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Neoplasms of the Anus: High-Grade Squamous Intraepithelial Lesions and Cancer

Outline for the Topic: Neoplasms of the Anus

1. Introduction

  • Overview of the perianal region and its anatomy.
  • Definition and classification of anal and perianal neoplasms.
  • Epidemiology of anal cancers, particularly squamous cell carcinoma (SCC).

2. Anatomy of the Anal Canal and Perianal Region

  • Description of the anal canal and its boundaries.
  • Importance of distinguishing between anal canal and perianal lesions.

3. Types of Anal and Perianal Neoplasms

  • Squamous Cell Carcinoma (SCC)
    • Epidemiology: Incidence, risk factors, and demographic data.
    • Presentation and Diagnosis: Common symptoms, diagnostic approach.
    • Staging and Spread: Pathways of metastasis and staging systems.
    • Treatment: Chemoradiation protocols, including the Nigro protocol.
    • Prognosis: Survival rates and prognostic factors.
  • Anal Canal Adenocarcinomas
    • Overview and comparison with rectal adenocarcinomas.
    • Treatment options and prognosis.
  • Perianal Neoplasms
    • Includes SCC, Buschke-Löwenstein tumors, Paget disease, and basal cell carcinoma.
    • Specific management strategies based on lesion type.
  • Anorectal Melanoma
    • Characteristics, diagnostic challenges, and treatment controversies.

4. Specific Lesions and Their Management

  • High-Grade Squamous Intraepithelial Lesions (HSIL)
    • Natural history, clinical features, and treatment strategies.
  • Buschke-Löwenstein Tumors (Verrucous Carcinoma)
    • Pathogenesis, clinical presentation, and treatment modalities.
  • Paget Disease
    • Diagnosis, management, and challenges in treatment.
  • Basal Cell Carcinomas
    • Differentiation from other anal lesions, treatment options, and outcomes.

5. Diagnostic Imaging and Evaluation

  • Importance of clinical and radiologic staging.
  • Imaging modalities: CT, MRI, ERUS, and FDG-PET/CT.
  • Role of imaging in treatment planning.

6. Treatment Protocols

  • Overview of chemoradiation protocols.
  • Role of surgery in primary and recurrent disease.
  • Advanced treatment techniques: Intensity-Modulated Radiation Therapy (IMRT).
  • Special considerations in HIV-positive patients.

7. Prognosis and Follow-up

  • Prognostic factors for different types of neoplasms.
  • Recommended follow-up and surveillance strategies.
  • Salvage surgery options and outcomes.

8. Recent Advances and Research

  • Emerging therapies and clinical trials.
  • Role of immunotherapy and targeted therapies in melanoma.

9. Conclusion

  • Summary of key points.
  • Future directions in research and treatment.

Neoplasms of the Anus: High-Grade Squamous Intraepithelial Lesions and Cancer

Overview

  • Perianal region includes:
    • Anal canal
    • Perianus
    • Perianal skin
  • Malignancies in these regions are uncommon, accounting for 2% of all lower gastrointestinal tract cancers
  • Common malignancies:
    • Squamous cell carcinoma (SCC) of the anal canal and perianus
    • Squamous intraepithelial lesions (SILs)
  • Uncommon neoplasms:
    • Adenocarcinoma
    • Melanoma
    • Buschke-Löwenstein tumors (verrucous carcinoma)
    • Paget disease
    • Basal cell carcinomas (BCCs)

Anatomy

Anal Canal

  • Starts at the pelvic floor where the rectum enters the puborectalis muscle
  • Ends where the stratified squamous epithelium becomes continuous with the perianal skin
  • Boundaries:
    • Anorectal ring superiorly
    • Intersphincteric groove (outer boundary of the internal sphincter) inferiorly
  • Contains:
    • Columnar epithelium above the dentate line
    • Squamous epithelium below the dentate line
    • Anal transition zone (ATZ):
      • 1–12 mm in length at the dentate line
      • Contains "transitional urothelium-like" epithelium
      • Includes cloacogenic, transitional, and basaloid epithelium
    • Transformation zone:
      • Squamous metaplasia involving the proximal anal canal above the dentate line
  • Average length:
    • Men: 3–6 cm
    • Women: 2–4 cm

  • Visualization:

    • Anal canal lesions are not visible or incompletely visible with gentle traction on the buttocks

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Perianus

  • Extends from the inferior boundary of the anal canal to approximately a 5 cm radius around the anus
  • Characteristics:
    • Stratified squamous epithelium
    • Skin appendages (apocrine glands, hair)
  • Lesions:
    • Easily visible within a 5 cm radius when gentle traction is applied
    • Previously referred to as the anal margin
    • Now referred to as perianal lesions

Skin Lesions

  • Located outside of the 5 cm radius of the perianus

Importance of Location

  • Management differs based on whether lesions are in the anal canal, perianus, or skin

Types of Cancers in the Anal Canal and Perianal Region

  • Diverse cell types lead to various cancers
  • Most frequent malignancy: Squamous cell carcinoma (SCC)
    • Types:
      • Nonkeratinizing
      • Keratinizing
      • Cloacogenic
      • Transitional
      • Basaloid
      • Mucoepidermoid carcinomas
    • Note: These distinctions are now grouped under SCC due to similar treatment and prognosis
  • Second most common: Adenocarcinomas
  • Other uncommon malignancies:
    • Melanoma
    • Verrucous carcinoma
    • Paget disease
    • Basal cell carcinoma (BCC)

Anal Squamous Cell Carcinoma (SCC)

Epidemiology

  • Represents 0.5% of all new cancers annually in the U.S.
  • Estimated cases (2017): Over 8,200
  • Annual deaths: Approximately 1,100 (0.2% of cancer deaths)
  • Incidence:
    • Increasing by 2.2% per year
    • Higher in women (2 per 100,000) than men (1.5 per 100,000)
  • Median age at diagnosis: 60 years
  • 5-year disease-specific survival (DSS):
    • Overall: 66%
    • Early-stage (Stage I & II): ~80%
    • Locally advanced (Stage III): 60%
    • Distant disease (Stage IV): 15%

Risk Factors

  • Gender: Female
  • Infections:
    • Human papillomavirus (HPV)
    • Human immunodeficiency virus (HIV)
  • Sexual behaviors:
    • Anal receptive intercourse
    • Multiple sexual partners
  • Associated cancers: HPV-related (e.g., vulvar, cervical)
  • Lifestyle: Smoking
  • Immunosuppression: Post-organ transplantation
  • Men who have sex with men (MSM):
    • 20 times more likely than heterosexual men
  • HIV-positive patients:
    • 30 times higher incidence rates
    • Incidence varies from 18 to 149 per 100,000 person-years
    • Highest rates in HIV-positive MSM

HPV and Anal SCC

  • Underlying etiology in ~95% of anal SCC
  • Most common strain: HPV-16 (89% of cases)
  • Oncogenic mechanisms:
    • E6 and E7 oncoproteins interact with tumor suppressor proteins (p53, pRB)
    • Disrupt cell cycle, leading to uncontrolled cell division

Presentation and Diagnosis

  • Common symptoms:
    • Anal pain
    • Bleeding
    • Anal discharge
    • Irritation
    • Discomfort
  • Additional symptoms:
    • Anal leakage or soiling
    • Fecal incontinence
    • Tenesmus (if sphincter complex involved)
  • Advanced disease:
    • Perianal sepsis
    • Fistulous disease
  • Asymptomatic cases:
    • Incidental findings after excision or hemorrhoid surgery
  • Diagnosis considerations:
    • Nonhealing fissures, chronic ulcers, or unresponsive fistulas
  • Initial work-up:
    • Complete history (risk factors)
    • Physical examination (inguinal lymph nodes)
    • Digital rectal examination (DRE)
    • Anoscopic examination with biopsy
    • Assess:
      • Lesion location and size
      • Sphincter complex involvement
      • Invasion into surrounding structures
    • Exam under anesthesia may be preferable

Diagnostic Imaging

Clinical Assessment

  • Useful for: Clinical staging of primary disease and inguinal nodes

Radiologic Evaluation

  • Purpose: Accurate determination of local, nodal, and distant disease extent

Imaging Modalities

  • Computed Tomography (CT) Scan:
    • Contrast-enhanced
    • Evaluates distant disease (liver, lungs)
    • Detects abnormal lymphadenopathy
  • Endorectal Ultrasound (ERUS):
    • Visualizes anal canal
    • Assesses depth of tumor penetration and sphincter involvement
    • Limited in evaluating mesorectal and pelvic lymphadenopathy
    • Not routinely recommended
  • Magnetic Resonance Imaging (MRI):
    • Accurate for primary lesion assessment
    • Evaluates surrounding organ involvement
    • Reliable for mesorectal and inguinal lymph nodes
    • Complements CT findings

FDG-PET/CT

  • Fluorodeoxyglucose Positron Emission Tomography–Computed Tomography
  • Benefits:
    • Evaluates lymph node involvement and distant metastases
    • Detects metabolically active nodes of normal size
  • Risk of inguinal node involvement:
    • Early-stage (T <3 cm): <5%
    • Advanced stages (T3, T4): ~20%
  • Impact:
    • Alters staging in ~20% of cases
    • Modifies treatment in 3–5% of patients
  • Guidelines:
    • NCCN includes PET/CT in routine diagnostic work-up

Staging

Spread Mechanisms

  • Direct extension: Invasion of adjacent structures (vagina, bladder, urethra)
  • Lymphatic spread: Perirectal, pelvic, and inguinal lymph nodes
  • Hematogenous spread: Distant organs (liver, lung)

Lymphatic Drainage

  • Above dentate line:
    • Superior rectal vessels to inferior mesenteric lymph nodes and vein
    • Lateral spread to internal iliac lymph nodes
  • Below dentate line:
    • Primarily to inguinal lymph nodes and internal iliac vein
    • May involve inferior and superior rectal lymph nodes

AJCC/UICC Staging System (8th Edition)

  • T Stage: Based on tumor size and extent of involvement
  • N Stage: Based on lymph node status
  • Regional lymph nodes:
    • Mesorectal
    • Superficial and deep inguinal
    • Superior rectal
    • External and internal iliac nodes
  • Distant metastasis: All other nodal groups

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Treatment

Early-Stage and Locally Advanced SCC

  • Standard therapy: Concurrent chemotherapy and radiation
  • Goals:
    • Achieve local control
    • Preserve quality of life (QoL)

Metastatic Disease

  • Symptomatic primary disease: Chemoradiation for symptom control
  • Asymptomatic patients: Palliative chemotherapy

Historical Perspective

  • Pre-1970s: Treated with abdominoperineal resection (APR)
    • 5-year survival: 40–70%
    • Required permanent colostomy
    • High local/regional recurrence (20–50% within 2 years)

Nigro Protocol

  • Introduced concurrent chemoradiation before surgery
  • Initial regimen:
    • 30 Gy external beam radiation
    • 5-day infusion of 5-fluorouracil (5-FU)
    • Single injection of mitomycin C
  • Outcomes:
    • High rates of complete response without surgery
  • Modified in subsequent trials

Current Standard Treatment

  • Concurrent chemoradiation:
    • Fluoropyrimidines (5-FU) and mitomycin C
    • Radiation doses between 50–60 Gy
    • Standard fractionated schedules: 1.8–2 Gy per fraction
  • Radiation fields include:
    • Primary tumor
    • Inguinal lymph nodes (prophylactic inclusion)
  • Modifications:
    • Based on patient comorbidities and disease characteristics
    • Omission of chemotherapy in immunosuppressed or medically frail patients

Intensity-Modulated Radiation Therapy (IMRT)

  • Advantages:
    • Precise delivery to tumor
    • Avoids normal tissues (perianal skin, genitalia, bladder, small bowel)
    • Reduces acute toxicities (gastrointestinal, genitourinary, hematologic, dermatologic)
    • Fewer treatment interruptions
  • RTOG 0529 Trial:
    • Compared IMRT to conventional 3D radiation
    • Findings:
      • Significant decrease in acute grade ≥2 toxicities
      • Reduced grade ≥3 dermatologic and gastrointestinal toxicities
  • Current Practice:
    • IMRT is the standard for radiation delivery in anal SCC

Prognosis and Prognostic Factors

  • Locoregional failure rate: ~40% with standard chemoradiation
  • Colostomy-free survival rate: 15–36%
  • Significant prognostic factors:
    • Nodal involvement
    • Tumor size (>5 cm)
    • Patients with N1 disease and tumors >5 cm have ~30% 3-year disease-free probability
  • Disease-Free Survival (DFS):
    • 3-year DFS ranges from 56–75% in studies
  • Overall Survival (OS):
    • Stage I: 77%
    • Stage II: 67%
    • Stage IIIA: 58%
    • Stage IIIB: 51%
    • Stage IV: 15%
  • Influencing factors:
    • Patient-related: Male gender, African-American ethnicity, age >65 (adverse)
    • Disease-related: HPV infection (favorable)
    • Treatment-related: Treatment breaks, incomplete therapy (negative impact)

Management in HIV-Positive Patients

  • Increased incidence despite HAART
  • Pre-HAART era:
    • Higher acute toxicities
    • Worse clinical outcomes
  • HAART era:
    • Decreased chemoradiation side effects
    • Similar outcomes to HIV-negative patients
  • Treatment considerations:
    • Standard chemoradiation can be used safely
    • CD4 counts >200/mm³ are favorable

Follow-Up and Surveillance

  • Tumor regression continues up to 12 weeks post-treatment
  • NCCN Guidelines suggest evaluation at 8 and 12 weeks
  • Patient classification post-treatment:
    • Complete responders
    • Stable but persistent disease
    • Progressive disease
  • Biopsy:
    • Not routinely recommended
    • Reserved for suspicious lesions
  • Persistent disease:
    • Monitored at 4-week intervals
    • Tumor regression may continue for several months
  • Recurrence monitoring:
    • Most occur within 3 years
    • Regular follow-up is crucial
  • Follow-up schedule:
    • History and physical examination
    • DRE and anoscopy
    • Inguinal node evaluation
    • Every 3–6 months for 5 years (every 3 months for 2 years, then every 6 months)
  • Imaging:
    • Routine CT scans for patients with advanced disease

Salvage Surgery

  • Indications:
    • Persistent or recurrent locoregional disease after chemoradiation
  • Treatment options:
    • Repeat radiation (limited data)
    • Salvage abdominoperineal resection (APR)
  • Outcomes:
    • 5-year survival: 40–60% post-salvage APR
    • Negative surgical margins (R0 resection) improve survival
  • Surgical considerations:
    • Wider lateral margins required
    • Possible en bloc resection of adjacent structures
    • Reconstructive tissue flaps may be needed (e.g., VRAM flap)
  • Complications:
    • Significant wound morbidity
    • Multidisciplinary approach recommended
  • Inguinal recurrence management:
    • Chemoradiation if groin not previously irradiated
    • Inguinal lymph node dissection for symptomatic patients post-radiation
    • Palliative chemotherapy for asymptomatic patients (poor prognosis)

Squamous Intraepithelial Lesions and Other Anal Neoplasms

1. Squamous Intraepithelial Lesions (SILs)

Definition

  • SILs are precancerous lesions of the anus.
  • Previously known as:
    • Bowen disease
    • Anal intraepithelial neoplasia (AIN) I, II, III
    • Anal dysplasia
    • Squamous cell carcinoma (SCC) in situ

Classification

  • Low-Grade Squamous Intraepithelial Lesions (LSILs)
    • Includes AIN I
    • Anal and perianal condylomas
  • High-Grade Squamous Intraepithelial Lesions (HSILs)
    • Includes Bowen disease, AIN II, AIN III
    • SCC in situ

Histologic Features

  • Differentiation based on:
    • Nuclear-to-cytoplasmic ratio
    • Relationship of atypical cells with the basement membrane

Epidemiology

  • Prevalence of HSIL: Less than 1%, but incidence is increasing.
  • High-risk factors:
    • HIV infection
    • Systemic immunosuppression
    • Long-term steroid use
    • History of cervical (CIN) and vulvar intraepithelial neoplasia (VIN)
    • Extensive condylomatous disease
  • Incidence in MSM:
    • 35 per 100,000
    • Doubles in HIV-positive MSM
  • Prevalence in non-immunocompromised patients:
    • 5% in women with VIN and CIN
    • 3–5% in renal allograft patients

Natural History

  • Progression to invasive cancer: Approximately 10% in 5 years
  • Factors influencing progression:
    • Immune status
    • Management of HSIL
  • Higher progression risk in HIV-positive and immunocompromised patients
  • Theoretical progression rates:
    • 1 in 600 per year in HIV-positive MSM
    • 1 in 4000 per year in HIV-negative MSM

Clinical Features

  • Often asymptomatic
  • Diagnosis often made during surgical excision of perianal lesions
  • Incidence in patients undergoing condyloma excision:
    • 28–35%, up to 60% in HIV-positive patients
  • Symptoms (if present):
    • Plaques
    • Erythema
    • Pigmentation
    • Perianal irritation or pain

Treatment Objectives

  • Prevent progression to anal SCC
  • Preserve anorectal function
  • Minimize treatment-related morbidity

Treatment Modalities

  • Surgical Excision
    • Wide local excision with negative margins
    • Associated with:
      • Significant wound morbidity
      • Adverse functional outcomes (incontinence, anal stenosis)
      • High local recurrence rates
  • High-Resolution Anoscopy (HRA)
    • Optimal approach for targeted treatment
    • Procedure involves:
      • Applying 3% acetic acid
      • Examining with an operating microscope
      • HPV-affected areas turn white
      • Lugol iodine applied to highlight HSIL
      • Biopsy and ablation (electrocautery or infrared coagulation)
    • Benefits:
      • Minimal morbidity
      • Lower rates of progression to invasive disease
  • Topical Treatments
    • Imiquimod (5% cream)
    • Topical 5-FU (5%)
    • May be used alone or in combination
    • Less effective than ablation; high recurrence rates

Recurrence and Monitoring

  • High risk of recurrence regardless of treatment
  • Close monitoring is essential, especially in HIV-positive patients and MSM
  • Regular follow-up minimizes risk of progression to anal SCC

2. Anal Canal Adenocarcinomas

Overview

  • Second most common anal canal malignancy (10–20%)
  • More aggressive than anal SCC
  • Arise from:
    • Columnar epithelium of anal glands
    • Can also arise de novo from mucosa

Risk Factors

  • Chronic inflammation
  • Anal fistulous disease
  • Crohn disease
    • Incidence in Crohn's fistulas: 0.3–0.7%

Clinical Features

  • Difficult to differentiate from distal rectal adenocarcinomas
  • Metastatic disease occurs more frequently

Prognosis

  • Disease-Free Survival (DFS): 20–60%
  • Depends on stage and treatment regimen

Treatment

  • Neoadjuvant chemoradiation followed by abdominoperineal resection (APR)
    • Offers greatest 5-year survival
  • Other options:
    • Primary surgical resection
    • Definitive chemoradiation
  • Prognostic factors: Tumor stage and differentiation

3. Perianal Lesions

Overview

  • Account for 3–4% of anorectal neoplasms
  • Involve the perianus (extends up to 5 cm around the anus)
  • Characterized by:
    • Stratified squamous epithelium
    • Skin appendages (apocrine glands, hair)

Common Lesions

  • Squamous Cell Carcinoma (SCC)
  • Buschke-Löwenstein tumors (verrucous carcinoma)
  • Paget disease
  • Basal Cell Carcinoma (BCC)

4. Perianal Cancers

A. Squamous Cell Carcinoma (SCC)

  • Similar to cutaneous SCC
  • Diagnosis:
    • Confirm location relative to anal canal
    • Biopsy to establish diagnosis
    • Differentiate from anal canal SCC based on:
      • Skin appendages
      • Keratinization
      • Location
  • Presentation:
    • May be asymptomatic or cause:
      • Irritation
      • Bleeding
      • Discomfort
    • Exam may reveal firm, erythematous lesions with ulcers
  • Metastasis:
    • Commonly to inguinal lymph nodes
    • Risk increases with size of lesion

Management

  • Small lesions (T1, N0):
    • Wide local excision with 1-cm margins
  • Lesions involving sphincter:
    • Chemoradiation to preserve continence
    • Alternative to APR
  • Larger lesions or nodal involvement:
    • Require chemoradiation
  • Radiation guidelines:
    • Lesions >2 cm: Radiate inguinal region
    • Lesions >5 cm: Include pelvic lymph nodes

B. Anorectal Melanoma

Overview

  • Accounts for <1% of melanomas; <4% of anal malignancies
  • Most common GI tract site for melanoma
  • More common in women
  • Median age: 60 years

Clinical Features

  • Nonspecific symptoms:
    • Bleeding
    • Irritation
    • Discomfort
  • Often misdiagnosed as benign conditions (e.g., hemorrhoids)
  • Amelanotic melanomas (25% of cases) complicate diagnosis
  • Metastatic disease present in ~50% at diagnosis

Prognosis

  • Overall survival: Less than 20%
  • High mortality due to metastatic disease

Treatment

  • Surgery is mainstay; optimal approach is debated
  • Local excision:
    • Preferred first-line treatment
    • Avoids morbidity of APR
    • Allows for salvage APR if recurrence occurs
  • Abdominoperineal Resection (APR):
    • Lower local recurrence but no survival benefit
  • Adjuvant therapies:
    • Radioresistant and chemoresistant
    • Targeted therapies and immune checkpoint inhibitors show promise
  • Clinical Trials:
    • Enrollment recommended due to poor prognosis

C. Buschke-Löwenstein Tumors

Definition

  • Also known as:
    • Verrucous carcinoma
    • Giant condylomata acuminata
  • Related to HPV infection (HPV-6, HPV-11)

Clinical Features

  • Present as large, cauliflower-like lesions in the perianal region
  • Characterized by:
    • Endophytic and exophytic growth patterns
  • May grow along fistula tracts
  • Rare progression to invasive disease, especially with HIV infection

Management

  • Wide local excision
    • Defects may heal by secondary intention or require grafts/flaps
  • APR may be necessary for:
    • Large lesions near sphincter complex
    • Invasive disease
  • Chemotherapy and Radiation:
    • Some cases show regression with these treatments

D. Paget Disease

Definition

  • Perianal Paget disease: Intraepithelial adenocarcinoma
  • Originates from:
    • Apocrine glands
    • Pleuripotent keratinocyte stem cells

Clinical Features

  • Occurs in older men and women
  • May be associated with other malignancies
  • Presents as chronic erythematous or scaling rash-like lesions with clear borders

Diagnosis and Treatment

  • Biopsy confirms diagnosis
  • Treatment depends on:
    • Extent of disease
    • Presence of underlying malignancy
  • Wide local excision with negative margins is common
    • High recurrence rates (up to 50%)
    • Achieving negative margins can be challenging
  • Advanced disease may require APR
  • Alternative treatments:
    • Radiation and chemoradiation
    • Mohs surgery
    • Photodynamic therapy
    • Topical agents (5-FU, imiquimod)
  • Treatment strategy should balance disease control with patient morbidity and quality of life

E. Basal Cell Carcinomas (BCC)

Overview

  • Rare in the perianal region (<1% of all BCCs)
  • Important to distinguish from basaloid SCCs of the anal canal

Clinical Features

  • More common in men in their sixth decade
  • May be associated with other skin lesions

Diagnosis and Management

  • Management:
    • Wide local excision
    • Lesions are generally not aggressive
  • Prognosis:
    • Recurrence rates up to 30%
    • Cancer-specific survival is 100%
  • Advanced cases:
    • Deep invasion may require APR
    • Local recurrences can be treated with repeat excision or radiation

Short Summary

  • SILs are precancerous anal lesions classified into LSIL and HSIL, with HSIL having a higher risk of progression to anal SCC.
  • HSIL is more common in HIV-positive individuals and requires careful monitoring and treatment to prevent cancer progression.
  • Anal canal adenocarcinomas are aggressive cancers arising from anal glands, with treatment typically involving neoadjuvant chemoradiation and surgery.
  • Perianal lesions include various cancers like SCC, melanoma, Buschke-Löwenstein tumors, Paget disease, and BCC, each requiring specific diagnostic and management approaches.
  • Anorectal melanoma has a poor prognosis; local excision is preferred to avoid extensive surgery without survival benefit.
  • Buschke-Löwenstein tumors are large HPV-related lesions managed primarily with wide local excision.
  • Paget disease is treated based on disease extent, balancing effective control with patient quality of life.
  • Perianal BCCs are rare and managed effectively with wide local excision, having an excellent prognosis.