HPV Virus Scientific Facts - Manifestations

Zuna RE, Allen RA, Moore WE, Mattu R, Dunn ST. Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.

High-grade squamous intraepithelial lesions of the cervix are heterogeneous in their invasive potential. Comparison of human papillomavirus types between invasive cervical carcinoma and high-grade squamous dysplasia may provide insight into this biological variability. Liquid-based Pap specimens from 55 high-grade intraepithelial lesions and 47 invasive cervical carcinomas were analyzed by reverse line blot for 27 human papillomavirus types designated high, intermediate, or low risk. Human papillomavirus DNA was present in all high-grade intraepithelial lesions (23 different types) and in 94% (13 types) of invasive carcinomas. High-risk types were present in 81% of invasive carcinomas compared to 58% of high-grade intraepithelial lesions. Severe dysplasias harbored more (79%) high-risk human papillomaviruses as compared to moderate dysplasias (37%). In 40% of high-grade dysplasia cases (59% of moderate dysplasias; 21% of severe) and 13% of invasive carcinomas, intermediate-risk genotypes were identified in the absence of high-risk HPV types. Human papillomavirus 16 was the most common type in all categories, including 47% of high-grade squamous dysplasias (26% moderate; 68% severe) and 61% of invasive carcinomas. Both high-risk type (P=0.0004) and type 16 (P=0.0007) human papillomaviruses were positively associated with increasing severity of diagnosis. The heterogeneous nature of high-grade squamous dysplasias as compared to invasive carcinoma is evident by the wider spectrum of associated human papillomavirus types. Likewise, moderate dysplasia appears to be more heterogeneous in viral type than severe dysplasia. Moderate cases were more often associated with intermediate-risk types, while high-risk types were more prevalent in severe dysplasias and invasive cancers. Moderate dysplasia cases harboring viral types infrequently found in cancers may have a low risk for progression. Human papillomavirus genotyping of high-grade squamous intraepithelial lesions may be important in assessing risk for progression to invasion.

Gynecol Oncol. 2005 Feb;96(2):452-61.

Immune responses to human papillomavirus in genital tract of women with cervical cancer.

Nguyen HH, Broker TR, Chow LT, Alvarez RD, Vu HL, Andrasi J, Brewer LR, Jin G, Mestecky J. Department of Microbiology, University of Alabama at Birmingham, 845 19th Street South, Bevill Biomed. Res. Building, Room 746, Birmingham, AL 35294-2170, USA.

OBJECTIVES: To address a question whether immune responses to HPV infection play a role in control of cervical cancer, we analyzed systemic and mucosal immune responses to HPV in women who underwent radical hysterectomy for cervical cancer (HCC) or loop conization due to cervical dysplasia (LOOP), or had hysterectomy for other reasons (HNN). METHODS: HPV-specific antibodies in sera and vaginal washes were determined by ELISA using recombinant HPV 16 E7 oncoprotein. Cytokines in vaginal washes were assayed by Linco cytokine multiplex method using Luminex technology. Differential gene expression profiling in cervical tumor was determined by microarray analysis and Real-time RT-PCR. RESULTS: While levels of HPV-16 E7-specific IgG in vaginal wash were significantly higher in women undergoing HCC and HNN, the levels of the HPV-16 E7-specific IgA in vaginal wash of women with cervical cancer and cervical dysplasia were lower as compared to patients in HNN. Proinflammatory cytokines, such as IL-6 and IL-8, were dominant in vaginal washes of all subjects studied. However, no pattern of Th1-type and Th2-type cytokine induction was observed as demonstrated by protein analysis as well as differential gene expression profiling in cervical tumor. CONCLUSIONS: These results suggest a selective down-regulation of local HPV-specific IgA responses in women with cervical cancer.

Am J Surg Pathol. 2004 Nov;28(11):1474-84.

Eosinophilic dysplasia of the cervix: a newly recognized variant of cervical squamous intraepithelial neoplasia.

Ma L, Fisk JM, Zhang RR, Ulukus EC, Crum CP, Zheng W. Department of Pathology, Yale University School of Medicine, New Haven, CT 06520-8070, USA.

A proportion of cervical squamous intraepithelial lesions encountered in surgical pathology practice contain both metaplastic features and some degree of atypia [so-called eosinophilic dysplasia (ED)] that defy classification according to established criteria. To elucidate the nature of these lesions, we compared 44 cases of ED to 20 classic high-grade squamous intraepithelial lesions (HSILs) and 10 squamous metaplasias using a panel of biomarkers and human papillomavirus (HPV) testing. EDs were defined as 1) lack of normal maturation; 2) relatively abundant eosinophilic cytoplasm and distinct cell borders compared with conventional HSIL; 3) mildly to moderately increased nuclear to cytoplasmic ratio; and 4) focal dysplastic nuclei showing nuclear enlargement, hyperchromasia, variable nuclear membrane irregularities, and appreciable nucleoli. Expression of p16 (p16), MIB-1 (Ki-67) labeling index, and HPV DNA detection and typing were performed on each case. The majority of EDs showed more than three atypical cells in an entire lesion but lack of apparent features of HSIL. It was common to find neighboring cervical squamous metaplasia and/or conventional SILs (either HSIL or low-grade squamous intraepithelial lesion [LSIL]). Among the 44 cases, 18 (45%) ED lesions were found to be associated with HSIL, 15 (34%) with LSIL or condylomatous lesions, and 13 (30%) EDs were seen without any SILs in the entire specimens. Area of benign squamous metaplasia was found in all ED cases. High levels of p16 and MIB-1 expression were seen in 41 (93%) of 44 ED cases with degrees of immunoreactivity closely resembling those seen with HSIL. Of 16 EDs tested, 13 (81%) were positive for HPV DNAs. Among 10 HPV-positive cases subtyped, 9 (90%) cases contained intermediate- and/or high-risk HPVs and 1 case contained a novel HPV. In the follow-up of pure ED cases, the majority showed presence of dysplastic lesions of either HSIL or LSIL on either loop electric excision procedures or Papanicolaou test samples after a 6- to 10-week period. Therefore, ED represents an unrecognized and potentially clinically significant subgroup of cervical intraepithelial lesions. Based on the unique histologic appearance of ED, its association in some cases with HSIL, the overall immunohistochemical findings, frequent association of ED with intermediate- and/or high-risk HPV infection, and limited follow-up data, we believe that ED represents a variant of HSIL (CIN 2). Since ED possesses histologic features of both dysplasia and metaplasia, we speculate that it may arise from metaplastic cervical squamous epithelium that has subsequently become infected with intermediate- or high-risk HPV.

Hum Pathol. 2004 Apr;35(4):396-402.

Comment in:

• Hum Pathol. 2004 Apr;35(4):393-5.

Telomerase and human papillomavirus as diagnostic adjuncts for cervical dysplasia and carcinoma.

Jarboe EA, Thompson LC, Heinz D, McGregor JA, Shroyer KR. Department of Pathology, University of Colorado Health Sciences Center, Denver, CO, USA.

Telomerase and human papillomavirus (HPV) DNA were evaluated as potential markers of high-grade dysplasia in cervical cytological specimens. Cytology specimens were collected from patients at the time of colposcopic evaluation for management of a previous abnormal cytology test result. Telomerase activity was evaluated by the telomeric repeat amplification protocol (TRAP), and HPV DNA was detected by polymerase chain reaction with L1 consensus-sequence primers and filter hybridization genotyping. Telomerase was detected in 8 of 97 (8.2%) cases with normal cytology or benign cellular changes, in 7 of 98 (7.1%) cases of atypical squamous cells of undetermined significance (ASCUS), in 3 of 95 (3.2%) cases of low-grade squamous intraepithelial lesion (LSIL), and in 17 of 48 (35.4%) cases with high-grade squamous intraepithelial lesion (HSIL). High-risk HPVs were detected in 23 of 97 (23.7%) cases with normal/reactive cellular changes (RCC) cytology, in 28 of 98 (28.6%) cases of ASCUS, in 69 of 95 (72.6%) cases of LSIL, and in 35 of 48 (72.9%) cases of HSIL. Telomerase expression did not correlate with the detection of high-risk HPVs in any cytological diagnostic categories. Telomerase and HPV test results of cytological specimens were correlated with the histological diagnoses of concurrent cervical biopsy specimens. Telomerase showed a sensitivity of 29.9% and a specificity of 94.0% for biopsy-confirmed cervical intraepithelial neoplasia (CIN) II/III. In contrast, high-risk HPVs were detected in 70.1% of cases with underlying CIN II/III, with a specificity of 62.5%. A relatively high proportion of normal/RCC or ASCUS cases with telomerase-positive test results had underlying high-grade dysplasia on cervical biopsy. Thus, technical and practical limitations of the TRAP assay in cervical cytology specimens limit the practical application of telomerase as a diagnostic adjunct in cervical cytopathology.

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