Tumor-Like Lesions and Benign Tumors of the Uterine Cervix





Tumor-Like Lesions


Metaplasias and Ectopias


Squamous Metaplasia ( Figs. 4.1 4.2 )





  • This normal process within the transitional zone of postpubertal women results in the replacement of endocervical surface and glandular epithelium by squamous epithelium, resulting in a cephalad migration of the squamocolumnar junction. The replacement may sometimes be incomplete with persistence of endocervical glands on the ectocervix. Extensive glandular epithelium on the ectocervix is occasionally associated with vaginal adenosis.



  • Florid squamous metaplasia within endocervical glands or endocervical polyps can simulate well-differentiated ISqCC. Features favoring the former include a superficial location; nests of cells with smooth contours consistent with replaced endocervical glands; bland nuclear features; no stromal response; residual mucinous epithelial cells, gland lumina, or luminal mucin; and absence of dysplasia in the adjacent squamous epithelium.



  • Immature squamous metaplasia is characterized by less maturation resulting in an appearance that can be misconstrued as SIL and therefore is considered in Chapter 5 in the differential diagnosis of SILs.




Fig. 4.1


Florid squamous metaplasia in a cervical polyp.



Fig. 4.2


Florid squamous metaplasia in an endocervical curettage. Occasional residual gland lumens are seen.


Transitional Cell Metaplasia ( Figs. 4.3 4.4 )





  • This process (TCM) is typically an incidental microscopic finding in postmenopausal and occasionally premenopausal women and prepubertal females. TCM may result in an abnormal Pap smear, but the distinctive appearance of the cells differentiates them from SILs and typical atrophy.



  • TCM in postmenopausal women and women receiving androgen therapy for gender reassignment suggests hypoestrinism as a cause in some cases. In one case, TCM was associated with the adrenogenital syndrome and cervical ectopic prostatic tissue.



  • TCM usually involves the ectocervical epithelium, less commonly the surface or glandular epithelium of the endocervix and transformation zone. Occasionally, invagination of the involved epithelium results in isolated stromal nests of transitional cells.



  • Multiple layers of cells with pale, uniform, oval to spindle nuclei are usually oriented vertically in the deeper layers, and horizontally (with a streaming or whorled pattern) superficially. Perinuclear halos may be present. A superficial layer of ‘umbrella’ cells is a rare finding.



  • The N:C ratio is usually high and the nuclei have finely stippled chromatin, inconspicuous nucleoli, and occasional longitudinal nuclear grooves; mitotic figures are rare to absent. Rarely, the cells have superimposed dysplastic changes.



  • TCM is CK13+/CK17+/CK18+/CK20− whereas urothelial transitional cell epithelium is CK13+/CK17+/CK18+/CK20+.




Fig. 4.3


Transitional cell metaplasia. The monotonous full-thickness abnormality may suggest a high-grade intraepithelial lesion. Even at this magnification a lack of mitotic activity can be appreciated.



Fig. 4.4


Transitional cell metaplasia. The nuclei are elongated and appear to be ‘streaming’. Some nuclei have grooves.


Differential diagnosis





  • HSIL. The lack of normal maturation can suggest an HSIL, but that diagnosis is excluded by bland nuclear features, absent or rare mitotic figures, and usually negative p16 staining. However, rare otherwise typical HPV− TCMs in older women with atrophic squamous epithelium enigmatically show block positivity for p16.



  • Atrophy. The numerous layers of cells and nuclear grooves distinguish transitional cell metaplasia from atrophic squamous epithelium, although the cells of the latter occasionally appear transitional.



Tubal, Tuboendometrioid, and Endometrioid Metaplasia ( Figs. 4.5–4.10 )


General features





  • Tubal metaplasia (TM) refers to the replacement of the endocervical columnar epithelium by tubal-type epithelium. Less commonly, the epithelium is intermediate in appearance between that of tubal and endometrioid epithelium (tuboendometrioid metaplasia, TEM), or rarely, it is purely endometrioid (endometrioid metaplasia, EM).



  • These metaplasias are usually an incidental microscopic finding, but occasionally may account for abnormal glandular cells in a Pap smear.



  • TM has been found in ~20% of cone biopsy and ~60% of hysterectomy specimens. TEM was found in ~25% of post-cone biopsy hysterectomy specimens in one series, suggesting that it is a reparative response in some cases.



  • Vang et al. reported an unusual form of TM associated with in utero exposure to diethylstilbestrol (DES) (see below).




Fig. 4.5


Tubal metaplasia. Cellular stroma forms a prominent cuff around the glands, most of which are cystically dilated.



Fig. 4.6


Tubal metaplasia. The glands vary in size and shape, and some are cystic. The periglandular stroma is more cellular than normal endocervical stroma.



Fig. 4.7


Tubal metaplasia. Most of the epithelial cells are ciliated.



Fig. 4.8


Tubal metaplasia, p16 immunostain. This process may show strong positivity in some cases, but staining is not uniform (see left of image).



Fig. 4.9


Tuboendometrioid metaplasia. Two glands show marked pseudostratification with admixed ciliated and nonciliated cells.



Fig. 4.10


Endometrioid metaplasia.


Microscopic features





  • In TM, the endocervical surface or glandular epithelium is replaced by a single layer of admixed ciliated, nonciliated, and peg cells in varying combinations although ciliated cells often dominate. TEM is similar to TM except for the presence of fewer ciliated cells. The nonciliated columnar cells of TM and TEM may have apical snouts that may represent an early manifestation of TM.



  • The glands involved by TM and TEM are usually similar to normal endocervical glands in size, shape, and distribution. Mild periglandular hypercellularity is common and may be diagnostically helpful. Unusual findings in TM and TEM include variability in gland size and shape, cystic dilatation, focal crowding, a deep location (see Deep Glands and Cysts ), and prominent periglandular stromal hypercellularity or edema.



  • Vang et al. reported cases of TM associated with in utero DES exposure that had a haphazard pseudoinfiltrative pattern and involvement of the resection margins. In one case there was moderate atypia and mitotic activity.



  • TM and TEM are distinguished from adenocarcinoma in situ (AIS) by a usual admixture of cell types, a typical absence of atypia, an absence or paucity of mitotic figures, and absence of apoptosis, and from invasive adenocarcinoma by the absence of an infiltrative pattern. TM and TEM can occasionally be p16+ but without the strong diffuse staining of AIS.



  • Rarely TM may merge with atypical TM and ciliated AIS ( Chapter 6 ).



Differential diagnosis





  • Typical endometriosis of the cervix (see below). In contrast to TEM or EM, endometrial-type periglandular stroma is usually present in endometriosis, but may be sparse and partly obscured by inflammatory cells. Distinction between TM and atrophic endometriosis (with no or minimal stroma) may be impossible in some cases but is of no clinical importance, as is also the occasional difficult distinction of the cellular stroma of TM from endometriotic stroma.



  • Ciliated AIS ( Chapter 6 ). This lesion is distinguished from TM and TEM by the presence of malignant nuclear features.



  • Low-grade endocervical glandular dysplasia (EGD). Subtle or incompletely developed cases of TM may be diagnosed as low-grade EGD, a diagnosis we avoid (see Chapter 6 ).



  • Mesonephric hyperplasia (see corresponding heading) with endometrioid-like glands. The usual deep location of the process, admixture of more typical mesonephric tubules with their colloid-like luminal secretions, and GATA3 positivity facilitate the diagnosis.



Endometriosis ( Figs. 4.11–4.15 )





  • Cervical endometriosis may be superficial (mucosal) or deep. The superficial form is often localized to areas of prior biopsy or cautery, suggesting implantation of endometrium or trauma-induced metaplasia. Deep cervical endometriosis is usually an extension of cul-de-sac involvement associated with typical pelvic endometriosis.



  • Superficial endometriosis is usually an incidental microscopic finding, but occasionally it can cause a thickened, granular, or hemorrhagic mucosa, or result in abnormal glandular cells in a Pap smear. The lesion is almost always confined to the superficial one-third of the cervical wall, most often just beneath the surface epithelium.



  • The endometriotic glands are typically well spaced and round to oval but occasionally may show irregularity in size and shape and crowding. They most commonly resemble the glands of a proliferative or weakly proliferative endometrium, including the presence of occasional mitotic figures, but occasionally have a secretory appearance.



  • Endometriotic stromal cells are usually obvious although they may be sparse and/or obscured by edema, hemorrhage, and inflammation.




    • The presence of the characteristic small arterioles and extravasated erythrocytes can facilitate the recognition of the stromal component in such cases.



    • Special stains may help but are rarely needed. Reticulin and trichrome stains reveal that endometriotic stroma typically has dense reticulin and sparse collagen with the opposite findings in normal endocervical stroma. Endometriotic stromal cells are CD10+/CD34−, whereas endocervical stromal cells exhibit the opposite findings, although some periglandular endocervical stromal cells may stain for CD10.




  • If endometriosis is not recognized microscopically, reactive atypia and/or mitotic activity in the endometriotic glands and their occasional p16 positivity may suggest endocervical glandular dysplasia or AIS.




    • An absence of both marked nuclear atypia and numerous apoptotic bodies and recognition of the endometriotic nature of the stromal cells facilitate the diagnosis.



    • Additionally, the p16 staining is usually more focal than in AIS and the epithelial cells of endometriotic glands are strongly bcl2+, whereas those of AIS are bcl2−.




  • Stromal endometriosis, an uncommon variant of endometriosis, is characterized by an exclusive component of endometriotic stroma.




    • Usually well-delineated foci within the superficial cervical stroma are composed of endometrial stromal cells, small blood vessels, and extravasated erythrocytes.



    • In some cases, the appearance may cause concern for Kaposi’s sarcoma. Although we are not aware of any cervical cases of Kaposi’s, this diagnosis would be favored in the presence of a fascicular arrangement of mitotically active spindle cells with hyaline globules and an HSV8+/CD10−/ER− immunoprofile.



    • The differential diagnosis might rarely include a mucosal deposit by endometrial stromal sarcoma, but cervical involvement by the latter would usually be associated with an obvious infiltrative process.





Fig. 4.11


Endometriosis. The hyperchromatic appearance of the glands and endometrial stroma are both conspicuous.



Fig. 4.12


Endometriosis. Two foci of endometriosis contrast with normal endocervical glands (right). Note the surrounding cellular stroma and hemorrhage.



Fig. 4.13


Endometriosis. This superficial example would lend itself to misinterpretation as adenocarcinoma in situ if only the surface epithelium and associated gland (upper left) were procured.



Fig. 4.14


Endometriosis. High-power view showing hyperchromatic mucin-poor cells with sporadic mitotic figures, potentially causing confusion with glandular neoplasia. Note the helpful finding of endometrial-type stroma with hemorrhage.



Fig. 4.15


Stromal endometriosis of endocervix at low- and high-power magnifications. Note hemorrhage between the endometriotic stromal cells. The appearance could suggest a diagnosis of Kaposi’s sarcoma.


Endocervicosis ( Figs. 4.16–4.18 )





  • This term refers to the rare occurrence of ectopic benign-appearing endocervical-type glands ( Chapter 19 ). In cervical cases, the outer cervical wall and paracervical connective tissue are usually involved. One case was associated with chronic pelvic pain following cesarean section.



  • Variability in gland size and shape, an infiltrative pattern, a stromal response to extravasated mucin, and the deep location of the glands may suggest minimal deviation adenocarcinoma (MDA) ( Chapter 6 ).



  • Features distinguishing endocervicosis from MDA include absence of a mucosal-based adenocarcinoma merging with the deep glands, absence of overtly dysplastic or malignant glands, and the occasional admixture of other benign müllerian-type glands, endometriotic stroma, or both.




Fig. 4.16


Endocervicosis. The endocervicosis (bottom) is separated from normal endocervical glands (top) by a zone of unremarkable stroma.



Fig. 4.17


Endocervicosis. Endocervical-type glands with an irregular size and shape lie within the outer wall of the cervix.



Fig. 4.18


Endocervicosis. Endocervical-type glands are surrounded by a reactive stroma, an appearance that initially raised concern for minimal-deviation adenocarcinoma (adenoma malignum).


Endosalpingiosis ( Figs. 4.19 4.20 )





  • Although uterine involvement is typically confined to the uterine serosa ( Chapter 19 ), endosalpingiosis rarely can involve the wall of the cervix and lower corpus, sometimes resulting in a clinically evident mass and on gross examination a thickened wall with multiple cysts.



  • Extensive cervical mural endosalpingiosis has been misinterpreted as MDA. The absence of a mucosal-based tumor, the admixture of cell types including ciliated cells, and the absence of more than mild nuclear atypicality facilitate the diagnosis.




Fig. 4.19


Endosalpingiosis. Transmural involvement of the cervical wall is present in this striking case.



Fig. 4.20


Endosalpingiosis. Glands lined by tubal-type epithelium lie within the deep endocervical stroma.


Deep Glands and Cysts ( Figs. 4.21 4.22 )





  • Otherwise typical endocervical glands and their cystic counterparts (nabothian cysts) uncommonly extend into the outer third of the cervical wall. Deep glands are an incidental microscopic finding, but deep nabothian cysts may result in a striking gross appearance.



  • In contrast to the glands of adenocarcinoma, deep glands and cysts are usually widely spaced, relatively uniform in size and shape, and lack cytologic atypia and a periglandular stromal response.




Fig. 4.21


Deep Nabothian cysts.



Fig. 4.22


Deep Nabothian cysts.


Intestinal and Gastric (Pyloric) Metaplasia





  • Intestinal metaplasia is characterized by the presence of goblet and occasionally argentaffin cells within endocervical glands. It is rare in a pure (nondysplastic) form, as it is usually associated with nuclear features of AIS (intestinal-type AIS) ( Chapter 6 ).



  • Simple gastric (pyloric) metaplasia is a subtle finding in which isolated endocervical glands are lined by columnar cells with abundant, pale, eosinophilic, HIK1083+ cytoplasm (Mikami and McCluggage). Similar glands are occasionally seen in type A tunnel clusters (see corresponding heading) and may be found adjacent to gastric-type adenocarcinomas ( Chapter 6 ).



Oxyphilic Metaplasia ( Figs. 4.23 4.24 )





  • Oxyphilic metaplasia is an incidental microscopic finding of no clinical significance. The change is invariably focal, involving only a few glands or even a single gland.



  • The normal endocervical glandular epithelium is replaced by a single layer of large cells with eosinophilic cytoplasm and variably sized, hyperchromatic nuclei but without mitoses.



  • A lack of cellular stratification, apoptosis, and mitoses facilitates distinction from endocervical glandular dysplasia and AIS. These lesions also usually lack abundant oxyphilic cytoplasm.




Fig. 4.23


Atypical oxyphilic metaplasia. Several glands are lined by cells with conspicuous eosinophilic cytoplasm and hyperchromatic nuclei.



Fig. 4.24


Atypical oxyphilic metaplasia. High power of another case shows variation in nuclear size and shape.


Ectopic Prostatic Tissue and Ectopic Skene’s Glands ( Figs. 4.25–4.28 )





  • Almost 40 cervical examples of a finding variably labelled ectopic prostatic tissue or ectopic Skene’s glands have been reported. The women were of reproductive or postmenopausal age and otherwise normal except for one who had adrenogenital syndrome, elevated testosterone levels, and cervicovaginal transitional cell metaplasia, and two female-to-male transgender patients who were receiving testosterone.



  • The ectopic tissue, which is typically ectocervical, is usually an incidental microscopic finding, but rarely forms a mural mass comprised of typical prostatic glandular tissue including basal cells, secretory cells, and in some cases squamous metaplasia. Squamous elements may predominate, potentially obscuring the glandular component. Rarely, sebaceous glands and basaloid formations resembling hair follicles may also be found.



  • The glandular cells (but not the squamous cells) are typically PSA+ and/or PAP+ although occasionally both markers are absent. The basal cells are 34βE12+. The glands and squamous elements are typically AR+, whereas only the squamous elements are ER+.




Fig. 4.25


Ectopic prostatic tissue.



Fig. 4.26


Ectopic prostatic tissue. Secretory and basal type cells are clearly seen.



Fig. 4.27


Ectopic prostatic tissue. Tufts of squamous epithelium (center) are variably conspicuous in this process.



Fig. 4.28


Ectopic prostatic tissue. Gland with squamous metaplasia (left). The gland is immunoreactive for prostate-specific antigen (right).


Other Ectopias ( Figs. 4.29 4.30 )





  • Doldan et al. found mature adipose tissue in 17% of cone/LEEP specimens, usually within the deep cervical stroma around large vessels, but occasionally in the superficial stroma around endocervical glands. The differential diagnosis includes pseudolipomatosis ( Chapter 7 ).



  • Rarely, sebaceous and sweat glands, hair follicles, glia, and bone (including dermoid cyst-like structures) are incidental microscopic findings in the cervix, including endocervical polyps. Some such cases represent retained fetal tissues, as confirmed by DNA genotyping in a case of cervical glial tissue (see Chapter 7 ).




Fig. 4.29


Fat within endocervical stroma (see text).



Fig. 4.30


Ectopic sebaceous glands within the endocervical stroma.


Endocervical Glandular Hyperplasias


Tunnel Clusters ( Figs. 4.31–4.34 )





  • Tunnel clusters (TCs) were first described by Fluhmann, who recognized a non-cystic type (type A) and the much more common cystic type (type B). The appearance of TCs and their strong association with multiparity suggest that they may represent an involution of pregnancy-induced endocervical glandular hyperplasia.



  • TCs are almost always an incidental pathologic finding that occurs in 10% of adult women. Rare cases may be associated with a mucoid discharge. Cystic TCs are grossly visible in a minority of cases.



  • TCs are multiple in 80% of cases, and are occasionally confluent. They are usually superficial but occasionally extend deeply and lack a stromal response.



  • Each TC is a rounded aggregate of oval, round or irregular closely packed glands of varying size that are lined by a single layer of flattened to cuboidal cells when cystic, or cuboidal to columnar cells when noncystic.



  • The nuclear features are usually bland and mitotic figures absent. Focal mild to moderate nuclear atypia and rare mitoses are occasionally present, particularly in noncystic TCs.



  • Some gland clusters suggestive of noncystic TCs, in contrast to their cystic counterparts and normal endocervical glands, may contain neutral mucin (red staining with PAS/AB) and stain with HIK1083 and MUC6 (pyloric gland mucin), thus favoring lobular endocervical glandular hyperplasia (see corresponding heading).



  • A lobular arrangement and absence of overtly dysplastic glands, an infiltrative pattern, and a stromal response facilitate distinction from adenocarcinoma, including the minimal deviation variant.




Fig. 4.31


Tunnel cluster, cystic (type B). Abundant luminal mucin devoid of appreciable numbers of inflammatory cells is typically seen within the cystic glands.



Fig. 4.32


Tunnel cluster, noncystic (type A). A well-demarcated cluster of glands stands out sharply within the cervical stroma.



Fig. 4.33


Tunnel clusters, noncystic (type A). Two examples showing irregularity in gland size and shape (left and right) and abundant eosinophilic cytoplasm, an unusual finding (right). Mild nuclear atypia is an occasional finding in type A clusters (right).



Fig. 4.34


Tunnel clusters, noncystic and cystic (types A and B). In some cases, the cystic (bottom) and noncystic (top) glands are less well circumscribed than is typical and form a striking low-power appearance.


Microglandular Hyperplasia ( Figs. 4.33–4.42 )





  • Microglandular hyperplasia (MGH) is a distinctive proliferation of endocervical glands, often related to estrogen and progesterone stimulation (oral contraceptives, pregnancy), but can also occur in those receiving only estrogen, only progesterone, or in the absence of hormonal intake.



  • MGH is a common incidental microscopic finding, usually in the reproductive age group; <5% of cases are postmenopausal. The patients are usually asymptomatic, or rarely experience vaginal bleeding and/or discharge.



  • There is usually no grossly visible lesion, but MGH may appear as an erosion or polyp, or even a lesion suspicious for carcinoma. MGH is most commonly encountered as a microscopic finding, often within an otherwise typical endocervical polyp.



  • Microscopically, closely packed glands of varying shapes range from small to larger and cystic. The lumens often contain inspissated mucin and inflammatory cells. A typically scanty stroma is usually infiltrated with acute and chronic inflammatory cells.



  • The glands are lined by low columnar, cuboidal, or flattened cells, frequently with subnuclear vacuoles, and small regular nuclei with inconspicuous nucleoli and, in most cases, absent to rare mitotic figures. Focal squamous metaplasia and/or reserve cell hyperplasia are common.



  • Unusual microscopic features can increase concern for adenocarcinoma, but awareness of these features, merging or admixture with typical MGH, and a paucity of mitotic figures are helpful findings.




    • Solid, reticular, and trabecular patterns.



    • An edematous, myxoid, or hyalinized stroma, sometimes containing irregularly disposed epithelial aggregates, resulting in a pseudoinfiltrative pattern.



    • Unusual cell types including spindle-shaped cells, polygonal cells with abundant eosinophilic cytoplasm, and signet-ring-like cells.



    • Mild to moderate nuclear atypia.




  • Mitotic figures. Abi-Raad et al. reported nine cases of otherwise typical MGH that exhibited 5–11 mfs/10hpf. The Ki-67 index varied from 1 to 15%; all lesions were negative for p16. All patients had an uneventful follow-up.




    • p16 positivity. Roh et al. found that the cytoplasm and nuclei of the superficial columnar cells were p16+ in 44% of their cases, usually with <50% of the cells staining.




  • The differential is usually with endocervical or endometrial adenocarcinomas with MGH-like patterns ( Chapters 6 and 8 ), a distinction that may be particularly problematic in small biopsy specimens, such as a tiny fragment of MGH contaminating an endometrial specimen. Clear cell carcinoma (CCC) may also enter the differential.




    • Adenocarcinoma is indicated or favored in the presence of symptoms or a mass, marked nuclear atypicality, more than a rare mitotic figure, invasion, and strong diffuse positivity for one or more of: MIB1, p16, and CEA.



    • CCCs have findings absent in MGH, such as papillarity and cells with copious clear cytoplasm.



    • Admixture or merging of the lesion with normal endometrial tissue also favors adenocarcinoma as MGH does not occur in the endometrium, although endometrial carcinomas can exhibit MGH-like changes.





Fig. 4.35


Microglandular hyperplasia. Typical variably sized glands with inspissated mucin containing inflammatory cells. Abundant subnuclear vacuoles are conspicuous.



Fig. 4.36


Microglandular hyperplasia, typical appearance. Note subnuclear vacuoles.



Fig. 4.37


Microglandular hyperplasia. Typical glands with mucin are separated by a solid proliferation of vacuolated cells.



Fig. 4.38


Microglandular hyperplasia. Conspicuous vacuolated cells, many having a signet- ring configuration, form a focally solid pattern.



Fig. 4.39


Micrograndular hyperplasia. Irregular glands have fused and produced a reticular pattern. Focal mild cytologic atypia is present.



Fig. 4.40


Microglandular hyperplasia. A reactive-appearing myxoid stroma is present in this case.



Fig. 4.41


Microglandular hyperplasia. Prominent stromal hyalinization is seen in some cases. Note subtle subnuclear clearing, a clue to the diagnosis.



Fig. 4.42


Microglandular hyperplasia admixed with papillary cervicitis.


Diffuse Laminar Endocervical Glandular Hyperplasia ( Figs. 4.43 4.44 )





  • This rare incidental microscopic finding is characterized by a band-like proliferation of closely packed endocervical glands that is sharply circumscribed from the underlying stroma.



  • The usually normally sized glands are lined by endocervical columnar cells, sometimes with mild reactive cytologic atypia. Marked stromal chronic inflammation is common.



  • Distinguishing features from MDA ( Chapter 6 ) include a sharply circumscribed border, absence of invasion, and lack of focally malignant cytologic features and desmoplastic stroma.




Fig. 4.43


Diffuse laminar endocervical glandular hyperplasia at low (left) and medium (right) magnifications. Note the sharp interface with the subjacent stroma (left) and the chronic inflammatory infiltrate (right).



Fig. 4.44


Diffuse laminar endocervical glandular hyperplasia. Note the glandular hyperplasia with well-demarcated interface to the adjacent cervical stroma at the base of the lesion (left). The glands within the proliferation are often surrounded by a mantle of chronic inflammatory cells (right).


Lobular Endocervical Glandular Hyperplasia (LEGH) ( Figs. 4.45–4.48 )





  • This rare lesion, which some investigators refer to as pyloric metaplasia (see below), is usually an incidental microscopic finding in the reproductive and postmenopausal age groups. Less commonly, there is a mucoid or watery discharge, abnormal glandular cells on Pap smear, or a gross abnormality that may include cysts. An occasional association with Peutz–Jeghers syndrome and rarely with peritoneal pigmentation has been reported.



  • LEGH is usually a well-demarcated lesion occurring most commonly in the superior part of the cervix close to the internal os. It typically occupies the inner-half of the cervical wall, although rarely may extend more deeply.



  • Most or all of the cervical mucosa is involved by predominantly lobular proliferations of small to moderate-sized glands that often surround a large gland. Tightly packed small glands may result in a pseudocribriform appearance.



  • The glands are typically lined by benign-appearing endocervical columnar mucinous cells with basal nuclei, although the cells may be larger than usual with copious cytoplasm. Occasional findings include intraglandular bridging (including a cribriform pattern), intestinal metaplasia, focal mild atypia, and rare mitotic figures. Thin periglandular cuffs of fibroblasts are often present.



  • A pyloric gland immunophenotype is typical, with positivity for HIK1083, MUC6, M-GGMC-1, TFF1, TFF2, and PDX1. PAX2 is also typically positive (see Differential Diagnosis ). ER and PR are typically absent in contrast to nonspecific endocervical glandular hyperplasias. Scattered chromogranin+/synaptophysin+ neuroendocrine cells and focal p16 staining may be present. HPV has not been found.



  • Japanese investigators have suggested that some LEGHs are premalignant or represent gastric-type AIS as they may precede gastric-type endocervical mucinous adenocarcinomas (GTAs), including minimal deviation adenocarcinomas (MDAs) ( Chapter 6 ).




    • Kondo et al., Nara et al., and Tsuji et al. found LEGH associated with in situ or invasive endocervical mucinous adenocarcinomas.



    • have described atypical LEGH (epithelial infolding, papillae, nuclear atypia, mitoses) associated with 30% of MDAs.



    • Kawauchi et al. found that atypical LEGHs exhibited chromosomal imbalances matching those in cervical mucinous adenocarcinomas, including MDAs and other GTAs.



    • Takatsu et al., using clonality and mutational analyses of the STK11 gene (mutations of which occur in MDA), found that a subset of MDA-associated LEGHs were monoclonal, suggesting that a STK11 mutation may be involved in the progression of LEGH to MDA.



    • Matsubara et al. found mutations in 11 of 19 cases of LEGH: GNAS (8), STK11 (2), and KRAS (1), as well as GNAS mutations in 5% of endocervical-type mucinous adenocarcinomas. They concluded that LEGH is likely neoplastic rather than hyperplastic.



    • Asaka et al. found that immunostaining for trefoil factor family 2 protein (TTF2) and gastric mucin α1,4-linked N-acetylglucosamine residues (αGlcNAc-R) was present in the cytoplasm and luminal secretions of LEGH, AIS, and invasive adenocarcinomas but not in normal glands.





Fig. 4.45


Lobular endocervical glandular hyperplasia. Rarely the process is seen grossly as a solid zone interrupted by cysts. This example has a striking circumferential distribution.



Fig. 4.46


Lobular endocervical glandular hyperplasia.



Fig. 4.47


Lobular endocervical glandular hyperplasia. The epithelium sometimes has voluminous mucinous cytoplasm (left) whereas in other cases it has a pyloric appearance (right).



Fig. 4.48


Lobular endocervical glandular hyperplasia with focal glandular dysplasia.


Differential diagnosis





  • Tunnel clusters (TCs). This very common, probably involutional, finding (see separate heading) consists of well-circumscribed clusters of glands with flattened or low cuboidal cells, lacking the hyperplastic appearance and tall cells of LEGH. The glands of TCs, in contrast to those of LEGH, are confined to tight clusters, are usually more uniform in size and shape, and often contain inspissated mucin.



  • Minimal deviation adenocarcinoma (MDA). Typical LEGH differs from MDA ( Chapter 6 ) by its superficial location, a predominantly lobular pattern, no more than mild atypia and rare mitoses, absent desmoplasia, and strong diffuse nuclear reactivity for PAX2.



Endocervical Glandular Hyperplasia Associated with Cystic Fibrosis





  • Previs et al. reported a case of a florid endocervical glandular proliferation presenting as a mass in a 24-year-old woman with cystic fibrosis who used OCs. Although initially interpreted as well-differentiated adenocarcinoma, its circumscription, bland cytology, mitotic inactivity, and acute inflammation favored a hyperplastic process.



  • A similar or identical lesion was reported by Dooley et al. as ‘polypoid cervicitis’ in women with cystic fibrosis who were using OCs.



Endocervical Glandular Hyperplasia, NOS ( Fig. 4.49 )





  • This designation is appropriate for occasional examples of endocervical glandular hyperplasia that lack the specific features of the foregoing subtypes but that are clearly benign based on their architecture and bland cytology.



  • Within this group are rare cases characterized by a congerie of glands with benign characteristics based on their overall architectural and cytologic features. In some such cases the cells have pale to clear cytoplasm with a distinctive central location of the nucleus. This nuclear position can occasionally be seen in nonhyperplastic endocervical glands but is more striking in the hyperplastic cases.



  • We have also seen rare cases in which there is a band-like proliferation of endocervical glands separated by fibromatous stroma imparting an adenofibromatous appearance.




Fig. 4.49


Endocervical glandular hyperplasia, NOS. Occasional cases in this category have the appearance illustrated in which nuclei are centrally located with sub- and supranuclear clarity.


Adenoid Basal Hyperplasia ( Fig. 4.50 )





  • This rare lesion is usually an incidental microscopic finding in the reproductive and postmenopausal eras. Some examples have been associated with an adenoid basal carcinoma (ABC) ( Chapter 6 ).



  • Bud-like proliferations of cells with bland nuclear features arise in the area of the squamocolumnar junction in continuity with subcolumnar reserve cells with which they share the same morphology and immunoprofile (Kerdraon et al.).



  • The buds project into the adjacent stroma or form detached nests. Gland-like spaces may be seen in some of the buds and nests; squamous differentiation is rare. There is no stromal reaction and the overlying epithelium appears normal or mildly atypical.



  • This lesion may be confused with an ABC but differs from the latter in its tiny size, superficial location, and usual absence of: dysplasia, squamous differentiation, mitotic activity, and p16 staining.




Fig. 4.50


Adenoid basal hyperplasia.


Mesonephric Lesions


Mesonephric Remnants ( Figs. 4.51 4.52 )





  • Mesonephric remnants, which occur in the walls of the cervix in up to 10% of women, are an incidental microscopic finding in reproductive and postmenopausal age groups. Rarely there is an abnormal Pap smear. A few vaginal cases have also been reported.



  • Microscopic examination reveals one to several small, well-circumscribed lobular aggregates of usually small mesonephric tubules, sometimes with a central duct. The cells lining the tubules lack atypia and mitotic activity.



  • The most specific marker is GATA3 (nuclear staining), although the staining intensity and extent is quite variable. The apices of the cells and luminal contents are typically CD10+; the cytoplasm is p16+, a finding that can incorrectly suggest AIS.




Fig. 4.51


Mesonephric remnant. A mesonephric duct is surrounded by lobular clusters of mesonephric tubules.



Fig. 4.52


Mesonephric remnants. Tubules unassociated with parent duct may have a pseudoinfiltrative appearance.


Mesonephric Hyperplasia ( Figs. 4.53–4.56 )





  • This lesion usually occurs in reproductive and postmenopausal age groups. It is almost always an incidental microscopic finding, but rarely causes induration, nodularity, an erosion, or an abnormal Pap smear.



  • Remnants of the mesonephric duct are present in some cases. The proliferation may extend to the overlying endocervical mucosa or margins of a cone biopsy specimen. Extension into the deep cervical stroma and/or the lower uterine segment may be seen in hysterectomy specimens.



  • Tubules in a lobular (80% of cases) or diffuse pattern range from small and uniform to variably sized and shaped and cystic. The tubules often contain a characteristic eosinophilic, colloid-like, PAS-positive luminal secretion. There is no stromal response.



  • The tubules and cysts are usually lined by a single layer of mucin-free cuboidal to flattened cells. The nuclei are usually uniform, but occasionally mildly atypical. Mitotic figures are rare or absent.



  • Unusual features include cellular stratification and bridging and tubules lined by columnar cells imparting a pseudoendometrioid appearance.



  • The most specific marker is GATA 3 (nuclear staining, see above). Other markers include PAX2 and PAX8 (strong nuclear), CD10 (apical cytoplasm and luminal secretions), and p16 (focal moderate to strong cytoplasmic). p16 reactivity may incorrectly suggest an invasive adenocarcinoma, but unlike most of the latter, nuclear staining is absent and only rare cells are MIB1+. Mirkovic et al. found that the KRAS/NRAS mutations seen in mesonephric carcinomas are absent in mesonephric hyperplasia.



  • The postoperative clinical course is uneventful, including cases in which the lesion extends to the resection margins. Rare mesonephric neoplasms ( Chapter 6 ), however, have been contiguous with mesonephric hyperplasia.



  • The differential diagnosis is with adenocarcinoma, especially mesonephric carcinoma (see corresponding heading in Chapter 6 ), MDA, CCC, and endometrial carcinoma.




    • Features favoring mesonephric hyperplasia over MDA include an absence of a mass, no mucosal involvement, mucin-free cytoplasm, absence of a periglandular stromal response, and a GATA3+/PAX2+/CEA immunoprofile.



    • Features favoring or establishing a diagnosis of CCC over mesonephric hyperplasia include a mass, papillary and solid growth patterns, cells with clear glycogen-rich cytoplasm, hobnail cells, moderate to marked nuclear atypia, more than a rare mitotic figure, and a napsin+/GATA3 immunoprofile.




  • Endometrial endometrioid carcinomas (EECs) with cervical involvement characterized by small tubular glands ( Chapter 8 ). Awareness of, and continuity with, a primary EEC and negative GATA3 staining facilitate the diagnosis. However, a subset of ER-negative endometrioid carcinomas have been shown to express GATA3, a potential pitfall in this category.




Fig. 4.53


Mesonephric hyperplasia. Tubules are lined by bland cuboidal epithelium and some characteristic eosinophilic material.



Fig. 4.54


Mesonephric hyperplasia. The tubules may become more compact and appear solid (top left).



Fig. 4.55


Mesonephric hyperplasia. The tubules may be markedly dilated and extend close to the overlying epithelium. The picture here is somewhat reminiscent of tubulocystic clear cell carcinoma.



Fig. 4.56


Mesonephric hyperplasia. Small dilated tubules some lined by flattened epithelium may be seen and can mimic clear cell carcinoma.


Mesonephric Ductal Hyperplasia ( Figs. 4.57 4.58 )





  • This finding, in which the mesonephric duct is lined by hyperplastic epithelium typically in the form of micropapillary tufts, is most commonly associated with usual mesonephric hyperplasia but rarely is an isolated finding.



  • Misdiagnosis as a premalignant or malignant glandular lesion may occur, particularly when it is an isolated finding. Features favoring mesonephric ductal hyperplasia include an elongated duct, micropapillae, an absence of nuclear atypia, lack of association with endocervical glands, and GATA3 staining.




Fig. 4.57


Mesonephric duct hyperplasia. Two large ducts are focally lined by tufted epithelium.



Fig. 4.58


Mesonephric ductal hyperplasia. The epithelium has scant cytoplasm, hyperchromatic nuclei, and focally forms small intraluminal tufts.


Reactive and Reparative Lesions


Postbiopsy Pseudoinvasion of Squamous Epithelium ( Fig. 4.59 )





  • This finding is due to implantation of squamous epithelium at the time of a previous biopsy. It may be confused with squamous carcinoma because of a deep location, a lack of nearby endocervical glands, irregularity of the squamous nests, a granulation tissue-like and/or fibrotic stroma, and often a history of SIL in a previous biopsy



  • The correct diagnosis is suggested by the history of a previous biopsy, the presence of only one or a few nests, bland nuclear features, absence of abnormal epithelium between the deep nests and surface epithelium, and no nearby SIL.



  • An analogous finding is artifactual displacement of dysplastic squamous epithelium into vessels at the time of lidocaine injection prior to a LEEP.


Feb 9, 2020 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Tumor-Like Lesions and Benign Tumors of the Uterine Cervix
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