Patient Story
A 36-year-old woman presented for follow-up of a persistently abnormal Papanicolaou (Pap) test. She is a smoker and has had multiple new sexual partners in the last few years. Although she has had several “abnormal Pap tests” in the past, she states she has never needed treatment. She was found to have a dense acetowhite (AW) lesion on colposcopy that was biopsied (Figure 90-1). The pathology returned cervical intraepithelial neoplasia grade 3 (CIN 3) and the patient was treated with loop electrosurgery. She had negative margins on the loop electrosurgical excision procedure specimen and remained recurrence-free at 3 years.
Introduction
Epidemiology
- Overall rates of Pap test abnormalities are usually estimated from local or regional studies. For example, in an observational cohort study of routine cervical tests in the Northwest United States, in women of all ages (n = 150,052), high-grade squamous intraepithelial lesion was diagnosed at a rate of 0.8 per 1000 compared to negative routine tests that were diagnosed at a rate of 278.5 per 1000.1
Etiology and Pathophysiology
- In high-grade squamous intraepithelial lesions, the abnormalities are immature parabasilar cell types. They have an increased nuclear-to-cytoplasmic ratio, enlarged hyperchromatic nucleoli, few nucleoli, and a reticular or granular appearance.
- On histology, abnormal maturation and nuclear atypia defines CIN. Koilocytosis (perinuclear cytoplasmic vacuolization) is indicative of human papillomavirus (HPV) infection and may be found with high-grade CIN. High-grade CIN is diagnosed when immature basaloid cells with nuclear atypia occupy greater than the lower one third of the epithelium. With increasing lesion severity, there is also increased nuclear crowding, pleomorphism, normal and abnormal mitosis, and loss of polarity.2
- 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 CIN 1 and CIN 2 or 3, and detection of a low-grade squamous intraepithelial lesion. Pap greatly increases the risk that a high-grade CIN will be found on subsequent tests.
- 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 CIN 1 lesions regress or persist, the question has been raised as to whether high-grade CIN might be a process that develops concurrently and somewhat independently from low-grade CIN.
- This theory is supported by the fact that CIN 3 can develop without a detectable preceding low-grade CIN lesion, and high-grade CIN is almost always found closer to the squamocolumnar junction 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 CIN 1 and CIN 2 or 3 lesions developed within the same time frame in a large group of women who turned HPV-positive and were followed for 4 years.3
- Which theory is most correct is a matter of debate. Many practitioners still treat CIN 1 level lesions on the basis of the monoclonal theory or on the theory that if both lesions arise concomitantly, then treating CIN 1 lesions may be the best way of eliminating high-grade CIN. Others promote the idea of observing CIN 1 lesions and treating only high-grade CIN lesions.
Risk Factors
- HPV infection.4
- Nonuse of barrier protection and/or spermicidal gel during sexual intercourse.
- No Pap testing within the last 3 years in low-risk women with a cervix or within 1 year for high-risk women.
- Nonvaccination status for HPV-16 and HPV-18.
- Tobacco smoking.
Diagnosis
- Leukoplakia, as shown in Figure 90-2, is typically an elevated, white plaque seen prior to the application of acetic acid. It is caused by a thick keratin layer that obscures the underlying epithelium and may signal severe dysplasia or cancer. Although it may be associated with benign findings, it always warrants a biopsy.
- AW epithelium following the application of acetic acid is typical for CIN 2 and 3 lesions (Figure 90-1). The AW effect tends to develop more slowly than in lower-grade lesions and to persist longer. The margins of high-grade CIN are straighter and sharper compared to the vague, feathery, geographic borders of CIN 1 or HPV disease.
- With increasing levels of CIN, desmosomes (intracellular bridges) that attach the epithelium to the basement membrane are often lost, producing an edge that easily peels. This loss of tissue integrity should raise the suspicion of high-grade dysplasia. The extreme expression of this effect is the ulceration that sometimes forms with invasive disease.
- High-grade CIN lesions are usually proximal to or touch the squamocolumnar junction, even when contained in larger lesions (Figures 90-1, 90-2, 90-3, 90-4 and 90-5).
- Nodular elevations on the surface of lesions and ulceration are suspicious for high-grade or invasive cancer.
- Increases in local factors such as tumor angiogenesis factor or vascular endothelial growth factor, which are much more commonly produced by CIN 3 lesions, cause growth of abnormal surface vasculature, producing punctuation (Figures 90-3 and 90-4), mosaicism (Figures 90-5 and 90-6), and frankly abnormal vessels. However, most high-grade lesions do not develop any abnormal vessels.
- Punctation is a stippled appearance of small looped capillaries seen end-on, often found within AW area, appearing as fine-to-coarse red dots (Figures 90-3 and 90-4
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