Genital Intraepithelial Neoplasia Research Articles

A Longitudinal Study of Human Papillomavirus 16 Positivity in the Development of Lower Genital Intraepithelial Neoplasia in Immunosuppressed Women

Objectives. We studied a group of female renal transplant patients and patients receiving dialysis to determine the natural history of human papillomavirus (HPV) type 16 DNA infection in the two groups and its effect on lower genital tract intraepithelial neoplasia development and progression. Materials and Methods. Female renal transplant and dialysis patients were recruited from the renal unit of the hospital. Follow-up was every 6 months, and all women were seen at least twice. Assessment was obtained by cytology, colposcopy, directed biopsy, and HPV 16 DNA semiquantitative analysis by polymerase chain reaction. The oligonucleotide primers were designed to amplify a 233–base pair region of the HPV 16 E6 and E7 genes (nucleotides 491–714), with confirmation of the amplified product performed by Southern blotting and probing with an oligonucleotide probe specific to an internal portion of the ampli-con. Results. The 28 transplant patients and 14 dialysis patients were followed up for an overall mean of 14.6 months (range, 5–24 months; median, 18 months). Only one dialysis patient was positive for the HPV 16 genome, and this was in low copy numbers. The HPV status changed in some patients throughout the study period; however, no one who had medium-high or high copy numbers at enrollment became HPV 16 DNA–negative. From study entry, HPV 16 DNA positivity was associated with progression of preexisting intraepithelial disease and new disease development, although the association was not statistically significant by either log-rank or Cox’s proportional hazard model ( p = .76 and .77, respectively). Neither coexisting cervical intraepithelial neoplasia (CIN) nor type of renal disease nor the therapeutic regimen used at study entry appeared to influence disease development and progression ( p = .42 and .7, respectively). The only factor that influenced development and progression of CIN from study entry was the length of time from transplantation ( p = .01). Time from transplantation did appear to influence HPV 16 DNA positivity ( p = .04), but the combined influence did not hold up to scrutiny in a multivariate analysis using Cox’s proportional model ( p = .34), suggesting that HPV 16 positivity was a surrogate marker for time from transplantation. Conclusions. HPV 16 DNA positivity alone is an inadequate explanation for the development and progression of lower genital tract intraepithelial disease in women with renal transplant. The length of time from transplantation is an important factor, but the exact association between duration of immune suppression and CIN has yet to be clarified.

Guidelines for anal cytology--to make cytological diagnosis and follow up much more reliable.

Anal intraepithelial neoplasia is a difficult diagnostic and management problem, particularly when it occurs in women with synchronous or metachronous genital intraepithelial neoplasia. Diagnosis and follow up by colposcopy is too specialized for widespread use, and although anal cytology has been used before it has been thought of as too inconsistent for practical application. This study standardized collection of specimens and investigated interobserver variation. The aim of the study was to determine whether observers could reliably distinguish high grade anal intraepithelial neoplasia from other conditions. Standardized collection of anal preparations was achieved in the host centre. A meeting of experienced cytopathologists was convened to agree guidelines for anal cytology. These guidelines were sent to the panel of six observers who were subsequently circulated with 30 cytopathological preparations in random order and asked to report them all. The results were collected and processed centrally. Four individuals were in complete agreement about those preparations which were inadequate for reporting, but two others had a lower threshold for rejecting preparations as inadequate. There was agreement between the observers in over 95% of cases in distinguishing high grade intraepithelial neoplasia from other cytological conditions. Kappa values range from 0.66 to 1.00. This study demonstrates that the provision of guidelines for the interpretation of anal cytopathological preparations can result in a high degree of interobserver agreement about the clinically important distinction between high grade anal intraepithelial neoplasia and other conditions. Anal cytology is a more useful technique for diagnosis and follow up of 'at risk' individuals than has previously been suggested, and should be utilized more widely in this group of patients.

Condyloma acuminata in infants and children. A survey of colon and rectal surgeons.

Condyloma acuminata are anogenital warts caused by a human papillomavirus. Human papillomavirus is a tissue-specific, site-specific, double-stranded DNA virus, which is capable of inducing high-grade genital intraepithelial neoplasia and malignancy. The incidence of anogenital warts in the pediatric age group is rising, and sexual abuse has been implicated as a potential cause. Accumulated data from separate questionnaires sent to practicing colorectal surgeons who are members of The American Society of Colon and Rectal Surgeons and fellows in colon and rectal training programs have been analyzed. Thirty percent of those polled responded to our survey. Of the respondents, 93 percent see less than two pediatric cases per year. Seventy-two percent stated that tissue specimens would be sent routinely for histopathologic identification. Although 73 percent of surgeons consider anogenital warts a potentially sexually transmitted disease, only 26 percent reported screening for other sexually transmitted diseases. A diagnostic and therapeutic protocol is followed by 19 percent of respondents. Patient follow-up varied from six months (43 percent) to lifelong examinations (3 percent). Sixty-four percent of respondents agreed that a diagnostic and therapeutic protocol based on current knowledge would be beneficial. We conclude that colon and rectal surgeons have a low exposure to anogenital warts in infants and children. Furthermore, we believe that a diagnostic and therapeutic protocol based on the current literature would be helpful.

Two novel genital human papillomavirus (HPV) types, HPV68 and HPV70, related to the potentially oncogenic HPV39.

The genomes of two novel human papillomavirus (HPV) types, HPV68 and HPV70, were cloned from a low-grade cervical intraepithelial neoplasia and a vulvar papilloma, respectively, and partially sequenced. Both types are related to HPV39, a potentially oncogenic virus. HPV68 and HPV70 were also detected in genital intraepithelial neoplasia from three patients and one patient, respectively. Comparison with sequence data in the literature indicates that the subgenomic ME180-HPV DNA fragment, cloned from a carcinoma cell line, corresponds to an HPV68 subtype and that several HPV DNA fragments amplified by PCR from genital neoplasia represent worldwide distributed variants of HPV68 and HPV70.

Human papillomavirus infection and associated disease in persons infected with human immunodeficiency virus.

Genital infection with human papillomavirus (HPV) is the most common sexually transmitted infection in the United States. Genital or anal infection with oncogenic types of HPV, particularly types 16 and 18, can cause precancerous lesions of the squamous epithelium. Infection with human immunodeficiency virus (HIV) increases the risk for HPV-associated genital neoplasias in both women and men. Detectable cervical and anal HPV infection is more prevalent among women and men with HIV infection than among those who are HIV-seronegative, and the magnitude of the increase in prevalence is proportionate to the severity of immunosuppression. Coinfection with HIV and HPV increases the risk for genital intraepithelial neoplasia, and the increase in this risk also reflects the severity of immunosuppression. One difficulty complicating elucidation of the association between HIV and HPV infections is that the risk factors for acquisition and transmission of the two viruses are similar. The strength of this association represents a burgeoning health problem, yet there are no treatment guidelines aimed specifically at HIV-infected individuals with HPV-associated genital neoplasias. Treatment of HPV-associated cervical disease in HIV-infected women may be further complicated by a greater risk of treatment failure and recurrence than exists among HIV-seronegative women; it is not known whether dysplasia progresses to invasive disease more rapidly in women infected with HIV. A thorough understanding of the associations among HIV, HPV, and HPV-associated disease is essential to the development of effective strategies for intervention and prevention.

Anal intraepithelial neoplasia: Part of a multifocal disease process

Invasive carcinomas of the anogenital epithelium share a common aetiological factor—human papillomavirus (HPV) type 16. Although genital intraepithelial neoplasia may be multifocal, there have been no studies of the prevalence of anal intraepithelial neoplasia in women with intraepithelial neoplasia of the genital tract. We tested the hypothesis that women with high-grade cervical intraepithelial neoplasia are at higher risk of disease in the anus than are control women of similar age with no history of anogenital neoplasia. 29 (19%) of 152 women with cervical intraepithelial neoplasia grade III had histological evidence of anal intraepithelial neoplasia. Of the 29 patients, 11 had grade III anal lesions; 2 of those women had concomitant invasive anal squamouscell carcinomas. Only 7% (8/115) women with high-grade lesions of the cervix alone had evidence of anal intraepithelial neoplasia; by contrast, 57% (21/37) of those with more than one focus of intraepithelial neoplasia (cervix plus vulva, vagina, or both) had anal lesions. HPV 16 DNA was identified in 18 (51%) of 35 anal biopsy samples in the study group. No evidence of anal intraepithelial neoplasia was found in the control group (50 women), although 2 patients had grade I cervical lesions. HPV 16 DNA was identified in 12 (24%) of biopsy samples from the cervix and 7 (14%) from the anus in the control group; all 7 women with anal H PV 16 had concomitant cervical infection. The role of anal examination in the assessment of women with any focus of genital intraepithelial neoplasia requires further investigation.

Anal intraepithelial neoplasia: part of a multifocal disease process

Invasive carcinomas of the anogenital epithelium share a common aetiological factor—human papillomavirus (HPV) type 16. Although genital intraepithelial neoplasia may be multifocal, there have been no studies of the prevalence of anal intraepithelial neoplasia in women with intraepithelial neoplasia of the genital tract. We tested the hypothesis that women with high-grade cervical intraepithelial neoplasia are at higher risk of disease in the anus than are control women of similar age with no history of anogenital neoplasia. 29 (19%) of 152 women with cervical intraepithelial neoplasia grade III had histological evidence of anal intraepithelial neoplasia. Of the 29 patients, 11 had grade III anal lesions; 2 of those women had concomitant invasive anal squamouscell carcinomas. Only 7% (8/115) women with high-grade lesions of the cervix alone had evidence of anal intraepithelial neoplasia; by contrast, 57% (21/37) of those with more than one focus of intraepithelial neoplasia (cervix plus vulva, vagina, or both) had anal lesions. HPV 16 DNA was identified in 18 (51%) of 35 anal biopsy samples in the study group. No evidence of anal intraepithelial neoplasia was found in the control group (50 women), although 2 patients had grade I cervical lesions. HPV 16 DNA was identified in 12 (24%) of biopsy samples from the cervix and 7 (14%) from the anus in the control group; all 7 women with anal H PV 16 had concomitant cervical infection. The role of anal examination in the assessment of women with any focus of genital intraepithelial neoplasia requires further investigation.

Transcription patterns of human papillomavirus type 16 in genital intraepithelial neoplasia: evidence for promoter usage within the E7 open reading frame during epithelial differentiation.

Human papillomavirus (HPV) type 16 transcription was analysed by in situ hybridization using 125I-labelled subgenomic riboprobes, from 26 genital intraepithelial neoplastic (IN) lesions, in formalin-fixed biopsies from 18 different cases. Distinct transcription patterns separable by the presence or absence of late gene transcription were detected. In 12 lesions, late gene expression was absent; HPV transcripts corresponding to the E6 and E7 open reading frame (ORF) were detectable in all basal cells and were usually evenly distributed through all layers of the epithelium. Transcripts corresponding to the E1, E2 and E2/E4 ORFs were present in nine of 12 lesions and displayed a similar distribution. In 14 lesions late gene transcripts were present. E6 and E7 transcripts were detectable basally in all but one lesion. The levels of E7 but not E6 transcripts were markedly increased in the superficial cells of differentiating epithelia, with an identical distribution and at similar levels to those of the E2/E4 transcript. We propose that the most abundant transcript in genital IN lesions containing late gene expression is an E7/E1 [symbol: see text] E2/E4 transcript corresponding to that reported in HPV-6/11 condylomata and which is derived from a similar promoter within the E7 ORF.

Genome organization and nucleotide sequence of human papillomavirus type 39

The 7833-bp nucleotide sequence of human papillomavirus type 39 (HPV39), which is associated with genital intraepithelial neoplasias and invasive carcinomas, has been determined. The genome organization deduced from the sequence shares characteristic features with other genital papillomaviruses. According to sequence comparisons, HPV39 most closely resembles HPV18 and may be a member of a subgroup of genital papillomaviruses distinct from the HPV16/31/33 group. As a novel feature, we report a 1.3-kb open reading frame on the DNA strand which lacks major open reading frames in the other sequenced HPV genomes.

Monitoring the course of cervical carcinoma with the squamous cell carcinoma serum radioimmunoassay

Serum samples were collected from 611 gynecologic patients for measurement of squamous cell carcinoma antigen levels using the Abbott Laboratories squamous cell carcinoma antigen radioimmunoassay kit. Sixteen of 83 patients (19.3%) with cervical dysplasia and 72 of 135 (53.3%) with primary or recurrent cervical carcinoma had levels above 2.4 ng/mL. In contrast, only seven of 373 women (1.9%) without genital tract squamous cell intraepithelial neoplasia or carcinoma had squamous cell carcinoma antigen levels above 2.4 ng/mL. Fifty-six patients with cervical cancer were followed for correlation of squamous cell carcinoma antigen levels to disease course, and 20 had persistent or recurrent disease after therapy; rising squamous cell carcinoma antigen levels predicted disease in 15 of these 20 patients with recurrence (13 of 15 with elevated pre-treatment levels and two of five with normal pre-treatment levels). Rising squamous cell carcinoma antigen levels preceded the clinical detection of disease in ten patients by a mean of 4.6 months (range 2-7.5 months); in the remaining five, squamous cell carcinoma antigen levels were elevated only when disease recurrence was documented. Although measurement of squamous cell carcinoma antigen levels is not a sensitive screening method for cervical cancer (sensitivity 53.3%), the test has good specificity (94.3%); the majority of patients with false-positive elevations had other genital tract squamous cell neoplasias. The squamous cell carcinoma antigen assay may be a useful aid for monitoring the disease course of cervical carcinoma.

Regression of the malignant aspect of intraepithelial neoplasias following an LH—RH agonist treatment and detection of human papillomavirus by molecular hybridization

Patients presenting genital intraepithelial neoplasia and/or flat condyloma were treated with DTrp6-LH-RH (triptorelin) to induce a transitory suppression of estrogens. This treatment led in some cases to a complete clinical and histological regression accompanied by a disappearance of human papillomavirus sequences as detected by molecular hybridization.

Human papillomavirus type 16 alters human epithelial cell differentiation in vitro.

Human papillomavirus (HPV) types 16, 18, 31, and 33 have been implicated as etiologic agents of cervical and penile cancer. Using a cell culture system for keratinocytes which allows stratification and production of differentiation-specific keratins, we have examined the effects of one of these viruses, HPV-16, on the differentiation capabilities of human epithelial cells. A plasmid containing the HPV-16 genome and a neomycin-selectable marker was transfected into primary human epidermal cells and SCC-13 cells, an immortalized squamous cell carcinoma cell line. Cloned neomycin-resistant cell lines were isolated and examined by cell culture on raised collagen rafts. Cell lines containing HPV-16 DNA retained the ability to stratify and express differentiation-specific keratins in the raft system but otherwise failed to differentiate normally. The histological abnormalities induced by HPV-16 closely resembled those seen in genital intraepithelial neoplasia in vivo. Hence, our results support the role of HPV-16 as an etiologic agent in the development of genital neoplasias and suggest a specific system for the study of HPV-16-induced epithelial cancers.

Detection of specific types of human papillomavirus in cervical scrapes, anal scrapes, and anogenital biopsies by DNA hybridization.

Specific varieties of human papillomavirus (HPV) infecting the anogenital region were detected in clinical samples by use of a filter hybridization technique suitable for rapid screening of cervical and anal scrapes. In this way possibly benign types (HPV6 and HPV11) could be differentiated from types thought to be capable of malignant transformation (HPV 16 and HPV 18). Cervical or anal canal cells were applied directly to nylon filters and fixed by u.v. irradiation before hybridization with mixed viral DNA probes under both low- and high-stringency conditions. In addition, probe for the human Alu-repeated DNA sequence was used to assess the relative amount of total nucleic acids in each sample applied to the filter. HPV DNA was detected in 3 of 19 cervical scrapes from patients with no past or present history of wart virus infection or cervical dysplasia. Within a positive study group totalling 71 patients, HPV (6/11 or 16/18) was detected in cervical scrapes from 24% of 41 patients who did not have visible genital dysplasia, 30% of 27 patients with visible genital dysplasia or cervical intraepithelial neoplasia (CIN) I, and in 1 of 3 patients with past CIN II/III. In addition, HPV6/11 or 16/18 DNA was detected in anal scrapes from 3 of 6 male patients and in 85% of genital biopsies. A notably high proportion (4/6) of vaginal condylomata were positive with both the HPV6/11 and the HPV16/18 mixed viral DNA probes. Of the biopsies prepared for histopathology and positive for HPV DNA, the HPV group-specific antigen could be detected in only 60%.

A novel type of human papillomavirus associated with genital neoplasias.

The role of human papillomaviruses (HPVs) in the development of genital neoplasias has been well documented. The genomes of two HPV types, HPV16 and HPV18, have been found to be associated with about 70% of invasive carcinomas of the uterine cervix. As, under non-stringent hybridization conditions, HPV DNA sequences have been detected in about 90% of cervical carcinomas, it seems likely that additional HPV types are associated with these tumours. Here we report the molecular cloning and characterization of a novel HPV type, tentatively named HPV33, whose sequences have been detected in 4-8% of biopsies of genital intra-epithelial neoplasias and cervical invasive carcinomas, usually as free monomeric or oligomeric molecules. However, in one specimen of vulvar Bowen's disease, HPV33 DNA sequences were integrated in the host-cell genome. Thus, HPV33 probably represents an additional type of potentially oncogenic genital HPV.

A review of lower genital intraepithelial neoplasia and the use of topical 5-fluorouracil.

A review of lower genital intraepithelial neoplasia and the use of topical 5-fluorouracil.

The significance of laser margins when treating genital condylomata and vulvar intraepithelial neoplasia (VIN) with reference to latent human papillomavirus (HPV)

The significance of laser margins when treating genital condylomata and vulvar intraepithelial neoplasia (VIN) with reference to latent human papillomavirus (HPV)

The relationship between human papillomavirus and lower genital intraepithelial neoplasia in immunosuppressed women

In a group of 20 immunosuppressed women with lower genital neoplasia, evidence of associated human papillomaviral infection was found in all patients on the basis of the histologic identification of koilocytes in the upper strata of areas of mild or moderate dysplasia. Immunohistochemical study of similar areas disclosed human papilloma structural antigens in the lesions in 60%, while 50% had lesions in which human papilloma virions were detected by the electron microscope. An abnormal immunologic status, indicated by an altered T-helper/T-suppressor ratio, a deficient response to mitogenic stimulation, or both, was confirmed in 80% of the patients studied. Twelve of the 20 patients had unusually persistent and recurrent intraepithelial neoplasia, and in one the disorder progressed to invasive epidermoid carcinoma. The progressive behavior of human papillomavirus-associated neoplasia in these immunosuppressed patients might represent an accelerated version of the long-term course of such lesions in immunocompetent hosts.

The Effect of Immunodeficiency on the Female Genital Tract–A Review

ABSTRACT In females with immunodeficient states there is an increase in the frequency of genital papillomaviral infection, intraepithelial neoplasia, and invasive cancer. The target structures are those of the lower genital tract rather than the uterine body and ovaries. Human papillomaviral (HPV) infections are the likely first manifestation of the neoplastic spectrum, and possible progression to premalignant and invasive cancer is widely suspected. After a variable latent period, HPV infection is common in immuno-suppressed women, and incidence increases with duration of immune impairment. Even in this population, regression of HPV lesions and intraepithelial neoplasia can occur. While the overall number of women with immunodeficiency is not large, an understanding of this problem can shed light on many other clinical problems.

Symposium on Cervical Neoplasia I. Excisional Methods

Journal of Gynecologic SurgeryVol. 1, No. 4 Symposium on Cervical Neoplasia I. Excisional MethodsJOSEPH A. JORDANJOSEPH A. JORDANSearch for more papers by this authorPublished Online:28 Mar 2009https://doi.org/10.1089/gyn.1984.1.271AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail FiguresReferencesRelatedDetailsCited byCervical vaporization in LSIL and persistent HPV infectionTaiwanese Journal of Obstetrics and Gynecology, Vol. 57, No. 4Triage for management of cervical high-grade squamous intraepithelial lesion patients with positive margin by conization: a retrospective analysis10 May 2017 | Frontiers of Medicine, Vol. 11, No. 2Surgery for cervical intraepithelial neoplasia16 June 2010Surgery for cervical intraepithelial neoplasia26 July 1999THE MANAGEMENT OF GENITAL CONDYLOMAS, INTRAEPITHELIAL NEOPLASIA, AND VULVODYNIAObstetrics and Gynecology Clinics of North America, Vol. 23, No. 4Lasers in gynecology: Why pragmatic surgeons have not abandoned this valuable technologyLasers in Surgery and Medicine, Vol. 17, No. 3ErratumLasers in Surgery and Medicine, Vol. 17, No. 4 Volume 1Issue 4Jan 1984 To cite this article:JOSEPH A. JORDAN.Symposium on Cervical Neoplasia I. Excisional Methods.Journal of Gynecologic Surgery.Jan 1984.271-274.http://doi.org/10.1089/gyn.1984.1.271Published in Volume: 1 Issue 4: March 28, 2009PDF download

5-Fluorouracil/chemosurgery for intraepithelial neoplasia of the lower genital tract

Sixteen patients with lower genital intraepithelial neoplasia were treated by 5-fluorouracil (5-FU)/chemosurgery: colposcopically directed excision of neoplastic epithelium pretreated with topical 5-FU. 5-FU loosens the neoplastic epithelium, facilitating its removal from the underlying stroma in a safe, minimally traumatic fashion. 5-FU/chemosurgery was undertaken in patients with vaginal neoplasia or those with lower genital neoplasia who were immunosuppressed or had a neoplastic syndrome, because conventional methods are often difficult or inadequate for these problems. In all 16 patients, the neoplasia went into remission. Two immunosuppressed patients developed recurrences of lesser dysplasia when 5-FU maintenance therapy was interrupted because of pregnancy. It was found that 5-FU/chemosurgery, followed by monthly 5-FU maintenance, may be the best treatment for intraepithelial neoplasia of the vagina or lower genital intraepithelial neoplasia in patients who are immunosuppressed or have a neoplastic syndrome.