HSIL Terminology |
Clinical Significance of HSIL |
Virology of HSIL |
HSIL and Cytologic Screening |
HSIL Cytology |
HSIL Site and Topography |
HSIL Colposcopy |
A high-grade squamous intraepithelial lesion (HSIL) is a cytologic or histologic abnormality that encompasses nuclear and other cellular changes indicative of pre-invasive squamous neoplasia of a moderate to severe nature. This terminology came into use in 1988 with the creation of the Bethesda System, which standardized the nomenclature used for cervical cytology classification. “HSIL” is also used for histologic interpretations. In terms of previously accepted nomenclatures, HSIL encompasses the disease spectrum from moderate dysplasia / cervical intraepithelial neoplasia grade 2 (CIN2) to severe dysplasia / cervical intraepithelial neoplasia grade 3 (CIN3) and carcinoma-in-situ (CIS).
Cervical squamous intraepithelial lesions constitute a spectrum of disease. The divisions between CIN2, CIN3, and CIS are arbitrary and subjective. The distinction between these grades of disease on cytology or histology specimens is characterized by low inter- and intra-observer reproducibility. The use of the HSIL terminology clearly communicates an abnormality at the more severe end of the disease spectrum and is a more reliable, reproducible way to classify lesions with malignant potential.
CLINICAL SIGNIFICANCE OF HSIL
HSIL lesions are asymptomatic and invisible to unaided visual examination. In 1990, 70,000 cases of HSIL were treated in the United States. The incidence of HSIL appears to be increasing. The modal age at diagnosis has decreased from 35 in the 1960s to 25 in the 1990s. These are worrisome trends. HSIL lesions have significant malignant potential. It is estimated that 30 to 50% of HSIL lesions will progress to invasive disease if left untreated. Moderate dysplasia (CIN2) lesions exhibit progression and spontaneous regression rates intermediate to those of mild and severe dysplasia. Spontaneous regression may occur in up to 40% of CIN2 lesions. Nonetheless, HSIL lesions diagnosed by histopathology are treated because of their malignant potential. The 2001 ASCCP Consensus Guidelines do allow for the close follow-up of small CIN2 lesions in adolescents. This carries with it serious risk if the patient is noncompliant to follow-up.
VIROLOGY OF HSIL
HSIL is strongly associated with oncogenic (high-risk) types of human papillomaviruses (HPV). Infection with high-risk HPV (hrHPV) is essential to the development of cervical cancer. Such infection is very common in the general population and is asymptomatic and not apparent without special means of detection (subclinical infection). Low-risk, warty infections are productive of new viral particles and therefore demonstrate cytopathic HPV effects (koilocytosis) typical of LSIL. However, in HSIL, HPV infection is not productive and is instead transforming, with oncogenic HPV becoming integrated into host DNA. The cytopathic effects seen in LSIL lesions are less pronounced or absent in HSIL cytology and histology. Integration of the HPV DNA into the host (human) DNA leads to the over-expression of the viral E6 and E7 genes. This interferes with the function of host tumor suppressor gene products. This can lead to the development of cervical neoplasia. HSIL lesions are usually monoclonal. Their infectivity, as compared with low-risk, productive HPV infections, is uncertain.
HSIL AND CYTOLOGIC SCREENING
- The cytologic diagnosis of HSIL is more frequent with liquid-based cytology. This suggests, but does not prove, that liquid-based cytology may be more sensitive for HSIL than conventional smears. Nonetheless, conventional smears remain an acceptable and effective technique for cervical cancer screening.
- HPV DNA testing is of no use for Pap smears read as HSIL since over 90% are hrHPV DNA positive.
- Due to the significant false-negative rate of a single Pap smear, cytology should not be relied upon or delay the evaluation of a patient whose history and / or physical exam are suspicious for cervical cancer.
- Relatively small cells
- Abnormal cells may be isolated or in groups
- Round or oval cells with nuclear pleomorphism
- Hyperchromatic, granular chromatin
- Denser, thin rim of basophilic cytoplasm
HSIL SITE AND TOPOGRAPHY
- HSIL lesions are usually within the transformation zone; the most severe disease is found at the most proximal (cephalad) extent of lesion.
- May extend into endocervical canal
- Usually single lesions
- May be located alongside or within low-grade lesions
- Size of lesions variable but tends to correlate with severity of disease and risk of occult invasion
- Size of lesion correlates with risk of treatment failure
Normal Saline and Green Light Filter: Colposcopy of HSIL cytology should start with the application of normal saline to remove mucous, and allow visualization of any obvious findings indicative of invasive cancer such as erosion, surface contour abnormality, leukoplakia, or exophytic lesions. The prominent, abnormal vascular patterns of HSIL and cancer can be more visible before the application of acetic acid and should be looked for with the aide of a red-free (green) filter.
Acetic Acid and Lugol’s Iodine: The next step is the application of 3 to 5% acetic acid to the cervix. This should be done in a manner without abrading the surface epithelium, as HSIL lesions can detach from the underlying stroma relatively easily and peel away. Lesion margins, color, and vascular patterns are then assessed and graded, with biopsies taken from the areas that are judges as the most severe. The application of Lugol’s iodine is optional. It may help determine the most abnormal area if there is extensive disease, or assist in locating a lesion when none is apparent after the application of acetic acid.
The following descriptions refer to the colposcopic appearance of HSIL lesions after the application of acetic acid.
- Sharply demarcated lesion edges, often with very straight contours; lack the geographic, feathered, or indistinct margins of LSIL.
- HSIL often coincides with and may be difficult to distinguish from a larger LSIL lesion. Internal margins (borders) describe abrupt change in the nature of a lesion(s) as the examining eye moves radially from outer to inner (proximal) transformation zone. A so-called “lesion within a lesion” or “border within a border” is a feature of high-grade neoplasia, with the inner, more proximal lesion being more severe.
- Severe lesions have raised, rolled, or peeling margins (avoid trauma to epithelium during exam).
- Distinct, denser acetowhitening than LSIL lesions
- Dull surface due to increased nuclear density and less reflection of incident light
- Dull or gray-white to oyster gray color
- More prompt and persistent aceticowhite change
- Fine vascular patterns of normal and LSIL epithelia absent
- Absence of vessels due to increased lesion density and occlusion small of vessels consistent with HSIL
- “Coarse” vascular patterns (punctation, mosaicism, or both) characterized by:
- Larger and varied caliber of vessels
- Larger and variable intercapillary distances
- “Umbilicated” mosaic patterns, with punctation in the middle of the “tiles” suggests CIN3 / carcinoma-in-situ.
- Vascular patterns can be striking and visible even at lower magnification
- Vascular patterns change as acetic acid effects develop, then fade: keep watching!
- Prominent and dilated vessels may blunt acetowhite change; Don’t miss the HSIL or invasive cancer because the examining eye is drawn to acetowhite change and away from the less-white HSIL or cancer!
Iodine Staining: HSIL lesions are strongly non-staining with the application of Lugol’s iodine; appearing bright yellow or pink. (Normal epithelium stains dark purple-black or brown with iodine in estrogenized women because it is glycogenated).
Histology of HSIL
- Cellular maturational abnormality extends into the upper third of the epithelial thickness; basement membrane intact
- Cellular and especially nuclear hyperchromasia and pleomorphism; some mitoses may be seen
- Modern Colposcopy Textbook and Atlas, Second Edition. American Society for Colposcopy and Cervical Pathology. Kendall-Hunt Publishing Co., Dubuque, 2004. Chapters 3, 18.
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