Debashis Biswas and Thankamma Ajithkumar
Case history
A 49-year-old woman presented with a 12-month history of a painful lesion at her anus. Recently, she had been finding it difficult to evacuate her bowels because of local pain. Her general health was otherwise good. Clinical examination showed a 10cm × 8cm ulcer centred over the anus. There were no palpable inguinal lymph nodes. She declined an internal examination due to pain.
Question
1. How would you investigate further?
Answer
1. How would you investigate further?
Once a diagnosis of anal cancer is suspected, a biopsy and EUA are performed to document the extent of the tumour. In women vaginal examination should be included to screen for associated cervical cancer. A MRI of the pelvis is performed to determine the extent of local disease and a CT scan of the chest and abdomen to rule out distant metastasis.
The patient had a MRI scan (Fig. 14.1) and biopsy. Biopsy of the anal mass showed a well to moderately differentiated keratinizing invasive squamous cell carcinoma.
Fig. 14.1
Questions
2. What does the pelvic MRI scan show?
3. Describe the anatomy of anal canal and its lymphatic drainage.
Answers
2. What does the pelvic MRI scan show?
The MRI shows a large tumour involving the anal canal and margin (Fig. 14.1a) and displacing the posterior wall of the vagina forwards (Fig. 14.1b).
3. Describe the anatomy of anal canal and its lymphatic drainage.
The anal canal extends from the perianal region (the anal verge) to the anorectal junction. It is 3–4cm long and is divided by the dentate line. The mucosa is lined by squamous epithelium below the dentate line and by columnar epithelium above it. Tumours arising between the anorectal ring and the anal verge are classified as anal canal tumours (85%) and those arising distal to this are called anal margin tumours (15%). Lymphatics from below the dentate line drain to the inguinal and femoral nodes and subsequently to the external iliac and common iliac nodes. Above the dentate line the drainage is to the perirectal and superior rectal nodes and subsequently to the inferior mesenteric and para-aortic nodes.
Staging showed that the tumour extends 6 cm into the anus and measures 10cm × 8cm over the perineum. Inguinal lymph nodes were visible, but none measured more than 10mm. There were no distant metastases.
Questions
4. What is the stage of the disease?
5. What is your next step?
Answers
4. What is the stage of the disease?
rT4NxM0. Radiologically it involves the vaginal wall (T4), though inguinal nodes are visible on scan they are not assessed (Nx) and there is no metastatic disease (M0).
5. What is your next step?
She needs further investigations with PET/CT scan and histopathological examination of the inguinal nodes.
Approximately 50% of palpable or radiologically visible inguinal nodes do not contain metastasis. The incidence of inguinal nodal metastasis increases with the size of primary tumour: 0% with a tumour <2cm, 24% with a 2–5cm tumour, and 67% with a tumour >5cm. CT and MRI are less sensitive than PET/CT (62% versus 89%, respectively) in detecting inguinal node metastases, half of which are < 5mm. A PET-CT scan can have a significant impact on radiotherapy planning, especially in identifying patients who need a higher dose of radiotherapy to the groin and to rule out occult metastatic disease. PET/CT imaging changes the radiation volumes in up to 13% of patients. Therefore, it is important to rule out inguinal nodal metastasis by fine-needle aspiration cytology and/or inguinal node biopsy.
The PET scan was unsuccessful for technical reasons. Bilateral inguinal lymph node biopsies showed no evidence of malignancy.
Questions
6. What further investigations will you request?
7. Outline your treatment.
8. What common side-effects of radiotherapy would you include in the consent form?
9. What are the prognostic factors in anal cancer and what is her estimated survival?
10. How will you assess response to treatment and how will you follow her up?
11. If she were HIV positive how would you modify her treatment?
Answers
6. What further investigations will you request?
The risk factors for anal cancer include persistent infection with high-risk genotype human papilloma virus (HPV 16 is detected in 70% of anal cancers), cervical dysplasia or cancer, HIV seropositivity, smoking, anoreceptive intercourse, and immuno-suppression following a solid organ transplant. There is a strong association between anal cancer and in situ/invasive cervical cancer so a clinical assessment of cervix, vagina, and vulva and screening for cervical and vaginal cancer should be carried out. If there is a history of possible HIV infection HIV testing is also recommended.
7. Outline your treatment.
Radical radiotherapy with concomitant chemotherapy using 5-FU and mitomycin C is the standard treatment for localized anal cancer. Primary surgery with abdominoperineal resection (APR) results in a 5-year survival of 50–70% with a local failure rate approaching 50%. Randomized phase III trials have shown that chemoradiotherapy results in a 5-year survival of 72–89% with a local failure rate of 14–37% and 5-year colostomy-free survival rate of 70–86%.
Radiotherapy is delivered in two phases as per the ACTII trial protocol giving a total dose of 50.4Gy in 28 fractions (phase I, 30.6Gy in 17 fractions; phase II, 19.8Gy in 11 fractions).
The GTV consists of the primary tumour and involved lymph nodes, which are contoured on the planning CT scan. The phase I PTV is defined by the following borders:
♦ superior border 1–2cm above the inferior aspect of the sacroiliac joint or 3cm above the upper limit of the known macroscopic disease (if there are pelvic nodes on the scans or the primary tumour extends to within 3cm of this border);
♦ lateral border, lateral to the acetabulum and covering both inguinal node regions;
♦ inferior border 3cm below the anal margin (for disease confined to the anal canal) or 3cm below the most inferior extent of tumour (for anal margin tumours).
The PTV for phase II consists of the GTV with 3cm margin in all directions.
8. What common side-effects of radiotherapy would you include in the consent form?
Radiation dermatitis is inevitable and can necessitate gaps in the treatment or premature discontinuation of therapy in severe cases. Diarrhoea and urinary symptoms (dysuria and frequency) are also common. Late toxicities include anal ulceration, stenosis, and necrosis necessitating a colostomy in up to 10% of patients. Patients can develop urgency, frequency, and faecal incontinence. Vaginal stenosis and premature ovarian failure can occur, but women should be advised to continue contraception until ovarian failure is proven. Male patients should be offered sperm banking to guard against temporary or permanent azoospermia.
9. What are the prognostic factors in anal cancer and what is her estimated survival?
In the absence of metastases, the size of primary tumour is the most useful predictor of survival, local control, and preservation of anorectal function. The 5-year overall survival is 75%, which is reduced by 20% in node-positive patients (i.e. to 55%). Overall survival is approximately 86% for T1–T2, 60% for T3, and 45% for T4 cancers. Anal margin cancers have a more favourable prognosis than those of the anal canal due to the decreased risk of nodal metastases. The median survival of patients with distant metastases is 9 to 12 months.
Since she has a T4N0 disease, her estimated 5-year survival is 45%.
10. How will you assess response to treatment and how will you follow her up?
A clinical assessment by physical examination is done 6–8 weeks after completion of treatment. Since squamous cell carcinomas regress slowly and continuously there is controversy regarding the optimal time to assess treatment response and plan salvage surgery. ACT II trial data showed that the complete clinical response (cCR) rate increased over time irrespective of the treatment arm: 60% of patients who did not achieve cCR at 11 weeks achieved it at 26 weeks. The cCR at 26 weeks correlated with PFS and OS. Thus, any decision of surgical salvage for persistent disease should be deferred until at least 26 weeks.
After cCR patients should to be followed up with DRE and inguinal examination every 3–6 months for 2 years and 6–12-monthly until 5 years, with the aim of detecting loco-regional recurrences or metastases and managing late effects of treatment proactively.
11. If she were HIV positive how would you modify her treatment?
Data from small series suggest that the outcome of HIV-positive patients is similar to that of HIV-negative patients. HAART (highly active antiretroviral therapy) needs to be started prior to commencing chemoradiotherapy. Radiotherapy and chemotherapy doses need to be modified due to the increased incidence of toxicities. Side-effects of radiotherapy can be more severe, with a dose of >30Gy necessitating diversion colostomy or APR in 6–12% of patients. Patients with haematological abnormalities or a previous history of significant opportunistic infections may not tolerate a full dose of mitomycin C and may require dose modification.
Further reading
Glynne-Jones R, Lim F. Anal cancer: an examination of radiotherapy strategies. International Journal of Radiation Oncology Biology Physics 2011; 79: 1290–1301.
Kochhar R, Plumb AA, Carrington BM, Saunders M. Imaging of anal carcinoma. American Journal of Roentgenology 2012; 199: W335–W344.
Lim F, Glynne-Jones R. Chemotherapy/chemoradiation in anal cancer: a systematic review. Cancer Treatment Reviews 2011; 37: 520–532.
Uronis HE, and Bendell JC. Anal cancer: an overview. The Oncologist 2007; 12: 524–534.