1、Anal Neoplasms- Dysplasia to Cancer,Paul A. Lucha Jr., D.O., FACOS, FAOCPr VAMC Salisbury, NC,Introduction,Histology Muscles of the anorectal region Anorectal spaces Vascular anatomy Lymphatic drainage,Anatomy,Surgical Anal Canal differs from anatomists description 4 cm length arises from anorectal
2、junction terminates at anal verge,Anatomists Anal Canal 2-3 cm in length begins at the pectinate line terminates at the anal verge,Anatomy,Anatomy,Anal Margin area caudal to anal canal Intersphinceric groove to approximately 5 cm circumference on the perineum non keratinized squamous epithelium kera
3、tinized squamous epithelium hair follicles and apocrine glands present,Histology,6-14 Columns of Morgagni 4-10 anal glands at crypts Pathogenesis of fistula/ abcess (Parks 1961) 2/3 glands enter internal sphincter 1/3 cross into intersphincteric plane none penetrate the external sphincter,Histology,
4、Transition from columnar epithelium to squamous epithelium (6-12 cm above dentate line) transition zone (cloacogenic anal cancer) Anal verge hair follicles present apocrine glands,Muscles of the Anorectal Region,Internal Sphincter thickening of the circular smooth muscle fibers of the rectum extends
5、 1-1.5 cm below the dentate line inervated by the pelvic autonomic plexus,Muscles of the Anorectal Region,Conjoined Longitudinal Muscle longitudinal muscle layer of the rectum joins with levator ani muscle complex descends between the internal and external sphincters,Muscles of the Anorectal Region,
6、External Sphincter somatic inervation perineal branch of the 4th sacral nerve Inferior rectal nerve,Muscles of the Anorectal Region,Levator Ani complex Puborectalis Iliococcygeus Pubococcygeus Inervated by 4th sacral nerve,Muscles of the Anorectal Region,Muscles of the Anorectal Region,anorectal rin
7、g junction of the rectum and anal canal composed of internal sphincter and puborectalis division results in incontinence,Anorectal Spaces,ischiorectal perianal intersphincteric Postanal supralevator retrorectal,Anorectal Spaces,Postanal space connects with ischiorectal fossa bilaterally,Vascular ana
8、tomy,anorectum has a profuse intramural vascular anastomotic network this prevents necrosis of the anus in low rectal resections,Vascular anatomy,Portal and systemic venous drainage,Lymphatic drainage,Important in rectal cancer Important in anal cancer Important in anal margin cancer,Innervation,Sym
9、pathetic innervation L1, L2, L3 preganglionic preaortic plexus postganglionic follow branches of the IMA enter via “lateral stalks” of the rectum,Innervation,Parasympathetic innervation S2, S3, S4 also called nervi erigenti upward path via IMA downward path follows the sympathetic postganglionic ner
10、ves,Innervation,Sexual function erection parasympathetic and sympathetic ejaculation parasympathetic emission sympathetic,Innervation,Internal anal sphincter Sympathetic L5 Parasympathetic S2, S3, S4,Levator Ani complex S2, S3, S4 perineal branch of the pudendal nerve inferior rectal nerves (puborec
11、talis),Innervation,External Anal Sphincter Inferior rectal branch of the pudendal nerve (S2, S3) and perineal branch of S4 Sensory- Inferior Branch Pudendal Nerve Meissners Corpuscles (touch) Krauses bulbs (cold) Golgi-Mazzoni bodies (pressure) genital corpuscles (friction) Concentrated at anal valv
12、e area,ANAL CANCER OVERVIEW,Carcinomas in the anal canal account for about 1.5% of gastrointestinal cancers in the United States, and approximately 80% of these are squamous cell carcinomas (SCCs). SCCs of the anus are frequently related to chronic infection with human papilloma virus (HPV),ANAL CAN
13、CER OVERVIEW,Usually occur in the sixth to seventh decade of life, occur in younger patients when they are immunocompromised Male:Female=2:1 HIV/AIDS, and the increasing use of immunosuppressive therapy for solid organ transplantation, inflammatory bowel disease and collagen vascular diseases has me
14、ant an increasing incidence of HPV infection and anal SCC.,ANAL CANCER OVERVIEW,Rare in general population, but high and growing in at-risk populations1 Men who have sex with men (HIV+/-) Women (HIV)Incidence Rates2, 3 Men who have sex with men (MSM) HIV- 35/100,000 HIV+ est 70/100,000 General Popul
15、ation 1/100,000,Anal Cancer 2010 cases4,1 Bean, SM, Chhieng, DC, Anal-Rectal Cytology: A Review. Diagnostic Cytopathology 2009; Vol 38 No 7, 538-546 2 Palefsky, J. Screening for Anal and Cervical Dysplasia in HIV-Infected Patients. The PRN Notebook. Volume 6, No. 3, Sept. 2001. 24-31. 3 Darragh, TM.
16、 Anal Cytology for Anal Cancer Screening: Is it Time Yet? Diagnostic Cytopathology, 2004; Vol 30, No 6, 371-374 4 American Cancer Society, Cancer Facts and Figures, 2010,ANAL CANCER OVERVIEW,Morphologic & biologic similarities between anal intraepithelial neoplasia (AIN) and cervical intraepithelial
17、 neoplasia (CIN)1Association with sexual transmission of oncogenic HPV, especially type 161Gardasil HPV-vaccine approved to prevent anal cancer2,2001 Bethesda guidelines includes appendix for anal cytology,1 Darragh, TM. Anal Cytology for Anal Cancer Screening: Is it Time Yet? Diagnostic Cytopatholo
18、gy, 2004; Vol 30, No 6, 371-374 2 FDA News Release , Dec 22, 2010 (http:/www.fda.gov/newsevents/newsroom/pressannouncements/ucm237941.htm)Gardasil is a registered trademark of Merck, Sharp, & Dohme Corp.,Anal cancer,Approx 4200 new cases annually in US May be an overestimation due to misclassificati
19、on of perianal or anal margin cancers as anal canal cancers Anal canal lesions may have more aggressive biology,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 openi
20、ng with gentle traction Skin lesions Outside of the 5-cm radius,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
21、 to 10 cm or more of distal rectal mucosa,Terminology,SCC in situ (CIS), anal intraepithelial neoplasia (AIN), anal dysplasia, squamous intraepithelial lesion (SIL), and Bowens disease are all used to refer to the same histopathology Normal, low-grade squamous intraepithelial lesions (LSIL), high-gr
22、ade squamous intraepithelial lesions (HSIL), or invasive cancer,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 n
23、odes,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 infec
24、tions that may harbor malignant potential (serotypes 16, 18, 31, 33, 35),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
25、anus does not mandate that it has occurred,HPV,After developing chronic infection, virus enters basal and parabasal cells Disruption in normal mucosal barrier Anoreceptive intercourse Other STDs (ulcers from syphilis, gonorrhea) Friable prolapsing hemorrhoid Firm bowel movement Can become widespread
26、 and persistent (for decades) if viral DNA gains access to nucleus of replicating cells Increased risk of cancer,HPV,Cell-mediated immunity important to cellular response prohibiting the virus from establishing prolonged presence Oncogenic viruses lead to cellular proliferation in latency phase Inte
27、rferes 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 angiog
28、enesis, decreased apoptosis Increased anal cancer rates observed in kidney transplant and HIV (+) patients, both populations with blunted cell-mediated responses,HPV,As the infection with oncogenic viruses persists, the anal tissues may progress through low-grade to high-grade dysplasia and cancer W
29、ith 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 Lugols sol
30、ution, 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 develo
31、pment of anal HSIL can also be visualized with the aid of acetic acid and Lugols 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 cance
32、r incidence,Bowens 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
33、examination may reveal scaly, discrete, erythematous, or pigmented lesions In the immunocompetent, 10% will progress to cancer,Bowens 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 th
34、e dentate line and around the anus in a clock-like manner Frozen sections establish the presence of Bowens 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
35、 and using an operating microscope, acetic acid, and Lugols 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 modaliti
36、es include topical 5-fluorouracil (5-FU) cream, imiquimod, photodynamic therapy, radiation therapy, laser therapy, and combinations of the above,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 ana
37、l 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,Clinical Characteristics,T
38、umors 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,
39、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
40、erroneous diagnoses of hemorrhoids, anal fissures, fistulas, eczema, abscesses, or benign tumors No significant difference in survival between correctly diagnosed and misdiagnosed patients,Staging,Based on size of the tumor and lymph node involvement Both correlate with prognosis Lymphatic drainage
41、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 5 cm Distal visceral mets at presentation is rare
42、 but should be evaluated with CT of the abdomen and pelvis to assess for liver metastases, as well as the presence of nodal diseaseChest X-ray can be performed for lung mets These tumors are generally slow growing and histologically are well differentiated with well-developed patterns of keratinizat
43、ion,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
44、-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 radi
45、ation 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
46、 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,SCC of the Anal Canal,All large-cell keratinizing, large-cell nonkeratinizing (transitional), and basaloid histologies Terms epidermoid, cloacoge
47、nic, 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 sy
48、mptoms 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
49、presentation,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 perirectal lymphadenopathy In w
50、omen, 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 phy
51、sical 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 sca
52、n 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,
