High reproducibility of histological diagnosis of human papillomavirus-related intraepithelial lesions of the anal canal

doi:10.1097/PAT.0000000000000246

Pathology

Volume 47, Issue 4, June 2015, Pages 308-313

https://doi.org/10.1097/PAT.0000000000000246 Get rights and content

Summary

In a natural history study of anal human papillomavirus (HPV) infection and HPV-related lesions, we examined the reproducibility of histological high-grade squamous intraepithelial lesion (HSIL). Three expert anogenital pathologists share the reporting of histological specimens from the Study of the Prevention of Anal Cancer (SPANC), utilising Lower Anogenital Squamous Terminology (LAST) criteria. In total, 194 previously reported biopsies were randomly chosen within diagnostic strata [50 HSIL–anal intraepithelial neo-plasia (AIN) 3; 45 HSIL–AIN 2; 49 ‘flat’ low-grade squamous intraepithelial lesion (LSIL); 50 ‘exophytic’ LSIL; and 50 negative for squamous intraepithelial lesion] and reviewed by each of these three pathologists. Consensus was defined as agreement between at least two review diagnoses, using a binary classification of HSIL and non-HSIL, or if consensus was not obtained in this way, it was achieved through a multiheader microscope session by the three pathologists. We found very high agreement between original and consensus diagnoses (Kappa = 0.886) and between each pathologist’s review and consensus (Kappas = 0.926, 0.917 and 0.905). Intra-observer agreement for the three pathologists was 0.705, 1.000 and 0.854. This high level of diagnostic reproducibility indicates that the findings of SPANC should be robust and provide reliable information about HPV-related anal canal disease.

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HPV-associated disease of the anal canal: A pathology primer
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Citation Excerpt :
Thus, improved interobserver agreement for the diagnosis of HSIL is seen with the conjunctive use of p16 immunostains with H&E morphology.32 LAST׳s recommendations for p16 use lead to improved accuracy and reproducibility of histologic diagnoses of precancer.33–35 In essence, the use of p16 immunostaining helps “polish the histologic gold standard” that informs patient management.36
Anal cancer is a rare disease. Screening for it in high-risk populations is based on the model borrowed from cervical cancer screening with cytology and high-resolution anoscopy-guided biopsy. Squamous cell carcinoma of the anus is associated with oncogenic HPVs, particularly type 16. Squamous intraepithelial lesions (SIL) are graded on both anal cytology and histology using 2 tiers. Low-grade SIL is reflective of a productive HPV infection; high-grade SIL is the potential precancer. High-risk HPV testing may not be an efficient screening or triage tool given the high prevalence of the virus in populations targeted for anal cancer screening. However, genotyping for HPV 16 may prove useful. On biopsy, p16 immunostaining is used to adjudicate equivocal diagnoses on routine H&E tissue sections; a positive p16 immunostain supports a diagnosis of high-grade SIL.
Prevalence and risk factors associated with high-grade anal squamous intraepithelial lesions (HSIL)-AIN2 and HSIL-AIN3 in homosexual men
2016, Papillomavirus Research
Citation Excerpt :
In addition, biopsy reporting was performed in accordance with the LAST Project [13], limiting potential misclassification of histological HSIL. Also, there was a very high degree of inter-rater reliability and intra-rater repeatability in histological diagnosis in the study [35]. Finally, the limited sensitivity of anal cytology and HRA to detect HSIL was addressed by using a composite cytology-histology endpoint.
Anal intraepithelial neoplasia grade 2 (AIN2) and AIN grade 3 (AIN3) are commonly grouped together as high grade squamous intraepithelial lesions (HSIL). We assessed risk factors for HSIL-AIN2 and HSIL-AIN3 in a cohort of homosexual men.
At the baseline visit in the Study for the Prevention of Anal Cancer (SPANC), all men completed a questionnaire and underwent anal swabbing for cytology and HPV genotyping, followed by high resolution anoscopy.
Composite-HSIL prevalence was 47% and 32% among 220 HIV-positive and 396 HIV-negative men, respectively. HSIL-AIN3 (37.7% versus 24.7%; p<0.001), but not HSIL-AIN2 (9.5% versus 7.6%; p=0.395) was more common in HIV-positive men. Recent receptive anal partners (p-trend=0.045), and increasing number of high-risk (HR)-HPV types (p-trend<0.001) were associated with HSIL-AIN2. Lifetime receptive partners (p-trend<0.001), HIV status (OR 1.74; 95% CI: 1.05–2.87) and HPV16 (OR 3.00; 95% CI: 1.56–5.75) were associated with HSIL-AIN3. HPV16 was the most common HR-HPV type detected in men with HSIL-AIN3, both HIV-negative (61.1%) and HIV-positive (54.9%). HPV16 was less commonly detected in men with HSIL-AIN2.
Grouping HSIL-AIN2 and HSIL-AIN3 as HSIL may mask considerable heterogeneity in anal cancer risk. Given the strong link between HPV16 and anal cancer, men with HSIL-AIN3 and HPV16 are likely to be at greatest risk of cancer.
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The multicenter Nephrotic Syndrome Study Network (NEPTUNE) digital pathology scoring system employs a novel and comprehensive methodology to document pathologic features from whole-slide images, immunofluorescence and ultrastructural digital images. To estimate inter- and intra-reader concordance of this descriptor-based approach, data from 12 pathologists (eight NEPTUNE and four non-NEPTUNE) with experience from training to 30 years were collected. A descriptor reference manual was generated and a webinar-based protocol for consensus/cross-training implemented. Intra-reader concordance for 51 glomerular descriptors was evaluated on jpeg images by seven NEPTUNE pathologists scoring 131 glomeruli three times (Tests I, II, and III), each test following a consensus webinar review. Inter-reader concordance of glomerular descriptors was evaluated in 315 glomeruli by all pathologists; interstitial fibrosis and tubular atrophy (244 cases, whole-slide images) and four ultrastructural podocyte descriptors (178 cases, jpeg images) were evaluated once by six and five pathologists, respectively. Cohen's kappa for inter-reader concordance for 48/51 glomerular descriptors with sufficient observations was moderate (0.40<kappa≤0.60) for 17 and good (0.60<kappa≤0.80) for 8, for 52% with moderate or better kappas. Clustering of glomerular descriptors based on similar pathologic features improved concordance. Concordance was independent of years of experience, and increased with webinar cross-training. Excellent concordance was achieved for interstitial fibrosis and tubular atrophy. Moderate-to-excellent concordance was achieved for all ultrastructural podocyte descriptors, with good-to-excellent concordance for descriptors commonly used in clinical practice, foot process effacement, and microvillous transformation. NEPTUNE digital pathology scoring system enables novel morphologic profiling of renal structures. For all histologic and ultrastructural descriptors tested with sufficient observations, moderate-to-excellent concordance was seen for 31/54 (57%). Descriptors not sufficiently represented will require further testing. This study proffers the NEPTUNE digital pathology scoring system as a model for standardization of renal biopsy interpretation extendable outside the NEPTUNE consortium, enabling international collaborations.
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The Natural History of Anal High-grade Squamous Intraepithelial Lesions in Gay and Bisexual Men
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High reproducibility of histological diagnosis of human papillomavirus-related intraepithelial lesions of the anal canal

Summary

Lancet Oncol

Gynecol Oncol

Comparison of the performance of anal cytology and cervical cytology as screening tests

Sex Health

Interventions for anal canal intraepithelial neoplasia

Cochrane Database Syst Rev

Interobserver and intraobserver bias exists in the interpretation of anal dysplasia

Dis Colon Rectum

Longitudinal evaluation of interobserver and intraobserver agreement of cervical intraepithelial neoplasia diagnosis among an experienced panel of gynecologic pathologists

Am J Surg Pathol

Interobserver agreement in the interpretation of anal intraepithelial neoplasia

Cancer

Interobserver reproducibility of cervical cyto-logic and histologic interpretations: realistic estimates from the ASCUS-LSIL Triage Study

JAMA

Interobserver variation in the reporting of the histopathological grading of anal intraepithelial neoplasia

J Clin Pathol

The Study of the Prevention of Anal Cancer (SPANC): design and methods of a three-year prospective cohort study

BMC Public Health

The Lower Anogenital Squamous Terminology Standardization Project for HPV-Associated Lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology

J Low Genit Tract Dis