What are the causes, pathophysiology, clinical manifestations, diagnosis, and management of cervical malignancy?

Cervical Malignancy: Comprehensive Overview

Causes

Persistent infection with high-risk human papillomavirus (HPV) is the necessary cause of virtually all cervical cancers, detected in 99% of cases. 1

Primary Etiologic Agent

• HPV type 16 is the single most carcinogenic genotype, accounting for 55-60% of all cervical cancers worldwide and 50-60% of invasive squamous cell carcinomas 2
• HPV type 18 is the second most common, responsible for 10-15% of cervical cancers and causes a disproportionately higher percentage of adenocarcinomas (32%) compared to squamous cell carcinomas (8%) 2
• Together, HPV 16 and 18 cause approximately 70% of all cervical cancers globally, including 68% of squamous cell cancers and 83% of adenocarcinomas 2
• Approximately 10 other high-risk HPV genotypes (including HPV 31,33,45,52, and 58) collectively cause the remaining 25-35% of cervical cancers 2

Co-factors Modifying Risk

• Chronic immunosuppression, particularly HIV infection, increases risk for HPV persistence and progression to cervical cancer 2
• Early age of onset of coitus and larger number of sexual partners are epidemiologic risk factors 2

Pathophysiology

HPV-induced cervical carcinogenesis is a multi-step process taking an average of 12-15 years from persistent infection to invasive cancer. 3

Mechanism of Carcinogenesis

• HPV acquisition occurs through sexual and genital skin-to-skin contact, with prevalence peaking within a few years after sexual debut 2
• Most HPV infections (~90%) are transient, becoming undetectable within one to two years 2
• Persistent HPV infection is the critical step—women whose infections persist are at significant risk of developing precancerous lesions 2
• One-year or two-year HPV persistence, especially by HPV 16, strongly predicts a 20-30% risk of CIN3+ (high-grade precancer) over 5 years 2
• The virus infects mucocutaneous epithelium and produces viral particles in matured epithelial cells, causing disruption in normal cell-cycle control through viral oncogenic proteins E6 and E7 4, 5
• Altered transcriptional regulation of viral E6/E7 oncogenes results in genomic instability, distinguishing cell transformation from productive viral infection 3
• Additional (epi)genetic alterations accumulate in high-grade CIN lesions, resulting in overt malignancy via immortality and growth conditions that become less sensitive to growth-modulating influences 3
• Untreated CIN3 has a 30% probability of becoming invasive cancer over 30 years 2

Clinical Manifestations

Abnormal vaginal bleeding, including post-coital, intermenstrual, or post-menopausal bleeding, is the hallmark presentation of cervical cancer. 6

Primary Symptoms

• Abnormal vaginal bleeding represents the most common symptomatic manifestation, including post-coital bleeding, intermenstrual bleeding, and post-menopausal bleeding 6
• Intermittent spotting is frequently reported, particularly in women with early stages of disease 6

Secondary Symptoms

• Vaginal discharge is prominent, particularly with adenocarcinoma histology 6
• Pelvic pain occurs in locally advanced disease and represents a later-stage symptom, often indicating parametrial or pelvic sidewall involvement 1, 6
• Dyspareunia is an associated symptom 6

Critical Clinical Pitfall

• Many early cervical cancers are completely asymptomatic, which is precisely why screening programs exist 6
• The probability of cervical cancer in women presenting with post-coital bleeding varies dramatically by age: 1 in 44,000 for women aged 20-24 years versus 1 in 2,400 for women aged 45-54 years 6

Diagnosis

Histopathology

• The WHO recognizes three categories of epithelial tumors: squamous, glandular (adenocarcinoma), and other epithelial tumors including neuroendocrine tumors and undifferentiated carcinoma 1
• Squamous cell carcinomas account for 70-80% of cervical cancers and adenocarcinomas for 10-15% 1
• Squamous carcinomas are classified into keratinizing and nonkeratinizing types, with keratinizing tumors characterized by keratin pearls and less frequent mitoses 1

Physical Examination

• Gross appearance is variable: carcinomas can be exophytic (growing out of the surface) or endophytic (with stromal infiltration and minimal surface growth) 1
• Some early cancers are not appreciable, and even deeply invasive tumors may be deceptive on gross examination 1
• If examination is difficult or there is uncertainty about vaginal/parametrial involvement, examination should be done under anesthesia together with a radiotherapist 1
• Papillary tumors are more commonly adenocarcinomas 1

Screening and Detection

• Papanicolaou smears are used in classical primary screening 1
• HPV DNA testing is well diffused in developed countries and is more sensitive than cytology as primary screening 1, 4
• HPV testing is clinically valuable in triaging low-grade cytological abnormalities 4

Management

Prevention Strategies

Primary Prevention: Vaccination

• Three HPV vaccines are licensed: bivalent (2vHPV), quadrivalent (4vHPV), and nine-valent (9vHPV) 1
• All three vaccines provide protection against HPV 16 and 18 1
• 4vHPV also includes HPV 6 and 11, which cause 90% of genital warts 1
• 9vHPV covers five additional oncogenic HPV types (31,33,45,52, and 58), which cause an additional 15% of HPV-related cancers in women 1
• All three vaccines are efficacious against related infection and cervical, vaginal, vulvar, and anal dysplasia 1
• Post-licensure reports indicate beneficial population-level effects as early as 3 years after introduction, including decreases in high-grade cervical abnormalities 1
• Prophylactic vaccines targeting HPV 16/18 have the potential to prevent more than two-thirds of worldwide cervical carcinomas 7

Secondary Prevention: Screening

• Most developed countries have introduced HPV vaccines into routine vaccination programs, with more than 60 million doses distributed by 2010, guaranteeing a protection rate of approximately 70% 1
• Large geographic variation in cervical cancer rates reflects differences in screening availability, which allows detection and removal of precancerous lesions 2
• In women aged >30 years, HPV testing can identify high-grade cervical intraepithelial neoplasia earlier than Pap smears with acceptable specificity 8
• The high sensitivity of HPV testing suggests that such testing could permit increased intervals for screening 8

Epidemiologic Context

• Cervical cancer is the third most common cancer in women, with an estimated 529,828 new cases and 275,128 deaths reported worldwide in 2008 1
• More than 85% of the global burden occurs in developing countries, where it accounts for 13% of all female cancers 1
• In developing countries, the age-standardized mortality rate is 10/10,000—more than three times higher than in developed countries 1
• Five-year relative survival for European women diagnosed with cervical cancer in 2000-2007 was 62%, ranging from 57% in Eastern Europe to 67% in Northern Europe 1
• Survival decreased with advancing age at diagnosis, from 81% for 15-44-year-olds to 34% for women 75 years 1
• FIGO stage is one of the most important prognostic factors 1