question

Cervical dysplasia and HPV disease

answer

Cervical dysplasia has been the model to understand HPV- associated disease and malignant transformation

question

Pap smear

answer

Cytologic screening test for cervical cancer utilizing exfoliated cervical cells collected transvaginally Classifications: -NILM: Negative for Intra-epithelial Lesions or Malignancy -ASCUS: Atypical Squamous Cells of Undetermined Significance -SIL: Squamous Intraepithelial Lesion -LSIL: low-grade, squamous intraepithelial lesions -HGSIL: high-grade SIL

question

LSIL

answer

Low-grade, squamous intraepithelial lesions Other terms used for LSIL: mild dysplasia, low grade cervical intraepithelial neoplasia, CIN1 Considered an HPV effect Low risk for progression to invasive cancer

question

HGSIL

answer

High-grade SIL Other terms used for HGSIL - moderate and severe dysplasia, high grade cervical intra-eptihelial neoplasia, CIN2/3, Carcinoma in situ, CIS High risk for progression to invasive cancer

question

HPV, generally

answer

Infection with human papillomavirus (HPV) is very common +140 different HPV types/strains -about 40 of which cause anogenital infections Low risk and high risk HPV types have been identified based on their oncogenic potential Most low risk and high risk HPV infections will clear spontaneously

question

Low-risk HPV infections

answer

Association with ano-genital condyloma and low grade cervical dysplasia (LSIL, CIN 1) HPV 6 and 11 account for over 90% of ano-genital warts and low-grade dysplasia Other common non-oncogenic viral types: 40, 42, 43, 44, 54

question

High-risk HPV types

answer

*16*, *18*, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68 The most prevalent HPV types that are associated with high grade dysplasia (HGSIL, CIN3, CIS) and cervical cancer are HPV types 16 and 18 -about 70% of all cervical cancers (16: 55%, 18: 15%) HPV 31, 33, 45, 52, 58 cause about 10% of cervical cancers worldwide Persistent HPV infection is the major risk for malignant transformation

question

HPV and cancer types

answer

+99% of cervical cancers are associated with high risk HPV types Cervical cancer is not the only cancer associated with high-risk HPV types Infection with high-risk HPV types are associated with 70%-85% of anal cancers 40%-50% of vulva and vaginal cancers 40%-50% of penile cancers 25% - 60% of in oral and oropharyngeal cancers

question

HPV Incidence

answer

Risk of acquiring a new HPV infection 6.2 million new infections each year in the US From college cohort studies: -Penetrative sexual contact: cumulative incidence exceeds 40% after 3 years -Non-penetrative sexual contact: cumulative incidence ~ 2.5% after 2 years

question

HPV Prevalence

answer

Risk of having an HPV infection -About 15% of people ages 15-49 are currently infected with HPV -More than 50% of sexually-active men and women will acquire a genital HPV infection -About 10% of Pap smears in women aged 40-49 have evidence of HPV infection with high risk HPV types (atypical cells of undetermined significance or squamous intra-epithelial lesions)

question

Cervical cancer risk from HPV

answer

Infection with oncogenic HPV is necessary but not sufficient to cause malignant transformation of cervical cells Most HPV infections (both those with high-risk and low-risk types) will in fact clear spontaneously Multiple suspected co-factors -Long-term use of oral contraceptives -High number of full-term pregnancies -Tobacco smoking -Past infection with HSV-2 and Chlamydia trachomatis

question

Suspected co-factors for HPV -> cervical cancer

answer

Multiple suspected co-factors -Long-term use of oral contraceptives -High number of full-term pregnancies -Tobacco smoking -Past infection with HSV-2 and Chlamydia trachomatis

question

Natural history of an infection with an oncogenic HPV type

answer

1. Sexual activity 2. HPV infection 3a. Transient infection 3b. Persistent infection -normal cervical epithelium -> low-grade lesions -> high-grade lesions -> *invasive cervical cancer*

question

Cytologic abnormalities and HPV infections

answer

1. Normal cervix + HPV infection 2. Mild cytologic abnormalities 3a. Clearance -> normal cervix 3b. Progression -> precancerous lesions 4a. Regression -> mild abnormalities 4b. Invasion -> cancer

question

HPV 16/18

answer

Compared to other oncogenic HPV types, more likely to have persistent infection Additionally, have a shorter period of latency from exposure -> clinically-significant disease

question

HPV Testing

answer

1. Serology -not clinically useful 2. Type-specific testing

question

Serology for HPV

answer

NOT clinically useful Under-estimates the number of infected individuals Many people with current or prior HPV infection or associated conditions do not develop antibodies +70% with HPV infection (as judged by positive PCR) will be seropositive to that type Only 30-70% of patients with HPV-associated cancers will be seropositive

question

HPV Tests

answer

Type-specific testing Pooled test for the 13 most common high-risk types

question

Cervical cancer screening

answer

Pap smear: cytologic screening test for cervical cancer utilizing exfoliated cervical cells collected transvaginally Current recommendation: combine cytology and HPV testing 1. Women 30 years old: co-testing -cytology + HPV screening -every three years 3. HPV screening along -recent data suggests that primary HPV screening alone may have higher sensitivity and specificity to primary cytologic screening

question

Evaluation of the cervix

answer

T zone: squamocolumnar junction Koilocytes on pap smear: large nucleus with halo, eosinophilic cytoplasm Colposcopy to look for abnormalities

question

Pap NILM + HPV negative

answer

No further evaluation Repeat Pap in 3 years

question

Pap NILM + HPV 16/18 positive

answer

Colopsocopy/biopsy for further evaluation

question

Pap NILM + HPV high-risk (non 16/18)

answer

Repeat Pap/HPV in one year

question

Pap is ASCUS/HPV positive

answer

Colopsocopy/biopsy for further evaluation

question

Pap is LGSIL or HGSIL

answer

Colposcopy/biopsy for further evaluation

question

Biopsy-proven LGSIL

answer

Close observation

question

Biopsy-proven HGSIL

answer

Further follow-up with excisional biopsy - either LEEP (Loop Electrosurgical Excision Procedure) or cold-knife cone biopsy

question

HPV and anal cancer

answer

4% of all lower-GI-tract cancers in US -5000 new cases per year -rates increasing Risk factors: -number of lifetime sexual partners -receptive anal intercourse -immunosuppression 75%-80% related to HPV (mostly HPV 16/18) HPV4 vaccine trials in MSM population have demonstrated efficacy in reducing cancer precursors (AIN) as well as infection with high risk HPV types

question

HPV and colon cancer

answer

HPV is NOT associated with colon cancer

question

Anal T-zone

answer

Transition from stratified squamous to columnar epithelium similar to cervical T-zone -vast majority of anal dysplastic lesions occur here AIN (neoplastic precursors analogous to CIN) exist

question

Screening and treatment for anal pre-cancer

answer

Contrast to cervical cytology: efficacy and cost-effectiveness of anal cytology screening has not been established, especially in a broad population Contrast to cervical treatment: entire transformation zone of the anal canal cannot be safely removed -recurrences are thus more frequent and pervasive Even if precancerous lesions can be identified for treatment, there is no standardized treatment approach -patients face a difficult clinical course, frequently complicated by pain, bleeding, anal stenosis

question

HPV and penile cancer

answer

Rate: 0.8/100,000 -decreasing 40% -50% are causally linked to HPV Risk factors -lack of circumcision -chronic inflammation

question

HPV and oropharyngeal cancer

answer

Rate: 5.2/100,000 Risk factors -tobacco -alcohol -number of lifetime sexual partner Worldwide, rates of HPV associated oropharyngeal cancers are ncreasing dramatically -in the US, up to 60% of these cancers may now be HPV-16 associated. Best method to detect HPV in oral and oropharyngeal cancers is controversial -no screening test analogous to the cervical pap smear exists

question

Natural history of HPV-associated oral infections

answer

Not well understood -median time from infection to cancer? -factors that affect persistence and progression? Five-year survival rate for HPV-related oral cancer is ~75% -about half that for smoking-related oral cancer Women with oral pharyngeal squamous cell cancer have a significantly elevated risk of developing HPV-related genital cancer -strongly suggests co-infections

question

Structure of HPV

answer

Non-enveloped DNA virus Icosahedral capsid composed of 72 capsomeres Contains double stranded circular DNA genome of about 7900 base pairs

question

Genomic organization of HPV

answer

Similar to all papillomaviruses Early (E) region: codes for proteins that control DNA replication -Viral replication proteins E1, E2, E3, E4 -Oncogenic transforming proteins E6 and E7 Late (L) region: codes for the major capsid protein (L1) and a minor capsid protein (L2) Non-coding upstream regulatory region

question

E2 viral replication protein in HPV

answer

Viral replication protein represses the transcription of E6 & E7 (oncogenic transforming proteins)

question

E6 and E7 proteins of HPV

answer

Oncogenic transforming proteins With integration of the viral episome into host DNA, over-expression of E6 and E7 can occur E6: inhibits p53 function -promotes loss of cell-cycle control -inhibits apoptosis E7: binds to PRB (retinoblastoma anti-oncoprotein) -degrades PRB -accelerates DNA synthesis -disrupts cell-cycle control E2 viral replication protein represses the transcription of E6 & E7

question

Mechanisms of HPV Carcinogenesis

answer

SLIDE 46

question

HPV evasion of the immune system

answer

No infection or replication in antigen-presenting cells (APCs) Infected keratinocytes may be less susceptible than other infected cells to cytotoxic lymphoctye-mediated (CTL) lysis Little tissue destruction associated with HPV HPV only infects the epithelium (epitheliotropic) without a blood-borne phase of infection Poor immune response to early viral proteins Variable immune response to late viral capsid proteins -limited and delayed expression of late viral capsid proteins

question

Classification of papillomaviruses

answer

Based predominantly on nucleotide sequence similarity L1 gene is used for classification and construction of phylogenetic trees HPV is classified as a different type if the L1 nucleotide sequence is at least 10% dissimilar 189 currently characterized PVs -grouped into 16 Genera -5 Genera represent human PVs: Alpha, Beta, Gamma, Mu, and Nu

question

HPV Vaccines

answer

All commercially available HPV vaccines are type specific, sub-unit vaccines Antigen: virus-like particle (VLP) When expressed in cell systems, capsid proteins (either L1 or L1/L2) can self-assemble into VLPs -these VLPs are not infectious

question

HPV2, HPV4, and HPV9 vaccines

answer

Not biological equivalents 1. Different antigens -HPV: baculovirus expression vector system in insect cells -HPV4/HPV9: yeast expression system 2. Different adjuvant -Alum adjuvant -HPV2 is first vaccine in US with ASO4 (includes aluminum hydroxide salts and monophosphoryl lipid A): more potent BUT: generally show similar clinical efficacy in Phase III trials for primary study endpoints -HPV 16/18 associated cervical dysplasia/cancer

question

HPV2 and HPV4: immunogenicity

answer

Both highly immunogenic -induce antibody titers higher than from natural infection after the third dose Minimal protective threshold is not known HPV2 shows higher neutralizing antibodies to both HPV16 & HPV 18 at 7 and 48 months To date, no evidence of waning clinical efficacy with either vaccine in about 8 years of follow-up

question

Current HPV vaccine development

answer

Trying to understand comparative immune responses of the quadrivalent (HPV 6,11,16 & 18) versus bivalent (HPV 16 & 18) vaccine Different adjuvants -bivalent vaccine has more potent adjuvant) -adjuvant might influence duration of immune response, cross-protection against other HPV types not in the vaccine, as well as safety profile Completed studies have assessed the potential benefits of adding additional HPV types to the qudrivalent vaccine: Types 31, 33, 45, 52, 58 -additional protection versus immune interference -recent recommendations replace HPV4 recommendations with HPV9

LEC 36: Human Papillomavirus – Flashcards

Unlock all answers in this set

Haven't found what you were looking for?

Search for samples, answers to your questions and flashcards