Detection and typing of human papillomavirus DNA in uterine cervices with coexistent grade I and grade III intraepithelial neoplasia: biologic progression or independent lesions?

Abstract

Objective:

To examine the HPV type infection of cervical cone specimens with coexistent CIN1 and CIN3 lesions, in order to define if coexistence of low- and high-grade lesions in the same cervix represent different stages of evolution in a continuing process that is caused by a single viral type or independent lesions induced by different HPV types.

Study design:

The examined material included 43 cases with coexistent CIN1 and CIN3 in the cone biopsy specimen. Detection and typing of HPV was made by RFLP-PCR.

Results:

All CIN1 lesions were HPV positive, while three CIN3 lesions were HPV-negative. The proportion of agreement of the HPV type in the two lesions, excluding negative cases (n = 40), was 60% (95% confidence interval: 43.3–75.1). HPV 16 was the most common type in both CIN3 (56.8%) and CIN1 (46.5%).

Conclusions:

The so-called morphologic progression of CIN is not always synonymous with biologic progression, since many coexistent CIN lesions are caused by different HPV types, and so represent different cell clones. Clonality of coexistent CIN lesions may be implicated in the evolution of CIN as other recent studies have shown.

Introduction

Cervical intraepithelial neoplasia (CIN) is the precursor lesion of cervical cancer. CIN is considered to progress in severity over time, passing from grade I (CIN1 or mild epithelial dysplasia), over grade II (CIN2 or moderate dysplasia) to grade III (CIN3 or severe dysplasia), and then to invasive carcinoma [1], [2]. However, according to an extensive critical literature survey of almost 100 prospective follow-up studies, the progression rate of CIN3 to invasive carcinoma is approximately 12%, while the corresponding rate of CIN1 is estimated only at 1% [3]. More studies have confirmed these observations [4], [5]. Human papillomavirus (HPV) is the necessary cause of both cervical cancer and its precursors [6], [7], even though accumulating experimental and epidemiological data suggest that other co-factors are also implicated in this process [8]. The latter probably explains why most CIN remain stable or regress. Pathological examination of specimens with CIN often reveals that multiple lesions with varying histological severity are synchronously present in a significant number of cases. This phenomenon is regarded as the morphological basis of CIN progression. However, it has been shown that the natural history of CIN evolution rather depends upon the HPV type that infects the cervix [9]. Thus, synchronous appearance of CIN of different severity in the same cervix may represent infection by different HPV types; and consequently, these lesions may follow a different clinical outcome [10]. In addition, infection of the same cervix by multiple HPV types has been observed in cervices with a single grade CIN lesion as well as in cervices with multiple grade CIN lesions [11].

The objective of the present study was to examine the HPV type infection of cervical cone specimens with coexistent CIN1 and CIN3 lesions, in order to define if coexistence of low- and high-grade lesions in the same cervix represent different stages of evolution in a continuing process that is caused by a single viral type or independent lesions induced by different HPV types. Only one previous study has addressed the same question by HPV typing of coexisting CIN lesions, but it included a smaller number of patients than ours [10]. We chose to investigate CIN1 and CIN3 lesions (and not CIN2) because: (1) CIN1 and CIN3 represent the two extremes of the CIN spectrum, so they are more easily separated histologically, and (2) CIN1 is theoretically the least likely to progress to CIN3.