Cervix-Printer Friendly Version

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Gross, EM and immunohistochemistry images are needed for most cervix disorders

Micro images (histology, not cytology) are particularly needed for these cervix lesions:

Normal: atypical oxyphilic metaplasia, intestinal metaplasia

Infections: actinomycosis, bacterial vaginosis, Candida/fungi, Chagas’ disease, chlamydia, Enterobius, granuloma inguinale, granulomas, Trichomonas, Wuchereria

Benign/non-neoplastic lesions: adenosis, atrophy, cervical pregnancy, decidual nodule, diffuse laminar endocervical glandular hyperplasia, ectopic tissue/heterotopia, florid deep glands, glial polyp, inflammatory pseudotumor, lobular endocervical hyperplasia, melanosis, necrobiotic granulomas, pagetoid dyskeratosis, papillary endocervicitis, post-operative spindle cell nodule, pseudosarcomatous fibroepithelial stromal polyps

Premalignant/preinvasive lesions: stratified mucin producing intraepithelial lesions

Carcinoma: small cell squamous cell carcinoma, endocervical microcystic adenocarcinoma, basaloid squamous cell carcinoma

metastases to cervix, spindle cell (sarcomatoid) carcinoma, urothelial carcinoma, warty (condylomatous) carcinoma

Sarcoma/lymphoma/other: alveolar soft parts sarcoma, stromal sarcoma, Wilm’s tumor

Cervix-embryology

Mesoderm derived mullerian ducts fuse at day 54 post-conception and form uterovaginal canal, lined by mullerian columnar epithelium

Uterovaginal canal joins endoderm lined urogenital sinus at mullerian tubercle, which becomes vaginal orifice at hymenal ring

Epithelium stratifies at caudal uterovaginal canal to become squamous; epithelium proliferates to become almost purely squamous in vagina by day 77

Endocervical glands and vaginal fornices appear between days 91 and 105

Cervix responds to estrogenic stimulation by marked growth

Cervix-normal anatomy

Lower 1/2 to 1/3 of uterus, cylindrical, connects uterus to vagina via endocervical canal

Consists of portio vaginalis (portion that protrudes into vagina) and supravaginal portion

2.5 to 3.0 cm long and 2.0 to 2.5 cm in diameter

Anteriorly abuts on bladder; posteriorly is covered by peritoneum that forms lining of cul-de-sac

Endocervix: relates to endocervical canal

Ectocervix (exocervix): vaginal portion of cervix

External os: opening of endocervical canal to ectocervix

Fornix: reflection of vaginal wall that surrounds ectocervix

Internal os: indistinct upper limit of endocervical canal

Transformation zone: see also under histology; usually appears red due to rich capillary network and is called cervical erosion, although ectropion is a better term

Cardinal ligaments: fibromuscular bands that fan out from lower uterine segment and cervix to lateral pelvic walls and provide main support for cervix

Uterosacral ligaments: connective tissue surrounding cervix and vagina that extends towards vertebrae

Lymphatics: cervix is drained by parametrial, cardinal and uterosacral ligament routes

Cervix-normal histology

Most of cervix is composed of fibromuscular tissue

Epithelium is either squamous or columnar

Endocervix: lined by columnar epithelium that secretes mucus; epithelium has complex infoldings that resemble glands or clefts on cross section; mucosa rests on inconspicuous layer of reserve cells

Ectocervix (exocervix): covered by nonkeratinizing, stratified squamous epithelium, either native or metaplastic; has basal, midzone and superficial layers; after menopause is atrophic with mainly basal and parabasal cells with high N/C ratio that resembles dysplasia; prepubertal girls have similar appearing epithelium

Stem cells are in suprabasal layer

Squamocolumnar junction: where squamous and glandular epithelium meets; usually in exocervix; nearby reserve cells are involved in squamous metaplasia, dysplasia and carcinoma

Transformation zone: also called ectropion, between original squamocolumnar junction and border of metaplastic squamous epithelium; epidermalization and squamous differentiation of reserve cells transform this area to squamous epithelium; site of squamous cell carcinomas and dysplasia

Note: endocrine cells and melanocytes are seen occasionally in cervix; multinucleated giant cells may be a normal finding, often accompanied by edema (Archives 1985;109:200)

Basal cells (reserve cells): cuboidal to low columnar with scant cytoplasm and round/oval nuclei; acquire eosinophilic cytoplasm as they mature; positive for low molecular weight keratin and estrogen receptor; negative for high molecular weight keratin and involucrin

Suprabasal cells: have variable amount of glycogen, detectable with Lugol/Schiller’s test (application of iodine) or microscopically by PAS stain; positive for high molecular weight keratin and involucrin

Glandular epithelium: positive for estrogen receptor

Menarche: ovaries produce estrogen, which stimulates glycogen update by cervical and vaginal mucosa, which promotes growth of endogenous vaginal microorganisms, which produce acid and drop in vaginal pH; basal/reserve cells respond by proliferating, causing squamous and columnar metaplasia; squamous epithelium overgrows columnar epithelium, obstructing crypt openings and forming Nabothian cysts; also produces acute and chronic inflammatory infiltrate

Metaplasia in cervix

Defined as change in differentiation pathway to which the stem cell progeny commit

Not neoplastic

DD: metaplastic growth pattern, which may be neoplastic

Atypical oxyphilic metaplasia of cervix

Very rare

Incidental finding with benign behavior

Mean age 48 years, range 41 to 62 years

Case reports: 37 year old woman (Cesk Patol 2000;36:60)

Micro: large, cuboidal or polygonal epithelial cells with dense eosinophilic, focally vacuolated cytoplasm; variable nuclear atypia in endocervical glands due to enlarged, hyperchromatic or multinucleated / multilobated nuclei; rarely apical snouts; no mitotic figures, no stratification

References: Int J Gynecol Pathol 1997;16:99

Epidermoid metaplasia of cervix

Very rare

Associated with uterine prolapse, prolonged irritation or synthetic steroids (Obstet Gynecol 1974;44:53)

Case reports: 44 year old woman with ectocervical lesion (Archives 2004;128:1052)

Micro: epidermis, sebaceous glands and hair follicles

DD: mature teratoma

Immature squamous metaplasia of cervix

Micro: resembles squamous metaplasia but without cytoplasmic glycogen; mild reactive changes include mild variation in nuclear size and hyperchromasia; often surface maturation; when acutely inflamed may resemble SIL, but cells are not crowded or disorganized, nuclei are round and uniform and not hyperchromatic, background cells have prominent nucleoli (reactive changes); often overlying mucinous epithelium

Intestinal metaplasia of cervix

Rare, may have mucin extravasation into stroma

Case reports: with HSIL (Histopathology 1985;9:551), with florid endocervical glandular hyperplasia (Gynecol Oncol 1999;74:504), with cervical dysplasia and leiomyosarcoma (Rev Chil Obstet Ginecol 1993;58:481), with villous adenoma and adjacent adenocarcinoma (Int J Gynecol Pathol 1986;5:163)

Micro: goblet cells, occasionally Paneth cells

Squamous metaplasia of cervix

See also immature squamous metaplasia above

Replacement of endocervical epithelium by subcolumnar reserve cells, which differentiate into immature and then mature squamous epithelium (see also normal histology above)

Common response to chronic irritation in nonsquamous tissue; present in almost every cervix

Centered on transformation zone

May also arise from ingrowth of squamous epithelium from ectocervix (squamous epithelialization)

Not a premalignant condition by itself

Keratosis: appearance of granular and horny epithelial layers, often associated with prolapsed uteri (see pagetoid dyskeratosis below)

Micro: squamous epithelium overlies endocervical glands, may replace glands; metaplastic cells may be immature, intermediate or mature; resembles epithelium normally lining ectocervix with flat architecture; may have cytologic atypia

Tuboendometrial metaplasia of cervix

Common (1/3 of women); in upper portion of endocervical canal, often in deep glands

Often seen after cervical cone biopsy; may represent response to injury

Micro: tubal metaplasia - endocervix contains ciliated cells (clear cytoplasm, abundant apical cilia and large, oval, variably hyperchromatic nuclei), secretory cells (nonciliated with dark eosinophilic or basophilic cytoplasm, apical cytoplasmic protrusions but no mucin vacuoles, basal nuclei); and intercalated cells (also called peg cells, scant cytoplasm, thin and long nuclei), as found in normal fallopian tube; glands are regular; minimal mitotic activity, rare crowding or atypia; also associated with endometrial type cells; usually near squamocolumnar junction, usually no inflammation

May have cystic glands and periglandular stromal alterations suggestive of premalignant conditions, or deep glands with periglandular edema suggestive of well differentiated adenocarcinoma, but cells are ciliated with bland cytology, no mitotic figures, no definite desmoplastic stroma (AJCP 1995;103:618)

Positive stains: CEA (not helpful in differential diagnosis below)

DD: endometrioid adenocarcinoma (invasive growth pattern, marked nuclear atypia, increased Ki-67 staining), adenocarcinoma in situ (lesion at squamocolumnar junction involving superficial but not deep glands; cells do not resemble fallopian tube or endometrium; have coarse nuclei, abundant mitotic figures)

References: Archives 1993;117:734, Mod Path 2000;13:261

Urothelial metaplasia of cervix

Also called transitional cell metaplasia

An incidental microscopic finding of exocervical squamous epithelium associated with atrophic changes in the elderly

May represent basal cell hyperplasia or atrophy associated with androgen exposure

Case reports: with ectopic prostatic tissue in 23 year old woman with adrenogenital syndrome (Int J Gynecol Pathol 2004;23:182)

Micro: hyperplastic epithelium without maturation composed of urothelial type cells with tapered ends, spindled nuclei with longitudinal nuclear grooves and perinuclear halos, but minimal nuclear atypia, low N/C ratios and rare/no mitotic activity

Positive stains: CK13, CK17, CK18; basal cells-calcitonin, serotonin

Negative stains: CK20 (same as normal urothelium)

DD: HSIL (high N/C ratio, cellular disorganization and pleomorphism, high mitotic rate)

References: AJSP 1997;21:510, Mod Path 2000;13:252

Inflammation of cervix

Inflammation of cervix-general

At menarche, the ovaries produce estrogen, leading to glycogen uptake by cervix and vaginal squamous mucosa; shedding cells promote the growth of vaginal aerobes and anaerobes, leading to a reduced (acidic) vaginal pH, which causes metaplastic transformation of transformation zone mucosa from columnar to squamous in exposed endocervix; squamous epithelium overgrows columnar epithelium, obstructing crypt openings and forming Nabothian cysts; also produces acute and chronic inflammatory infiltrate

Actinomycosis of cervix

Actinomycetes normally reside in the female genital tract, so presence does not indicate disease (Am J Obstet Gynecol 1999;180:265)

Associated with IUDs with colonization rate of 11%, increases with duration of use (J Reprod Med 1994;39:585, IPPF Med Bull 1983;17:1)

Less common than pseudoactinomycotic radiate granules that form around microorganisms or biologically inert substances

Micro: tangled clumps of gram positive filamentous organisms, often with acute angle branching, sometimes showing irregular wooly appearance; swollen filaments may be seen with clubs at periphery; often cotton ball-like acute inflammatory response

Amebiasis of cervix

May simulate or accompany carcinoma (Am J Trop Med Hyg 1992;46:759, Int J Gynaecol Obstet 1987;25:249, Archives 1985;109:1121)

Gross: polypoid and ulcerated mass; may engraft on pre-existing carcinoma

Bacterial vaginosis

Candida / fungi

Chagas’ disease of cervix

Case reports: HIV+ patient (Hum Path 2000;31:120)

Chlamydia trachomatis of cervix

Most common sexually transmitted disease (STD) in Western world; 4 million new cases annually in US

Affects cervix, uterus, adnexae; not vulva/vagina

Chlamydia trachomatis is an obligate intracellular parasites with elementary bodies (infectious but incapable of cell division) and reticulate bodies (multiply within cytoplasm, but not infectious until they transfer back into elementary bodies)

Causes infertility

Diagnose based on culture, PCR of urine or enzyme immunoassay on cervical / urethral swab (Archives 2000;124:840)

Nucleic acid amplification of urine has similar sensitivity as samples from cervix or urethra (Ann Intern Med 2005;142:914)

Does NOT cause dysplasia

Micro: lymphoid germinal centers (follicular cervicitis-sensitive but not specific for chlamydia), plasma cells, reactive epithelial atypia

Positive stains: immunocytochemistry can detect organisms

Chronic cervicitis

Found in almost all women (see normal histology above)

Depending on etiology, may cause endometritis, salpingitis, pelvic inflammatory disease (PID) or chorioamnionitis

Organisms of concern are gonococci, Chlamydia, Mycoplasma, HSV

Micro: affects squamocolumnar junction and endocervix; produces intercellular edema (spongiosis), submucosal edema, mononuclear inflammation, fibrosis

CMV of cervix

Patients are usually NOT immunocompromised (J Clin Pathol 2004;57:691)

Viral shedding common in HIV+ women (Med Virol 1999;59:469)

Micro: large, basophilic intranuclear inclusions or intracytoplasmic eosinophilic inclusions in occasional endocervical glandular epithelial cells; inclusions also in endothelial and stromal cells but not squamous cells; associated with fibrin thrombi, dense acute inflammatory infiltrate, lymphoid follicles, vacuoles in glandular cells, reactive changes in glandular epithelial cells

Enterobius of cervix

Granuloma inguinale of cervix

Also called donovanosis

Due to gram negative rod, Calymmatobacterium granulomatis, which has characteristic bipolar staining

Sexually transmitted disease which affects genital skin and mucosa and causes inguinal lymphadenopathy; rarely becomes disseminated

May occur in children of infected mothers via birth canal (AJCP 1997;108:510)

May mimic carcinoma (Genitourin Med 1990;66:380)

Granulomas of cervix

Rare

Usually foreign body-type; also diffuse

Associated with prior biopsy or surgery (AJCP 2002;117:771)

Only rarely associated with sarcoidosis or systemic conditions

Ceroid (with early lipofuscin) granulomas may be related to endometriosis

Case reports: ceroid granulomas (Int J Gynecol Pathol 2002;21:191, Histopathology 1992;21:282), due to pinworms (J Trop Med Hyg 1981;84:215)

References: ceroid granulomas (J Clin Pathol 1995;48:1057)

Herpes simplex virus (HSV) of cervix

Relatively common; 3% (HSV1) and 8% (HSV2) of women visiting US physicians in one study (J Clin Virol 2005;33:25)

Neonatal herpes may occur if infant is delivered vaginally during maternal genital herpes

Micro: epithelial ulcers with acute and chronic inflammatory cells, epithelial cell necrosis; multinucleate cells with intranuclear inclusions that are smudged (ground glass) or discrete are usually at periphery of ulcer; usually affects squamous cells, not endocervical glandular epithelium

EM: ground glass appearance is due to intranuclear viral particles; enhancement of nuclear envelope is caused by peripheral chromatin margination

DD: inflammatory cells with multiple nuclei (lack discrete nuclear molding)

Pseudolymphoma of cervix

Also called lymphoma-like lesion; a form of chronic cervicitis

Rare; benign reactive lesions that resemble lymphoma

Usually reproductive age women

Case reports: 37 year old woman with cervical polyp containing lymphoid infiltrate resembling diffuse large B cell lymphoma (Gynecol Oncol 2005;99:481), with EBV+ tumor (Gynecol Oncol 1992;46:69)

Gross: soft, superficial, focal erosion

Micro: clusters or sheets of large lymphoid cells, mixed with plasma cells, neutrophils, macrophages and germinal cells; infiltrate is usually above endocervical glands; prominent mitotic activity, often starry-sky pattern; no deep invasion, no cellular monomorphism, no prominent sclerosis

Positive stains: polyclonal

References: Int J Gynecol Pathol 1985;4:289, Eur J Obstet Gynecol Reprod Biol 2001;97:235

Schistosomiasis of cervix

Also called bilharziasis

Diagnostic method of choice for S. haematobium is quantitative compressed biopsy technique (Am J Trop Med Hyg 2001;65:233)

HIV patients often lack a granulomatous response and obvious ova (Int J Gynecol Pathol 2004;23:403)

Case reports: 27 year old from Senegal with LSIL on Pap smear (Archives 2003;127:1637)

References: Acta Trop 2001;79:193.

Syphilis of cervix

May form primary chancre at cervix

May produce a mass suggestive of invasive carcinoma (AJCP 1995;104:643)

Due to Treponema pallidum infection

Trichomonas of cervix

Tuberculosis of cervix

May be simultaneous cervical and endometrial infections (J Indian Med Assoc 1995;93:167)

May be associated with HIV infection (Sex Transm Infect 2002;78:62); associated with infertility in Iran (Int J Gynaecol Obstet 2001;75:269)

Case reports: 38 year old woman in India

Gross: cervical hypertrophy or ulceration

Micro: pseudoepitheliomatous hyperplasia, noncaseating granulomas

Positive stains: usually acid-fast

Wuchereria bancrofti microfilariasis

Benign / non-neoplastic lesions of cervix

Adenomyoma of endocervical type

First described in 1996 (Mod Path 1996;9:220), although actually very common and often overlooked

Mean age 40 years, range 21 to 55 years

Either no symptoms (usually) or abnormal vaginal bleeding

Recommended to not use this diagnosis unless lesion is exophytic and does not grossly resemble a typical polyp

Case reports: 44 year old women (APMIS 2001;109:546, Pathol Int 1999;49:1019)

Gross: well circumscribed endocervical tumor 1 to 8 cm; may prolapse through external os; also large mural tumors (11-23 cm); gray-white, may have large mucin filled cysts or rarely be hemorrhagic

Micro: composed of glands and cysts lined by single layer of endocervical-type mucosa with smooth muscle; glands are large and irregular with papillary infolding, surrounded by smaller simple glands, often lobular; focal tubal-type epithelium often present; rarely endometrial-type glands and stroma; bland nuclear features, no/minimal mitotic activity, no desmoplasia

Positive stains: PAS+ neutral mucin, Ki-67+ (up to 20%), focal CEA

DD: minimal deviation adenocarcinoma (invasive glands, focal atypia, desmoplastic stroma)

Adenosis of cervix

DES was given to women in 1950’s to prevent miscarriages (although it didn’t actually do so)

In utero DES exposure is associated with adenosis of vagina and cervix and infertility in female offspring and testicular abnormalities in male offspring (Cochrane Database Syst Rev 2003;(3):CD004271, Int J Childbirth Educ 1992;7:21)

Tubal-type endocervical glandular proliferations resembling minimal deviation adenocarcinoma occur in women with DES exposure, may be a form a DES-related adenosis (Int J Gynecol Pathol 2005;24:391)

References: Development 2004;131:1639 (role of p63 in DES-induced adenosis)

Arias-Stella reaction in cervix

First described in 1954 by Dr. Javier Arias-Stella (Arch Pathol 1954;58:112)

Nuclear changes in endocervix similar to those in endometrium commonly seen during pregnancy (10%) or post-partum

Age range 19-44 years

May present as cervical polyp or be an incidental finding

Gross: no mass

Micro: normal spatial distribution of enlarged, dilated glands (superficial or deep) lined by large, polyhedral cells with abundant eosinophilic or clear cytoplasm with large clear vacuoles and enlarged, hyperchromatic, pleomorphic and smudged nuclei; usually has hobnail cells, intraglandular tufts, delicate filiform papillae and intranuclear pseudoinclusions; glands may have only partial involvement; no prominent nucleoli, no invasion; no/rare mitotic figures; may be focal

DD: clear cell carcinoma (forms a mass, has desmoplasia, is infiltrative with irregular glandular distribution, uniformly marked cytologic atypia, high N/C ratio, mitotic activity)

References: AJSP 2004;28:608, Archives 1992;116:943

Atrophy of cervix

May resemble SIL

Micro: pseudokoilocytosis, immature but bland epithelium; may resemble urothelial metaplasia; may have focal nuclear enlargement and hyperchromasia; cells have prominent intercellular bridges; nuclei are uniform, evenly spaced, often elongated with grooves; no atypia in upper epithelial layers, no mitotic figures

Negative stains: Ki-67 (J Pathol 2000;190:545), cyclin E, p16

DD: SIL (strong Ki-67+ and p16 staining in 75-80%, strong cyclin E+ in 31%, J Low Genit Tract Dis 2005;9:100), adenoid basal carcinoma (sharply demarcated nests of tumor, may have minimal atypia)

Atypical polypoid adenomyoma

Also called atypical polypoid adenomyofibroma, APA

Occurs in endometrium, lower uterine segment and endocervix

Uncommon (< 150 cases reported), associated with Turner’s syndrome

Mean age 40 years, range 21-73 years

Symptoms of dysfunctional uterine bleeding

May persist or recur, but does not metastasize; may have increased risk for later carcinoma; may be contiguous with adenocarcinoma

Case reports: with hyperprolactinemia (Int J Gynecol Cancer 2001;11:326)

Treatment: conservative polypectomy and curettage or simple hysterectomy in peri/postmenopausal women, but with follow up

Gross: resembles endometrial polyp; single, well-circumscribed, polypoid mass up to 2 cm; usually confined to endometrium with pushing margin; remaining endometrium is often unremarkable

Micro: biphasic with hyperplastic and atypical endometrial glands (complex architecture, often severe cytologic atypia), separated by fascicles of bland smooth muscle and fibrous stroma; squamous metaplasia present (90%), often extensive or with central necrosis; minimal mitotic activity (<3 mitotic figures per 10 HPF); no desmoplasia

low malignant potential - with features resembling well differentiated adenocarcinoma

Positive stains: trichrome (smooth muscle); low Ki-67 proliferative activity

DD: adenocarcinoma with muscular invasion (has desmoplasia, older women, grossly invasive, large with hemorrhage and necrosis), MMMT (older women, stromal also malignant, diffuse atypia, increased mitotic activity)

References: AJSP 1996;20:1

Blue nevus of cervix

Present in up to 2% of cervices; may be more common in Japanese women, particularly if step sections are obtained (Acta Pathol Jpn 1991;41:751)

20% are multiple

Usually an incidental finding

Case reports: endocervical location in 2 patients (Ceska Gynekol 2004;69:411), incidental finding (Appl Immunohistochem Mol Morphol 2004;12:79)

Gross: blue/black, flat, up to 3 cm; usually ill-defined in lower endocervix

Micro: elongated, wavy dendritic cells in clusters or individually, below endocervical epithelium; cytoplasm has brown melanin; also stromal macrophages

Positive stains: Fontana-Masson (melanin turns black), S100, HMB45

Negative stains: iron stains

EM: dendritic cytoplasmic processes, electron-dense membrane bound melanin granules, premelanosomes (Archives 1983;107:87)

DD: melanosis (basal epithelium only, not in stroma), melanoma (junctional change, stromal infiltration by malignant cells), hemosiderin (coarse granules are refractile and iron+, Fontana-Masson negative; pigment is in macrophages, not spindle cells)

References: Hum Path 1985;16:79

Cervical pregnancy

Pregnancy is almost always terminated by methotrexate, uterine artery embolization or otherwise

Goal is to minimize maternal morbidity (from massive hemorrhage) and preserve the uterus (Fertil Steril 2005;84:509)

Case reports: pregnancy with live 1800g fetus delivered by caesarean section (Ginekol Pol 2005;76:304), live baby after hysteroscopic resection (Fertil Steril 2003;79:428), causing urinary retention (Am J Obstet Gynecol 2004;191:364), with Arias-Stella reaction (Acta Cytol 1994;38:218)

Decidual nodule in cervix

Occurs during pregnancy