Community Biopsy-Diagnosed Cervical Intraepithelial Neoplasia
Community Biopsy-Diagnosed Cervical Intraepithelial Neoplasia
We examined the predictors (cytologic interpretations, pathology review, human papillomavirus [HPV] testing results, and colposcopic impressions) of precancer among 545 women with clinical center biopsy diagnoses of cervical intraepithelial neoplasia (CIN) 2 in the ASCUS LSIL Triage Study. Among women with a CIN 2 biopsy result, there was an increasing likelihood that the loop electrosurgical excision procedure (LEEP) tissue sample was diagnosed as precancer (CIN 3) with an increasing number of clinical risk factors of cervical precancer (high-grade squamous intraepithelial lesion [HSIL] cytology, high-grade colposcopy, detection of HPV type 16; Ptrend < .0005). In a multivariate model, using a case definition of worst histologic diagnosis made by the quality control pathology review of biopsy and LEEP tissue samples, HPV-16 was positively associated (odds ratio [OR], 4.8; 95% confidence interval [CI], 2.6-8.8) with a CIN 3 diagnosis, whereas testing negative for HPV or positive for noncarcinogenic HPV types was negatively associated (OR, 0.32; 95% CI, 0.14-0.75) with a CIN 3 diagnosis. Although we found clear evidence that HPV-16 detection helped clarify whether a biopsy specimen diagnosed as CIN 2 represented HPV infection or cervical precancer, this relationship was not sufficiently robust to be clinically useful for reducing the overtreatment of women with HPV infection.
Prevention of cervical cancer has primarily relied on cytology-based screening, colposcopic evaluation of the cervix with biopsy of potentially abnormal tissue, and treatment of the lesion by excision or ablation of the cervical transformation zone for a biopsy specimen diagnosed as cervical intraepithelial neoplasia (CIN) grade 2 or worse. There is now strong epidemiologic, clinical, and laboratory evidence demonstrating that cervical infections by approximately 15 cancer-associated (carcinogenic) human papillomavirus (HPV) types cause virtually all cervical cancer and its precursor lesions.Based on the fundamental role of carcinogenic HPV as the necessary but not sufficient cause of cervical cancer, a new paradigm of cervical carcinogenesis had been developed based on 4 reliably measured stages: HPV acquisition, HPV persistence (vs clearance), progression to precancer, and invasion.This conceptual model of HPV and cervical carcinogenesis has firm empirical support. It now seems unlikely that cancer develops according to a former morphology-based model of stepwise progression from normal to atypia to CIN 1 to CIN 2 to CIN 3 to cancer.
Nevertheless, histopathologic results remain the foundation of clinical care where screening and colposcopy programs have been established. In the United States and Europe, diagnosis of CIN 2 or worse is the clinical threshold leading to ablative or excisional therapy. However, CIN 2 as a separate diagnostic category remains a clinical enigma, given its poor reproducibility,and there is evidence that CIN 2 is significantly more likely to regress than CIN 3.6 In its most simple definition, CIN 2 is defined as "...the immature basaloid cells occupy up to two-thirds of the epithelial thickness but do not extend into the upper third of the epithelium. Similarly mitoses are found in the lower two-thirds of the epithelium but not in the upper third."On biopsy, however, the orientation of the tissue specimen can make the distinction between CIN 1 and CIN 2 difficult to the point of arbitrary. Moreover, pathologists do not necessarily agree on additional cytomorphologic criteria for histologic diagnoses of CIN 2 or even the conceptual definition of whether a CIN 2 diagnosis should be considered a low-grade or high-grade lesion.
Thus, CIN 2 diagnoses may represent an equivocal diagnosis rather than a separate biologic stage in cancer development. It certainly overlaps with CIN 1, which is synonymous with signs of (usually recently acquired) HPV infection, and CIN 3, which is essentially carcinoma in situ. In its heterogeneity, CIN 2 may be in some ways conceptually analogous to ASCUS (atypical squamous cells of undetermined significance) cytology, which is an equivocally abnormal cytologic interpretation that represents an admixture of HPV-associated cytologic abnormalities and benign reactive changes. For ASCUS, carcinogenic HPV DNA testing clarifies true abnormality from the mimics, ie, carcinogenic HPV+ ASCUS poses a similar risk of precancer as cytologic low-grade squamous intraepithelial lesion (LSIL) and colposcopy is recommended, whereas carcinogenic HPV– ASCUS poses little risk for precancer and colposcopy is not recommended.
We do not know how to subdivide CIN 2 for optimal clinical management. Given the potential negative impact of the loop electrosurgical excision procedure (LEEP) on reproductive outcomesand the frequency of CIN 2 in young women, there is value to increasing our understanding of CIN 2 with the hope of eventually distinguishing CIN 2 diagnoses that represent transient HPV infection from those that represent true precancer, which warrants treatment. As a first step, we sought to characterize the biopsy diagnoses of CIN 2 by the clinical center in the ASCUS and LSIL Triage Study (ALTS) by comparing this initial diagnosis with our reference biopsy diagnosis, the diagnosis of the tissue removed at LEEP treatment, and the worst diagnosis on biopsy or LEEP specimens as made by the Pathology Quality Control (QC) Group (QC Pathology Group).
We examined the predictors (cytologic interpretations, pathology review, human papillomavirus [HPV] testing results, and colposcopic impressions) of precancer among 545 women with clinical center biopsy diagnoses of cervical intraepithelial neoplasia (CIN) 2 in the ASCUS LSIL Triage Study. Among women with a CIN 2 biopsy result, there was an increasing likelihood that the loop electrosurgical excision procedure (LEEP) tissue sample was diagnosed as precancer (CIN 3) with an increasing number of clinical risk factors of cervical precancer (high-grade squamous intraepithelial lesion [HSIL] cytology, high-grade colposcopy, detection of HPV type 16; Ptrend < .0005). In a multivariate model, using a case definition of worst histologic diagnosis made by the quality control pathology review of biopsy and LEEP tissue samples, HPV-16 was positively associated (odds ratio [OR], 4.8; 95% confidence interval [CI], 2.6-8.8) with a CIN 3 diagnosis, whereas testing negative for HPV or positive for noncarcinogenic HPV types was negatively associated (OR, 0.32; 95% CI, 0.14-0.75) with a CIN 3 diagnosis. Although we found clear evidence that HPV-16 detection helped clarify whether a biopsy specimen diagnosed as CIN 2 represented HPV infection or cervical precancer, this relationship was not sufficiently robust to be clinically useful for reducing the overtreatment of women with HPV infection.
Prevention of cervical cancer has primarily relied on cytology-based screening, colposcopic evaluation of the cervix with biopsy of potentially abnormal tissue, and treatment of the lesion by excision or ablation of the cervical transformation zone for a biopsy specimen diagnosed as cervical intraepithelial neoplasia (CIN) grade 2 or worse. There is now strong epidemiologic, clinical, and laboratory evidence demonstrating that cervical infections by approximately 15 cancer-associated (carcinogenic) human papillomavirus (HPV) types cause virtually all cervical cancer and its precursor lesions.Based on the fundamental role of carcinogenic HPV as the necessary but not sufficient cause of cervical cancer, a new paradigm of cervical carcinogenesis had been developed based on 4 reliably measured stages: HPV acquisition, HPV persistence (vs clearance), progression to precancer, and invasion.This conceptual model of HPV and cervical carcinogenesis has firm empirical support. It now seems unlikely that cancer develops according to a former morphology-based model of stepwise progression from normal to atypia to CIN 1 to CIN 2 to CIN 3 to cancer.
Nevertheless, histopathologic results remain the foundation of clinical care where screening and colposcopy programs have been established. In the United States and Europe, diagnosis of CIN 2 or worse is the clinical threshold leading to ablative or excisional therapy. However, CIN 2 as a separate diagnostic category remains a clinical enigma, given its poor reproducibility,and there is evidence that CIN 2 is significantly more likely to regress than CIN 3.6 In its most simple definition, CIN 2 is defined as "...the immature basaloid cells occupy up to two-thirds of the epithelial thickness but do not extend into the upper third of the epithelium. Similarly mitoses are found in the lower two-thirds of the epithelium but not in the upper third."On biopsy, however, the orientation of the tissue specimen can make the distinction between CIN 1 and CIN 2 difficult to the point of arbitrary. Moreover, pathologists do not necessarily agree on additional cytomorphologic criteria for histologic diagnoses of CIN 2 or even the conceptual definition of whether a CIN 2 diagnosis should be considered a low-grade or high-grade lesion.
Thus, CIN 2 diagnoses may represent an equivocal diagnosis rather than a separate biologic stage in cancer development. It certainly overlaps with CIN 1, which is synonymous with signs of (usually recently acquired) HPV infection, and CIN 3, which is essentially carcinoma in situ. In its heterogeneity, CIN 2 may be in some ways conceptually analogous to ASCUS (atypical squamous cells of undetermined significance) cytology, which is an equivocally abnormal cytologic interpretation that represents an admixture of HPV-associated cytologic abnormalities and benign reactive changes. For ASCUS, carcinogenic HPV DNA testing clarifies true abnormality from the mimics, ie, carcinogenic HPV+ ASCUS poses a similar risk of precancer as cytologic low-grade squamous intraepithelial lesion (LSIL) and colposcopy is recommended, whereas carcinogenic HPV– ASCUS poses little risk for precancer and colposcopy is not recommended.
We do not know how to subdivide CIN 2 for optimal clinical management. Given the potential negative impact of the loop electrosurgical excision procedure (LEEP) on reproductive outcomesand the frequency of CIN 2 in young women, there is value to increasing our understanding of CIN 2 with the hope of eventually distinguishing CIN 2 diagnoses that represent transient HPV infection from those that represent true precancer, which warrants treatment. As a first step, we sought to characterize the biopsy diagnoses of CIN 2 by the clinical center in the ASCUS and LSIL Triage Study (ALTS) by comparing this initial diagnosis with our reference biopsy diagnosis, the diagnosis of the tissue removed at LEEP treatment, and the worst diagnosis on biopsy or LEEP specimens as made by the Pathology Quality Control (QC) Group (QC Pathology Group).