Department of Pathology, Sinai Hospital of Baltimore Pathology, Baltimore, MD, USA
Cervical biopsies are common and nearly always performed for the purpose of evaluating squamous or glandular dysplasia . Usually the patient will have a history of an abnormal Pap test or a prior abnormal biopsy finding. Correlation with prior pathology is nice, but lesions can be focal and/or transient, so perfect agreement is not required.
There are several types of specimens. The smallest is usually the endocervical curettage . This is meant to be a sampling of the endocervix and so should contain endocervical (columnar) mucosa. These tissue scrapings may have tiny and maloriented fragments, and the tissue can be spread out over a wide area on the slide.
If a lesion is seen by the clinician on colposcopy, there may be a cervical biopsy performed, which is a crescent-shaped chunk taken out of the cervix. This tiny specimen is uninked and unoriented. A high-grade lesion requires a cone biopsy , where the transition zone is taken out in a conical fragment with the goal of completely excising the lesion. The cone biopsy may be done with cautery (loop electrosurgical excision procedure, LEEP) or blade (cold-knife cone). The proximal/endocervical margin should be identified and inked to make sure the lesion is not extending up into the canal where it cannot be seen or sampled. The ectocervical margin is also inked, but a positive ectocervical margin is unusual.
Normal Histology of Cervix
The cervix is covered by a nonkeratinized squamous epithelium that merges into the surrounding vaginal wall. The squamous cells may be full of glycogen and have a plump cleared-out cytoplasm (refer to Figure 4.8). In postmenopausal women, the epithelium may become thin and atrophic, with an immature look.
The transition zone represents an abrupt transition to mucous-secreting columnar and glandular epithelium and may be located at the os or within the endocervical canal. Irritation or inflammation at the transition zone may lead to acute and/or chronic inflammation and squamous metaplasia overlying the glandular mucosa. This state is so universal that “chronic cervicitis and squamous metaplasia” is synonymous with normal. Squamous metaplasia, by definition, can only occur at or above the transition zone (Figure 16.1), and so mentioning it confirms that the transition zone was sampled. If you see no endocervical component at all, you may phrase it as “benign squamous mucosa.”
Squamous metaplasia at the transition zone. Mature squamous epithelium is seen to the right of the arrow, and squamous metaplasia is seen to the left. In squamous metaplasia, the nuclei may be larger and more immature-appearing and the cytoplasm more dense.
Endocervical glands are branching and complex glands that are pale with a dark outline due to the large cytoplasmic mucin vacuole pushing aside a small crescent-shaped nucleus (Figure 16.2). Fragments of glands on endocervical curettage may have a papillary or inside-out look, which is not significant. Squamous metaplasia or dysplasia may fill up and replace glands and must be distinguished from invasive cancer . Crowding of otherwise benign-looking glands is not a feature of concern, as it is in the endometrium.
Endocervical glands . Normal endocervical glands are composed of tall columnar cells with apical mucin and small basal nuclei (arrow).
The cervical stroma is very fibrotic (as you will find when cutting through one), so it looks pink and spindly. There are a variety of normal cysts and glandular proliferations that may occur within the stroma.
The Approach to the Endocervical Curettage
First look at the slide on the tray, and circle a single level of the tissue, so you don’t miss cells at the periphery. At low power, look for fragments of squamous epithelium and endocervical glands. The presence or absence of each is noted in the diagnosis. There may be a fair amount of background mucus (stringy pale pink amorphous substance) and inflammation. At higher power, at least 10×, concentrate on the actual epithelial fragments, if there are any. A smear of scattered endocervical cells (columnar cells with apical mucin) may be all you get, but ideally there are fragments of squamous epithelium to evaluate. These are evaluated by the same criteria as the biopsy, described next. Endometrial malignancies may also extend into the endocervical canal, so fragments of adenocarcinoma are not necessarily of endocervical origin.
The Approach to the Biopsy
On low power, first survey the squamous epithelium and the endocervical glands to look for areas that stand out as being more disorganized, darker, denser, or more inflamed than other areas. This applies to the squamous epithelium as well as to individual endocervical glands. Any suspicious area should be studied at higher magnification to look for dysplasia. The old three-tier system for classifying dysplasia has been condensed into a two-tier system that reflects the Bethesda system for cytology; this applies to biopsy material from the entire anogenital tract. What was once called CIN-1 (or VIN-1 , or VaIN-1 , or AIN-1 ) is now called LSIL (low-grade squamous intraepithelial lesion) and represents the viral cytopathic changes of HPV infection. LSIL lesions may contain either low-risk or high-risk HPV subtypes. Exophytic LSIL lesions may also be called condyloma.
On the other hand, the moderate and severe categories of CIN 2 and CIN 3 are now grouped into HSIL (high-grade squamous intraepithelial lesion) and reflect a true dysplastic transformation as a result of HPV infection. These lesions are nearly always associated with high-risk HPV subtypes.
A viral cytopathic effect that affects primarily the upper cell layers of the epithelium.
The cells have pleomorphic, wrinkled, hyperchromatic nuclei with a perinuclear cleared halo; these are called koilocytes . Binucleation is common (Figure 16.3).
LSIL. The hallmark of LSIL is the koilocyte, which is a squamous cell with HPV viral cytopathic effect. The nuclei are hyperchromatic (dark) and raisinoid (crinkly; see arrows), with a surrounding clear halo in the cytoplasm. Other good features include superficial nuclei that are larger than the nuclei below them, and binucleated cells.
The N/C ratio remains low, despite the marked atypia of the nuclei. The degree of nuclear atypia alone does not upgrade the lesion to HSIL.
It can look haphazard at low power, but the basal layer should be maintained as a discrete layer, and mitoses should not be higher than the lower one third.
A persistence of immaturity along with dysplastic changes. Essentially, the basal cells are becoming “immortalized,” like a cancerous cell, and are not maturing and differentiating as they should. Therefore, the basal cell appearance persists up into higher levels of the epithelium.
The overall impression is of a denser and darker epithelium due to high N/C ratios. The high N/C ratio is the same feature that allows these cells to be identified on Pap smear.
Atypia is seen in all cell layers, from the bottom up. The nuclei may not be as large or as bizarre as LSIL but are uniformly crowded, enlarged, and hyperchromatic with clumped chromatin and irregular membranes (boulder nuclei), and mitoses are present in the upper two thirds (Figure 16.4).
HSIL . In a high-grade lesion, paradoxically, the nuclei may not look as abnormal as in LSIL. The hallmark of HSIL is a persistence of immature-appearing cells throughout the epithelium. The nuclei are hyperchromatic and may have slightly irregular nuclear outlines, but the most striking feature at low power is the high N/C ratios present from top to bottom.
CIN 2 may show maturation at the surface or overlying LSIL, versus CIN 3, which shows full-thickness immaturity and atypia. The distinction is only significant in some subpopulations in which CIN 2 may be treated more conservatively.
HSIL can grow into endocervical glands, which should be mentioned in the diagnosis.