Anus & perianal area

Premalignant

Squamous dysplasia



Last author update: 30 November 2022
Last staff update: 30 November 2022

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PubMed Search: Squamous dysplasia

Irene Y. Chen, M.D.
Xiaoyan Liao, M.D., Ph.D.
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Cite this page: Chen IY, Liao X. Squamous dysplasia. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/anusdysplasia.html. Accessed January 28th, 2023.
Definition / general
  • Noninvasive neoplastic proliferation of the anal squamous epithelium with cytologic and architectural abnormalities
  • Associated with human papillomavirus (HPV) infection
Essential features
  • Often associated with human papillomavirus genotypes
    • Low risk HPV mediates the development of low grade lesions
    • High risk HPV mediates the development of high grade lesions
  • Most cases are incidental findings in asymptomatic patients
  • Immunocompromised patients are at increased risk
  • Progression to squamous cell carcinoma is influenced by immune status and smoking
Terminology
  • Squamous intraepithelial lesion (SIL)
  • Anal intraepithelial neoplasia (anal IEN / AIN)
  • Anal squamous intraepithelial neoplasia (ASIN)
ICD coding
  • ICD-O:
    • 8077/0 - squamous intraepithelial neoplasia, low grade
    • 8077/2 - squamous intraepithelial neoplasia, high grade
  • ICD-11:
    • 2E92.5 & XH3Y37 - benign neoplasm of anus or anal canal & esophageal squamous intraepithelial neoplasia (dysplasia), low grade
    • 2E61.2 & XH9ND8 - carcinoma in situ of anal canal & esophageal squamous intraepithelial neoplasia (dysplasia), high grade
Epidemiology
  • Rising incidence due to evolving sexual behavior and an increase in HPV infection rates
  • Immunodeficient (HIV and non-HIV immunosuppression) patients are at increased risk and present at a younger age
  • Additional risk factors: anoreceptive intercourse, coinfection with other sexually transmitted diseases and cigarette smoking (Papillomavirus Res 2017;4:90, Br J Cancer 2015;112:1568)
  • Incidence is higher in women and is unrelated to the prevalence of HIV, unlike in men
Sites
  • Anus: anal canal, usually the transitional zone
  • Also occurs in the perianal skin (< 5 cm to the anal verge / margin)
Pathophysiology
  • HPV associated oncoproteins:
    • E6
      • Inactivates p53, allowing survival of cells with genotoxic damage
      • Inhibits p21, leading to loss of cyclin E / CDK2 inhibition and progression through the cell cycle
    • E7
      • Inhibits RB1, leading to a continuous proliferation of mutation bearing cells
        • Loss of RB1 leads to overexpression of p16, which is used as a diagnostic surrogate marker
  • Reference: World J Gastrointest Oncol 2022;14:369
Etiology
  • Human papillomavirus (HPV) (Tumour Virus Res 2022;14:200239)
    • Double stranded DNA virus of Papillomaviridae family
    • Infects humans only
    • More than 200 types
      • Low risk genotypes (6, 11, 42, 43, 44) associated with low grade lesions
        • HPV 6 and 11 are most common in > 90% of condyloma acuminatum
      • High risk genotypes (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68) associated with high grade lesions and invasive squamous cell carcinoma
        • HPV 16 is most common in 28% of low grade and 68% of high grade lesions
      • > 1 serotype may be found in lesions
  • Subdivided based on tissue tropism (Cancer Epidemiol Biomarkers Prev 2008;17:1611):
    • Anogenital
    • Cutaneous
    • Other mucosal sites
    • Multicentricity is common; > 33% of women with anal HPV also have cervical HPV
  • Most are asymptomatic or resolve within 12 months (J Natl Cancer Inst 2008;100:513)
  • A small fraction persists or progresses to squamous dysplasia or squamous cell carcinoma
Clinical features
  • Often asymptomatic, some present with bleeding or pruritis
  • Most cases are incidental findings in benign minor surgical specimens such as hemorrhoids
  • May present as papules, plaques, polyps or mass lesions
Diagnosis
Prognostic factors
Case reports
Treatment
  • Treatment modalities vary by geographic location
    • Fulguration with electrocautery during anoscopy
      • For lesions that are too large for the office based procedure
    • Office based ablation techniques
      • Via infrared coagulation, hyfrecation, argon plasma coagulation or radiofrequency
    • Topical therapy (Lancet Oncol 2013;14:346)
      • 5-fluorouracil (5FU)
      • Imiquimod
      • Trichloroacetic acid (TCA)
    • HPV vaccination (N Engl J Med 2011;365:1576, Hum Vaccin Immunother 2016;12:1348)
      • Decreases the risk of recurrence in high grade lesions
      • Effective in anal cancer prevention when administered early
  • Posttreatment surveillance is required given the high rate of local recurrence
  • Reference: J Anus Rectum Colon 2022;6:92
Clinical images

Contributed by Xiaoyan Liao, M.D., Ph.D.
Condyloma acuminatum

Condyloma acuminatum



Images hosted on other servers:

Anoscopy

Gross description
  • May present as papules, plaques or mass lesions
  • When present at the anal canal or dentate line, may be mistaken as rectal polyp
Microscopic (histologic) description
  • Diagnosis and grading of dysplasia is based on cellular atypia, degree of maturation and mitotic rate (Hum Pathol 2022 Jul 16 [Epub ahead of print])
    • Mild dysplasia (AIN1, condyloma acuminatum)
      • Cytologic and architectural atypia involving the lower 33% of the epithelial thickness
        • Often shows koilocytic changes characterized as perinuclear cavitation and nuclear features of low grade squamous intraepithelial lesion, to include nuclear enlargement, coarse chromatin and irregular nuclear membranes (StatPearls: Koilocytosis [Accessed 4 November 2022])
          • Pathognomonic but not required for diagnosis
      • Condyloma acuminatum is exophytic, papillary growth of squamous lesion with parakeratosis and koilocytosis
    • Moderate dysplasia (AIN2): cytologic and architectural atypia involving > 33% but < 66% of the epithelial thickness
      • Increased nuclear enlargement and coarse chromatin, compared to AIN1
      • Increased mitosis
    • Severe dysplasia (AIN3): cytologic and architectural atypia involving > 66% of the epithelial thickness
      • Significant nuclear enlargement and atypia, high N:C ratios, increased mitosis with often atypical mitotic figures
      • Sometimes interchangeable with carcinoma in situ, which is full thickness squamous dysplasia without any maturation
  • Diagnostic terms are now unified under the lower anogenital squamous terminology (LAST) standardization project (Arch Pathol Lab Med 2012;136:1266)
    • Low grade squamous intraepithelial lesion (LSIL)
      • Cytologic and architectural alteration involving < 33% of the epithelium
      • Includes lesions that were previously classified as mild dysplasia, anal IEN 1 (AIN1) and condyloma acuminatum
    • High grade squamous intraepithelial lesion (HSIL)
      • Cytologic and architectural alteration involving > 33% of the epithelium
      • Includes lesions that were previously classified as moderate dysplasia, severe dysplasia, carcinoma in situ, Bowen disease and bowenoid papulosis
Microscopic (histologic) images

Contributed by Xiaoyan Liao, M.D., Ph.D. and @AnaPath10 on Twitter
Flat squamous proliferation

Flat squamous proliferation

Papillary squamous proliferation

Papillary squamous proliferation

Papillary squamous proliferation, parakeratosis and koilocytosis Papillary squamous proliferation, parakeratosis and koilocytosis

Papillary squamous proliferation, parakeratosis and koilocytosis

Condyloma with invasion

Condyloma with invasion


Invasive squamous cell carcinoma arising in condyloma

Invasive
squamous cell
carcinoma arising
in condyloma

High grade squamous intraepithelial lesion

HSIL

At the anal transitional zone

HSIL at the anal transitional zone

Involving a hemorrhoid

Involving a hemorrhoid

Squamous dysplasia

Squamous dysplasia


Squamous dysplasia

Squamous dysplasia

p16 immunohistochemistry

p16 immunohisto-
chemistry

HPV in situ hybridization

HPV in situ hybridization

Squamous dysplasia Squamous dysplasia

Squamous dysplasia

Cytology description
  • Can be categorized as LSIL, HSIL or atypical squamous cells of uncertain significance (ASCUS)
  • LSIL: hyperchromasia, nuclear irregularity, koilocytotic atypia and > 3 fold nuclear enlargement compared to superficial squamous cells
  • HSIL: small, immature appearing cells with markedly increased N:C ratio, coarse chromatin and irregular nuclear contour
  • ASCUS: typical cells that do not meet the criteria for LSIL or HSIL
  • Reference: Diagn Cytopathol 2010;38:538
Cytology images

Contributed by Irene Y. Chen, M.D.
Anal pap smear

Anal Pap smear



Images hosted on other servers:

LSIL

Positive stains
  • p16:
    • Positive is defined as diffuse, strong, nuclear and cytoplasmic block-like staining
    • Surrogate marker for high risk HPV infection
    • Can be positive in LSIL / AIN1 (37%) (Am J Surg Pathol 2021;45:1573)
      • Morphology is still the key for diagnosis
      • p16 is not recommended when histologic diagnosis is clear cut
  • HPV immunostain: positive nuclear staining highlights virally infected cells
  • HPV RNA in situ hybridization
    • Detect HPV E6 / E7 mRNA transcripts in both transcriptionally active state and formalin fixed paraffin embedded (FFPE)
    • Positive staining with dot-like cytoplasmic and nuclear staining
    • High sensitivity and specificity (Am J Surg Pathol 2017;41:607)
    • More sensitive than HPV immunostain
  • HPV DNA in situ hybridization
    • High specificity (89%) but lower sensitivity (83%)
  • Ki67: proliferation beyond the basal layer
Negative stains
  • p16: negative or weak and patchy in low grade lesions
Molecular / cytogenetics description
  • Polymerase chain reaction
    • Quantitative reverse transcriptase PCR to detect HPV E6 / E7 mRNA
      • Considered the gold standard by the FDA
      • Limited utility due to exclusiveness to fresh frozen tissue
    • Quantitative PCR to detect HPV DNA
      • Cannot distinguish transcriptionally active infection versus passenger
  • Reference: Infect Agent Cancer 2020;15:46
Sample pathology report
  • Anal canal, right lateral, biopsy:
    • High grade squamous intraepithelial lesion (moderate dysplasia, AIN2)
Differential diagnosis
  • Inflammatory changes / repair:
    • Superficial maturation and cellular polarity are maintained
    • Round nuclei and may have prominent nucleoli
    • No hyperchromasia
  • Radiation atypia:
    • Cytomegaly and karyomegaly with the maintenance of a low N:C ratio
    • Smudgy chromatin with prominent nucleoli
  • Squamous cell carcinoma:
    • Foci of invasion
    • Mass forming
    • Adjacent area may show AIN as a precursor lesion
Board review style question #1

An anal lesion is excised from a 33 year old woman (see image above). No area of invasion is identified on histologic examination. Which of the following statements is true?

  1. Immunocompromised patients are at increased risk and present at a younger age
  2. Most cases are incidental findings in asymptomatic patients and do not recur after excision
  3. Often associated with human papillomavirus genotype 6 and 11
  4. p16 is often patchy in high grade lesions
Board review style answer #1
A. Immunocompromised patients (particularly those HIV+) are at increased risk and present at a younger age

Comment Here

Reference: Squamous dysplasia
Board review style question #2
Regarding human papillomavirus (HPV), which of the following is correct?

  1. Diffuse p16 immunostaining positivity is a surrogate marker for both low and high risk HPV infection
  2. High risk HPVs can be associated with low grade lesions
  3. It is a single stranded RNA virus that does not insert into the human genome
  4. It only infects the squamous epithelium
Board review style answer #2
B. High risk HPVs can be associated with low grade lesions. While high risk HPVs are usually associated with high grade dysplasia, they can be associated with low grade lesions.

Comment Here

Reference: Squamous dysplasia
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