur
Carcinoma anal canal

2. POINTS to be covered:
• Introduction and Anatomy
• Epidemiology and aetiology
• Screening and prevention
• Pathology
• Signs and symptoms
• Staging
• Treatment
• Supportive care

3. Introduction
Important pointers-
• Low propensity for metastatic spread making loco regional control a
paramount end point in approach of disease.
• RCT: No definite benefit of neither radiation dose escalation nor substituting
cisplatin for MMC.
• Early stage: decrease rt dose
• Advanced : increase dose

4. Anatomy –
• The anal canal is 2.5 to 3.5 cm long and begins superiorly where the rectal
ampulla is narrowed by the puborectalis sling (the levator ani muscle,
which is palpable as the anorectal ring). It ends at the intersphincteric
groove. Nccn- Inferior border starts at the anal verge, the lowermost edge
of the sphincter muscles, corresponding to the introitus of the anal orifice.
• Externally, the anal canal is surrounded by the internal and external anal
sphincter muscles.
• The superior half of the anal canal contains a series of longitudinal ridges
called the anal columns (of Morgagni), which extend from the anorectal
junction superiorly to the anal valves inferiorly. The anal valves form an
irregular line called the dentate (or pectinate) line (colored purple in the
diagram), which is an important anatomic landmark. The portions of the
anal canal superior and inferior to it have different origins of arterial supply,
nerve innervation, venous/lymphatic drainage, and epithelial lining.
• The anal canal is internally lined with mucous membrane above the
dentate line and the anoderm below it. The upper portion of the anoderm
(anal verge) consists of smooth, hairless skin; the lower portion of the
anoderm (perianal skin) contains pigmented skin containing hair follicles
and glands.

5. Epidemiology and etiology
• 1-2% of all large bowel cancers.
• male : female = 1.5: 2.1
• Median age = 61 years
• Rising incidence = Hpv , hiv increase
• > 10 sexual partners = increase risk ( odd 's ratio 4.5 women and 2.5 for men )
• H/0 anal warts and receptive anal intercourse in women: highest risk

6. • Age 67% >55 years
• Smoking: adjusted odds ratio for women=3.8( 95% CI) , men = 3.9 ( 95% CI).
Also related to no. Of pack years
• Immuno suppression: 6 times higher risk
• Benign anal lesions don't contribute.

7. HPV
• 16 ( 75 % ) and 18 (10%)
• > 80% = demonstrated more than one genotype Of HPV
• Homosexual men 15 times higher risk of hpv related cancer
• Women with high grade cervical or vulvar dysplasia: → cervical or vulvar hpv
infection → escalates anal HPV infection risk: therefore more risk of anal
cancer

8. HIV infection
• Twice the risk of anal cancer.
• HAART has increased rates
• earlier recurrences by 20 months
• Median survival similar.

9. Screening and prevention
• Anal squamous Intra epithelial lesions _ SlL or anal Intra epithelial neoplasia _
AIN recognised as precursors.
• High-risk groups like HIV have increased rates of progression with a relative
risk of 2.4 and increasing to 3.1 for those with CD4 count less than 200
• The recommended screening test in HIV patients is an anal Pap smear that
evaluates cells in the anal canal for abnormal cytology . it is then followed by
high-resolution anoscopy (HRA) That allows biopsy and/or removal.
• Management of low-grade and high-grade SIL remains controversial.
• HRA with directed biopsy is the gold standard for detection of HSIL.

10. • International anal neoplasia society ( IANS) decides the guidelines for this clinical
service.
• Tong et al. Found that 23.8% of patients diagnosed with high-grade dysplasia on
HRA screening regressed to low-grade or normal histology without any ablative
therapy. The rate of regression was actually higher than progression to cancer
indicating that not all lesions warrant treatment .
• SPANC Australian study is currently underway to address this issue so that
definitive evidence-based guidelines can be generated.
• Treatment options for high-grade AIN include ablation with electro cautery, topical
trichloroacetic acid, topical 5FU or imiquimod _ Lesion control rates 60 to 80%

11. • ANCHOR (anal cancer/HSIL outcomes research) Study is an NCI sponsored trial .it will
randomise 5058 HIV positive patients with anal high-grade dysplasia to undergo either active
monitoring (with frequent HRA) or lesion directed treatment. Time to the development of anal
cancer will be measured as the primary outcome with at least five years of follow-up for all
patients. Other outcome measures to be investigated include tolerance and safety of the various
treatment modalities, quality of life parameters and behaviour or risk factors as well as
biomarkers for HSIL progression to cancer .
• Quadri Valent HPV vaccine Gardasil has demonstrated efficacy for prevention of HPV 6 11 1618
related genital warts and has been shown to protect against cancers of Anus, vagina and vulva.
• In the context of limited availability and sub optimal outcomes of anal screening programmes,
vaccination may reflect the best long-term approach for reducing anal cancer risk and is
recommended for girls and boys at ages 11 or 12 years and girls 13 to 26 years of age who have
not been previously vaccinated .

12. • Deshmukh et al Calculated that vaccination reduced the lifetime risk of anal
cancer by 60.77% and was highly cost-effective with decreased lifetime costs
and increased quality adjusted life expectancy. These findings were robust
irrespective of reasonable changes in vaccine efficacy and age at vaccination.

13. Pathology
• Tumour is classified as squamous
which encompasses tumours as
basaloid ,cloacogenic, transitional,
mucoepidermoid, and verrucous
mucoepidermoid and non squamous .
Not included in current WHO subtypes.
• SCC consists of a lesion with rolled
edges often with central ulceration with
a minority consisting of polyploid
lesions .

15. • Immuno histochemistry for P 16
protein may be used as a marker to
confirm the diagnosis of HPV related
anal HSIL ,also being used as a
surrogate marker for the presence of
HPV genome and tumour cells in the
cervical and head and neck cancers.
• Once disease has reached grade 3
AIN, regression is less common.
• Grade 1 AIN corresponds to
LSILand and grade2 and 3 to HSIL.
.
.

16. • Tong et Al Found that HPV 16 E6 specific CD4 T-cell responses were
associated with spontaneous regression of high-grade lesions.
• Additional non squamous carcinomas include small cell carcinoma,
neuroendocrine tumours, and undifferentiated carcinomas, melanomas and
rarely lymphomas and sarcomas .
• It should be noted that histology is generally more important than location
which usually dictates overall patient management.

17. • Verrucous carcinoma also known as a giant condyloma or buschke lowenstein
tumour – these tumours are sometimes mistakenly considered to be benign and
misdiagnosed as condyloma acuminata with the subsequent a histology century
analysis revealing invasion. These are often large , have a cauliflower appearance,
are locally destructive and are HIV related. They are slow-growing and can be
present for many years before coming to medical attention. Local recurrence after
excision are high and malignant transformation can be seen in up to 50%.
• Another perianal disease is Bowen disease which consist of a slow growing intra
epidermal SCC that may mimic perianal dermatitis as well as paget disease which
is similar to the entity seen associated with breast cancer with an eczematous
appearance. Approximately half of the paget disease patients will harbour an
underlying adeno carcinoma notably in the colorectum.

18. Clinical presentation :
• Most common presentation is bleeding from the anus.
• Other symptoms include bleeding, pain, itching, anal discharge, tenesmus and a sense of
fullness or a lump in the anal canal.
• More extensive lesions may present with incontinence, passage of gas or stools from the
vagina, or significant change in bowel habits.
• Less frequently, an enlarged lymph node is reported, and 20% of patients are initially
asymptomatic.
• Symptoms may be dismissed as haemorrhoids or other benign causes and it is crucial to
further evaluate by a physical examination and anoscopy.

19. Staging

20. • Of all patients with palpable inguinal
lymph nodes, only approximately 50%
are malignant: therefore fine needle
aspiration is often recommended in
suspected cases and a positive result
may guide radiation field design and
dose.
• SLN: a systematic review of 16 published
series evaluating the outcome of SLN
biopsy of inguinal nodes included 323
patients and the success in identifying
the SLN was 86%. however the exact
role of SLN pre-treatment evaluation
remains undetermined.

21. NCCN pointers
• One major change in the 8th edition is that cancers of the Peri anal skin ( within 5 cm of the anal verge)
are staged and treated the same as anal canal cancers rather than squamous cell cancers of the skin.
• The perianal region starts at the anal verge and includes the perianal skin over a 5-cm radius from the
squamous mucocutaneous junction.
• PET/CT performed skull base to mid-thigh.
• Carboplatin/paclitaxel is the only regimen supported by randomized data and may be preferred over 5-
FU/cisplatin due to toxicity profiles.
• Based on the results of the ACT-II study, it may be appropriate to follow patients who have not achieved
a complete clinical response with persistent anal cancer up to 6 months following completion of radiation
therapy and chemotherapy as long as there is no evidence of progressive disease during this period of
followup. Persistent disease may continue to regress even at 26 weeks from the start of treatment.
James RD, et al. Lancet Oncol 2013;14:516-524.

25. Follow of management
• SCC of the anus can regress slowly following treatment completion up to 12
months, it is generally recommended that patients who have progressive disease
do not undergo repeat biopsies -given this may lead to non-healing ulceration
and chronic wound infection in previously irradiated tissues.
• Less intense follow-up needed after three years given that only 7% of relapses
occur beyond this time point.
• Lesions persisting beyond three months following treatment or more concerning
for residual disease .however as stated previously it is important to assess
changes over time. If tumour continues to shrink then close clinical surveillance is
advised. Chronically persistent or recurrent tumour should be biopsied for
confirmation of SCC.( size consideration)

28. Consider the use of immunotherapy (nivolumab or pembrolizumab) (category
2B) before proceeding to APR. Institutional experience has demonstrated some patients receive a good response and can avoid surgery.

29. Prognostic factors
Clinical –
• RTOG 98 –11 study: tumour size>5cm, involved lymph nodes N + and male sex were associated with worse five year
disease-free survival and OS.
• EORTC 22861 study indicated that skin ulceration ,lymph-node involvement and male sex are independent variables
associated with local original failure- LRF and OS in multivariate analysis.
• UKCCCR anal cancer trial ACT1 indicated that palpable lymph nodes as well as males sex portended a poor
prognosis similar to previous studies.
• Lower HB and higher WBC counts were also prognostic in terms of anal cancer death and worsened OS respectively.
• Tumour site, T classification and platelet levels had no influence on outcomes.
• However not all studies have confirmed gender as an independent prognostic factor in terms of local control
metastasis or OS.
• Histological subtypes have demonstrated no significant difference in survival amongst cloacogenic , well differentiated,
moderately or poorly differentiated anal carcinomas .

30. Prognostic factors
Molecular –
• Lampejo And colleagues performed a systematic review on anal Canal prognostic
biomarkers after reviewing 29 studies for final analysis. They found that for 13
biomarkers were associated with anal cancer outcomes in only one study whereas P
53 and P 21 as prognostic markers by more than one study.
• Studies found that in anal carcinoma, P 53 was over expressed with a range of 34%
to 100%. Wong et al. described that increased p53 expression was associated with
worse local regional control( P = 0.02) and DFS (P= .01).
• P 21 gene protein, a cyclin dependent kinase (CDK) inhibitor is considered to be a
mediator of the P 53 gene function. Lack of P 21 expression is associated with poor
prognosis in patients with SCCA. Nilsen and colleagues reported that absence of the
same P 21 expression was also responsible for an increased LRF rate( P < 0.05)

31. • Adani and colleagues reported EGFR expression was observed in 86% of
patients with anal cancer.Multivariate models of same study suggested that KI 67
( negatively coefficient: -0.04 ), nuclear factor kappa B (NFKB) , sonic hedgehog (
shh) and gli-1 ( positive coefficient ) were Associated with DFS.
• Recent: Elevated pre treatment NLR in blood samples and P 16 expression in
tumour tissue , both of which were associated with high risk of recurrence.
Elevated NLR was also significantly associated with worse OS and cancer
specific survival. On the other hand HPV positivity was found to be a positive
prognostic factor for DFS possibly due to better chemo sensitivity as has been
shown in orpharyngeal squamous cell cancer.
• .

32. Treatment of localized squamous
cell carcinoma

33. P
• Reserved for small well differentiated superficial lesions and confined to the perianal skin not involving the
internal sphincter and without nodal involvement.
• For lesions with residual microscopic disease or has close surgical margins less than 1MM, further local
excision, if technically possible, maybe pursued, or adjuvant chemo radiation should be considered.
• Alfa wali et al recently published favourable outcomes in a retrospective analysis of 15 HIV positive patients
with T1 N 0M0 tumours at the anal verge that underwent complete local excision. There were no complications
or recurrence at a median follow-up of four years.
• A review of 118 anal cancers treated with APR reported an OS rate of 70% and overall recurrence rate of 40%.
of these more than 80% established recurrent sites had either local recurrence alone or some component of
such. similarly results from other surgical series using surgery alone suggested higher rates of regional
recurrence( upto 60%) following local excision or APR alone across a variety of stages.
• Local excision may be an option for carefully selected patients with very favorable, small (<1 cm) superficially
invasive tumors that are completely excised and have ≤3 mm of basement membrane invasion and a maximal
horizontal spread of ≤7 mm. (uptodate)

35. Definitive chemo radiotherapy
• Given the relatively poor outcomes obtained with APR alone, nigro and colleagues from Wayne Pioneered
incorporating concurrent pelvic radiation therapy and chemotherapy ( 5 FU and mitomycin) prior to surgical to
section, resulting in higher rates of pathological complete response and survival.
• A study by EORTC randomised 103 patients with T3-4N0-3 or T1-2N1-3 anal cancer to radiation therapy (45 gray
with the booster of 15 to 20 gray) following a six-week break, based on disease response with or without concurrent
chemotherapy using infusional 5FU (750 mg/m²/day, Day 1-5 and days 29 - 33 with MMC given on day one at 15
mg/m² . Surgery was reserved for patients with less than a partial response. Outcomes from this study revealed that
patients treated with concurrent chemotherapy had a higher complete response rate ( 80% versus 54% )with
significant improvement in local regional control (68% vs 50%), colostomy free (72% versus 40%) and event free
survival at five years with addition of chemotherapy. Similarly, OS was improved in patients receiving chemotherapy
(72% versus 65%)- three year OS, although this did not reach statistical significance. Rates of high-grade toxicity
were deemed similar between two groups although the rates of late anal ulceration were higher with the use of
concurrent chemotherapy.
• The results from this trial and UKCCCR trial demonstrated that the addition of chemotherapy To definitive radiation
therapy significantly improves LRF rates as well as relapse free and colostomy free survival rates although at the
expense of increased toxicity.

36. • In a recent study comparing oral vs infusional 5 FU : capecitabine combined with MMC was equally effective as
standard chemo radiotherapy (clinical complete response 98.7% versus 89.1%); three year local regional control,
(79% versus 76%); three year OS, (86% versus 78%).
• A similar comparative study between these two regimens demonstrated lower rates of grade 3 to 4 neutropenia
with the use of capecitabine along with fewer (primarily haematology) toxicity related breaks.
• Although the original regimen, described as the "Wayne State or Nigro regimen," used infusional FU 1000
mg/m2 on days 1 to 4 and 29 to 32 (plus mitomycin 10 to 15 mg/m2 on day 1 only) concurrent with RT ,
consensus-based National Comprehensive Cancer Network (NCCN) guidelines suggest a modified regimen
as was used in the Radiation Therapy Oncology Group (RTOG) 98-11 trial . The chemotherapy consists of
infusional FU 1000 mg/m2 on days 1 to 4 and 29 to 32 plus mitomycin 10 mg/m2 on days 1 and 29, maximum
20 mg per dose. European guidelines suggest a similar infusional FU plus mitomycin regimen, but utilizing
mitomycin 12 mg/m2 on day 1 only (maximum 20 mg single dose). In our view, either approach is
acceptable.
• In our view, the combination of capecitabine and mitomycin is an acceptable substitute for infusional FU plus
mitomycin for chemoradiotherapy.- uptodate

39. • Taken together, these data suggest that FU plus mitomycin remains the standard of
care, but that FU and cisplatin could be considered a reasonable approach as well.
European guidelines emphasize the point that any marginal benefit for cisplatin over
mitomycin in terms of less hematologic toxicity is likely to be offset by the extra
resources needed to administer cisplatin [6].
• There appears to be no role for induction chemotherapy or a continuation of
chemotherapy beyond concurrent chemoradiotherapy.
• NCCN guidelines recommend definitive chemoradiotherapy using standard dose FU
and mitomycin for all patients with anal canal SCC, even those with T1-2N0M0 tumors.
We agree with this approach. For the extremely aged population with T1N0 tumors, or
those with significant comorbidities, reduction of mitomycin and FU doses during RT
could be considered, although this is not a standard approach. - uptodate

40. Principles –
• IMRT:
Radiotherapy
.

41. Principles of Radiotherapy NCCN
• The consensus of the panel is that intensity-modulated RT (IMRT) is preferred over 3D conformal RT in the treatment of anal carcinoma.
• IMRT requires expertise and careful target design to avoid reduction in local control by so-called “marginal-miss.” The clinical target
volumes (CTV) for anal cancer used in the RTOG-0529 trial have been described in detail.
• Patients can be simulated in the supine or prone position and there are benefits to each approach in the appropriate clinical setting. Prone
setup with a false tabletop allows for improved small bowel avoidance and may be useful in individuals with a large pannus and pelvic node
involvement. Supine setup is usually more reproducible with less setup variability, potentially allowing for reduced planning target volume
(PTV) margins and smaller treatment fields. Patients are typically simulated for anal cancer IMRT planning in the supine position with legs
slightly abducted (frog-legged) with semi-rigid immobilization in vacuum-locked bag or alpha-cradle. Patients are instructed to maintain a full
bladder for simulation and treatment.
• In males, the external genitalia are typically positioned inferiorly such that setup is reproducible. In females, a vaginal dilator can be placed
to help delineate the genitalia and move the vulva and lower vagina away from the primary tumor. A radiopaque marker should be placed at
the anal verge and perianal skin involvement can be outlined with radio-opaque catheters. It may be helpful to place a catheter with rectal
contrast in the anal canal at the time of simulation for tumor delineation.
• In patients with adequate renal function, IV contrast facilitates identification of the pelvic and groin vasculature (which approximates at-risk
nodal regions). Oral contrast identifies small bowel as an avoidance structure during treatment planning. For tumors involving the perianal
skin or superficial inguinal nodes, bolus should be placed as necessary for adequate dosing of gross disease in these areas. Routine use of
bolus may not be necessary as the tangential effect of IMRT may minimize skin sparing. In situations where adequate dosing of superficial
targets is uncertain, in vivo diode dosimetry with the first treatment fraction can ensure appropriate dose at the skin surface.

42. • The pelvic and inguinal nodes should be routinely treated in all patients.
• In defining the gross disease CTV around the primary tumor, an approximately 2.5-cm margin around GTV should be used
with manual editing to avoid muscle or bone at low risk for tumor infiltration. To define the gross disease CTV around involved
nodes, a 1-cm expansion should be made beyond the contoured involved lymph node with manual editing to exclude
areas at low risk for tumor infiltration.
• At-risk nodal regions include mesorectal, presacral, internal and external iliac, and inguinal nodes. The mesorectal
volume encompasses the rectum and surrounding lymphatic tissue. The presacral nodal volume is typically defined as an
approximately 1-cm strip over the anterior sacral prominence.
• To contour the internal and external iliac nodes, it is recommended to generally contour the iliac arteries and veins with
approximately 0.7-cm margin (1–1.5 cm anteriorly on external iliac vessels) to include adjacent lymph nodes.
• In order to include the obturator lymph nodes, external and internal iliac volume contours should be joined parallel to the
pelvic sidewall. The inguinal node volume extends beyond the external iliac contour along the femoral artery from
approximately the upper edge of the superior pubic rami to approximately 2 cm caudal to saphenous/femoral artery junction.
• The inguinal node volume should be contoured as a compartment with general margins. The medial and lateral borders may
be defined by adductor longus and sartorius muscles, respectively.

43. • Target Volume Definition : The high-risk elective nodal volume typically includes the gross disease CTV
plus the entire mesorectum, presacral nodes, and bilateral internal and external iliac lymph nodes
inferior to the sacroiliac joint.
• In patients with gross inguinal nodal involvement, the bilateral or unilateral inguinal nodes may be
included in the high-risk elective nodal volume. The low-risk elective nodal volume should include the
gross disease CTV, high-risk elective nodal CTV, and presacral, bilateral internal, and external iliac
nodes above the inferior border of the sacroiliac joint to the bifurcation of the internal and external iliac
vessels at approximately L5/S1 vertebral body junction. If there is no obvious involvement of the bilateral
inguinal nodes, these are included in the low-risk elective nodal volume.
• PTV should account for effects of organ and patient movement and inaccuracies in beam and patient
setup. PTV expansions should typically be about 0.5–1.0 cm depending on use of image guidance and
physician practice with treatment setup for each defined CTV. To account for differences in bladder and
rectal filling, a more generous CTV to PTV margin is applied in these regions. These volumes may be
manually edited to limit the borders to the skin surface for treatment planning purposes.

44. Novel biologic radiosensitizing agents:
• EGFR inhibitors are being studied.
• KRAS mutations in anal cancer have been documented to support the
potential value of EGFR targeted therapy.

47. • Supportive Care:
• Female patients should be considered for vaginal dilators and instructed on the symptoms of vaginal stenosis.
• Urogenital dysfunction after resection and/or pelvic radiation.: Screen for sexual dysfunction, erectile dysfunction,
dyspareunia, and vaginal dryness . unless contraindicated, topical estrogen (one to three times weekly) applied in the first six
months following radiation may reduce dyspareunia and improve vaginal caliber.
• Screen for urinary incontinence, frequency, and urgency. Consider referral to urologist or gynecologist for persistent
symptoms.
• Potential for pelvic fractures/decreased bone density after pelvic radiation.
• Female patients should be counselled on sexual dysfunction and infertility risks and given information regarding oocyte, egg,
or ovarian tissue banking prior to treatment.
• Male patients should be counselled on sexual dysfunction and infertility risks and given information regarding sperm banking.
• Bowel function changes: chronic diarrhoea, incontinence, stool frequency, stool clustering, urgency, cramping: Consider
antidiarrheal agents, bulk-forming agents, diet manipulation, pelvic floor rehabilitation, and protective undergarments.
• Consider daily aspirin 325 mg for secondary prevention.

48. Adeno carcinoma anal canal
The treatment paradigm for anal adenocarcinomas, which are much less common than anal SCCs, is similar to that for rectal
adenocarcinomas, with resection representing an important component of multimodality therapy for most patients.
For staging purposes, such tumors are classified as rectal cancers if their epicenter is located more than 2 cm proximal to the
dentate line or proximal to the anorectal ring on digital examination, and as anal canal cancers if their epicenter is 2 cm or less
from the dentate line .
Prognosis of anal adenocarcinomas is worse than it is with either anal squamous cell cancer or distal rectal adenocarcinoma.
the management of adenocarcinomas arising in the anal canal should follow the same principles as those applied to the
treatment of rectal cancer. For most patients this will include resection and either preoperative or postoperative
fluoropyrimidine-based chemoradiotherapy. This recommendation is consistent with guidelines from the NCCN [5]. There are
no European guidelines for management of anal adenocarcinoma [6]. Others prefer an approach that includes preoperative
chemoradiotherapy plus 12 to 16 weeks of oxaliplatin-based chemotherapy prior to surgery, which is termed "total neoadjuvant
therapy" .

49. Thank you.