ANAL CARCINOMA

Embryology Caudal growth of hindgut forms anal canal Hindgut fuses with the anal dimple Residual anal membrane dissolves in 8th week of gestation = dentate line Dentate line marks border between tissues derived from endoderm and from ectoderm Anatomy

Histology Proximal anal canal: columnar epithelium, really a continuation of the rectum Transitional zone: to ~1 cm above dentate line, mix of cell types Distal to dentate line: o Anoderm: nonkeratinized squamous epithelium, no accessory skin structures o Skin: keratinized squamous epithelium Definitions Anal canal: from upper edge to lower edge of internal anal sphincter Anal verge: line that marks transition from anoderm to skin Anal margin: the perianal skin extending 5cm out from anal verge So, what is anal cancer? Histology: squamous cell carcinoma Anatomy: arising from the anal canal or the anal margin

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Etiology Anal cancers comprise only 2-3% of large bowel cancers Incidence 0.6 per 100,000 in USA Increasing incidence in urban centers Risk Factors History of cervical dysplasia / cancer Human Papillomavirus Present in 88% of patients with anal cancer HPV subtype 16, 18, 31, 33, 35 with highest oncogenic potential (especially16) Same as in cervical cancer Welton ML et al. Surg Onc Clin N Am 13 (2004) 263-275 Other sexually transmitted diseases are independent risk factors for the development of anal cancer: o Herpes simplex o Chlamydia o Gonorrhea o HIV Rousseau DL et al. Surg Onc Clin N Am 13 (2004) 249-262 Cigarette smoking Immunosuppresion o Organ transplantation o Chronic steroid use o Autoimmune disease o HIV No association with IBD Welton ML et al. Surg Onc Clin N Am 13 (2004) 263-275 Presentation Pain: 60% Bleeding: 59% Pruritis / Discharge: 26% Diagnosis: 50% of anal margin cancers were not made until more than 2 years after onset of symptoms

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30-50% patients present with locally advanced disease Khatri VP et al. Surg Onc Clin N Am 13 (2004) 295-308

Lymphatic spread Proximal to dentate line o Drains to inferior mesenteric and then periaortic nodes Distal to dentate line o Drains to inguinal lymph nodes Lymphatic drainage

Metastasis Visceral metastases present in 10% of patients at diagnosis Liver is most common site o Median survival of 9 months in patients with hepatic metastases Lung Bone Staging T1 T2 T3 T4 Tumor less than 2cm Tumor >2cm and <5cm Tumor >5cm Any size that invades adjacent organs

N1 N2 N3

Metastasis in perirectal nodes Metastasis in unilateral iliac/inguinal nodes Metastasis in bilateral iliac/inguinal nodes

M0 M1

No distant metastasis Distant metastasis

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Ultrasound useful to evaluate local extension of tumor Palpable lymph nodes should have FNA CT to evaluate for metastases

Ultrasound Endoscopic anal ultrasound has not been as helpful as in rectal cancers Layers are not as easily identified Can be used to ascertain the depth of tumor invasion Khatri VP et al. Surg Onc Clin N Am 13 (2004) 295-308

Normal anal canal Anal cancer Treatment In the past, anal cancer treated with APR o 27-47% local failure rate o 5-year survival 40-78% (depending on size of tumor) Disappointing results led to trials of neoadjuvant chemoradiation Rousseau DL et al. Surg Onc Clin N Am 13 (2004) 249-262 Pioneering work of Nigro et al in 1970s Soon became apparent that APR did not add to success of chemoradiation Combined-modality therapy is now standard of care: 240

o External beam radiation o 5-FU o Mitomycin C or Cisplatin Recent trials of XRT +/- chemotherapy XRT alone, vs XRT + 5FU and Mitomycin UK Coordinating Committee on Cancer Research study o Prospective randomized trial o 585 patients w/ SCC of anal canal or margin

UKCCCR Study Chemo + XRT has Significant reduction of local failure rate (presence of disease or colostomy creation): 39% vs. 61% Significantly lower mortality from anal cancer at 3 years: 28% vs. 39% No significant difference in overall survival at 3 years: 58% vs 65% Higher rate of toxic events with chemotherapy UKCCCR Working Party, Lancet 1996; 348:1049-54

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Treatment Anal cancer continues to respond for 6 to 9 months after treatment completed Only after failed non-operative therapy x2 is salvage APR recommended 50% 5 year survival rate after salvage APR Those with residual disease after salvage surgery have dismal prognosis High morbidity, 30-60% with non-healing wounds No curative treatment for distant disease Prognosis Difficult to quantify due to relatively small numbers of patients Studies often combine all stages Overall 5-year survival data 60-90% Surveillance Every 3 months for 2 years, and twice a year thereafter o Digital rectal exam o Anoscopy o Biopsy of any suspicious areas

Umut Sarpel, M.D. December 5, 2005

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