Lower Anogenital Standardized Terminology—The LAST Step?

June 1, 2014

By David C. Hoak, M.D.

Diagnostic terminology for preneoplastic lesions of the lower anogenital tract has a long history marked by disparate diagnostic terms derived from multiple specialties. For many years, “dysplasia” of vulva, anus and cervix was classified mild, moderate or severe dysplasia with no mention or regard to site of origin and with poor interobserver reproducibility between sites.

Objections to the meaning of dysplasia (“disordered growth”) in the 1970‘s led to the alternative paradigm of “intraepithelial neoplasia”. This Richart terminology incorporated the site of the lesion. For example, cervical lesions were classified as CIN 1 (mild dysplasia), CIN 2 (moderate dysplasia) or CIN 3 (severe dysplasia). Vulvar lesions were categorized using the VIN acronyms VIN1, VIN2, VIN3. Similarly, vaginal lesions became VAIN1, VAIN2, VAIN3, anal lesions AIN1, AIN2, AIN3, and penile lesions PeIN1, PeIN2, PeIN3.

The plethora of terms preceding the -IN classification used for anogenital lesions raised potential communication problems between the laboratory and clinicians regarding diagnosis and treatment.

Over the past few decades, new insights into the biology of HPV-associated neoplasia and a clearer understanding of the limitations of pathologist diagnostic reproducibility - as well as the limitations of colposcopy - have been realized. In cytopathology, the principles underlying the Bethesda System For Reporting Cervical Cytology attempted to standardize the communication of clinically relevant information using Pap test terminology that was reproducible between laboratories. The Bethesda System helped put an end to diagnostic terminology such as “reactive atypia” and “koilocytotic atypia” that was confusing to clinicians in trying to manage their patients from pathology findings.

A growing desire for unified terminology to describe the pathologic and clinical spectrum of lesions was led by the American Society for Colposcopy and Cervical Pathology (ASCCP) and the College of American Pathologists (CAP).

The resulting Lower Anogenital Squamous Terminology (LAST) Project was initiated to reassess and harmonize biopsy and cytology terminology used to report human papillomavirus associated squamous lesions of the lower anogenital tract. The distinction between cancer precursors and those without malignant potential helped provide consistency in the interpretation of management guidelines and the therapeutic options.

The goal of the LAST project was to have clear, comparable and reproducible communication of diagnosis between and among pathologists and clinicians. It was undertaken to modify histopathology terminology for HPV-associated squamous lesions of the lower anogenital tract (LAT) which would be reflective of a unified biology and which would address the variability and reproducibility issues in tissue diagnosis, much in the way that the Bethesda System did for cytopathology.

The process was led by a steering committee and five workgroups made up of experts in the field, including surgical pathologists, gynecologic pathologists, dermatopathologists, and medical and surgical specialists, including gynecologists, gynecologic oncologists, dermatologists, infectious disease specialists, and representatives from government organizations. The workgroups performed an extensive literature review and posted draft recommendations online for a public comment period.

After the open comment period, the draft recommendations were presented at a consensus conference in 2012 which was attended by LAST work group members, advisors, and representatives from 35 stakeholder organizations, including professional societies and government agencies. Recommendations were finalized and voted on at the consensus meeting. The approved recommendations standardize biologically relevant histopathologic terminology for HPV associated squamous intraepithelial lesions, and superficially invasive squamous carcinomas across all lower anogenital tract sites. LAST terminology also details the appropriate use of specific biomarkers to clarify histologic interpretations and enhance diagnostic accuracy. A plan for disseminating and monitoring LAST implementation was also developed.

Implementation of the new consensus recommendations attempts to provide more reliable and reproducible diagnoses based on our current knowledge of the biology of HPV – ultimately leading to more effective patient management and improved patient outcome. Physicians will receive more consistent biopsy diagnoses to help assess management options, including conservative follow-up or treatment, thereby helping to more accurately evaluate a patient’s risk of having precancer.

As part of its recommendations for a standardized terminology, the biomarker workgroup recommended that the p16 biomarker be used in conjunction with H&E staining to aid in differential diagnosis between high grade dysplasia and mimics of pre-cancer. The p16 immunohistochemical stain helps to adjudicate when there is professional disagreement about a diagnosis, as well as in several other situations, such as cases in which the results of a Pap test indicate high-grade pre-cancerous changes and the biopsy appears to be normal or low-grade precancerous disease. A significant percentage of the time, this extra step can highlight an area of equivocal or missed high grade dysplasia and will save the patient a second biopsy.

As with any new set of recommendations or guidelines, implementation can take time and concerted educational effort. The LAST group is actively involved in efforts to disseminate LAST recommendations via publications, presentations at national/ international meetings, webinars, and development of web-based educational resources. The LAST group is also working with other stakeholders besides physicians - federal and state agencies, nurse practitioners, advocacy groups, and educational/certification bodies - in order to address the implications of this terminology change on the work done by these groups.

The primary goals of the conference were:

• Standardize terminology used for reporting histopathology diagnoses of HPV-related mucocutaneous squamous lesions of the lower genital tract, including intraepithelial lesions and minimally invasive cancers but excluding non-HPV related dermatologic and vulvar lesions.
• Harmonize a two-tier terminology for histopathology with the Bethesda System for reporting gynecologic and anal cytology.
• Standardize terminology across the various lower anogenital tract sites with current evidence-based knowledge regarding the biology of HPV-related squamous lesions and their clinical management.
• Assess the use of new technologies to validate proposed terminology standards and provide guidelines for appropriate use.

Recommendations of the LAST project include:

• A two-tiered nomenclature for dysplastic lesions as either low-grade squamous dysplasia or high-grade
  squamous dysplasia.
• A unified histopathological nomenclature to be used with a single set of diagnostic terms for all HPV-associated
  preinvasive squamous lesions of the lower anogenital tract.
• A preferred SIL nomenclature that may be further qualified with appropriate intraepithelial neoplasia
  (-IN) terminology. For instance, cervical HSIL may be further qualified as CIN 2 or CIN 3.
• That p16 immunohistochemistry be considered when the morphologic differential diagnosis is between
  high-grade dysplasia and a non-neoplastic mimic, when the pathologist is considering the biologically
  equivocal diagnosis of -IN2, or when there is an interobserver or cyto-histologic discrepancy. Routine
  use of p16 however, is not recommended.
• The terms “superficially invasive squamous cell carcinoma” (SISCCA) be applied to minimally
  invasive squamous cell carcinoma of the lower anogenital tract that has been completely excised
  and is potentially amenable to conservative surgical therapy.