A 56-year-old woman makes an appointment with her physician to discuss the results of her cervical cancer screening. She has been menopausal for 2 years and does not take hormone replacement therapy. Her previous Pap smear showed low-grade squamous intraepithelial lesion (LSIL); no HPV testing was performed. Her gynecologic examination is unremarkable. The results of her current Pap smear is as follows: Specimen adequacy satisfactory for evaluation Interpretation low-grade squamous intraepithelial lesion Notes atrophic pattern Which option is the next best step in the management of this patient?

Intravaginal estrogen therapy followed by repeat Pap smear in 1 week

A 31-year-old female presents to her gynecologist for a routine Pap smear. Her last Pap smear was three years ago and was normal. On the current Pap smear, she is found to have atypical squamous cells of unknown significance (ASCUS). Reflex HPV testing is positive. What is the best next step?

Repeat Pap smear and HPV testing in 5 years

Loop electrosurgical excision procedure (LEEP)

A 55-year-old postmenopausal woman comes to the physician for a screening Pap smear. She has no history of serious illness. Her last Pap smear was 10 years ago and showed no abnormalities. She has smoked one-half pack of cigarettes daily for 20 years and drinks 3 bottles of wine per week. She is sexually active with multiple male partners and uses condoms inconsistently. Her paternal grandmother had ovarian cancer and her maternal aunt had breast cancer. Pelvic examination shows multiple red, fleshy polypoid masses on the anterior vaginal wall. A biopsy is obtained and histology shows large cells with abundant clear cytoplasm. Which of the following is the most significant risk factor for this diagnosis?

Diethylstilbestrol exposure in utero

Family history of breast and ovarian cancer

A 27-year-old woman comes to the physician for a routine health maintenance examination. She feels well. She had a chlamydia infection at the age of 22 years that was treated. Her only medication is an oral contraceptive. She has smoked one pack of cigarettes daily for 6 years. She has recently been sexually active with 3 male partners and uses condoms inconsistently. Her last Pap test was 4 years ago and results were normal. Physical examination shows no abnormalities. A Pap test shows atypical squamous cells of undetermined significance. Which of the following is the most appropriate next step in management?

Perform loop electrosurgical excision procedure

Human papillomavirus for USMLE Step 2 CK: High-Yield Microbiology Lessons

HPV Virology - The Naked Truth

Family: Papillomaviridae
Structure: Non-enveloped ("naked") icosahedral capsid, making it environmentally stable.
Genome: Circular, double-stranded DNA.
Subtypes & Risk:
- High-Risk (Oncogenic): 16, 18, 31, 33. Associated with cervical, penile, and oropharyngeal cancers.
- Low-Risk (Non-oncogenic): 6, 11. Associated with condylomata acuminata (genital warts).

HPV virion structure with DNA, histone, and capsid protein

⭐ The viral genome is episomal (circular DNA) in benign lesions but often integrates into the host genome in malignant cancers.

Pathogenesis - Hijacking the Cell

Infects basal keratinocytes of squamous epithelium, requiring a break in the skin or mucosa.
Viral oncoproteins E6 & E7 are the primary drivers of oncogenesis.
- E6 → promotes degradation of the p53 tumor suppressor.
- E7 → promotes degradation of the Rb (Retinoblastoma) tumor suppressor.
Histological hallmark: Koilocytes (enlarged keratinocytes with a clear perinuclear halo and a wrinkled, hyperchromatic nucleus).

Koilocytes in cervical smear (HPV infection)

⭐ In high-risk HPV types (e.g., 16, 18), the viral DNA integrates into the host genome, leading to constitutive expression of E6 and E7. In low-risk types, it typically remains episomal.

Clinical Syndromes - Warts and Worse

Low-risk HPV (Types 6, 11): Primarily associated with benign lesions.
- Condylomata acuminata: Anogenital warts, often appearing as soft, cauliflower-like growths.
- Recurrent Respiratory Papillomatosis: Benign tumors in the respiratory tract, most commonly the larynx.
High-risk HPV (Types 16, 18): Strong association with malignancy.
- Causes squamous cell carcinoma of the cervix, anus, penis, vulva, vagina, and oropharynx.
- Integration into the host genome and expression of oncoproteins E6 (inhibits p53) and E7 (inhibits pRb) drive carcinogenesis.

⭐ While HPV 16 is the most oncogenic type, coinfection with HPV 18 significantly increases the risk for rapid progression to cervical cancer.

Koilocytes in Pap smear, indicative of HPV infection

Screening & Prevention - Guarding the Gates

Screening Workflow:

Diagnostic Tests:
- Pap Smear: Detects koilocytes (perinuclear halos), a sign of HPV infection and dysplasia.
- HPV DNA/RNA Testing: Identifies high-risk viral types (e.g., 16, 18).
- Biopsy: Definitive diagnosis of Cervical Intraepithelial Neoplasia (CIN).

Koilocytes on Pap smear, indicative of HPV infection

Prevention:
- Gardasil 9 Vaccine: Protects against HPV types 6, 11 (genital warts) and 16, 18, 31, 33, 45, 52, 58 (oncogenic).
- Recommended for ages 9-26; catch-up vaccination possible up to age 45.

⭐ Exam Favorite: Most HPV infections (>90%) are transient and resolve spontaneously within 2 years without causing disease.

High‑Yield Points - ⚡ Biggest Takeaways

Human Papillomavirus (HPV) is a non-enveloped, dsDNA virus transmitted via direct contact.

High-risk types (16, 18) are the primary cause of cervical, anal, and oropharyngeal cancers.

Low-risk types (6, 11) cause condylomata acuminata (anogenital warts).

Oncogenesis is driven by viral oncoproteins E6 (inhibits p53) and E7 (inhibits Rb).

Koilocytes on a Pap smear are the classic cytopathic finding.

Prevention is highly effective with the HPV vaccine (Gardasil 9).

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