Nonneoplastic Lesions of the Cervix

Clinical Features

Squamous metaplasia is the replacement of the mucinous endocervical epithelium by stratified squamous epithelium through a process of subcolumnar reserve cell proliferation and differentiation. Squamous metaplasia is a very common finding in women of reproductive age. On colposcopy, squamous metaplasia can be appreciated as pink to white areas with branching surface vessels located in transformation zone. With acetic acid, these areas become pale to glassy with a membranous appearance. They will acquire a mahogany brown or black color with Lugol’s iodine.

Pathologic Features

Immature squamous metaplasia is located adjacent to the physiologic squamocolumnar junction and undergoes maturation as it extends along the surface toward the ectocervix. Nests of immature squamous cells are found subjacent to the surface within replaced endocervical glands ( Fig. 7.4A ). Reflecting the lack of maturation, the cells have a high nuclear to cytoplasmic ratio throughout all layers of the epithelium, yielding an increased nuclear density. However, the cells often have distinct cell borders and conspicuous spinous processes and the nuclei are evenly spaced without overlap. The nuclei are uniform in size and shape and contain fine chromatin and nucleoli discernible at high power magnification. Mitotic activity is variable and usually confined to the basal and parabasal layers. Residual endocervical cells or mucin droplets may be present at the superficial/luminal aspect ( Fig. 7.4B ). Immature squamous metaplasia develops into mature squamous metaplasia, which is virtually indistinguishable from the ectocervical epithelium, except for its location in the surface of the endocervix and the underlying endocervical glands ( Fig. 7.4C ).

Atypical immature metaplasia (AIM) is a vague and controversial term, formerly used to describe metaplastic squamous epithelium with greater cellularity and more prominent cytologic atypia but absent to equivocal koilocytosis and rare mitoses. AIM actually represents a heterogeneous group of lesions reclassified as benign (metaplastic or reactive) or HPV-related squamous intraepithelial lesions based on MIB-1 proliferation index, p16 staining and HPV status. Thus, this term is no longer recommended as nowadays most lesions with this equivocal morphology can be correctly classified using morphology and ancillary testing.

Ancillary Studies

Squamous metaplasia is positive for squamous markers such as p63 and p40. It is negative for p16 or shows only patchy, discontinuous, and mostly cytoplasmic positivity. ProExC is usually negative and MIB-1 immunoreactivity is confined to the basal and parabasal layers.

Differential Diagnosis

Squamous metaplasia is a well-known benign mimic of HPV-related HSILs . HSILs are distinguished by crowded nuclei with a high nuclear to cytoplasmic ratio, nuclear pleomorphism, hyperchromasia, and coarse chromatin, and mitotic activity in the upper two-thirds of the epithelium, including atypical mitoses. HSIL with an immature metaplastic phenotype can be especially difficult to identify, as the partial maturation resembles metaplasia and masks the HPV-related nuclear changes. Immunohistochemical studies are quite helpful in challenging cases. The recent CAP/ASCCP Lower Anogenital Squamous Terminology Standardization project for HPV-associated lesions recommends the use of p16 immunohistochemistry when the differential diagnosis is between a precancerous lesion and a benign mimic such as squamous metaplasia or atrophy. Strong and diffuse cytoplasmic and nuclear p16 staining within at least the lower third of the squamous epithelium (“block positive” pattern) supports the diagnosis of an HSIL. ProExC (MCM2/TOP2A), which is a newer marker targeted against DNA topoisomerase IIA and mini-chromosome maintenance protein 2, is also potentially useful in this differential diagnosis. Almost all HSILs display strong nuclear staining with ProExC within the full thickness of the lesion. A combination of ProExC and p16 provides higher specificity for the detection of HSIL than either marker alone.

Prognosis and Treatment

Immature squamous metaplasia is a benign process and does not require treatment, as it naturally evolves towards a mature squamous metaplastic phenotype.

Adenoid Basal Hyperplasia

Adenoid basal hyperplasia is a rare lesion of the cervix that resembles adenoid basal carcinoma and is postulated to arise from the sub-columnar reserve cells. It is an incidental microscopic finding in women of reproductive or postmenopausal age. Adenoid basal hyperplasia is found close to the squamocolumnar junction. It consists of nests of basaloid cells that are in continuity with the reserve cell basal epithelium. Small gland-like spaces are present at the center of some nests. Squamous differentiation is rare. Adenoid basal hyperplasia is differentiated from adenoid basal carcinoma by its small size, superficial location with attachment to the overlying epithelium and absence of stromal infiltration, uncommon squamous differentiation, lack of mitotic activity and inconsistent association with HPV infection.

Squamous Papilloma

Noncondylomatous, nondysplastic squamous papillomas of the cervix are very rare and the diagnosis should be rendered only after the exclusion of other entities in the differential diagnosis, including exophytic LSIL and HSIL, and more importantly squamous cell carcinoma of the papillary/squamotransitional variant.

Inverted Transitional Cell Papilloma

Inverted transitional cell papillomas of the cervix are very rare benign lesions that resemble the entity of the same name in the bladder. It must be distinguished from papillary squamotransitional cell carcinoma of the cervix and urothelial carcinoma with secondary cervical spread, both of which exhibit cytologic atypia, mitotic activity, and in some cases, evident invasion.

Clinical Features

Metaplasia of tubal or tuboendometrioid type is a common finding in the cervix. Tubal metaplasia is present in approximately 30% of cervical specimens, including 60% of hysterectomies and 20% of cone biopsies, according to one large series. It is found in patients spanning a wide range of ages, often following cervical biopsy, Loop Electrosurgical Excision Procedure (LEEP), or cold knife cone excision. Although it has been suggested that estrogen contributes to this phenomenon in the endometrium, the same is unknown for the cervix. It is important to note that the junction between the upper endocervix and the lower uterine segment (isthmus) is characterized by tubal-like ciliated epithelium, and thus, some lesions labeled as tubal metaplasia may simply represent sampling of this area.

Pathologic Features

Tubal metaplasia is characterized by replacement of the mucinous endocervical epithelium with tubal-like epithelium consisting of ciliated cells, nonciliated (secretory) cells, and intercalary (peg) cells ( Fig. 7.7 ). Tuboendometrioid metaplasia has, in addition to tubal-type epithelium, alternating areas of columnar nonmucinous and nonciliated cells with apical snouts, similar to the inactive endometrium ( Fig. 7.8A ). Both forms of metaplasia lack cytologic atypia and mitotic activity. The metaplastic epithelium is found within architecturally normal endocervical glands and overlying surface epithelium, more commonly in the upper than the lower endocervix, and usually confined to the superficial third of the cervical wall. Importantly, the periglandular stroma can appear reactive with hypercellularity, edema, myxoid change, and inflammation, especially in metaplasia after cervical procedures ( Fig. 7.8B ).

Tubal and tuboendometrioid metaplasia may raise concern for in situ or invasive adenocarcinoma. It may be present in deep glands and can display stromal changes similar to desmoplasia. In addition, worrisome features such as nucleomegaly, cellular crowding, and varying degrees of pseudostratification are common. Few reports in the literature have described typical and atypical tubal metaplasia with a pseudoinfiltrative growth pattern and atypical tuboendometrioid adenosis as forms of extensive adenosis of the cervix related to in utero diethylstilbestrol (DES) exposure.

Ancillary Studies

Tuboendometrioid metaplasia is positive for bcl-2 and hormone receptors. In addition, these lesions show negative to patchy immunoreactivity for p16, and the MIB-1 proliferation index is usually less than 10%.

Differential Diagnosis

HPV-related adenocarcinoma in situ (AIS) and invasive adenocarcinoma are the major considerations in the differential diagnosis. At low magnification, both adenocarcinoma and tubal metaplasia stand out against the background of normal mucinous endocervical epithelium due to a more darkly stained appearance. At higher magnification, AIS and adenocarcinoma of the usual type are characterized by pseudostratified columnar cells with mucin depletion, malignant nuclear features, apoptotic bodies, and apical “floating” mitoses. A ciliated variant of AIS, rarely reported in the literature, poses a greater diagnostic challenge, but can be recognized by the presence of nuclear dysplastic features, conspicuous proliferation, and immunohistochemical results. An immunohistochemical panel including bcl-2, ER, p16, and MIB-1 may be useful in challenging cases. In contrast to tubal and tuboendometrioid metaplasia, endocervical adenocarcinoma is strongly and diffusely positive for p16 (nuclear and cytoplasmic), and negative for bcl-2 and ER. An MIB-1 proliferation index is typically greater than 30% in AIS versus less than 10% in benign mimics. Endometriosis is composed of Mullerian glands with an endometrioid/tuboendometrioid appearance, thus overlapping with tuboendometrioid metaplasia. Endometriosis can be recognized by the presence of periglandular endometrial-type stroma and evidence of chronic bleeding (hemosiderin-laden macrophages).

Prognosis and Treatment

Tubal and tuboendometrioid metaplasia is a benign condition that does not require treatment.

Gross Findings

Cervical endometriosis may be associated with gross abnormalities in cervical excisions and hysterectomies, such as thickened, diffusely granular, or heaped up and hemorrhagic mucosa; a polypoid mass; or cervical stenosis. In many cases, no gross abnormality is appreciated.

Microscopic Findings

Superficial endometriosis is generally confined to the superficial third of the cervical wall immediately beneath the surface epithelium, sometimes with overlying ulceration ( Fig. 7.10 ). The lesions range from few glands to several millimeters in greatest dimension. The glands tend to resemble those of proliferative endometrium, being well-spaced and round-to-oval, although occasionally they show irregularity in size and shape and crowded spacing. Mitotic figures can be conspicuous depending on the hormonal state. Glands are embedded within dense but occasionally sparse endometrial-type stroma with small arterioles and extravasated red blood cells. Stroma usually contains varying amounts of hemosiderin and hemosiderin-laden macrophages. Other nonspecific findings include chronic inflammation, edema, fibrosis, and elastosis. Stromal endometriosis is an uncommon variant composed predominantly to exclusively of endometrial-type stroma (thus, with absence or paucity of glands). Rarely, endometriosis can grow in a polypoid fashion resembling an endometrial polyp (“polypoid endometriosis”) or a polypoid adenomyoma.