Richard Reid

Sexually transmitted papillomaviral infections: I. The anatomic distribution and pathologic grade of neoplastic lesions associated with different viral types☆☆☆

Multiple colposcopic biopsy specimens were collected from 160 women, with sampling of principal cervical and vulvar lesions as well as secondary areas of either minor acetowhitening or normal epithelium. Papillomaviral deoxyribonucleic acid was detected by Southern blot hybridization in 197 (90%) of the 218 principal biopsy specimens and 93 (46%) of 198 secondary biopsy specimens. Although different papillomaviruses were found at different sites in 31 women, only six of 416 specimens contained multiple types within the same sample. Specific viral types were associated with specific disease patterns. Only one of 80 type 6 or 11 infections had a diagnosis greater than cervical intraepithelial neoplasia, grade 2. In contrast, 42 of 48 (90%) biopsy specimens of cervical intraepithelial neoplasia, grade 3, or invasive cancer contained type 16, 18, or 31. Nonetheless, 12 of 124 (10%) cases of condyloma and cervical intraepithelial neoplasia, grade 1, were associated with types 16, 18, and 31 infections. Of 58 women with multicentric disease, 46 had positive hybridizations for both cervical and vulvar lesions (32 showing the same type in both samples and 14 showing different viruses). Differing patterns of papillomavirus-induced disease arise partly from the predilection of specific viral types for certain anatomic sites and partly through variations in host response. Detection of viral deoxyribonucleic acid in 46% of the secondary biopsy specimens suggests that disease expression may represent focal breakdown of host surveillance within a field of latent papillomaviral infection.

Analysis of individual cervical human papillomavirus types in neolasia: A possible role for type 18 in rapid progression

Histologic and molecular analyses of 214 cervical biopsy specimens were performed to test the hypothesis that certain individual human papillomavirus types that are usually grouped together are differentially distributed in various grades of cervical intraepithelial neoplasia and invasive squamous carcinoma. Specifically, types 16 and 18, which are commonly grouped together, were analyzed separately and compared. Biopsies obtained from three different geographic sites in the United States and Brazil were analyzed by Southern blot hybridization and correlated with the histologic diagnosis from the same tissue sample. There was a highly significant correlation between papillomavirus type and histologic grade comparing all grades of cervical intraepithelial neoplasia with invasive cancer ( p p

Genital warts and cervical cancer

Human papillomaviral infection is now widely implicated in the causation of cervical neoplasia. Genotype analysis provides the best guide to biologic outcome; most polyploid lesions regress and most aneuploid ones persist or progress. This prospective survey examined the relationships between cell ploidy and 24 objectively validated criteria of human papillomaviral infection or premalignant change in 52 biopsies from a dysplasia clinic. Histologic evidence of benign warty expression and human papillomaviral capsid antigen production decreased steadily as DNA content ranged from diploidy to polyploidy to aneuploidy. In contrast, premalignant change increased with progressive distortion of nuclear DNA content. No absolute discriminants were found between polyploidy and aneuploidy, as evidenced by the detection of human papillomaviral proteins in three of 21 aneuploid epithelia and the recognition of abnormal mitotic figures in five of 17 polyploid lesions. Polyploid and aneuploid lesions differed only in severity, and it appears that some polyploid epithelia may be transition forms between diploidy and aneuploidy.

Should cervical cytologic testing be augmented by cervicography or human papillomavirus deoxyribonucleic acid detection

Criticism of the Papanicolaou smear in the lay press and recent federal legislation regulating cytology laboratories indicate a need to reappraise cervical cancer screening programs. This study directly compares three potential screening tests, used alone or in combination. A total of 1012 women aged 18 to 35 years were screened by cytologic testing, cervicography, and hybridization for human papillomavirus deoxyribonucleic acid, with discrepancies being referred by the last two authors. After findings from the entire lower genital tract were combined, 116 women (11.5%) showed definite clinical abnormalities (either exophytic vulvovaginal condylomas or cervical squamous intraepithelial lesions). Another 72 (7.2%) had positive Southern blot hybridizations without accompanying viral expression, yielding a cumulative frequency for established disease or latent infection of 18.6%. When associated vulvovaginal condylomas are disregarded, final groupings with regard to cervical pathologic classification were: 23 high-grade and 71 low-grade squamous intraepithelial lesions, 164 cases of equivocal atypia (34 of which had detectable human papillomavirus deoxyribonucleic acid), and 754 cases with negative results (38 of which had detectable human papillomavirus deoxyribonucleic acid). Cervical screening tests were compared principally by plotting increasingly liberal recall criteria onto receiver operating characteristic curves (i.e., graphs of true-positive results on the Y axis versus false-positive results on the X axis). Used individually, each screening test was valid, but none was substantially better than the others. No matter how liberal the recall criteria, no single test was able to detect all of the 23 definite precursors in this sample. Applying conventional recall criteria (i.e., high- or low-grade lesion suspected), cytologic testing alone detected 12 high-grade squamous intraepithelial lesions (52.2%), at a cost of having to perform colposcopy in 8.7% of the sample. Combining all three tests and setting the end point as just a high-positive result by at least one test, 19 high-grade squamous intraepithelial lesions (83%) were detected, with a recall of 7%. Optimal test performance (96% sensitivity, 4% recall) would have been attained by recalling all patients with high-grade cytologic results or positive cervicography results, plus any patients with low-grade morphologic atypia in which hybridization detected an oncogenic human papillomavirus type. Our conclusions are as follows: (1) Cytologic detection rates are markedly improved by a second or third test; (2) increased screening costs could be offset by not recalling patients with minor lesions with no apparent potential for progression.

Genital warts and cervical cancer: IV. A colposcopic index for differentiating subclinical papillomaviral infection from cervical intraepithelial neoplasia☆

Five colposcopic signs (thickness, color, contour, vascular atypia, and iodine staining) were graded into three objective categories representing (1) subclinical papillomaviral infection, (2) lower-grade dysplasia, and (3) grade 3 cervical intraepithelial neoplasia. Seventy-two colposcopically different biopsy specimens (25 of subclinical papillomaviral infection and 18 of grade 1, 18 of grade 2, and 11 of grade 3 cervical intraepithelial neoplasia) were collected from 52 women and interpreted by validated, quantitative histologic analysis. Attempts to grade lesions by the prominence of the acetowhitening reaction or the mere presence of aberrant surface capillaries were unsuccessful. In contrast, each of five new colposcopic criteria were significantly correlated with histologic severity. Differences in color, vascular atypia, and iodine staining were more predictive than those of thickness and contour. Combined into a weighted index, these colposcopic features were 96% correct in forecasting approximate histologic findings. Because this method relies upon critical analysis rather than pattern recall, the use of this colposcopic index greatly simplifies the learning of colposcopy.

Genital warts and cervical cancer. III. Subclinical papillomaviral infection and cervical neoplasia are linked by a spectrum of continuous morphologic and biologic change

Human papillomaviral (HPV) infection is now widely advanced as an important etiologic factor in cervical cancer. This study was undertaken to clarify morphologic relationships within the biologic spectrum linking subclinical papillomaviral infection (SPI) to cervical intraepithelial (CIN). Two pathologists analyzed 72 colposcopic biopsies, using a semi‐objective rating scheme that scored 24 different histologic criteria. Each individual criterion was checked for reproducibility, and validated against an objective measure of papillomaviral infection (immunoperoxidase staining) or premalignant change (microspec‐trophotometry). The individual criteria were then combined into histologic indices of benign warty change, presumed viral atypia, abnormal cell phenotype, and disturbed tissue maturation. Histologic expression of papillomaviral infection decreased with increasing degrees of premalignant change. Plotting the index of abnormal cell phenotype against that of disturbed tissue maturation produced a linear plot in which cases clustered into four diagnostic groups. The histologic indices of papillomaviral infection displayed significant curvilinear correlations with genotypic distortion, benign warty change being maximal in the CIN 1 range and presumed viral atypia in the CIN 2 range. Disturbance of nuclear DNA content also increased with worsening diagnosis; diploidy being most common in SPI (67%), polyploidy in CIN 1 (59%), and aneuploidy in CIN 2 (65%) and CIN 3 (82%). Conversely, capsid antigen production decreased from 36% in SPI to 9% in CIN 3. Three aneuploid epithelia were immunoperoxidase positive. These inverse relationships between late viral expression and nuclear distortion fit experimental models of viral oncogenesis. The gradual transition and morphologic overlap between diagnostic groups support the postulate that SPI and CIN are a single disease spectrum, in which differences are those of degree rather than of kind.

Superficial laser vulvectomy

The rationale for using the carbon dioxide laser to treat either vulvar intraepithelial neoplasia or extensive papillomaviral infections is to destroy the entire area of abnormal epithelium to a shallow depth, so that rapid healing will occur from normal keratinocytes in the underlying pilosebaceous glands. After the first laser impact, anatomic landmarks in the crater base are disguised by a layer of charred proteins, and any structure that is visible will already have suffered thermal necrosis. Accurate control of depth depends upon special surgical strategies that correlate the level of the underlying zone of thermal necrosis with specific visual appearances within the zone of vaporization. Maneuvers that limit depth of penetration to one of three desirable surgical planes (basement membrane, papillary dermis, midreticular dermis) are described.

Correlation of the Histologic Appearance of Intraepithelial Neoplasia of the Cervix with Human Papillomavirus Types. Emphasis on Low Grade Lesions Including So-called Flat Condyloma

Cervical condylomas and intraepithelial neoplasia (CIN) were correlated with human papillomavirus (HPV) types and analyzed for the presence of abnormal mitotic figures. Colposcopically directed cervical biopsies were divided in half and processed for routine microscopy and Southern blot hybridization. Of 83 specimens from 71 patients, 70 (84%) contained HPV-DNA sequences. The HPV distribution was as follows: HPV 16 in 6/25 flat condylomas (FC), 2/8 CIN I, 8/18 CIN II, 12/14 CIN III; HPV 18 in 1/25 FC; HPV 31 in 3/25 FC, 3/18 CIN II, and 1/14 CIN III; HPV 6/11 in 12/18 exophytic condylomas (EC), 5/25 FC, 2/8 CIN I, and 3/18 CIN II. Uncharacterized HPVs were identified in 4/18 EC, 5/25 FC, 2/8 CIN I, and 1/18 CIN II. A similar heterogeneous distribution of HPV types was found in flat condylomas and CIN I. A more homogeneous distribution was noted in the exophytic condylomas and high grade CIN lesions, with HPV 6/11 found in the former and predominantly HPV 16 in the latter. Abnormal mitotic figures were predominantly seen in the high grade CIN lesions. Based on our findings, we would recommend that the term flat condyloma be abandoned and that low grade flat lesions of the cervix be graded according to CIN criteria.

Superficial laser vulvectomy: III. A new surgical technique for appendage-conserving ablation of refractory condylomas and vulvar intraepithelial neoplasia

Despite the unique properties of the carbon dioxide laser, many surgeons do not know how to exploit the full potential of this sophisticated instrument. Effective laser operation on the vulva depends upon the accuracy of delineation of disease, the use of optimum power densities, and the ability to exercise precise control over depth of ablation. This article describes a surgical technique that capitalizes upon these principles, thereby maximizing the margin between favorable and poor outcomes. Superficial laser vulvectomy is a safe and efficient procedure in the hands of expert physicians, but should not be attempted by those who are less experienced. Indications for this operation and safeguards against surgical misadventure are also discussed.

Superficial laser vulvectomy. I. The efficacy of extended superficial ablation for refractory and very extensive condylomas.

Sixteen refractory (present for more than 1 year) and 16 very extensive (affecting greater than 60% of the vulva or multiple lesions greater than 1 cm) condylomas were treated by superficial carbon dioxide laser ablation of all papillomavirus-infected epithelium within the lower genital tract. Accurate depth control was maintained by using a special surgical technique to create a plane that limited penetration to the basement membrane. All patients were healed within 3 to 5 weeks, without scarring or significant complications. Of 16 patients with extensive condylomas, 15 were cured by the first laser therapy and the other patient by a second treatment. In contrast, only five of 16 refractory condylomas responded to the first operation, seven to a second procedure and another three to a third treatment. Thirty-one of these 32 patients were finally cured by superficial laser vulvectomy. The other patient required deep dermal destruction and skin grafting. This 97% eventual success rate is encouraging, particularly since there are no other satisfactory alternatives in such difficult cases.