Definition | Epidemiology and Role of HPV | Spectrum of Disease | References

Definition

The incidence and mortality of invasive cervical cancer in the United States and other developed countries has decreased over 70% over the past 50 years due cervical cancer screening programs. The Pap test, despite its limitations, is the most effective screening test of modern medicine. In this country, the numbers of cases of cervical cancer diagnosed each year has been stable for over a decade at approximately 11,000; the numbers of deaths each year number just around 4,000. These numbers remain stable despite population growth and the rapid rise in the incidence of pre-invasive disease since the 1960s, coincident with the increase in number of sexual partners and earlier age of onset of sexual relations in the general population. It is important to note that over half of the women diagnosed with and dying from cervical cancer have never undergone cytologic screening, or have been inadequately screened. Older women, socio-economically disadvantaged women, and recent immigrants to the United States from underdeveloped countries are at highest risk for lack of adequate screening.

Over the past three decades, we have come to understand that human papillomaviruses (HPVs) are present in essentially all true cervical neoplasia, explaining the epidemiology of the disease. Of the more than 100 types of HPVs approximately 40 may involve the anogenital tract. Approximately 15 HPV types are considered oncogenic, causing virtually all cases of cervical cancer. HPV 16 alone accounts for over 50% of cancers and HPV 18 is responsible for an additional 10-15%. Identified risk factors for cervical cancer such as early age at first intercourse and multiple sexual partners are proxies for risk of HPV infection. However, HPV infection is very common and cervical cancer is not. Co-factors such as smoking, high parity, and host immune responses also play a role.

Serologic measurements of antibodies against HPV capsid antigens, indicative of past infection, provide evidence that a majority of sexually active individuals have been infected with HPV at some point. Prevalence studies show that between 5% and 20% of the general population has HPV DNA detectable in cervical samples; prevalence is higher in younger women (> age 30), compared to those over age 30. In most cases, infection with HPV—including carcinogenic HPV—is transient and may or may not be associated with cervical abnormalities of LSIL or CIN1. Typically, viral DNA is no longer detected in cervical samples after 1 to 2 years. It is persistent infection with an oncogenic HPV that dramatically increases the risk for developing CIN3 or cancer.

Potentially cancerous precursor lesions found on the uterine cervix are referred to as cervical intraepithelial neoplasia, or CIN. Traditionally, high-grade CIN is thought to arise as a small focus within a larger area of low-grade CIN that expands and eventually replaces much of the low-grade lesion. This "monoclonal" theory is supported by the fact that there is a 5-year difference between the peak prevalence of CIN1 and CIN2,3, and detection of a LSIL Pap greatly increases the risk that a high-grade CIN will be found on subsequent smears. It has been difficult to document the rate of progression because most studies use cervical biopsy to establish an accurate diagnosis, which influences the rate of disease progression.

With the discovery that most CIN1 and CIN2 lesions regress or persist unchanged, the question has been raised as to whether high-grade CIN might be a process that develops concurrently with low-grade CIN. This theory is supported by the fact that CIN3 can develop without a detectable preceding low-grade CIN lesion, and high-grade CIN is almost always found closer to the squamo-columnar junction (SCJ) than concomitant low-grade lesions. It has also been found that women who turned HPV 16/18 positive had a 39% rate of high-grade CIN at 2 years compared to HPV negative women. Schiffman, et al. reported that both CIN1 and CIN2,3 lesions developed within the same time frame in a large group of women who turned HPV positive and were followed for 4 years. Currently, most experts believe CIN1 has minimal potential for progression to cancer and simply reflects underlying HPV infection, while CIN2,3 is of indeterminate malignant potential.  CIN3 is considered a true cancer precursor.

Epidemiology and Role of HPV

NATURAL HISTORY AND MALIGNANT POTENTIAL OF CERVICAL NEOPLASIA

Cervical cancer was once a leading cause of cancer death in the United States. Now, invasive cervical cancers are relatively uncommon. This change is probably mostly due to effective identification and eradication of cancer precursor lesions (CIN). Laboratory surveys from the College of American Pathologists (CAP) indicate that more than 1 million women each year are diagnosed with low-grade intraepithelial lesions, and >250,000 will be found to have CIN2 or CIN3 level lesions.

Persistent human papillomavirus (HPV) infection is requisite to the development of cervical neoplasia. Oncogenic HPV types have a molecular advantage in establishing a persistent infection that disrupts the apoptotic machinery of the cervical epithelial cell. This leads to disorganized, unchecked proliferation of cells and loss of normal maturation as they progress upwards through the epithelial cell layers. HPV persistence is demonstrated before the appearance and even after the regression of cervical cytological abnormalities (Castle, Schiffman). Multiple studies (Ho, Kulaga, Peyton, Giuliano) have shown that the mean duration of an HPV infection is between 4 and 10 months and is longer when the infecting HPV type is oncogenic versus non-oncogenic. Parity (Molano) and cytological abnormalities (Dalstein) correlate with a greater persistence of HPV and therefore an increased risk of cervical dysplasia.

The natural history and potential outcomes of cervical intraepithelial neoplasia (CIN) can be estimated from previous studies (Table 1) (Ostor).

Factors that may determine the biologic behavior of cervical dysplasia remain elusive. Age greater than 35 years old, smoking, co-infection with HIV or Chlamydia have all been proposed as promoters of the malignant progression of cervical dysplasia to cancer, but none have been definitely proven. Future research should provide insight into molecular surrogates of dysplasia (e.g. HPV diagnostics, gene methylation patterns, proliferation markers) that could help predict outcomes and the safety of expectant management or need for closer follow-up and treatment.

Spectrum of Disease

It is well established that invasive carcinoma of cervix is preceded by a precursor lesion that morphologically resembles the adjacent invasive squamous carcinoma. This lesion is termed “carcinoma in situ” (CIS). However, CIS in itself is preceded by a spectrum of lesions with varying degrees of abnormality. The term “dysplasia” was introduced to refer to this spectrum of progressive cervical abnormality from normal epithelium to CIS. The word “dysplasia” means “abnormality of development.” Histologically, dysplasia is sub-classified into mild, moderate, or severe based on the extent to which the cervical epithelium is involved with abnormal cells: 1/3, 2/3 or full thickness respectively. This classification reflects the biological potential of the precursor lesions to progress to invasive carcinoma. The majority of mild dysplasia lesions are of little if any malignant potential, but a few, perhaps 10%, will progress to a higher grade. At this time, it is not possible to distinguish which will progress clinically other than to watch over time. Because most of these lesions regress and treatments risks can be substantial, treatment of CIN1 is not recommended. Moderate and severe dysplasias are considered true pre-malignant lesions with a progression rate to invasive cancer of 30% to 50% over time.

In 1960, the term “cervical intraepithelial neoplasia” (CIN) was introduced and implied the concept that precursor lesion to squamous cell carcinoma represented a single, continuous disease process. CIN nomenclature for histology is more specific to the cervix than the general term “dysplasia,” and makes clear the pre-invasive nature of lesions. The CIN nomenclature divides cervical cancer precursors into CIN1, CIN2, and CIN3, corresponding to mild, moderate and severe dysplasia/carcinoma in situ. It is the most widely used histologic terminology for cervical cancer precursors. However, while of descriptive value, the concept that these lesions represent an oncogenic continuum is now known to be erroneous, as most CIN1 will regress without treatment.

With the identification of human papillomavirus (HPV) as the etiologic agent for cervical cancer and its precursors in the 1980s, other more confusing terms became prevalent such as flat condyloma, atypical condyloma, condylomatous atypia, etc. appeared on cytology and histopathology reports. Our current understanding of the pathogenesis of cervical precursors is that that CIN is not a single disease process but rather represents two distinct entities: 1) a viral stage of productive infection which is usually self-limited and 2) neoplastic transformation in a minority of HPV-related lesions. This insight into the pathogenesis of CIN has revolutionized our understanding and approach to cervical disease. It also has lead to the development of a completely new nomenclature for cervical cytologic interpretation that better reflects this biologic process: the Bethesda System (1988, revised 1991, 2001). The Bethesda terminology for cytologic reporting subclassifies squamous cervical precursor lesions into low-grade squamous intraepithelial lesion (LSIL), for lesions previously classified as koilocytic atypia (HPV) and/ or CIN1, or high-grade squamous intraepithelial lesion (HSIL) encompassing CIN2 or 3 changes. Although originally introduced for cytologic reporting, the “SIL” terminology can be used for histologic classification as well, thus minimizing the confusion resulting from different terminologies for cytology and histology.

References

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