Case 35

Published on 18/02/2015 by admin

Filed under Allergy and Immunology

Last modified 22/04/2025

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CASE 35

CW is a 30-year-old woman in your practice whose recent annual “Pap” smear results have just come to your attention. The diagnosis reads CIN type II (CIN = cervical intraepithelial neoplasia), which indicates inflammatory change and abnormal preneoplastic cells. You arrange a biopsy for her with your referring gynecologist, who confirms this result. In the meantime you order a serologic study for measurement of human papillomavirus 16 (HPV-16) antibody titers and a cervicovaginal lavage specimen to test for the presence of HPV-16 DNA. HPV-16 is implicated as a causative agent in cervical cancer. Based on recent findings in the literature, you wonder whether this woman could be considered for HPV-16 immunization. What other recommendations should you make?

QUESTIONS FOR GROUP DISCUSSION

1. What is a “Pap” smear?
2. Human papillomavirus is transmitted sexually. Most infections are benign, despite the fact that there are more than 50 types that can infect the genitalia. Which type has been isolated from over 50% of cancers of the cervix?
3. Explain why a serologic test is performed even though it is not diagnostic for a present infection.
4. What is the rationale for performing a DNA test for HPV-16? Why is an amplification test (e.g., polymerase chain reaction [PCR]) more likely to detect HPV than other types of DNA tests?
5. What is the generally accepted form of treatment for a CIN type II?
6. Where does the immunogenicity of papillomaviruses reside?
7. Explain how “empty viral capsids” are generated and why they have been considered as potential vaccines for women at high risk for cervical malignancy.
8. Discuss the results of a double-blind randomized study using this vaccine.
9. How would you advise the women in the study who experienced seroconversion but who did not have any evidence for cervical changes?
10. Explain the role of the HPV transformation proteins E6 and E7.

RECOMMENDED APPROACH

Implications/Analysis of Family History

No family history is provided and this is not particularly relevant at this time. Although there are a number of non-HPV factors that contribute to subsequent malignancy, among them being genetic predisposition, the particular contributing gene has not been identified. One could speculate that genetic alterations in any one of a number of immune components could impact on the individual’s ability to eliminate viral infections and hence susceptibility to progression to malignancy. However, at this time, these are not well enough defined to be included in the assessment of the patient.

Implications/Analysis of Clinical History

CW’s clinical history is consistent with the majority of cases of CIN type II in that she did not have any clinical manifestations and this was only detected with the Papanicolaou (Pap) smear, a screening test that has substantially reduced the incidence of mortality resulting from cervical cancer, because of early detection. CIN type II typically indicates infections with HPV-16, one of the many types of HPV that infect the genital tract. A different HPV type is associated with a more common clinical manifestation, condylomata (warts), which are associated with infection with HPV types 6 and 11.

We are not provided any information regarding CW’s immunologic status, which is a significant negative because drug therapies that lead to immunosuppression, and HIV is included in the list of non–HPV-related risk factors for HPV-induced malignant progression.

Implications/Analysis of Laboratory Investigation

A Pap smear is a cytologic test performed on a sample of cells from the uterine cervix. This is a screening test to identify patients with premalignant lesions/cellular changes that could progress to malignancy. The quality of the specimen obtained and degree of accuracy with which the cytology is interpreted play a key role in correct diagnosis. When abnormal cells are identified on a Pap smear a colposcopy may be performed for a magnified look at the cervix (Fig. 35-1).

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FIGURE 35-1 Cervical smear cytology showing CIN I (A), CIN II (B), and CIN III (C). Micrographs are from preparations obtained by Papanicolaou methodology. CIN I (low-grade squamous intraepithelial lesion) shows normal squamous cells and clumps of mildly dysplastic cells with large dark-stained nuclei, irregular contour, and coarse nuclear chromatin. CIN II shows abnormal epithelial cells with larger nuclear:cytoplasmic ratio and coarser hyperchromatic nuclei. Normal epithelial cells are also seen. In CIN III the nuclear:cytoplasmic ratio is greater, although cells are smaller.

Pap smears that are not normal are graded on a classification system. CIN type I lesions often revert spontaneously, but CIN type II lesions require treatment to prevent transformation to cervical cancer. CW’s Pap smear indicated CIN type II lesions. She was referred to the gynecologist who performed a biopsy that confirmed the Pap smear results. CIN type III lesions are considered malignant and are classed as stages 1 through 4, with stage 4 indicating metastasis.

Additional Laboratory Tests

At least 50 different types of HPV have been shown to infect the genital tract. Of these, HPV-16 has been detected in about 50% of cervical cancers. Other types that play a prominent role in cervical cancer include types 18, 31, and 45. Genital warts are caused by HPV types 6 and 11.

Serologic testing is generally done using an enzyme-linked immunosorbent assay (ELISA) to determine the presence of IgG antibodies. The presence of antibodies is an indication that CW has been infected with HPV-16, but it does not provide information regarding a present infection. To confirm a current infection, a test to detect HPV DNA in the cervical sample was requested.

A number of different tests are commercially available to detect HPV DNA in a clinical sample, but amplification techniques (e.g., PCR) increase the likelihood of detecting HPV in a sample. CV’s serology and DNA test for HPV-16 were both positive.

DIAGNOSIS

CW was diagnosed with HPV-16 infection as the likely cause of the CIN type II Pap smear result.

THERAPY

Therapy for CIN type II lesions includes laser vaporization or cryotherapy, a process that uses liquid nitrogen to freeze the tissue. Although a vaccine for HPV may soon be available, there is no evidence for a role for postexposure vaccination of HPV-16–positive individuals. CW should be counseled regarding the use of condoms to avoid transmission to her partner(s).

ETIOLOGY: HUMAN PAPILLOMAVIRUS INFECTION

HPV is a sexually transmitted disease. Most infections are benign, but certain serotypes are implicated in cervical and other anogenital cancers, with HPV-16 the most highly linked, being present in about 50% of cervical cancers and high-grade CIN changes and about 25% of low-grade CINs.

Papillomaviruses are small, nonenveloped double-stranded DNA particles. The capsid consists of 360 copies of the major capsid protein L1. Small amounts of capsid protein L2 are also present. The immunogenicity of papillomaviruses involves antigen presentation of conformational epitopes displayed on viral capsids composed of L1 protein. Expression of recombinant L1 and L2 in an expression system results in self-assembly of a virus-like particle (VLP) that is similar to the capsid structure of the native particles (empty viral capsids). As such, these have been used in place of papillomavirus as antigen source for a vaccine.

Vaccine

Vaccination with L1 virus-like particles in animal model systems has led to evidence for protection from disease. This has formed the basis for consideration of use of such treatment for women at high risk for cervical malignancy. In a recently reported double-blind randomized study, HPV-16–negative women received three such vaccinations and were followed over an 18-month period for evidence of seroconversion and altered cervical pathology. Essentially all vaccinated individuals seroconverted, and only subjects in the control (nonvaccinated) group developed any evidence for CIN. The level of antibody seen in vaccinated individuals was about 60-fold higher than in women naturally seroconverting (evidence for HPV-16 infection and disease). None of the vaccinated females showed evidence for HPV-16 DNA in cervical tissue after vaccination.

Pathogenesis

Two proteins encoded by the HPV genome play an important role in malignant transformation of epithelial cells by HPV. These are the E6 and E7 proteins, which are expressed in malignant tissues. E6 and E7 interact with TP53 and RB, respectively, and this interaction leads to the degradation of both TP53 and RB. Because these proteins are tumor suppressors, their degradation plays an important role in the process of malignant conversion of infected cells.

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