Anal cancer

1. Anal cancer Topic Review 3/16/11

2. Anal cancer • Approx 4200 new cases annually in US • May be an overestimation due to misclassification of perianal or anal margin cancers as anal canal cancers • Anal canal lesions may have more aggressive biology

4. Three Regions • Intraanal lesions • Cannot be visualized or only slightly visualized with gentle traction on the buttocks • Perianal lesions • Completely visible • Within a 5-cm radius of anal opening with gentle traction • Skin lesions • Outside of the 5-cm radius

5. Transformation Zone • 0-12 mm in length • Beginning at the dentate line • “Transitional urothelium-like” epithelium in rectal mucosa instead of columnar mucosa • Squamous metaplasia may be found overlying the normal columnar mucosa involving up to 10 cm or more of distal rectal mucosa

6. Terminology • SCC in situ (CIS), anal intraepithelial neoplasia (AIN), anal dysplasia, squamous intraepithelial lesion (SIL), and Bowen’s disease are all used to refer to the same histopathology • Normal, low-grade squamous intraepithelial lesions (LSIL), high-grade squamous intraepithelial lesions (HSIL), or invasive cancer

7. Lymphatic Drainage • Above the dentate line • Superior rectal lymphatics to inferior mesenteric lymph nodes and laterally to internal iliac nodes • Below the dentate line • Inguinal nodes • May also involve the inferior or superior rectal lymph nodes

8. HPV • Necessary but not sufficient cause for development of anal cancer • DNA papovavirus with 8-kb genome • Most common viral sexually transmitted infection • Most patients clear virus with only 1% developing genital warts with low oncogenic potential (serotypes 6 &11) • 10-46% develop subclinical infections that may harbor malignant potential (serotypes 16, 18, 31, 33, 35)

9. HPV • Not prevented by condoms • Virus pools at the base of the penis and scrotum • In women, may pool and extend from vagina to anus • Anoreceptive intercourse associated with intraanal disease but condylomata or dysplasia within the anus does not mandate that it has occurred

10. HPV • After developing chronic infection, virus enters basal and parabasal cells • Disruption in normal mucosal barrier • Anoreceptive intercourse • Other STD’s (ulcers from syphilis, gonorrhea) • Friable prolapsing hemorrhoid • Firm bowel movement • Can become widespread and persistent (for decades) if viral DNA gains access to nucleus of replicating cells • Increased risk of cancer

11. HPV • Cell-mediated immunity important to cellular response prohibiting the virus from establishing prolonged presence • Oncogenic viruses lead to cellular proliferation in latency phase • Interferes with cell cycle control mechanisms through p53 binding and degradation • Leads to accumulation of genetic errors • These cells then proliferate, accumulate, and involve the entire thickness of epithelium • Disease progression from low-grade to high-grade dysplasia • Increased proliferation and angiogenesis, decreased apoptosis • Increased anal cancer rates observed in kidney transplant and HIV (+) patients, both populations with blunted cell-mediated responses

12. HPV • As the infection with oncogenic viruses persists, the anal tissues may progress through low-grade to high-grade dysplasia and cancer • With this disease progression is an associated increased proliferation and angiogenesis, and decreased apoptosis • In the cervix, angiogenic changes have long been recognized as an important and visible step in the progression of dysplasia to cancer • Colposcopy with the aid of acetic acid and Lugol’s solution, allows for direct visualization of characteristic vascular patterns seen with LSIL and HSIL • Therapeutic intervention, in combination with screening Pap smears, has led to the belief that cervical cancer is a largely preventable cancer • Fortunately, the angiogenic changes associated with development of anal HSIL can also be visualized with the aid of acetic acid and Lugol’s solution in the perianal skin, anus, and distal rectum through an operative microscope, colposcope, or loops in the office or operating room • Targeted destruction is safe and may result in the same decrease in anal cancer incidence

13. Bowen’s disease • SCCA in situ and HSIL • Is frequently found as an incidental histologic finding after surgery for an unrelated problem, often hemorrhoids • Clinically unapparent but histologically reveals SCC in situ • May present with complaints of perianal burning, pruritus, or pain • Physical examination may reveal scaly, discrete, erythematous, or pigmented lesions • In the immunocompetent, <10% will progress to cancer

14. Bowen’s disease • Standard recommendation for lesions found after hemorrhoidectomy is to return the patient to the OR for random biopsies taken at 1-cm intervals starting at the dentate line and around the anus in a clock-like manner • Frozen sections establish the presence of Bowen’s disease and these areas are widely locally excised with 1-cm margins • Large defects are covered with flaps of gluteal and perianal skin • A less radical approach involves taking patients to the OR and using an operating microscope, acetic acid, and Lugol’s solution to visualize and target for electrocautery destruction • May also simply be locally excised • The deep margin is kept equally close because wide local excision seems of limited benefit and increases morbidity • Other therapeutic modalities include topical 5-fluorouracil (5-FU) cream, imiquimod, photodynamic therapy, radiation therapy, laser therapy, and combinations of the above

15. SCC of the Anal Margin • Arises from both the anal margin and the anal canal • Immunohistochemical studies of squamous cell tumors from the anal margin and anal canal demonstrate differences in expression of cadherin, cytokeratins, and p53 confirming that these tumors are of distinct histogenetic origin • The anal margin is defined as the skin starting at the distal end of the anal canal to a 5-cm margin surrounding the anal verge

16. Clinical Characteristics • Tumors of the anal margin resemble SCC of other areas of skin • Staged and often treated in a similar manner • Rolled, everted edges with central ulceration • May have a palpable component in the subcutaneous tissues • Sphincter complex is not usually involved • Patients present in the seventh decade of life, M=F • Presenting symptoms include a painful lump, bleeding, pruritus, tenesmus, discharge, or even fecal incontinence • Anal margin tumors may have a delay in diagnosis because of their location and indistinct features • Almost one-third are misdiagnosed at their first physician visit • Patients were given erroneous diagnoses of hemorrhoids, anal fissures, fistulas, eczema, abscesses, or benign tumors • No significant difference in survival between correctly diagnosed and misdiagnosed patients

17. Staging • Based on size of the tumor and lymph node involvement • Both correlate with prognosis • Lymphatic drainage of the anal margin extends to the femoral and inguinal nodes and then to the external and common iliac nodes • Lymph node involvement is associated with the size and differentiation of the tumor • Incidence of inguinal lymph node metastasis • 0% for tumors <2 cm, 23% for tumors 2–5 cm in size, and 67% in tumors >5 cm • Distal visceral mets at presentation is rare but should be evaluated with CT of the abdomen and pelvis to assess for liver metastases, as well as the presence of nodal disease • Chest X-ray can be performed for lung mets • These tumors are generally slow growing and histologically are well differentiated with well-developed patterns of keratinization

18. Treatment Options • Traditionally consisted of surgical resection with wide local excision for smaller-sized tumors and APR for larger, invasive tumors • Wide local excision alone results in high locoregional recurrence rates (18%–63%) • Should be reserved for those lesions that can be excised with a 1-cm margin, are Tis or T1, and do not involve enough sphincter to compromise function • Since it was introduced in the early 1970s, radiation therapy has become the mainstay of therapy for SCC of the anal canal and its application to tumors of the anal margin is increasing • Local control rates for radiation therapy reported by T stage: T1, 50%–100%; T2, 60%–100%; T3, 37%–100% • In patients with T1 or early T2 lesions, local excision or radiation therapy provides similar local control rates (60%–100%) • For less favorable lesions, chemoradiation is now used as the first-line therapy using a perineal field and inguinal fields, even without clinically detectable disease in the groin • Pelvic lymph nodes are also treated for those patients with T3 and T4 tumors

19. SCC of the Anal Canal • All large-cell keratinizing, large-cell nonkeratinizing (transitional), and basaloidhistologies • Terms epidermoid, cloacogenic, and mucoepidermoid carcinoma are all encompassed in the SCC group • SCC of the anal canal is 5 times more common than SCC of the anal margin • Incidence is 1/10 that of rectal cancer • The most common presenting symptom is bleeding • occurs in >50% of patients with many complaining of anal pain • Other symptoms include palpable lump, pruritus, discharge, tenesmus, change in bowel habits, fecal incontinence, and rarely, inguinal lymphadenopathy • A small number of patients will be asymptomatic • Unfortunately, most patients are diagnosed late, with up to 55% of patients being misdiagnosed at the time of presentation

20. Evaluation • PE should include a complete anorectal examination with external inspection of the anoderm, digital examination, anoscopy and proctoscopy and exam of inguinal areas • Notation should be made of size, location, and mobility of the mass, associated perirectallymphadenopathy • In women, a pelvic exam should be done to look for any associated lesions or invasion of tumor into the vagina • Additional workup should include an endoanal/endorectal ultrasound to assess the depth of the tumor, presence of perirectal lymph nodes, and invasion of adjacent organs as an adjunct to the physical examination • Enlarged lymph nodes can be reactive to secondary inflammation and should be biopsied with direct FNA or ultrasound-guided FNA • Studies of sentinel lymph node biopsy may result in more accurate staging but the actual impact on initial and subsequent management remains unclear • CT scan or MRI of the A/P can add to locoregional staging as well as evaluating for liver metastasis • CXR is used as a screening tool for lung lesions and, if suspicious, a chest CT should be performed. • Positron emission tomography (PET) scans are useful for assessing persistent or residual disease after treatment • Colonoscopy can exclude any associated lesions proximal to the anal canal • HIV test should be performed for those at higher risk • HIV-positive patients with CD4 counts <200 need better monitoring of opportunistic infections,

21. Radiation Therapy • Quite effective because this tumor is extremely radiosensitive • Can be given as external beam radiation, brachytherapy, or in combination • Response is dose dependent--best chance of tumor eradication with at least 54 Gy of external beam radiation • Benefit is lost when administered in a split-course manner • Local control and cure can be achieved in 70%–90% of selected patients with 60%–70% retaining sphincter function • When tumors are >5 cm or lymph nodes are involved, the cure rate decreases to 50% • Better results with higher doses of radiation must be exchanged with increased radiation-induced complications (when >40 Gy is administered) • Serious late complications: anal necrosis, stenosis, and ulcerations, diarrhea, urgency, and fecal incontinence, cystitis, urethral stenosis, and sbo • Dose-dependent effect on morbidity • Requirement of a colostomy in 6%–12% of patients--tumor size was the only risk factor • Brachytherapy used alone with external beam is also effective • Local control rates of 75%–79% and 5-year survival of 61%–65% • 3%–6% of patients had serious complications that required surgery

22. Chemoradiation Therapy • Introduction of by Nigro et al. in 1974 revolutionized the treatment of anal canal SCC • demonstrated equivalent local control and survival rates with preservation of sphincter function and thus avoidance of a colostomy • Described using 30-Gy external beam radiation with 5-FU and mitomycin C • Complete pathologic response in 21 of 26 patients (81%) • Since that time, has become the standard therapy for SCC of the anal canal • Operative treatment for anal canal SCC was largely abandoned and reserved for those patients with persistent or recurrent disease after chemoradiation • Cisplatin has replaced mitomycin C because it is a radiation sensitizer, is less myelosuppressive, and has been used for those patients who failed to respond to mitomycin C

23. Follow-up • No consensus has been reached on appropriate follow-up after treatment of SCC • Generally agreed that early intervention for persistent disease and recurrent locoregional disease can lead to successful salvage therapy • Routine examination with digital rectal examination and proctoscopy every 2 months in the first year, every 3 months in the second year, and every 6 months thereafter has been recommended • Ultrasound examination has also become popular in detecting recurrence although the literature is mixed on its benefit • CT scan or MRI performed after completion of chemoradiation may also be useful as a baseline for future comparison • MRI is useful for distinguishing surrounding tissues and detecting persistent or recurrent disease

24. Treatment of Residual or Recurrent Disease • Patients need to be restaged with a CT of the chest, abdomen, and pelvis • MRI may be useful to assess resectability of pelvic recurrence • PET may help differentiate tumor from radiation-induced tissue changes or other undetectable metastases • APR can be performed for tumor localized to the pelvis with a 5-year survival of 24%–47% • Positive margins, nodal disease at salvage, and persistent disease after chemoradiation have poorer outcomes • Morbidity for APR in this setting is significant with an increased risk of perineal wound complications • This has prompted the use of plastic surgery reconstruction using rotational or advancement flaps to promote healing • The benefit of adjuvant chemotherapy after APR is currently unknown • Clinically evident inguinal disease after chemoradiation of the primary tumor can be treated with radical groin dissection if radiation has already been administered • Additional radiotherapy can be considered if maximal doses of radiation were not delivered • Radical groin dissection in selected patients can result in a 5-year survival of 55% • Distant metastases have been found in 10%–17% of patients treated with chemoradiation, and are usually treated with systemic chemotherapy such as cisplatin or 5-FU for palliation • If the metastases are isolated in the liver or lung and the primary disease is controlled, resection can be considered

25. AJCC staging of SCC

26. AJCC staging of SCC

27. AJCC staging of SCC

28. AJCC staging of SCC • Stage grouping (3b does not exist for anal margin) • Stage 0 Tis N0 M0 • Stage 1 T1 N0 M0 • Stage 2 T2,3 N0 M0 • Stage 3a T1,2,3 N1 M0 or T4 N0 M0 • Stage 3b Any T N2,3 M0 or T4 N1 M0 • Stage 4 Any T Any N M1