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Dysplasia of the Anus

Definition

  • Non-invasive neoplastic changes of anal mucosa

Alternate/Historical names:

  • Low grade squamous intraepithelial lesion (LSIL):
    • Low grade dysplasia
    • Anal intraepithelial neoplasia grade I (AIN I)
    • Anal squamous intraepithelial lesion grade I (ASIL I)
  • High grade squamous intraepithelial lesion (HSIL):
    • AIN II or III
    • ASIL II or III
    • Bowen disease
    • Carcinoma in situ
    • High grade or severe dysplasia
    • Moderate dysplasia

Covered separately

Diagnostic Criteria

  • Superficial, non-invasive lesion of squamous mucosa or skin
  • Low grade squamous intraepithelial lesion (LSIL)
    • Frequently limited to superficial koilocytosis
      • Perinuclear clearing
      • Hyperchromatic “raisinoid” nuclei
        • Irregular nuclear membrane
        • May be binucleate
    • Orderly maturation
    • Low nucleus/cytoplasm ratio < 1:1
    • Mitotic figures basal unless inflamed
      • No atypical mitotic figures
    • Dyskeratosis may be present
  • High grade squamous intraepithelial lesion (HSIL)
    • Includes both moderate and severe dysplasia, AIN2 and AIN3
    • We require the following
      • Full thickness atypia
        • Disorderly maturation
        • Nucleus/cytoplasm ratio ≥ 1:1
      • Mitotic figures in upper levels
        • Atypical mitotic figures may be present
  • The usual condyloma demonstrates low grade squamous intra-epithelial lesion (LSIL)
    • Koilocytes are, by definition, at least LSIL
    • High grade squamous intra-epithelial lesion (HSIL) may also be seen
  • Invasive carcinoma may be associated with HSIL
    • Incidence reported to be 5-25%
Teri A Longacre MD
Robert V Rouse MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting/updates : 10/7/10

Supplemental studies

Immunohistochemistry

  • Staining for p16 is a useful surrogate for the presence of high risk HPV
    • 82% sensitive
    • 100% specific vs. hyperplasia and reactive atypia
    • Does not distinguish low from high grade lesions
      • More often seen in high than low grade lesions, but
      • Low grade lesions containing high risk HPV will be positive
        • Significance of this is not known
    • Positive reaction requires strong, band-like staining
      • Both nucleus and cytoplasm usually stained

Genetic analysis

  • Human papilloma virus (HPV) can be demonstrated by PCR
    • Low grade lesions including condyloma acuminatum usually HPV 6 and 11
    • High risk HPV is present in virtually all HSIL and invasive anal squamous carcinomas
      • May be absent in some poorly differentiated invasive carcinomas
    • Frequently HPV 16

Differential Diagnosis

Anus high grade squamous intraepithelial lesion (HSIL) Anus reactive atypia
Strong band-like staining for p16 At most patchy or weak staining for p16

 

Pagetoid Squamous Cell Carcinoma In Situ / HSIL Extramammary Paget Disease
Atypical cells usually merge with surrounding keratinocytes Discrete population of atypical cells
Atypical cells may keratinize Atypical cells may form lumens or be mucin positive
Desmosomes and keratohyaline granules may be visible in atypical cells Desmosomes and keratohyaline granules not present
HMWCK+, p63+, CK7 neg, BerEp4 neg CK7 >90%+, p63 & HMWCK neg (positive if underlying urothelial carcinoma), BerEp4+
GCDFP15 neg GCDFP15 positive if primary, variable if secondary

 

Anus high grade squamous intraepithelial lesion (HSIL) Bowenoid Papulosis
Usually a solitary enlarging plaque or found within a condyloma acuminatum Multiple small (2-10 mm) plaques
Does not spontaneously regress Lesions come and go spontaneously
Frequently develops invasive carcinoma Infrequent development of invasive carcinoma (may be increased in HIV patients)
Histologically indistinguishable
Both associated with HPV 16
Distinction is made on clinical grounds

 

  • Condyloma with podophyllin effect should be distinguished from HSIL
    • Podophyllin does not produce:
      • Cytologic dysplasia
      • Disturbance of maturation
      • Dyskeratosis
    • Early podophyllin effects (≤48 hours post application)
      • Intra- and intercellular edema
      • Necrotic keratinocytes in lower half of epithelium
      • Numerous mitotic figures in lower half of epithelium
    • Changes resolving by 72 hours
      • Necrotic keratinocytes now in upper half of epithelium
      • Fewer mitotic figures
    • Changes entirely resolved by one week

Clinical

  • Patients at high risk of developing dysplasia or carcinoma include those with:
    • Immunosuppression
      • HIV seropositivity and low CD4 counts
      • Solid organ allografts
    • History of lower genital tract neoplasia
    • Persistent high-risk HPV genotype infection or infection with multiple HPV genotypes
    • Heavy cigarette smoking
    • Frequent anoreceptive intercourse
    • Radiation
  • HSIL is generally treated by local excision
    • Frequently recurs (30% in 5 years)
    • We consider HSIL or the presence of high risk HPV to be an indication for high resolution mapping and targeted ablation or resection
    • We consider LSIL in high risk patients to justify topical therapy with surveillance

 

Grading / Staging / Report

Grading

Low grade squamous intra-epithelial lesion (LSIL) High grade squamous intra-epithelial lesion (HSIL)
Low nucleus/cytoplasmic (NC) ratio NC ratio ≥ 1
Orderly maturation Disorderly maturation
Atypical cells confined to superficial layer Atypical cells at all layers
Mitotic figures confined to basal layers unless inflamed Mitotic figures at all levels
No atypical mitotic figures Atypical mitotic figures may be seen

Staging

  • HSIL is staged as Tis

Report

  • Should offer alternative terminology for the level of dysplasia if required by the submitting physicians
  • If the dysplasia is present within a condyloma acuminatum the diagnosis should reflect the level present, e.g.:

Classification / Lists

Anal Tumors and Neoplasms

Extension from rectal lesions must be ruled out

Bibliography

  • Hamilton SR, Aaltonen LA eds. Pathology and genetics of tumours of the digestive system. World Health Organization classification of tumours, Vol. 2. Lyon: IARC Press 2000.
  • Longacre TA, Kong CS, Welton ML. Diagnostic problems in anus pathology. Adv Anat Pathol. 2008 Sep;15(5):263-78.
  • Wade TR, Ackerman AB. The effects of resin of podophyllin on condyloma acuminatum. Am J Dermatopathol. 1984 Apr;6(2):109-22.
  • Kong CS, Balzer BL, Troxell ML, Patterson BK, Longacre TA. p16INK4A immunohistochemistry is superior to HPV in situ hybridization for the detection of high-risk HPV in atypical squamous metaplasia. Am J Surg Pathol. 2007 Jan;31(1):33-43.
  • Sarmiento JM, Wolff BG, Burgart LJ, Frizelle FA, Ilstrup DM. Perianus Bowen's disease: associated tumors, human papillomavirus, surgery, and other controversies. Dis Colon Rectum. 1997 Aug;40(8):912-8.
  • Rüdlinger R, Buchmann P. HPV 16-positive bowenoid papulosis and squamous-cell carcinoma of the anus in an HIV-positive man. Dis Colon Rectum. 1989 Dec;32(12):1042-5.
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