Anal neoplasms

Cancer that occurs between where the rectum passes puborectalis, approximately 1-2cm above the dentate line, and the junction of squamous mucosa and perianal skin.

Squamous neoplasms

Squamous intra-epithelial lesions (SIL)

• • Dysplastic changes in the anal canal that are thought to be precursor lesions to invasive anal carcinoma
  • Risk factors
    • HPV 6, 11, 16, 18
      • Especially HPV 16 and 18
      • Small DNA viruses
      • HPV transcription products directly bind to p53, thus knocking out the tumour suppressor gene
      • There may also be other impacts
    • Anal warts
    • Multiple sexual partners
    • Anal receptive intercourse
    • History of rectal discharge
    • IVDU
    • Immunosuppression including HIV and transplant
    • Smoking
    • History of cervical/vulvar dysplasia or cancer
  • Histopathology/nomenclature
    • Roughly divided into low-grade SIL (LSIL) and high-grade SIL (HSIL)
      • LSIL is diagnosed when abnormal basaloid cells extend less than one-third of the thickness of the epithelium above the basal layer.
      • HSIL shows abnormal basaloid cells extending into the upper layers of the squamous epithelium.
    • HSIL is premalignant and may progress to invasive cancer, whereas LSIL is not a direct precursor but is considered a risk marker for having HSIL in the future.
      • LSIL seems to regress within two years in about half of patients, and progress to HSIL in about 16%, although these numbers are not very precise at all.
      • HSIL can also regress, but less likely, and can progress to anal cancer in about 2% by 4 years
    • Prior classification was AIN 1, 2, or 3, depending on the severity of the morphologic changes. This has been mostly overtaken by SIL in professional literature for simplicity (there was lots of inter-observer unreliability between AIN 2 and 3) and improved understanding (it is not really a morphologic continuum, as previously thought). AIN 1 roughly corresponds to LSIL, and AIN 3 to HSIL. P16-negative AIN 2 is LSIL and p16-positive AIN 2 is HSIL.
    • Bowen's Disease was previously used to refer to AIN 3 disease, although I think this is quite old terminology now
  • Presentation
    • Typically asymptomatic
    • Can have pruritis, pain, burning, bleeding, sometimes a mass
    • Erythematous, scaly skin change
  • Staging
    • Mapping punch biopsies (can also do this with high-resolution anoscopy, but more commonly done with patient in lithotomy)
      • Dilute acetic acid is applied to epithelium of anal canal and perianal region
      • Tissues that harbour AIN turn acetowhite
      • Lugol's solution can then be applied - those areas that fail to stain are suspicious for dysplasia, and should be biopsied - because they are de-differentiated and don't take up iodine normally
      • Colposcope can be used for high-resolution anoscopy
    • Excision for histologic evaluation
  • Screening
    • High-risk individuals (HIV > 35yo, women with HPV-associated genital cancers, solid organ transplant recipients, other immunocompromised patients
    • Pap smear every 2-3 years
  • Prevention
    • Quadrivalent HPV vaccines
  • Management
    • Approach:
      • Considerable controversy. The overall risk of progression is not well-established, so it is difficult to determine how aggressively to treat it.
      • Topical - imiquimod, podophyllin, 5-FU, 80% trichloroacetic acid (TCA)
      • Ablative - excision, IRC, and thermal ablation
    • Intra-anal HSIL: TCA where available for small lesions, or targeted ablation with IRC, RFA or electrocautery. Local ablation for larger lesions, although don't treat >50% of the transition zone at a time. Other topical therapies may also be used.
    • Perianal HSIL: same as intra-anal.
    • LSIL: UTD says treatment is optional.

Invasive SCC of anal canal

• • Risk factors
    • As above
    • Median age at diagnosis 60yo
  • Histopathology
    • Differentiate from SIL by invasion of tumour cells beyond basement membrane
    • Can be lumped in with primary rectal SCC which is very rare
    • Tend to be locally aggressive with early invasion of the anal sphincters, and then spread into the ischiorectal fossae, prostatic urethra and bladder or vagina.
    • Grows circumferentially - can result in narrowing and stenosis of the sphincter
    • Lymphatic spread occurs in 10-15%, to peri-rectal or inguinal nodes. Haematogenous spread occurs <10% of cases. Liver metastases can occur.
  • Presentation
    • Slow-growing intra-anal or perianal mass
    • Bleeding 45%
    • Pain 30%
    • Asymptomatic 20%
  • Workup
    • DRE
    • Anoscopy + biopsy
    • Check for evidence of inguinal lymphadenopathy (can be confirmed by FNA)
    • CT CAP for distant staging
    • MRI for locoregional staging
    • PET for T2-T4 or any nodal disease
  • Staging

Primary tumor (T)	TNM 2017
T category	T criteria
TX	Primary tumor not assessed
T0	No evidence of primary tumor
Tis	High-grade squamous intraepithelial lesion (previously termed carcinoma in situ, Bowen disease, anal intraepithelial neoplasia II-III, high-grade anal intraepithelial neoplasia)
T1	Tumor ≤2 cm
T2	Tumor >2 cm but ≤5 cm
T3	Tumor >5 cm
T4	Tumor of any size invading adjacent organ(s), such as the vagina, urethra, or bladder
Regional lymph nodes (N)
N category	N criteria
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Metastasis in inguinal, mesorectal, internal iliac, or external iliac nodes
N1a	Metastasis in inguinal, mesorectal, or internal iliac lymph nodes
N1b	Metastasis in external iliac lymph nodes
N1c	Metastasis in external iliac with any N1a nodes
Distant metastasis (M)
M category	M criteria
M0	No distant metastasis
M1	Distant metastasis
Prognostic stage groups
When T is...	And N is...	And M is...	Then the stage group is...
Tis	N0	M0	0
T1	N0	M0	I
T1	N1	M0	IIIA
T2	N0	M0	IIA
T2	N1	M0	IIIA
T3	N0	M0	IIB
T3	N1	M0	IIIC
T4	N0	M0	IIIB
T4	N1	M0	IIIC
Any T	Any N	M1	IV

• Treatment
  • Medical
    • Nigro protocol - 30 Grays over three weeks, with continuous fluorouracil for the first four days and on days 20-31, with bolus mitomycin on day one, which achieves a complete response in 64-86%, and an overall 5-year survival of about 75%
      • Pre-chemotherapy defunctioning stoma could be considered for patients with near-obstruction, fistula or difficult-to-manage perianal wounds
    • There is controversy over what to do with inguinal nodes if no mets there - some advocate irradiating anyway
    • Re-stage 3 months after completion, unless there is earlier evidence of disease progression or recurrence. Clinical examination (or anoscopy for more internal lesions) every three months for first two years.
      • Should be pale, soft scar tissue at site of tumour, but biopsy any hard, tender or rubbery areas
  • Surgical
    • Historically, APR and inguinal dissection
    • WLE for select patients with well-differentiated, early T1 tumours, especially those arising on a haemorrhoidal cushion; or in patients who wouldn't be eligible for other treatments
    • Now only indicated as salvage for persistent or recurrent disease after chemoradiotherapy (that is, 26 weeks after starting medical therapy)
      • In this setting, also need to have reasonable life expectancy and be a good operative candidate
      • Required in about 30% of patients
      • 75% 5-year survival if clear margins are achieved
      • Predictors of poor outcome of APR: tumour >5cm, adjacent organ involvement, male gender, associated comorbidities
      • Significant complication to this procedure in this setting
    • Most patients will need an APR, although some small tumours can have local sphincter-preserving surgery
      • Often significant subcutaneous nodal involvement
      • Take all malignant fistula tracts
      • TME dissection plane
      • Consider pelvic exenteration if involvement of the prostate
    • Inguinal lymphadenectomy
      • Comorbid: 24% wound infection, leg oedema 40%
      • Don't perform it prophylactically or after a good response
      • Indication is persistent or recurrent disease
      • Should access both superficial and deep inguinal basins
• Prognosis
  • 5 year survival in local disease up to 92%
  • If lymph node spread, 58%
  • Locoregional recurrence is more common than metastatic spread, but 10-15% will eventually develop distant mets - mostly liver and lungs
    • Treat with cisplatin and 5-FU
  • 5-year survival after surgery for persistent or recurrent disease is 30-50%
• Follow-up
  • To check for recurrence:
    • 6 monthly for 5 years: DRE, anoscopy (although not aware of people doing this in Australia), inguinal lymph node palpation
    • + CT CAP for pretreatment T3-T4 disease or N1 disease or previous APR

SCC of anal margin (can visualise whole tumour without entering anal canal)

• • Behave like skin cancers and are staged accordingly
  • Tend to be more symptomatic - pain, itching, burning, bleeding, palpable mass, and discharge
  • Typically seen as an ulcerated lesion with rolled, everted edges
  • Usually reported as well or moderately differentiated keratinising SCC
  • Distant metastases are rare - biologically less aggressive
  • Lymph node involvement is an important adverse prognostic factor
  • Bulky, advanced tumours extending into anal canal should be treated like anal canal SCC, but if limited to anal margin, treat like cutaneous SCC
  • Excise locally with 0.5-1cm margin. If margins are positive or close, radiotherapy can be administered with good results.
    • If impossible to manage like this due to local factors, consider definitive CRT or APR

Adenocarcinoma

• Makes up 3-10% of anal canal cancers
• Difficult distinction between these tumours and low rectal adenocarcinomas, however treatment is the same
  • Distinguishing features - prominent ductal structures, abundance of mucin with organised mucinous pools, and infiltration into peri-rectal tissue
• Usually originates from anal glands (and therefore not visible on colonoscopy) but can also develop in longstanding fistula-in-ano
• Pain, induration of anal canal, palpable mass, or abscess with mucus drainage
• Low-risk lesions <2cm - consider WLE
• >2cm - neoadjuvant CRT followed by APR

Perianal Paget's disease

• Rare - only a few hundred cases reported
• Probably represents an intra-epithelial carcinoma arising from dermal apocrine sweat glands
• Present with non-specific symptoms - pruritis, discharge, bleeding
• Appears as an erythematous plaque, which may be ulcerative and crusty or papillary
• Can represent primary or secondary disease (which is associated with anorectal adenocarcinoma - 50% of patients with anal margin Paget disease have synchronous colorectal neoplasm)
• Treatment - surgical - Mohs micrographic surgery or WLE for most patients
  • Locally invasive lesions and synchronous cancers may need APR, +/- neoadjuvant CRT
  • Radiotherapy is an alternative for those not able or willing to undergo radical surgery
• Recurrence rate 30-60% at 5 years

Other tumours:

Melanoma (2-4%)

• • Frequently not pigmented (30% amelanotic), frequently not looking particularly suspicious, can be confused with thrombosed haemorrhoid
  • Prognosis very poor - 10-26% 5-year survival
  • APR vs wide local excision, but APR does not seem to improve survival

Neuroendocrine

• • Local excision

Malignant lymphoma

• • Most commonly high-grade B cell in immunocompromised patients

BCC

• • Rare - 0.2% of BCCs in the body, <1% of all anorectal cancers
  • Mostly men 65-75yo
  • No association with HPV
  • Thorough skin check
  • Tumours <2cm are excised with a 1cm margin
  • Larger lesions, without anal canal extension, are excised primarily with skin flap coverage
  • MMS is an option
  • Extension into anal canal may need radiotherapy or APR
  • 5-year survival up to 100% after WLE