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

Micro: up to 4 cm, just below epithelium; uniform decidual cells with well defined cell membranes, granular pale cytoplasm, bland nuclei; no continuity with surface epithelium, no mitotic figures

Negative stains: keratin

DD: non-keratinizing squamous cell carcinoma, placental-site nodule

Decidual reaction in cervix

Multiple small, yellow/red elevations of cervical mucosa

Soft, friable, bleed easily; rarely are fungating and resemble carcinoma

Case reports: 28 year old pregnant woman with hemorrhage and abnormal colposcopy resembling invasive cervical carcinoma (J Low Genit Tract Dis 2005;9:52), decidual change in lymph nodes mimicking metastatic cervical carcinoma (Archives 2005;129:e117, Eur J Gynaecol Oncol 2005;26:499)

Micro: decidual cells with abundant pale granular cytoplasm, bland nuclei

Positive stains: vimentin, desmin, alpha-1-antitrypsin; variable PLAP, beta hCG

Negative stains: keratin

Diffuse laminar endocervical glandular hyperplasia

Also called nonspecific hyperplasia

Usually an incidental finding

First described in 1991 (AJSP 1991;15:1123)

Mean age 37 years, range 22 to 48 years

Non-neoplastic, incidental finding, no recurrences after surgery

Case reports: 54 year old woman with 7 year history of watery vaginal discharge (Pathol Int 1995;45:283)

Micro: diffuse proliferation of medium sized, evenly spaced, closely packed, well differentiated mucinous glands within inner third of cervical wall; area sharply demarcated from underlying stroma; cells have basal nuclei; associated with chronic inflammation and stromal edema; no significant cytologic atypia; no mitotic activity, no/rare apoptotic activity (Int J Gynecol Pathol 2002;21:125), not deeply invasive

Negative stains: CEA

DD: minimal deviation adenocarcinoma (irregular stromal infiltration, deeply invasive with desmoplastic stroma, cytologic atypia, not an incidental finding)

Ectopic prostate or heterotopia in cervix

Most common heterotopic tissue is cutaneous adnexae or mature cartilage islands

Heterotopic tissue may be due to fetal homografts (Obstet Gynecol 1983;61:261)

Case reports: 38 year old woman with ectopic prostate (Int J Gynecol Pathol 1997;16:291), urothelial metaplasia with ectopic prostatic tissue in 23 year old woman with adrenogenital syndrome (Int J Gynecol Pathol 2004;23:182), ectopic Darier’s disease of skin (Cytopathology 1996;7:414)

Positive stains: prostate-PSA, PAP, high molecular weight keratin (basal cells)

DD: MMMT, botyroid rhabdomyosarcoma

References: AJSP 2000;24:1224 (ectopic prostate)

Endocervical polyp

2-5% of adult women

Usually multigravida age 30-59 years

Produces bleeding or mucoid discharge

Probably secondary to chronic inflammation and not neoplastic

Case reports: with heterologous cartilage and adipose tissue (Pathol Int 2001;51:305), 5 year old girl with multilocular cystic polyp (Pediatr Pathol 1993;13:415)

Gross: usually single, up to 1 cm; rarely mimics malignant tumor protruding into endocervical canal

Micro: dilated endocervical (mucus) glands in inflamed, myxoid stroma; papillary endocervicitis if branching papillary structure; surface epithelium may show squamous metaplasia; thick-walled blood vessels at base of polyp; no mitotic figures

DD: superficial cervicovaginal myofibroblastoma

Endometrial polyp of cervix

Either endometrial polyps that protrude through endocervical canal, mixed endocervical and endometrial polyps or decidual polyps that occur in pregnancy

Case reports: endometrial polyp with sarcomatous stroma protruding through cervical os (Eur J Gynaecol Oncol 2003;24:565), composed of heterotopic skin with hair (J Reprod Med 1984;29:837)

Endometriosis of cervix

May cause abnormal uterine bleeding, post-coital bleeding

Mean age 37 years, range 20 to 51 years

Superficial endometriosis may be due to mechanical disruption of endometrium after D & C or cone biopsy

Case reports: myxoid endometriosis simulating pseudomyxoma peritonei (AJSP 1994;18:849), 47 year old woman with superficial cervical endometriosis with florid smooth muscle metaplasia (Virchows Arch 2001;438:302)

Gross: red/blue nodules

Micro: similar to endometriosis elsewhere; two of three present - endometrial glands with basal nuclei, spindled stroma, hemorrhage; usually involves superficial third of cervical wall, not deep wall; glands are evenly spaced and without atypia, are surrounded by stroma at least focally; inflammation and hemorrhage may obscure endometrial stroma; may have prominent mitotic activity; no thick collagen bundles

Positive stains: CD10; reticulin surrounds each cell (Int J Gynecol Pathol 2001;20:173)

DD: adenocarcinoma in situ, invasive carcinoma (no endometrial stroma, marked atypia), endocervical glandular dysplasia, tuboendometrial metaplasia

References: Arch Gynecol Obstet 2005;272:289, Int J Gynecol Pathol 1999;18:198

Stromal endometriosis of cervix

Endometriotic stroma only with no/rare glands

Mean age 43 years, range 29 to 64 years

Micro: well circumscribed foci within cervical superficial stroma containing endometrial stromal cells, small blood vessels, extravasated RBCs; usually no endometrial type glands

DD: low grade endometrial stromal sarcoma, Kaposi’s sarcoma (Pathology 1997;29:426)

References: AJSP 1990;14:449

Endosalpingiosis of cervix

Glands lined by ciliated tubal-type epithelium

Typically affects pelvic and abdominal peritoneum, usually as an incidental microscopic finding, but may be associated with ovarian serous neoplasms

Benign, but may have atypical epithelial changes

Rarely forms a cystic mass (florid cystic endosalpingiosis, Hum Path 2002;33:944, AJSP 1999;23:166)

May have psammoma bodies (J Reprod Med 2000;45:526, J Reprod Med 1991;36:675)

DD: extraovarian serous cystadenoma

Florid deep glands of cervix

Usually an incidental microscopic finding

Micro: diffusely scattered endocervical glands within endocervical stroma extending to outer third of cervical wall; less variability in size and shape of glands than minimal deviation adenocarcinoma; no atypia, no desmoplastic stroma, no vascular or perineural invasion

Negative stains: CEA

References: AJCP 1995;103:614

Glial polyp of cervix

Very rare; <100 cases reported

Benign, but may recur up to 5 years layer

May be due to implantation of fetal brain tissue at curettage/abortion (Obstet Gynecol 1983;61:261, AJCP 1980;73:718) or overgrowth of teratoma

Micro: discrete polypoid lesion of endocervix; moderately cellular glia containing bland astrocytes surround endocervical glands and invade stroma; astrocytes are evenly spaced, have long radiating processes, no atypia

Positive stains: PTAH (fibrillary processes), GFAP (astrocytic cells and stroma, Gynecol Oncol 1985;21:385)

Hemangioma of cervix

Capillary or cavernous

Arteriovenous malformations may also be present in cervix, due to surgery or as part of larger pelvic vascular abnormality

Inflammatory pseudotumor of cervix

Very rare

Case reports: 48 year old woman with bilateral parametrial involvement causing hydroureternephrosis and invasion into vagina (Gynecol Oncol 2005;98:325), 58 year old woman with pelvic pain (Int J Gynecol Pathol 1994;13:80)

Treatment: surgical excision

Micro: fibroblast-like spindle cells, dense inflammatory infiltrate of plasma cells and lymphocytes

Negative stains: smooth muscle actin

Inverted urothelial papilloma of cervix

Rare; resembles more common bladder tumor

Case reports: 54 year old woman (Ann Diagn Pathol 2002;6:49); two cases in young adult women (AJSP 1995;19:1138)

Micro: inverted epithelial nests separated by fibrovascular septa; epithelial nests have peripheral palisading and are composed of uniform cells containing “swirling” oval nuclei with longitudinal grooves; nests contain cystitis glandularis-type areas; no significant atypia; no/rare mitotic activity

Leiomyoma of cervix

Uncommon; only 8% of uterine leiomyomas occur in cervix

Clinically may mimic an endocervical polyp

Case reports: pedunculated leiomyoma with superficial squamous cell carcinoma (Gynecol Oncol 2005;97:253), large leiomyoma causing heavy hemorrhage (Clin Exp Obstet Gynecol 2003;30:144); associated with fatal intraperitoneal dissemination (Gynecol Oncol 1996;62:119)

Gross: firm, whorled cut surface similar to uterine leiomyoma; usually 1 cm or less

Micro: resembles uterine leiomyoma; often prominent thick walled blood vessels; may have mitotic figures below ulcerated areas

Lobular endocervical glandular hyperplasia of cervix, NOS

Rare; first described in 1999 (AJSP 1999;23:886)

Resembles pyloric gland metaplasia (AJSP 2000;24:325)

Mean age 45 years, range 37 to 71 years

Usually an incidental finding, but 37% have a visible gross abnormality or clinical symptoms

Benign, does not recur, but may progress to endocervical adenocarcinoma (Mod Path 2005;18:1199)

Micro: noninvasive proliferation of endocervical glandular cells without any obvious adenocarcinoma component; usually confined to inner half of cervical wall; lobular arrangement of hyperplastic small/medium sized, rounded endocervical glands lined mostly by single layer of columnar, mucin-rich epithelium that surround large, cystically dilated central glands; may have mild reactive nuclear atypia; non invasive, no desmoplasia, no mitotic figures, no squamous differentiation

Positive stains: PAS (neutral mucin), pyloric gland mucin (HIK1083)

Negative stains: CEA, p53

Molecular: HPV negative (Int J Gynecol Pathol 2005;24:296)

DD: minimal deviation adenocarcinoma (irregular stromal infiltration, deep invasion, desmoplastic stroma response, focally malignant cytologic features, Pathol Int 2005;55:412)

Melanosis of cervix

Case reports: after cryotherapy for dysplasia (AJCP 1990;93:802)

Gross: flat, dark lesion up to 3 cm

Micro: benign pigmented melanocytes in basal layer of epithelium; no thickening of epithelium; melanocytes are densely pigmented and dendritic, but do not involve the stroma

DD: blue nevus

Mesonephric papilloma of cervix

Also called mullerian papilloma

Rare, benign, polypoid lesion of cervix or vagina of young girls to adult women

May recur, but good prognosis

Treatment: local excision

Case reports: recurrent cervical tumor (J Pediatr Adolesc Gynecol 1998;11:29), 18 month girl with mullerian papilloma and multiple renal cysts (Urology 2005;65:388), borderline malignant change in vaginal tumor (J Clin Pathol 1998;51:875)

Micro: superficially located, composed of papillary stalks covered by mucinous epithelium with focal squamous metaplasia; stroma is highly cellular fibrous tissue; no atypia, minimal mitotic activity

Positive stains: CK7, CA125, EMA

Negative stains: CK20, CEA, smooth muscle actin

DD: botyroid rhabdomyosarcoma

References: Ultrastruct Pathol 2005;29:209 (EM findings)

Mesonephric rests / remnants of cervix

Remnants of mesonephric (Wolffian) ducts which form the epididymis and vas deferens in males, present in 1/3 of women

Unrelated to symptoms that cause excision of tissue; usually no clinical mass (AJSP 1990;14:1100, Archives 1991;115:1059)

Case reports: involvement by squamous CIS from cervix (AJSP 1994;18:1265, Cesk Patol 2004;40:109), atypical mesonephric rests associated with cervical osteosarcoma (Cancer 1988;62:1594)

Micro: dilated tubules of cuboidal cells with eosinophilic secretions, surrounded by endocervical stroma; may undergo atypical hyperplastic changes or malignant change

Positive stains: CD10, vimentin

Negative stains: CEA, p53, Ki-67, mucicarmine, PAS

DD: adenocarcinoma (involves overlying endocervical mucosa, invasive, has stromal response and cytologic atypia, no lobular pattern, no intraluminal eosinophilic material)

References: Histopathology 2003;43:144 (CD10), AJSP 2003;27:178 (CD10)

Mesonephric hyperplasia of cervix

Rare; usually an incidental finding

Mean age 38 to 47 years, range 21 to 81 years

Benign

Micro: prominent increase in number of tubules with increase in lobule size and extensive involvement of cervix; either lobular, diffuse (bland glands, no stromal reaction) or ductal patterns (large, dilated or irregular ducts in wall of cervix with micropapillary budding of pseudostratified epithelial cells without atypia); small round mesonephric tubules are often deep within cervical wall and extend to cervical surface; may appear infiltrative; often has intraglandular colloid-like material; up to 2 mitotic figures/10 HPF; no back to back glandular crowding, no nuclear atypia, no angiolymphatic invasion, no perineural invasion

Positive stains: CD10

Negative stains: CEA, p53, Ki-67

DD: mesonephric adenocarcinoma, well-differentiated endocervical adenocarcinoma, clear cell carcinoma

References: Gynecol Oncol 1993;49:41, AJSP 1990;14:1100, Mod Path 2000;13:261

Microglandular hyperplasia of cervix

Also called microglandular adenosis, microglandular change

Common cervical lesion associated with birth control pills or pregnancy in young women, although also in post-menopausal women

Usually incidental, may grow as a polypoid mass

Gross: polypoid, single or multiple; early lesions are sessile

Micro: complex proliferation of small back to back glands lined by cuboidal, columnar or flattened cells with prominent vacuoles above/below vesicular nuclei; indistinct nucleoli, usually no atypia; may be associated with immature or mature squamous metaplasia; may have areas of solid growth, mucin pools (resembling colloid carcinoma), pseudoinfiltrative pattern, signet ring cells, focal atypia, occasional mitotic figures, acute and chronic inflammation, hobnail cells

Positive stains: mucin (vacuoles and lumina)

Negative stains: CEA (usually), CD10, vimentin

DD: endocervical adenocarcinoma (atypia, infiltrative, CEA+), clear cell carcinoma (papillary processes, open glands and tubules with diffuse atypia, hobnail cells and marked mitotic activity, minimal inflammation, no vacuoles), microglandular hyperplasia-like mucinous endometrial adenocarcinoma (usually older women, mature but not immature squamous metaplasia, diffuse nuclear atypia, stromal foam cells, mitotic activity and Ki-67+, no vacuoles, AJSP 1992;16:1092, Int J Gynecol Pathol 2003;22:261), microglandular carcinoma of uterus (neutrophils and “dirty” lumina, endometrioid-type single glands, vimentin+, Ann Diagn Pathol 2003;7:180)

References: AJSP 1989;13:50 (worrisome patterns), Mod Path 2000;13:261 (cervical glandular lesions)

Myofibroblastoma of cervix

Mean age 55 to 58 years, range 23 to 80 years

Often vaginal or vulvar, may be cervical

Benign behavior, but may recur after excision

May be neoplastic proliferation of hormonally responsive mesenchymal cells native to subepithelial stroma of endocervix and vulva of adult women

Gross: well circumscribed, polypoid or nodular mass, mean 3 cm (range 1 to 6 cm) arising in the superficial lamina propria of cervix and vagina

Micro: well circumscribed cellular tumor composed of bland spindled and stellate mesenchymal cells in collagenous stroma with myxoid and edematous foci; often lacelike pattern in hypocellular area, vague fascicular growth pattern in cellular area; minimal mitotic activity; no atypical mitotic figures

Positive stains: vimentin, ER, PR, desmin, CD34, CD99, bcl2, calponin; also alpha smooth muscle actin (45%), muscle specific actin (25%)

Negative stains: S100, EMA, keratin, h-caldesmon, CD117

DD: fibroepithelial stromal polyp, angiomyofibroblastoma, aggressive angiomyxoma

References: Hum Path 2001;32:715, Pathology 2005;37:144, Histopathology 2005;46:137

Nabothian cysts

A normal finding; no treatment needed

Due to obstruction of crypt openings containing mucus by squamous epithelium, causing acute and chronic cervicitis; also form after subtotal hysterectomy due to ablation of cervical canal (J Reprod Med 1999;44:567)

Associated with endocervical tunnel clusters (AJSP 1990;14:895)

Deep cysts may resemble malignancy by imaging studies

Gross: single or multiple, up to 1.5 cm

Micro: uniform architecture; dilated mucin filled cyst lined by flattened mucinous epithelium without atypia; may rupture with extravasation of mucin into stroma and reactive changes; may penetrate deep into wall; no stratification, no mitotic figures

Positive stains: mucin

DD: well differentiated or minimal deviation adenocarcinoma (atypical nuclear features, invasive, Int J Gynecol Pathol 1989;8:340)

Necrobiotic granulomas of cervix

Resembles tuberculosis or rheumatic nodules

Seen after cervical surgery (AJSP 1984;8:841)

Micro: resembles rheumatoid nodules

Neurofibroma of cervix

Very rare in cervix

Case reports: 39 year old woman with multiple cutaneous neurofibromas and plexiform neurofibroma of cervix (Archives 2005;129:783), diffuse involvement of female genital tract (Obstet Gynecol 1996;88:699, AJSP 1989;13:873)

Treatment: wide excision recommended due to high recurrence rate (Int Braz J Urol 2005;31:153)

Pagetoid dyskeratosis of cervix

Reactive process in which some keratinocytes are induced to proliferate

Also found in intertriginous areas - may be due to friction

In cervix, associated with uterine prolapse (AJSP 2000;24:1518)

Micro: small numbers of large cells with central pyknotic nuclei, perinuclear halos and abundant cytoplasm; no mucin; resembles Paget’s disease

Positive stains: high molecular weight keratin

Negative stains: low molecular weight keratin, EMA, CEA

Molecular: negative for HPV

DD: artifact (signet ring morphology with eccentric pyknotic nuclei), glycogen-rich cells (large, vacuolated, pale-staining squamous cells with regular nuclei and “basket-weave” pattern), koilocytes (large cells with perinuclear clearing, cytoplasmic margination giving sharp edge to halo; large, irregular, hyperchromatic nuclei, often with binucleation; usually in midzone of superficial layer), extramammary Paget’s disease, pagetoid spread of carcinoma

Papillary adenofibroma of cervix

Uncommon in cervix, more common in endometrium

Usually post-menopausal women

Case reports: 55 year old woman with mass containing multiple cystic components (Ultrasound Obstet Gynecol 2005;26:186), 46 year old woman with clinical endocervical polyp (Pathologica 1996;88:135)

Gross: protrudes into endocervical canal; papillary or sessile, may be 5 cm or larger; firm, rubbery, tan-brown with focal hemorrhage; may have small cysts on cut surface; no invasion of underlying stroma

Micro: lobulated papillary configuration; blunt edged and branching papillae covered by bland endocervical epithelium with stromal proliferation; may have focal squamous differentiation; stromal cells are small, uniform, bland; no/rare mitotic figures; no increased cellularity around entrapped glands

DD: endocervical polyps (not branching, no stromal proliferation), adenosarcoma (increased mitotic figures in stroma and stromal atypia)

Papillary endocervicitis

Endocervical inflammatory process with papillary growth pattern

Micro: chronic cervicitis with papillary architecture at surface; papillae are short and edematous, often with lymphoid aggregates, covered by simple columnar epithelium with reactive nuclear changes; cells have finely stippled chromatin and prominent nucleoli; mitotic figures may be present but no atypia; no infiltrative pattern; often mast cells (Indian J Pathol Microbiol 2004;47:178)

Placental site nodule of cervix

Ages 27 to 45 years

Incidental finding; benign (AJSP 1990;14:1001)

Gross: may be visible but usually small; single or multiple

Micro: well defined hyalinized lesion, variably cellular, immediately below mucosa, composed of extravillous (intermediate) trophoblast cells with abundant amphophilic, glycogen rich or eosinophilic cytoplasm with vacuoles, irregular nuclei with degenerative features and possible atypia; occasional inflammatory cells, rare/no mitotic figures; resembles trophoblasts in chorion lavae

Positive stains: keratin, PLAP, inhibin alpha, CK18, HLA-G, p63; variable HPL

Negative stains: Ki-67 (<8% positivity)

DD: placental site trophoblastic tumor (larger, has mitotic activity, not degenerative), hyalinizing squamous cell carcinoma (definite squamous cells, atypia, HPL negative), cartilaginous tumors

References: Hum Path 1999;30:687

Post-operative spindle cell nodule of cervix

Associated with prior biopsy or curettage

More common in vulva/vagina (Histopathology 1995;26:571); also in bladder (J Urol 1990;143:824)

May recur after excision

Micro: resembles nodular fasciitis and granulation tissue; bundles or fascicles of proliferative spindle cells with infiltrative margins; nuclei are oval to spindled with mild hyperchromasia and pleomorphism; frequent mitotic figures; often edematous stroma, delicate capillary network, neutrophils and red blood cells

Pseudosarcomatous fibroepithelial stromal polyps of cervix

Median age 32 years, range 16 to 75 years

Often in pregnant patients or post-operative

May recur locally; no metastases

Positive margin status, which is common, apparently is not associated with recurrence

Gross: often multiple lesions, particularly in pregnant women; tender, skin-colored, sac-like

Micro: resemble fibroepithelial stromal polyps of vagina, cervix and vulva, but with bizarre morphology, frequent mitoses (>10/10 HPF), atypical mitotic figures or hypercellularity; clues to diagnosis are characteristic stellate cells and multinucleate stromal cells, and extension of lesions up to mucosal-submucosal interface

Positive stains: desmin, ER, PR

DD: aggressive angiomyxoma: deep, prominent vascular pattern cuffed by myoid bundles

angiomyofibroblastoma: well circumscribed subserosal nodule, no atypia, stromal cells cluster around vessels, which usually have delicate walls

botyroid embryonal rhabdomyosarcoma: early childhood, submucosal hypercellular zone/cambium layer, rhabdomyoblasts, myoglobin+, myogenin+

cellular angiofibroma: well circumscribed, less polypoid, diffusely vascular with hyalinized walls, no atypical stromal cells, desmin-

leiomyosarcoma: clear boundary of tumor cells with epithelium, smooth muscle differentiation

low grade endometrial stromal sarcoma: vessels resemble spiral arterioles, no central vascular core, thick bands of collagen in starburst pattern, dot like staining of desmin or keratin

malignant peripheral nerve sheath tumor: perivascular accentuation, 50% are S100+

References: AJSP 2000;24:231, Cancer 1983;51:1148 (vaginal)

Pyogenic granuloma of cervix

Gross: red-brown-blue-black, due to excessive capillary growth

Micro: lobulated collection of inflammatory cells, with neutrophils confined to surface of ulcerated lesions; prominent small vessels

Rhabdomyoma of cervix

Also in vagina and vulva

Micro: undifferentiated spindle shape cells and scattered muscle fibers within myxoid matrix, beneath intact squamous epithelium

adult type - abundant eosinophilic cytoplasm

fetal type - small cells and cells resembling fetal muscle

juvenile type - intermediate between adult and fetal types

Positive stains: desmin, myoglobin, myoD1, myogenin

DD: rhabdomyosarcoma

Squamous papilloma of cervix

Also called fibroepithelial polyp, fibroepithelial stromal polyp, mesodermal stromal polyp

Benign lesion of lower genital tract (vagina, vulva, less commonly in cervix), usually in women of reproductive age

15%+ occur during pregnancy; these cases are often multiple with more pleomorphism and atypia

May contain atypical stromal cells (see pseudosarcomatous fibroepithelial stromal polyp)

May regress spontaneously after delivery; may recur

May be a reactive hyperplastic process of myxoid stroma of lower female genital tract, because (a) no clearly defined margin, (b) stromal cells also present in normal vulva, vagina and cervix, (c) similar lesions at other sites, (d) ER+/PR+ suggests hormonal influence

May represent condyloma without koilocytosis

Treatment: excisional biopsy

Gross: usually 5 mm or less, solitary

Micro: fibrovascular stalk covered by mature squamous epithelium, or acanthotic stellate shaped cells growing in a chaotic manner; often no distinct boundary between stroma and epithelium; may have multinucleated stromal cells near epithelial-stromal interface or edematous stroma with occasional enlarged multinucleated fibroblasts; no arborizing pattern, no koilocytotic changes, no cambium layer, no rhabdomyoblasts, no/rare mitotic figures

Positive stains: vimentin, ER, PR, strong smooth muscle actin, weak desmin

DD: sarcoma (including rhabdomyosarcoma), condyloma (koilocytosis, marked arborization; Ki-67 and HPV tests may be helpful, AJSP 2000;24:1393), verrucous carcinoma, well differentiated squamous cell carcinoma, papillary SIL, papillary immature metaplasia, vaginal polyp (contains atypical stromal cells)

Traumatic neuroma of cervix

Reparative lesion at site of traumatic injury of peripheral nerves

Interruption in continuity of nerve causes wallerian degeneration (loss of axons in proximal stump and retraction of axons in distal segment), then exuberant regeneration of nerve and formation of mass of Schwann cells, axons and fibrous cells

Rare complication of cone biopsy (Archives 1989;113:945)

Microneuromas present in 55% of hysterectomy patients, associated with childbirth (Histopathology 1996;28:153)

Gross: irregular gray area up to 2 cm near cone biopsy margin or scar

Micro: haphazard nerves within mature collagenous scar with entrapped smooth muscle

Positive stains: S100

Tunnel clusters of cervix

Incidental finding with no associated gross abnormality

Benign, does not recur

80% have had 3+ prior pregnancies

Micro: lobular proliferation of endocervical glands (clefts) with side channels growing out of them; close to endocervical canal; may be dilated due to inspissated eosinophilic secretions; low power appearance is lobular with one or more discrete foci of cystically dilated endocervical glands; may extend deep into cervical wall; usually well circumscribed but may have pseudoinvasive appearance; benign nuclear features; minimal atypia; no stromal desmoplasia

Type A glands: smaller; noncystic tubules that resemble mucosal folds cut in various planes; may have florid glandular proliferation, and mild nuclear atypia, but are still lobular and have minimal mitotic activity

Type B glands: cystic or dilated tubules arranged in lobular units; often multifocal, up to 2 mm in diameter individually; lined by bland cells with no mitoses, no/minimal nuclear atypia

Negative stains: intracytoplasmic CEA, Ki-67 (or low)

DD: minimal deviation adenocarcinoma (not lobular, moderate/marked nuclear atypia)

References: AJSP 1996;20:1312 (type A with atypia), AJSP 1990;14:895 (early study), Mod Path 2000;13:261 (cervical glandular lesions)

Premalignant / preinvasive lesions of cervix

Human papilloma virus (HPV) of cervix

Causes spectrum of changes ranging from condyloma accuminatum (flat, spiked and inverted condyloma and warty atypia) to invasive squamous cell carcinoma

Family of 60+ viral types; nonenveloped viruses, 55 nm in diameter

Transmitted sexually; has predilection for metaplastic squamous epithelium

Koilocytosis / koilocytotic atypia: related to expression of viral E4 protein and disruption that this causes in cytoplasmic keratin matrix

Koilocyte is superficial or immature squamous cell with sharply outlined perinuclear vacuoles, dense and irregular staining peripheral cytoplasm, enlarged nucleus with undulating (raisin-like) nuclear membrane and rope-like chromatin; often bi- or multinucleation and variation in nuclear size

Nuclear changes are required for diagnosis of koilocytosis since glycogen accumulation is otherwise common (Archives 1990;114:1038), and perinuclear halos can be prominent in postmenopausal cervix without HPV

HPV E6 protein interacts with p53; HPV E7 protein interacts with Rb (retinoblastoma) protein; both induce genetic instability, which promotes selection of a malignant phenotype (J Clin Virol 2005;32 Suppl 1:S25)

Low risk HPV subtypes (associated with genital condyloma and low grade SIL): 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, CP6108

High risk HPV subtypes (associated with high grade SIL and invasive carcinoma): 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82; subtypes 26, 53 and 66 are “probably high-risk” (Low Genit Tract Dis 2005;9:154)

HPV 18: associated with lesions of glandular origin and small cell neuroendocrine carcinoma; recommended that patients with HPV18+ cervical smears have endocervical curettage, even if normal morphology (Best Pract Res Clin Obstet Gynaecol 2005 Dec 12 [Epub ahead of print])

Presence of HPV 16 or 18 confers a 200x relative risk for HSIL for 2 years after first detected (Eur J Obstet Gynecol Reprod Biol 2006;125:114)

Note: report presence of HPV associated changes, even if SIL is also present

Uses: to triage ASCUS cases (HPV+ are more likely to have HSIL at followup), to confirm cervical origin of squamous cell or adenocarcinoma

Micro: normal basal cell layer, expanded parabasal cell layer, orderly maturation, mitotic figures (normal), koilocytosis

Positive stains: Ki-67 (higher in HPV+ epithelium than inflamed or metaplastic squamous epithelium; very high with high risk HPV types)

Molecular: usually detected by Southern blot hybridization (“gold standard”) or in situ hybridization; HPV DNA may be detected by PCR in lesions without koilocytotic atypia (AJSP 1990;14:643)

EM: intranuclear crystalline or filamentous inclusions

References: Archives 2003;127:935 (HPV biology), HPV genome organization

Condyloma acuminatum of cervix

Common sexually transmitted, HPV-associated lesion

Usually associated with HPV 6 or 11; HPV16 is associated with high grade atypia

Benign

May enlarge dramatically during pregnancy and regress spontaneously

Treatment: excisional biopsy, cryosurgery or laser vaporization

Gross: polypoid lesion with spiked or cauliflower appearance; only 8% are multiple

Micro: papillomatosis, acanthosis, koilocytosis in middle and upper epithelium, inflammation; undulating epithelium on low power; minor atypia is common; if more severe, grade as HSIL (high grade squamous intraepithelial lesion) or LSIL (low grade)

Molecular: HPV 6 or 11 in 70-90% of cases, HPV 16 is occasionally seen and associated with high grade cytologic atypia

Immature condyloma of cervix

Also called papillary immature metaplasia

Considered a variant of LSIL

May be a variant of condyloma

May be due to HPV 6 or 11 (Mod Path 1992;5:391)

Gross: exophytic; involves proximal transformation zone and endocervix

Micro: filiform papillae composed of proliferation of immature squamous cells with mild atypia, often associated with mature areas of condyloma; variable cytologic atypia, frequent extension into endocervical canal with preservation of surface endocervical epithelium; usually no koilocytotic atypia, no/rare mitotic figures

Negative stains: marked reduction in Ki-67 staining in superficial cell layers vs. condyloma, HSIL or papillary carcinoma; p16

Molecular: HPV 6 and 11 are present in areas of koilocytotic atypia and immature metaplasia; high grade types not found, but rarely coexist with separate high grade lesion (J Korean Med Sci 2001;16:762)

DD: reactive metaplasia, HSIL (nuclear overlap, no discrete chromocenters, high mitotic activity and Ki-67 index), papillary squamous cell carcinoma (marked atypia, mitotic activity)

References: Hum Path 1998;29:641, Mod Path 2000;13:252

Atypical squamous lesion of cervix

May be neoplastic (HPV related, LSIL, HSIL) or reactive

In cervical smears, often related to SIL

Features suggestive of neoplastic (5 or more) vs. Nonneoplastic (0-2) are: mitotic figures, vertical nuclear growth pattern, no perinuclear halo, indistinct cytoplasmic border, primitive cells in upper 1/3 of squamous layer, p16+ cells in upper 2/3 of squamous layer, Ki-67+ cells in upper 2/3 of squamous layer (AJCP 2005;123:699)

Reactive changes are present in 2-3% of cervical smears, include normal N/C ratio, intercellular bridges, regular nuclear membrane, finely granular chromatin and prominent nucleoli, but no organization disruption, no/rare mitotic figures, no abnormal mitotic figures; may be occasional binucleated cells or neutrophils in epithelium

Atypical immature metaplasia of cervix

Squamous proliferation of transformation zone and endocervical glands associated with abnormal Pap smears and a colposcopically visible abnormality

Poorly understood - heterogeneous group of lesions including HSIL and reactive metaplasia

May be HPV infection of immature squamous metaplasia, but histologic appearance doesn’t predict HPV status

HPV+ cases are associated with future diagnosis of HSIL

Cytologically, are a subgroup (<10%) of ASC-H (atypical squamous cells, cannot exclude high grade lesion)

Treatment: based on size and distribution of lesion (Cancer 1983;51:2214)

Micro: not papillary; metaplastic squamous epithelium shows nuclear atypia; basal layer of uniform cells with a uniform chromatin pattern and variable hyperchromasia; overlying squamous cells are monomorphic with prominent chromocenters and regular nuclear membranes; normal cell polarity, rare/no cell crowding and mitoses; if present, mitoses are normal and confined to the lower third of the epithelium; occasional higher mitotic rates, multinucleation, nuclear enlargement and perinuclear halos

Positive stains: Ki-67 staining similar to LSIL, higher than normal cervix

Molecular: 2/3 have intermediate or high risk HPV; none have low risk HPV

DD: HSIL, papillary immature metaplasia (papillary architecture)

References: Hum Path 1999;30:345, Hum Path 1999;30:1161, Mod Path 2000;13:252

Squamous intraepithelial lesions (SIL) of cervix-general

Invasive carcinoma is usually preceded by SIL, which may exist for 20 years before tumor becomes invasive

Often occurs in teenagers and young women (mean age 26 years in one study)

Risk factors are similar as squamous cell carcinoma (sexual activity before age 17 years, multiple sexual partners, most likely related to HPV infection)

SIL cells are usually detected by cytologic examination (Pap smear or liquid based cytology), have similar histology as invasive cells, including nuclear enlargement and hyperchromasia, alteration of maturation, increased mitotic activity; also reduction in cytoplasmic glycogen (less iodine staining with Lugol or Schiller’s iodine test)

SIL morphologic abnormalities correlate with cytogenetics, ploidy, cell proliferation and molecular changes

SIL usually affects transformation zone near endocervical epithelium; may have abrupt borders, may extend up endocervical canal

Changes in pregnant women and post-radiation dysplasia may NOT regress

Postradiation dysplasia within 3 years of treatment is a poor prognostic factor

Dysplastic cells from cervix may cause vulvar/vagina dysplasia also (J Natl Cancer Inst 2005;97:1816)

Low grade SIL (LSIL): usually euploid or polypoid, 2/3 regress, 1/6 are unchanged, 1/6 progress

High grade SIL (HSIL): usually aneuploid, less regression; 1/3 become invasive at 9 years; associated with HPV types 16, 18, 31, 33; peaks during ages 30-39 years; 0.2% develop invasive carcinoma even after treatment; distinction between high grade dysplasia (HSIL) and carcinoma in situ is not reproducible between pathologists and is not usually made anymore

Classification systems: (a) mild, moderate or severe dysplasia or carcinoma in situ; (b) cervical intraepithelial neoplasia (CIN) - CIN I, CIN II, CIN III; (c) low grade SIL (LSIL) or high grade SIL (HSIL) - SIL terminology is currently recommended

Treatment for LSIL: controversial since most lesions regress

Treatment for HSIL: cone, LEEP, electrodiathermy, cryosurgery, laser; long term followup is necessary

Note: treatment of HIV+ patients must be more aggressive (Eur J Obstet Gynecol Reprod Biol 2005;121:226)

Features to report: LSIL or HSIL (or use terminology at institution), presence of endocervical glandular involvement, presence in multiple quadrants, presence of HPV related changes, margin involvement (including endocervical margin), involvement of endocervical clefts

Prognostic factors for recurrence after LEEP: positive margins, positive glandular involvement, multiple quadrant disease (Mod Path 1999;12:233)

Gross: identified best with colposcopic examination after application of acetic acid; more common on anterior lip of cervix than posterior lip; rarely occurs laterally

Micro: squamous intraepithelial lesions with abnormal proliferation and abnormal maturation, nuclear enlargement and nuclear atypia; abnormal proliferation begins at basal and parabasal layers with an increased number of immature parabasal type cells in intermediate and superficial epithelium; abnormal maturation is due to loss of polarity and cellular disorganization; also increased number of mitotic figures and abnormal mitotic figures, particularly in HSIL

Positive stains: Ki-67/MIB

MIB-1 staining of cluster of 2 nearby nuclei in upper 2/3 of epithelial thickness may distinguish SIL from reactive lesions (AJSP 2002;26:1501); MIB-1 staining is a strong indicator of HSIL, less reliable for immature LSIL (AJSP 2001;25:884); MIB-1 staining may be helpful in equivocal cases (AJSP 2002;26:70)

LSIL / CIN I / low grade dysplasia of cervix

Slightly raised (condylomas) or flat; thickened (acanthotic) epithelium with koilocytotic atypia (viral cytopathic effect) in middle or upper epithelium

Most flat LSILs are associated with high risk HPV; use caution is diagnosing LSIL on any flat immature lesion

HPV negative LSIL: not a distinct biologic entity; often false positive LSIL or false negative HPV (Cancer 2005;105:253)

HPV16+ LSIL or ASC have higher risk for HSIL than HPV16- LSIL/ASC (J Natl Cancer Inst 2005;97:1066)

Micro:

Sternberg’s approach to diagnosis:

(a) low power epithelial disorganization compared to surrounding epithelium, due in alterations in thickness, absence of mucin droplets and metaplastic changes, hyperchromasia in upper layers or other changes in nuclear density, cell arrangement or halo contour

(b) at high power, should be 3x difference in size of nuclei compared to normal intermediate cells, although often not present; combination of nuclear and cytoplasmic changes and growth pattern alterations may be sufficient

(c) subtle features include binucleation (2+ binucleated cells per high power field is supportive, particularly if enlarged or hyperchromatic); also small densely hyperkeratotic binucleated cells; binucleation occasionally is found in reactive changes; irregular cytoplasmic halos are useful, if a rim of dense cytoplasm forms a basket weave in the superficial epidermis; however may be non-specific

Diagnosis is often subjective, with interobserver variation

Koilocytotic changes are present in HPV negative squamous component of endometrioid carcinoma of endometrium or ovary; are not present in HPV+ cervical adenocarcinoma

Presence of meganuclei in superficial epithelial layers is associated with high risk HPV (Hum Path 1998;29:1068)

Koilocytotic atypia (koilocytosis): nuclear pleomorphism, wrinkled nuclei, hyperchromasia, binucleation (almost always present, Mod Path 1993;6:313), perinuclear halos with distinct clear zone around nucleus and condensation of denser cytoplasm around the periphery; few/no mitotic figures, particularly in lower half of epithelium, no atypical mitotic figures

Positive stains: Ki-67 throughout epithelium

EM: perinuclear cytoplasmic necrosis with cytoplasmic fibrils condensed along cell periphery; viral particles are present in nuclear crystalline array

DD of LSIL:

(a) vaginal papillomatosis: papillary epithelium is normal in vagina; may have cytoplasmic halos; usually no prominent acanthosis, no nuclear atypia, no atypical parakeratosis

(b) reactive epithelial changes: cytoplasmic halos are associated with glycogenated cells, mild atypia associated with inflammation, but no pleomorphism is present; small binucleated cells may be seen in a background of metaplasia; reactive changes usually have regular nuclear spacing, distinct nucleoli, no nuclear atypia in upper layers, superficial maturation

(c) postmenopausal squamous atypia: pseudokoilocytosis with uniform/round halos with central nuclei, slightly hyperchromatic, occasional grooves, occasional binucleation; associated with urothelial metaplasia and atrophy; NOT associated with HPV (Mod Path 1995;8:408

(d) HSIL: nuclear enlargement and atypia throughout full thickness of epithelium

(e) cytoplasmic vacuolization due to glycogen of normal squamous epithelium: usually diffuse, normal epithelial maturation, no nuclear atypia

References: AJSP 2002;26:1389 (p16)

HSIL / CIN II / moderate dysplasia of cervix

Micro: persistent abnormal differentiation towards prickle and keratinizing layers with at least focal maturation; atypical basal cells involve between 1/3 and 2/3 of epithelial thickness or less with disproportionate atypia; increased N/C ratio, pleomorphic nuclei with hyperchromasia, loss of polarity, increased mitotic activity

Cytology: see Cervix-cytology

HSIL / CIN III / severe dysplasia of cervix

1-7% are associated with early invasive disease; 10-20% are estimated to progress to carcinoma if untreated

Poor prognostic factors include extensive involvement of surface epithelium and deep endocervical clefts, luminal necrosis, intraepithelial squamous maturation

Case reports: HSIL involving deep mesonephric remnants (AJSP 1994;18:1265)

Micro: epithelium is totally replaced by atypical cells in at least part of the lesion with loss of maturation; koilocytes often have smaller and more concentric halos and denser hyperchromasia; may have less pleomorphism than low grade lesions, although nuclei are uniformly enlarged, crowded or irregularly spaced; hyperchromatic or binucleated; increased mitotic activity is present; may have surface parakeratotic cells with abnormal nuclei; nuclear abnormalities are often more prominent in basal/parabasal cells

Note: LSIL and HSIL often coexist

Positive stains: MIB-1; also MUC4 (Hum Path 2001;32:1197)

EM: loss of intercellular cohesion due to marked reduction in desmosomes, presence of extremely complex cell surface, loss of surface pseudopodia

DD of HSIL:

(a) reactive/reparative changes: intercellular edema (spongiosis), evenly spaced nuclei, minimal variation in nuclear size, prominent nucleoli, neutrophils, superficial maturation of epithelium, no hyperchromasia; binucleation may be present

(b) immature squamous metaplasia: mucin droplets, neutrophilic infiltration, often overlying mucinous epithelium, minimal variation in nuclear size, no hyperchromasia

(c) atrophy: hyperchromatic but uniform nuclei, elongated and grooved nuclei, minimal atypia in superficial epithelium, no mitotic activity, even spacing of nuclei, conspicuous intracellular bridges, MIB-1 negative; Ki-67/MIB1 and p16 negative are helpful in diagnosis in postmenopausal women (J Low Genit Tract Dis 2005;9:100); in older women, can apply estrogen to induce maturation and rebiopsy

(d) adenoid cystic carcinoma

(e) radiation changes: abundant cytoplasm with vacuoles, nuclear enlargement and hyperchromasia with smudged chromatin, prominent nucleoli, uniform nuclear spacing, normal N/C ratio, minimal mitotic activity

(f) placental site nodule: (strongly keratin and PLAP positive)

(g) sheets of macrophages

(h) urothelial hyperplasia

(i) iodine effect: can induce shrinkage, cytoplasmic eosinophilia, vacuolization and epithelial pyknosis

DD (clinical): hyperkeratosis and metaplastic squamous epithelium

SIL Variants of cervix

Keratinizing SIL of cervix

HSIL with immature metaplastic differentiation of cervix

Immature flat lesions with uniform population of small, metaplastic-type cells, reduced superficial cell maturation, high nuclear density on surface with hyperchromasia

DD: papillary immature metaplasia (papillary not flat, less nuclear pleomorphism and atypia), air drying artifact

HSIL with eosinophilic dysplasia of cervix

Present in 10% of HSIL lesions

Associated with HPV infection and classic HSIL in adjacent areas

May arise from metaplastic cervical squamous epithelium that has become infected with high risk HPV

Micro: lack of normal maturation; compared to classic HSIL, cells have distinct cell borders and abundant eosinophilic cytoplasm, increased N/C ratio and focal dysplastic nuclei with nuclear enlargement, hyperchromasia, variable nuclear membrane abnormalities and distinct nucleoli; associated with classic SIL and squamous metaplasia

Positive stains: p16, MIB1 expression, HPV

DD: glassy cell carcinoma

References: AJSP 2004;28:1474

Endocervical glandular atypia / dysplasia

More severe cases are called endocervical glandular dysplasia (atypical hyperplasia)

Some use terminology of CIGN - cervical intraepithelial glandular neoplasia

Not a reproducibly defined entity with a specific cause or outcome

Patients with diagnosis based on cervicovaginal smears often have squamous dysplasia (Obstet Gynecol 1992;79:101)

Appears to NOT be a precursor to adenocarcinoma in situ (Hum Path 2000;31:656, AJCP 1998;110:200)

Atypical oxyphilic metaplasia: incidental finding of endocervical glands lined by large cuboidal or polygonal epithelial cells with dense, eosinophilic, focally vacuolated cytoplasm and variable nuclear enlargement, hyperchromatism, multiple lobes or multinucleation; no mitotic activity or stratification; benign behavior (Int J Gynecol Pathol 1997;16:99)

Micro: glandular atypia - glandular cells with hyperchromatic nuclei with only occasional mitotic figures and minimal pseudostratification; no cribriform areas, no papillary projections, no crowding, no mitotic figures; alternatively there is marked atypia involving only a single gland; normal N/C ratio

glandular dysplasia - resembles adenocarcinoma in situ but nuclei are not malignant and have fewer mitotic figures, OR malignant involvement of only one gland

Positive stains: p16 (in dysplasia, Hum Path 2004;35:689, but not atypia or reactive lesions, AJSP 2003;27:187)

Negative stains: HPV (usually)

DD: inflammation, radiation, Arias-Stella reaction, tamoxifen or oral contraceptives, microglandular hyperplasia, metaplasia

References: AJSP 2003;27:452 (scoring system), Mod Path 2000;13:261

Adenocarcinoma in situ (AIS) of cervix

May be increasing in incidence

Average age 35 to 40 years at presentation, range 27 to 74 years

30-60% have associated SIL

HPV 16 or 18 are risk factors (Br J Cancer 2006;94:171); are present in 50-90% of cases

Precursor to most cases of invasive adenocarcinoma of cervix; may progress to invasive adenocarcinoma or be adjacent to microinvasive disease

Arises from reserve cells with capacity to undergo columnar differentiation, or from columnar epithelium

Case reports: with HSIL in pregnant patient (Arch Gynecol Obstet 2004;270:116)

Treatment: cone biopsy or hysterectomy (cold knife with negative margins may still lead to invasive, residual or recurrent disease); follow up with cytology and HPV testing

Gross: no distinctive gross appearance; often multifocal involving multiple quadrants of cervix; often superior to squamocolumnar junction

Micro: low power diagnosis; normal glandular architecture with malignant, darkened glands at squamocolumnar junction involving part or all of epithelium lining glands or forming the surface, composed of hyperchromatic, enlarged, crowded nuclei with coarse chromatin, small single or multiple nucleoli, frequent mitotic figures (mean 18/10 HPF); apoptotic bodies common (mean 16/10 HPF); may have abrupt transition to normal epithelium; endocervical type most common; also endometrioid (no mucin production, no goblet cells, no cells with clear or light-staining cytoplasm, cells have scanty cytoplasm with marked nuclear stratification), intestinal types; may have periglandular inflammation; presence of glands close to thick walled vessels (within diameter of vessel) is suggestive of invasion (Int J Gynecol Pathol 2005;24:125); no extension below normal glands, no infiltration of stroma, no desmoplasia

Positive stains: CEA (specific if strongly positive), Cdc6 and MIB1 (Cdc6 stains only scattered cells, Archives 2002;126:1164), p16 (non specific, Hum Path 2004;35:689, AJSP 2003;27:187), keratin (50%)

Negative stains: ER and PR, vimentin, bcl2

Molecular: HPV (70% by in situ hybridization)

DD: tubal or tuboendometrial hyperplasia (involves only a single gland or portion of a gland, no significant nuclear atypia), nonspecific glandular atypia or dysplasia, invasive adenocarcinoma (infiltrating glands with budding, desmoplasia, extension of glands beyond normal glandular depth), Arias-Stella reaction (usually focal glands or focal portion of glands, hobnail type cells, no/rare mitotic activity), microglandular hyperplasia (polypoid, smaller and more uniform glands, bland nuclei, no mitotic activity), endometriosis (endometrial-type cells with basal nuclei but no atypia; surrounded by endometrial-type stroma which is CD10+), mesonephric remnants (deep in stroma, bland nuclei, have intraluminal secretions), viral induced changes (inflammation present, viral nuclear inclusions)

References: AJSP 1998;22:434 (apoptotic bodies), Mod Path 2000;13:261

Radiation atypia of cervix

Can involve endocervical cells or squamous epithelial cells

Gross: fibrosis, induration, stenosis of endocervix, surface irregularity or no abnormality

Micro: similar to changes in other organs; hyalinized stroma or reactive changes with ectatic vessels; sparse, well-spaced tubular or dilated glands in endocervix; abundant cytoplasm with vacuoles; uniformly dispersed nuclei with minimal crowding, but marked nuclear atypia of endocervical glandular cells with enlarged, pleomorphic and smudged nuclei, prominent nucleoli; chromatin is fine and degenerated; no/rare mitotic figures, low N/C ratio

Positive stains: scattered CEA

References: Int J Gynecol Pathol 1996;15:242

Stratified Mucin producing Intraepithelial Lesions (SMILE) of cervix

Rare cervical intraepithelial lesion that is a variant of endocervical columnar cell neoplasia, consistent with neoplasm arising in reserve cells in transformation zone

Associated with SIL and invasive carcinoma

May be a marker of phenotype instability

Micro: multilayered epithelium resembling SIL with conspicuous cytoplasmic clearing or vacuoles in lesions otherwise resembling HSIL due to more extreme nuclear pleomorphism and hyperchromasia and higher proliferation index; mucin present throughout the epithelium; usually associated SIL or AIS; usually no squamous differentiation

Positive stains: high MIB-1 index, mucin

Negative stains: keratin 14, p63

DD: adenocarcinoma in situ, atypical immature squamous metaplasia

References: AJSP 2000;24:1414

Carcinoma of cervix

WHO classification of cervical tumors

Epithelial tumors

Squamous lesions and precursors

Squamous cell carcinoma, not otherwise specified

Keratinizing

Nonkeratinizing

Basaloid

Verrucous

Warty (condylomatous)

Papillary (transitional)

Lymphoepithelioma-like

Squamotransitional

Early invasive (microinvasive) squamous cell carcinoma

Squamous intraepithelial neoplasia / lesions (SIL)

High grade (usually lumped with carcinoma in situ) or low grade

Cervical intraepithelial neoplasia (CIN) - different terminology than SIL

CIN 1 (mild dysplasia, low grade SIL)

CIN 2 (moderate dysplasia, high grade SIL)

CIN 3 (severe dysplasia, carcinoma in situ, high grade SIL)

Benign squamous cell lesions

Condyloma acuminatum

Squamous papilloma

Fibroepithelial polyp

Glandular tumors and precursors

Adenocarcinoma

Mucinous adenocarcinoma (endocervical, intestinal, signet ring, minimal deviation, villoglandular subtypes)

Endometrioid adenocarcinoma (may have squamous metaplasia)

Clear cell adenocarcinoma

Serous adenocarcinoma

Mesonephric adenocarcinoma

Early invasive adenocarcinoma

Adenocarcinoma in situ

Glandular dysplasia

Benign glandular lesions

Mullerian papilloma

Endocervical polyp

Other epithelial tumors

Adenosquamous carcinoma

Glassy cell carcinoma variant

Adenoid cystic carcinoma

Adenoid basal carcinoma

Neuroendocrine tumors

Carcinoid tumor

Atypical carcinoid tumor

High grade neuroendocrine carcinoma - small cell or large cell types

Undifferentiated carcinoma

Mesenchymal tumors and tumor like conditions

Leiomyosarcoma

Endometrioid stromal sarcoma, low grade

Undifferentiated endocervical sarcoma

Embryonal rhabdomyosarcoma (sarcoma botyroides)

Alveolar soft parts sarcoma

Angiosarcoma

Malignant peripheral nerve sheath tumor

Leiomyoma

Genital rhabdomyoma

Postoperative spindle cell nodule

Mixed epithelial and mesenchymal tumors

Carcinosarcoma (malignant mullerian mixed tumor)

Adenosarcoma

Wilms tumor

Adenofibroma

Adenomyoma

Melanocytic tumors

Malignant melanoma

Blue nevus

Miscellaneous tumors

Germ cell tumors (yolk sac tumor, dermoid cyst, mature cystic teratoma)

Lymphoid and hematopoietic

Malignant lymphoma (specify type)

Leukemia (specify type)

Secondary tumors

Squamous cell carcinoma of cervix

4,500 deaths/year in US, #8 cause of cancer death in women in US (was #1 in 1940's); still #1 in other countries

Reduction due to Papanicolaou smear test to detect premalignant lesions (1 million cases of SIL detected per year in US, 13,000 new invasive carcinomas, Cancer 2004;100:1035)

Mean age 51 years, uncommon before age 30 years but most are ages 45-55 years

Risk factors: early age at first intercourse, multiple sexual partners (Br J Cancer 2003;89:2078), male partner with multiple prior sexual partners, history of HSIL; HLA associations in Mexican women (Hum Path 1999;30:626)

Also: oral contraceptives (some studies), cigarette smoking (Int J Cancer 2006;118:1481), parity, family history, associated genital infections, no circumcision in male partner

Human papillomavirus (HPV): causes vulvar condyloma acuminatum (sexually transmitted), found in DNA of 95% of cervical cancers, 90% of condylomas and premalignant lesions

High risk HPV types for cervical carcinoma: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68 and others

Low risk HPV types for cervical carcinoma: 6, 11, 42, 44 (associated with condyloma)

HPV acts via E6 and E7 genes, which differ in high vs. low risk HPV types; HPV is integrated in premalignant lesions with tumor DNA vs. present in episomes (not integrated) in condylomas; in HPV 16 and 18, E6 binds to p53, causing its proteolytic degradation; E7 binds to retinoblastoma gene (Rb) and displaces transcription factors normally bound by Rb

Other co-factors are important, because (a) most with HPV don’t get cervical cancer, (b) 10-15% of cervical cancer is NOT associated with HPV

HIV or HTLV-1 infection adversely affect the prognosis, may be associated with rapidly progressive course

Detect clinically via white patches after application of acetic acid to cervix; cervix also has mosaic vascular patterns at colposcopy

Prognostic factors: clinical stage, nodal status, size of largest node and number of involved nodes, tumor size, depth of invasion, endometrial extension, parametrial involvement, angiolymphatic invasion; HPV negative patients do poorer; possibly S phase fraction; possibly tissue associated eosinophilia (poorer survival in one study, Hum Path 1996;27:904); also squamous cell carcinoma antigen serum level in patients with advanced disease (Anticancer Res 2005;25:1663)

Not relevant: microscopic tumor grade, tumor type, angiogenesis

Spreads usually through cervical lymphatics in sequential manner; via direct extension to vagina, uterus, parametrium, lower urinary tract, uterosacral ligaments; distant metastases to aortic and mediastinal lymph nodes, lung, bones, ovary (1%)

2/3 are stage I or II when diagnosed

Case reports: after amebiasis (Archives 1985;109:1121), with endometrial tuberculosis in India (Arch Gynecol Obstet 2004;269:221), with granulocytosis (Obstet Gynecol 2004;104:1086, Korean J Intern Med 2005;20:247), decidua in pelvic lymph nodes of pregnant patient may mimic metastases (Eur J Gynaecol Oncol 2005;26:499), with coexisting HPV negative clear cell carcinoma (Gynecol Oncol 2005;97:976), with CLL/SLL (Gynecol Oncol 2004;92:974), on surface of pedunculated cervical leiomyoma (Gynecol Oncol 2005;97:253)

metastases - to pulmonary capillaries causing cor pulmonale (Archives 1992;116:187), to lung presenting as lymphangitis carcinomatosis (Gynecol Oncol 2004;94:825), causing right ventricular mass (Jpn J Thorac Cardiovasc Surg 2005;53:645), to cerebellum confirmed using PCR (Hum Path 1999;30:587), to cerebrum (MedGenMed 2005;7:26), to ovarian Brenner tumor (Mod Path 1995;8:307), to incisional scar (Int J Gynecol Cancer 2005;15:1183), to scalp (Clin Exp Dermatol 2003;28:28, Int J Gynecol Cancer 2001;11:244), extensive subcutaneous metastases in HIV+ patient (Int J Gynecol Cancer 2001;11:78), to spleen (South Med J 2004;97:301, Eur J Gynaecol Oncol 2004;25:742), to psoas muscle (Cancer Radiother 2003;7:187)

Treatment: surgery (note: trachelectomy means cervicectomy), radiation therapy, radioactive implants (for early lesions), pelvic extenteration (for post-radiation therapy relapse; 5 year survival is 23%; frozen section may be necessary to rule out extra-pelvic spread)

5 year survival of patients treated 1993-1995 by stage: Ia1-Ib1: > 95%, Ib2-IIb: 80-90%, III: 50%, IV: 25-35%

Gross: polypoid or deeply invasive

Micro: see subtypes below; invasion characterized by desmoplastic stroma, focal conspicuous maturation of tumor cells with prominent nucleoli, blurred or scalloped epithelial-stromal interface, loss of nuclear polarity; may have pseudoglandular pattern due to acantholysis and central necrosis; rare findings are amyloid (Archives 1993;117:199), signet-ring cells (Int J Gynecol Cancer 1992;2:152), melanin granules (Int J Gynecol Pathol 2003;22:285)

Grading does not correlate with prognosis and is optional

Well differentiated: predominantly mature squamous cells with abundant keratin pearls, occasional well-developed intercellular bridges, minimal pleomorphism, minimal mitotic activity

Moderately differentiated: less distinct cell borders and less cytoplasm than well differentiated tumors; also more nuclear pleomorphism and more mitotic activity

Poorly differentiated: small primitive appearing cells with scant cytoplasm, hyperchromatic nuclei and marked mitotic activity; no/rare keratinization; resembles HSIL

Positive stains: keratin (almost 100%), CEA (90%), progesterone receptor, mucicarmine (some, but does not make them adenocarcinomas), p63 (Hum Path 2001;32:479), thrombomodulin, involucrin

Negative stains: p53 (usually), MDM2 gene, EBV (usually, Archives 1999;123:1098)

EM: well developed intracytoplasmic tonofilaments, desmoplastic-tonofilament complexes and intercellular microvilli in well differentiated tumors, lost with decreasing differentiation

Molecular: aneuploid, but tumor may exhibit heterogeneity; HPV16 is associated with 3q amplification

DD: immature squamous metaplasia (uniform cell size and shape, no significant nuclear atypia), squamous metaplasia with extensive glandular involvement or marked decidual reaction (no atypia, no/rare mitotic figures; decidua is keratin-), placental site nodule (well circumscribed nodules of intermediate trophoblast cells, no/rare mitotic activity, HPL+), clear cell carcinoma (papillary and tubulocystic areas, hobnail cells, no squamous differentiation, may be associated with DES exposure), small cell neuroendocrine carcinoma (diffuse infiltration of small cells with scant cytoplasm and hyperchromatic nuclei; often rosettes, trabeculae or ribbons; often crush artifact; immunoreactive for neuroendocrine markers)

References: EMedicine, Cancer 2005;103-1258 (mortality trends), Molecular Cancer 2005;4:38 (epigenetics)

Large cell keratinizing squamous cell carcinoma of cervix

Rare, locally aggressive; spreads by direct extension

More radioresistant than nonkeratinizing carcinomas (5 year survival for stage I is 54%)

Not associated with HPV or SIL; not associated with sexual risk factors

Often normal Pap smear, but may be large and high stage at diagnosis

Histologically similar to HPV negative vulvar and penile cancers

Gross: usually large

Micro: must have keratin pearls and intercellular bridges to be keratinizing; keratin pearl is rounded nest of squamous epithelium with circles of squamous cells surrounding a central focus of acellular keratin; cells are large with abundant eosinophilic cytoplasm; nuclei may be enlarged or pyknotic; extensive parakeratosis and hyperkeratosis without atypia in non-malignant portion of cervix, marked hyperkeratosis in invasive area with keratin pearls, intercellular bridges, >25 cells per nest, extensive infiltration of adjacent tissues, relatively low mitotic activity, no vascular invasion

Molecular: HPV negative by PCR

References: AJSP 2001;25:1310

Large cell nonkeratinizing squamous cell carcinoma of cervix

More radiosensitive than large cell keratinizing (5 year survival for stage I is 84%)

Micro: rounded nests of neoplastic squamous cells with no keratin pearls, but may have individual cell keratinization or clear cells; relatively uniform cells with indistinct cell borders and numerous mitotic figures

Occult squamous cell carcinoma of cervix

Tumor discovered after simple hysterectomy

Stage Ib lesions > 3.1 mm (or 5 mm) in length

Mean age 43 years

5 year survival of 96% vs. 86% for clinical stage Ib

Case reports: tumor in uterus removed for prolapse (Pakistan J Med Res 2002;41)

Treatment: radical hysterectomy and lymph node dissection

References: Int J Radiat Oncol Biol Phys 1999;43:1049

Papillary squamourothelial carcinoma of cervix

Rare, resembles urothelial carcinoma, but lacks true urothelial differentiation (J Low Genit Tract Dis 2005;9:149)

May behave aggressively with late metastases and local recurrence

Usually postmenopausal women who present at advanced stage (Eur J Gynaecol Oncol 1998;19:455)

Superficial biopsies with this pattern should be considered invasive until proven otherwise

Micro: papillary architecture with fibrovascular cores lined by multilayered, basaloid/urothelial-type epithelium with mitotic activity and without maturation, resembling HSIL; stromal invasion is usually at base of tumor but may be within fibrovascular core

Positive stains: CK7, CK5/6

Negative stains: CK20 (usually)

Molecular: often HPV16+ (Cancer 1998;83:521)

References: AJSP 1997;21:915

DD: verrucous carcinoma (bland epithelium, broadly invasive front), condyloma (maturation, koilocytosis)

Small cell squamous cell carcinoma of cervix

Mean age 50 years

Lower rate of nodal metastases and recurrence than small cell neuroendocrine carcinoma

5 year survival for stage I is 42%

Micro: well-defined nests of basaloid-type cells resembling small cell neuroendocrine carcinoma, but with more cytoplasm, coarser chromatin and prominent nucleoli; 60% also have SIL

Positive stains: keratin

Negative stains: neuroendocrine markers

DD: small cell neuroendocrine (undifferentiated) carcinoma

References: Mod Path 1991;4:586

Microinvasive squamous cell carcinoma of cervix

3 mm or 5 mm (varies by author) or less of stromal invasion; also known as “early stromal invasion” or “superficially invasive”

Approximately 20% of invasive carcinoma cases in US (higher figure than in the past; lower rate where patients typically present with advanced disease, Bull Soc Pathol Exot 2005;98:183)

Note: FIGO stage Ia is lesion with maximum depth of invasion of 5 mm and maximum horizontal spread of 7 mm; is subdivided into Ia1 (3 mm or less) and Ia2 (more than 3 mm but not more than 5 mm)

1% with 3 mm of invasive disease have nodal metastases (more if angiolymphatic invasion) vs. 13% with 3-5 mm of invasive disease

In recent study, recurrence in 6% with up to 3 mm vs. 13% with up to 5 mm of invasive disease (Eur J Gynaecol Oncol 2003;24:513)

Almost always arises from SIL, usually in anterior lip of cervix; associated with delayed screening (BJOG 2005;112:807)

Prognostic factors: lymph node metastases; recurrence associated with angiolymphatic invasion, depth of invasion and distance between tumor margin and apex of cone (Int J Gynecol Cancer 2005;15:88); also positive margins

Report depth of invasion (measure from most superficial epithelial-stromal interface of adjacent intraepithelial process - image), length of entire lesion, whether length is composed of one or multiple lesions, presence of vascular invasion (DD: retraction artifact, displacement of tumor into vascular spaces during biopsy or anesthetic injection), margins, presence of SIL, presence of glandular differentiation (i.e. adenocarcinoma)

Obtain levels as needed to confirm invasion

Case reports: superficial spread through endometrial cavity (J Obstet Gynaecol Res 2004;30:363), disseminated recurrence although initial disease < 1 mm deep and 1 mm wide (Gynecol Oncol 2003;90:443)

Treatment: clinical course resembles HSIL, so treat with cone biopsy or simple hysterectomy (versus radical hysterectomy with pelvic lymph node dissection for more invasive disease)

Gross: resembles HSIL; often abnormal vessels at colposcopy

Micro: irregularly shaped tongues of epithelium projecting into stroma; invasive cells exhibit individual cell keratinization, loss of polarity, pleomorphism, cellular differentiation, prominent nucleoli, desmoplastic stroma rich in acid mucosubstances with metachromatic staining properties, breach of basement membrane by reticulin stains (also type IV collagen or laminin); may also see scalloped margins at epithelial-stromal interface, duplication of neoplastic epithelium or pseudoglands

DD: crypt involvement of SIL with tangential sectioning (each nest is discrete and separate from its neighbors), cautery/crush artifact due to prior biopsy, pseudoepitheliomatous hyperplasia or other reactive changes, blurring of epithelial-stromal border by inflammation, placental implantation site

Adenocarcinoma of cervix and variants

5-15% of invasive cervical carcinomas, higher percentage in Jewish women

Incidence increasing in US, now up to 25% of cervical cancers, due to decreasing rates of squamous cell carcinoma and difficulty in diagnosis using current screening methods; increased frequency in young women (Cancer 2004;100:1035)

Usually associated with in-situ adenocarcinoma (mean 5 year interval, which is less than for SIL)

Suspected but still unproven association with oral contraceptives

Endocervical adenocarcinoma is associated with ovarian mucinous adenocarcinoma and ovarian endometrioid adenocarcinoma

30-50% false negative reports by cytology

p16 may be sensitive/specific for diagnosing adenocarcinoma (invasive or in-situ) by histology or Thin-Prep (AJSP 2003;27:187, but see Hum Path 2002;33:899)

Often vaginal bleeding, pelvic pain

Spreads first to pelvic structures, then pelvic lymph nodes; metastases to ovaries, upper abdomen, distant organs

Usually EBV negative (Archives 1999;123:1098)

Mixed if there is 10% or more of a second component

Survival by stage: I-79%, II-37%, III/IV-less than 9%

Poor prognostic factors: high stage (including depth > 5 mm, Int J Gynecol Cancer 2004;14:104), angiolymphatic invasion, high grade (Gynecol Oncol 2004;92:262); also HER2 overexpression, elevated serum CA125

Case reports: ovarian recurrence after radical trachelectomy (Am J Obstet Gynecol 2005;193:1382), mixed with urothelial carcinoma (Pathol Int 2004;54:63, Int J Gynecol Pathol 2003;22:220)

metastases - choriocarcinomatous metastases to lung (Gynecol Oncol 2006 Jan 20; [Epub ahead of print]), to brain (Int J Gynecol Cancer 2005;15:561), vaginal metastasis associated with traumatic vaginal tear (Gynecol Oncol 2005;96:857)

Treatment: surgery (simple or radical hysterectomy or fertility sparing surgery), radiation therapy, cisplatin or other chemotherapy (Curr Treat Options Oncol 2004;5:119)

Gross: exophytic mass, ulcerated plaque or barrel-shaped cervix (diffuse enlargement)

Micro: often well differentiated with endocrine morphology and mucin that may leak into stroma; may also be poorly differentiated, papillary, endometrioid or have psammoma bodies

microscopic invasion: individual cells or incomplete glands lined by malignant cells at a stromal interface or malignant glands surrounded by a desmoplastic host response; other evidence of invasion is architecturally complex, branching, or small glands, which grow confluently or in a labyrinthine pattern; cribriform growth pattern of malignant epithelium devoid of stroma within a single gland profile; and the presence of glands below the deep margin of normal glands; rare findings are focal cilia (Acta Cytol 2005;49:187)

Tumor grade of adenocarcinoma:

Grade 1: well-differentiated (10% or less solid growth); tumor contains well-formed regular glands with papillae; cells are elongate and columnar with uniform oval nuclei; minimal stratification (fewer than three cell layers in thickness); infrequent mitotic figures

Grade 2: moderately differentiated (11% to 50% solid growth); tumor contains complex glands with frequent bridging and cribriform formation; solid areas up to 50% of tumor; nuclei more rounded and irregular; small nucleoli present; mitoses more frequent

Grade 3: poorly differentiated (over 50% solid growth); sheets of malignant cells; few glands are discernible; cells are large and irregular with pleomorphic nuclei; occasional signet cells are present; mitoses are abundant with abnormal forms; marked desmoplasia; necrosis is common

Positive stains: Alcian blue, mucicarmine, CEA, keratin, EMA, p16, ER and PR in 25%, p53

Negative stains: CD10 (positive only in mesonephric adenocarcinomas), p63 (Hum Path 2001;32:479), vimentin (usually)

Molecular: associated with HPV 16 and 18 in 85-95% of cases (AJCP 1996;106:52, Br J Cancer 2005;93:1301)

DD: endometrioid adenocarcinoma extending to cervix (no in situ cervical adenocarcinoma, continuity between cervix and endometrial tumors, usually myometrial invasion, often bland squamous differentiation, CEA and mucin are negative or focal and superficial; positive for vimentin, ER and PR, negative for HPV by PCR, AJSP 2002;26:998, AJSP 2003;27:1080), metastatic adenocarcinoma (usually clinical evidence of widespread disease, angiolymphatic invasion, no surface involvement), adenocarcinoma in situ (no glands below deep margin of normal endocervical glands), microglandular hyperplasia (does not extend below deep margin of normal endocervical glands, usually young women taking oral contraceptives or pregnant, few mitotic figures), mesonephric remnants (deep, don’t extend to surface, contain eosinophilic secretions, CD10+, no mitotic activity, no atypia)

References: Cancer 2005;103:1258 (mortality trends), Mod Path 2000;13:261

Endocervical (mucinous) type of adenocarcinoma of cervix

70-90% of all adenocarcinomas

Micro: tumor cells resemble endocervical mucosa; cells are arranged in simple or branching glands; often glands are close to thick-walled vessels (within thickness of vessel wall, Int J Gynecol Pathol 2005;24:125); usually brisk mitotic activity

DD: endocervicosis (often in outer cervix, zone of normal stroma between lesion and endocervical glands, no atypia, no mitotic figures, Int J Gynecol Pathol 2000;19:322)

Endocervical microcystic adenocarcinoma of cervix

Mean age 49 years, range 34 to 78 years

Presents with abnormal Pap smears or vaginal bleeding

Micro: cysts occupy 50-90% of tumor, 1-8 mm in diameter; lined by flat to low cuboidal to pseudostratified epithelium; luminal mucin is common, resembles contents of mesonephric tubules; variable desmoplastic stroma

DD: tunnel clusters, deep Nabothian cysts, lobular endocervical gland hyperplasia, mesonephric hyperplasia (no foci of atypia or architecturally abnormal glands, usually low mitotic rate)

References: AJSP 2000;24:369

Endometrioid adenocarcinoma of cervix

See below

Intestinal type of adenocarcinoma of cervix

Rare

Micro: mimics colonic epithelium; glands lined by pseudostratified, malignant appearing cells with intracytoplasmic mucin vacuoles; goblet cells, occasionally Paneth cells (Archives 1990;114:731)

Positive stains: CEA, CK7

Negative stains: CDX2, CK20

DD: metastatic colorectal adenocarcinoma (very rare; CDX2+, CK7-, CK20+, Archives 2003;127:1586, Jpn J Clin Oncol 1999;29:640)

Signet ring adenocarcinoma of cervix

Rare to be pure; usually is mixture with other subtypes

Case reports: with glassy cell carcinoma (Pathol Int 2004;54:787), with neuroendocrine differentiation (Int J Gynecol Cancer 1999;9:433)

Micro: solid cell nests surrounded by pools of mucin

Positive stains: CEA, CK7

Negative stains: CDX2, CK20

DD: metastatic adenocarcinoma from breast (Gynecol Oncol 1998;71:461) or stomach (Cancer 1993;71:3472, Acta Cytol 1997;41:291)

Microinvasive adenocarcinoma of cervix

Usually defined as stromal invasion up to 3-5 mm in depth

Excellent prognosis (Obstet Gynecol 2001;97:701)

Associated with minimal metastases to nodes (Int J Gynecol Cancer 2004;14:104)

May have associated SIL

Report: depth of invasion measured from surface, horizontal extent, margin involvement, infiltrative vs. expansile invasion, degree of cell differentiation, presence of angiolymphatic invasion

Case reports: 62 year old woman with FIGO stage IA1 disease and bilateral pelvic nodal metastases (Gynecol Oncol 2000;77:467), metastasis to episiotomy scar and subsequent death from disease (Gynecol Oncol 1995;59:297)

Treatment: depends on horizontal extent and nodal involvement; simple hysterectomy is usually adequate (Gynecol Oncol 2002;85:327)

Micro: up to 5 mm of invasive disease as measured from surface; budding of cells from adenocarcinoma in situ gland; vesicular nuclei with prominent nucleoli (similar to invasive squamous cell carcinoma); desmoplastic stroma; glands deeper than normal endocervical glands or invasive growth pattern

Positive stains: CEA, keratin (50%)

References: AJSP 2003;27:187 (p16), AJSP 2002;26:1389 (p16), IARC/WHO definition

Adenoid basal carcinoma of cervix

Uncommon, <100 cases reported, occurs in elderly (mean age 60 to 71 years, range 30 to 91 years), often blacks

May derive from cervical reserve cells, since similar immunophenotype (Jpn J Clin Oncol 1997;27:437)

Often an incidental finding; associated with HSIL and HPV 16

Excellent prognosis; slow growing, usually indolent with favorable prognosis, mean depth of tumor invasion 4 mm (range 2 to 10 mm); no nodal metastases, no tumor recurrence, no/rare distant metastases

Some recommend calling adenoid basal epithelioma due to indolent behavior (AJSP 1998;22:965)

May also have an invasive carcinoma component that requires aggressive treatment (Hum Path 2005;36:82); may represent the epithelial component of carcinosarcoma/MMMT (AJSP 2001;25:338, Int J Gynecol Pathol 1998;17:211)

Case reports: 79 year old black woman with HSIL on pap test (Archives 2004;128:485), with carcinosarcoma (Int J Gynecol Pathol 2002;21:186)

Treatment: hysterectomy; cone biopsies may not completely excise these lesions

Gross: usually no mass identified; may have vague nodular distortion

Micro: basaloid islands of small cells with peripheral nuclear palisading (similar to basal cell carcinoma) and microcyst formation, occasional central squamous or glandular differentiation or acinar arrangement; ulcerated infiltrating growth pattern; cells are uniform, round/oval with scant cytoplasm and hyperchromatic nuclei; no stromal reaction; associated with SIL (usually HSIL)

Negative stains: CK7

Molecular: usually HPV16+ (Int J Gynecol Pathol 1997;16:301)

EM: cribriform patterns with gland-like structures covered by basal lamina; cells have scant cytoplasm, irregular nuclei; no myoepithelial features (Med Electron Microsc 2000;33:241)

DD: adenoid cystic carcinoma (larger tumors, extensively involves surface, has glands with cylindromatous pattern, usually type IV collagen+ and laminin+), small cell carcinoma, carcinoid tumor, basaloid squamous cell carcinoma (larger neoplastic cells with nuclear pleomorphism, central comedonecrosis, CK7+, Pathol Int 2005;55:445), pseudoepitheliomatous hyperplasia (nests are connected with or close to surface, usually associated inflammation)

References: AJSP 1980;4:235, Hum Path 2000;31:740

Adenoid cystic carcinoma of cervix

Uncommon (1% of primary cervical adenocarcinomas), occurs in elderly, black women with multiple pregnancies

Rarely occurs in women under 40 years (Gynecol Oncol 1989;32:26)

Poor prognosis due to frequent local recurrences and distant metastases

May be epithelial component of carcinosarcoma (AJSP 2001;25:338, Eur J Gynaecol Oncol 2000;21:292)

Case reports: 83 year old white woman with cervical mass (Archives 2004;128:817)

Treatment: radiotherapy and chemotherapy in elderly, surgery

Gross: irregular, polypoid, friable cervical mass

Micro: nests of cells in cribriform pattern with eosinophilic / hyaline cores, resembling adenoid cystic carcinoma of salivary glands but without myoepithelial cells; may resemble adenoid basal carcinoma but has more nuclear atypia, expansile growth pattern, distinct stromal reaction and necrosis; mitotic figures, angiolymphatic invasion and hyalinized stroma are common; may have focal solid growth or squamoid pattern

Positive stains: keratin, type IV collagen, laminin (extracellular basement membrane), HHF45, focal CEA and EMA

Negative stains: usually S100 and actin

Molecular: HPV16+ (J Clin Pathol 1996;49:805)

EM: redundant basal lamina forming pseudocysts, intercellular spaces, and occasional true lumens with microvilli (AJCP 1982;77:494)

DD: adenoid basal carcinoma (no intraluminal hyaline material, smaller and less pleomorphic nuclei, usually no type IV collagen or laminin, AJSP 1999;23:448)

References: AJSP 1988;12:134, Int J Gynecol Pathol 1992;11:2 (solid variant)

Adenosquamous carcinoma of cervix

May arise from subcolumnar reserve cells in basal layer of endocervix

More common during pregnancy

Same prognosis as other cervical carcinomas when stratified by grade and stage, but most cases are high grade

Most undifferentiated cervical carcinomas have ultrastructural features of squamous or glandular differentiation

Case reports: with vaginal and endometrial extension (Int J Gynecol Cancer 2004;14:625), myometrial recurrence during pregnancy (Gynecol Oncol 2000;76:409), metastasis to port site (Gynecol Oncol 1999;74:130)

Micro: usually defined as biphasic pattern of well defined malignant glandular and squamous components clearly identifiable without special stains; glandular component usually endocervical and poorly differentiated with cytoplasmic vacuoles or luminal mucin; squamous component also is poorly differentiated; if endometrioid call endometrioid carcinoma with squamous differentiation

Positive stains: p63 (squamous component), CK7

EM: glandular features include mucous secretory vacuoles, true lumen formation and scattered glycogen; also tonofilaments and secretory products

DD: squamous cell carcinoma with focal mucin droplets, adenoid basal carcinoma (Pathol Int 2005;55:445), extension of endometrial adenocarcinoma (bulk of tumor is in endometrium), adenocarcinoma with coexisting SIL (usually no mixing of tumor elements)

Basaloid squamous cell carcinoma of cervix

Aggressive behavior

Micro: squamous cell carcinoma with well defined nests of small, oval-shaped basaloid cells with scant cytoplasm; prominent peripheral palisading, infiltrative growth, minimal stromal reaction; resembles tumors of same name at other sites (Adv Anat Pathol 2002;9:290); often necrosis or focal keratinization but no keratin pearls

DD: adenoid basal carcinoma, adenoid cystic carcinoma

Carcinoid tumor of cervix

Rare; very aggressive with 3 year survival of 12-33% (World J Surg 2005;29:92)

Neuroendocrine tumors of cervix are classified as carcinoid, atypical carcinoid and neuroendocrine carcinoma (small cell or large cell)

Survival may be similar between carcinoid tumors (classic and atypical) and neuroendocrine carcinoma (J Exp Clin Cancer Res 2001;20:327)

Case reports: with local spread and liver metastases (Arch Anat Cytol Pathol 1989;37:88), with brain metastases (Gynecol Oncol 1988;30:114), associated with microinvasive adenocarcinoma (Acta Pathol Jpn 1987;37:1183)

Micro: resembles carcinoid tumors elsewhere

Positive stains: neuroendocrine stains show intracytoplasmic endocrine granules; may also represent adenocarcinoma with carcinoid features

EM: secretory granules

Atypical carcinoid of cervix

Carcinoid tumor with cytologic atypia and increased mitotic activity

Case reports: 46 year old woman with atypical carcinoid and carcinoid syndrome (J Clin Endocrinol Metab 1999;84:4209)

DD: adenocarcinoma

Clear cell carcinoma (adenocarcinoma) of cervix

Formerly called (incorrectly) mesonephric carcinoma of cervix - actually of mullerian origin (Cancer 1978;42:2435)

4% of cervical adenocarcinomas; less common in cervix than ovary and endometrium

Most common form of cervical carcinoma in young women

Associated with in utero DES exposure (women born in 1950’s, N Engl J Med 1987;316:514); also older women without DES exposure; rare in children

Good survival - 55% at 5 years and 40% at 10 years

Case reports: with squamous cell carcinoma (Gynecol Oncol 2005;97:976), associated with GU malformation (Obstet Gynecol 2000;96:834)

Treatment: radical hysterectomy and pelvic lymphadenectomy; trachelectomy to preserve fertility (Gynecol Oncol 2005;97:296)

Gross: involvement of ectocervix (if DES exposure) or endocervical canal (no DES exposure); may resemble cervical polyp

Micro: tubulocystic, solid, papillary or microcystic patterns of cells with abundant clear or eosinophilic cytoplasm, large irregular nuclei; hobnailing of cells (nuclei protrude into lumina); intraglandular papillary projections; in situ changes at squamocolumnar junction; may have hyalinized stroma or papillary cores, may have eosinophilic material within tubules or cysts

EM: continuous lamina densa, numerous mitochondria and rough endoplasmic reticulum, abundant glycogen and blunt microvilli; also vesicular aggregates in nucleoplasm, perinuclear cytoplasm or between membranes of nuclear envelope (Acta Cytol 1976;20:262)

DD: microglandular hyperplasia (polypoid, focal or no atypia, usually also squamous metaplasia), mesonephric hyperplasia (no significant atypia, glands are deep in cervix), Arias-Stella reaction (history of pregnancy or birth control pills, no infiltration, atypia is focal, no mitotic figures), squamous cell carcinoma (no areas resembling clear cell carcinoma although cells may have cytoplasmic clearing due to glycogen), metastatic renal cell carcinoma (rare, history important), yolk sac tumor (rare, children), alveolar soft parts sarcoma (rare)

References: Centers for Disease Control

Endometrioid adenocarcinoma of cervix

Second most common type of cervical adenocarcinoma after endocervical type

Incidence rates may be increasing (Cancer 2000;89:1291)

May be associated with synchronous (existing at same time) or metachronous (existing at different time) ovarian tumor

Micro: resembles tumor in uterine corpus and ovary; often well differentiated; complex branching of glands lined by pseudostratified cells with scant cytoplasm and no mucin vacuoles present on H&E; crowded and stratified nuclei; often accompanied by adenocarcinoma in situ

Positive stains: HPV, CEA (usually, Hum Path 1996;27:172)

Negative stains: vimentin (usually)

DD: primary endometrial adenocarcinoma spreading into cervix (endometrial hyperplasia present, no adenocarcinoma in situ in cervix, no involvement of endocervical stroma, vimentin+, ER+, PR+, CEA-, HPV-, AJSP 2003;27:1080), endocervical type adenocarcinoma with minimal intracellular mucin

References: minimal deviation endometrioid adenocarcinoma - AJSP 1993;17:660 and Histopathology 1992;20:351

Epithelioid trophoblastic tumor of cervix

Rare tumor (100 cases reported) in women of reproductive age with abnormal vaginal bleeding

Associated with a gestational event, mean 6 years prior

Usually elevated serum hCG

In uterine fundus, lower uterine segment or endocervix

Neoplastic counterpart to placental site nodule, with malignant intermediate trophoblast

Metastases in 25%, death in 10%; similar behavior as placental site trophoblastic tumor; less aggressive than choriocarcinoma

Case reports: 36 year old with clinical squamous cell carcinoma of cervix and high beta hCG (Gynecol Oncol 2002;87:219), 53 year old woman with gestational event 25 years prior (Int J Gynecol Cancer 2003;13:551)

Micro: resembles placental site trophoblastic tumor; invasive nodules of monomorphic intermediate-sized intermediate trophoblast cells with abundant eosinophilic or clear cytoplasm, medium/large irregular nuclei with distinct nucleoli; occasional multinucleated cells; tumor cells surround extensive necrosis and hyaline-like matrix; 2+ mitotic figures/10 HPF; at periphery, tumors infiltrate normal tissue in small round nests or cords, including focal replacement of surface or glandular epithelium with stratified neoplastic cells; often decidualized stroma nearby; usually no definite SIL

Positive stains: MIB-1 (18%), AE1/AE3, CK18, HLA-G, EMA, E-cadherin, p63, inhibin-alpha (Int J Gynecol Pathol 1999;18:144), focal HPL, focal hCG

Negative stains: PLAP, MEL-CAM

DD: placental site trophoblastic tumor (larger cells, more nuclear pleomorphism, infiltrative pattern), invasive squamous cell carcinoma, lymphoepithelioma-like carcinoma with hCG production (Int J Gynecol Pathol 2000;19:179)

References: AJSP 1998;22:1393, Mod Path 2006;19:75)

Glassy cell carcinoma of cervix

Distinct type of poorly differentiated adenosquamous carcinoma

1-2% of cervical carcinomas

Younger age group (mean 41 years), associated with pregnancy, HPV 18 and 16

Historically considered more aggressive with poorer prognosis than ordinary adenosquamous carcinoma or adenocarcinoma (APMIS Suppl 1991;23:119), although recent studies show less or no difference (Am J Obstet Gynecol 2004;190:67, Gynecol Oncol 2002;85:274)

May have peripheral blood eosinophilia

Cytokeratin expression is similar to that of reserve cells or immature squamous cells of cervix (Int J Gynecol Pathol 2002;21:134)

Poor prognostic factors: angiolymphatic invasion, deep stromal invasion, large tumor size

Treatment: radical hysterectomy and adjuvant radiation

Case reports: 33 year old woman; combined with signet ring cell carcinoma (Pathol Int 2004;54:787)

Gross: exophytic mass or barrel shaped cervix

Micro: solid nests of markedly pleomorphic, polygonal tumor cells with prominent cell membrane, glassy and eosinophilic cytoplasm, large eosinophilic nuclei, prominent nucleoli, surrounded by heavy inflammatory infiltrate containing eosinophils; frequent mitotic figures; pure cases have no histologic evidence of glandular or squamous differentiation (i.e. no intracellular bridges, no dyskeratosis, no intracellular glycogen), which is detectable only by EM; often less invasion than is suspected

Cytology: see Cervix-cytology

Positive stains: PAS+ cell wall, vimentin, focal mucin, focal CEA

Negative stains: p63, HMB45, ER and PR (usually)

EM: glassy features may be due to cytoplasmic polyribosomes, abundant tonofilaments and abundant dilated rough endoplasmic reticulum (AJCP 1991;96:520); adenosquamous features include well developed desmosomal complexes and microvilli; occasional intracellular lumina (Cancer 1983;51:2255)

DD: large cell nonkeratinizing squamous cell carcinoma (cell membrane is less well defined, cytoplasm is less finely granular, coarser chromatin distributed along nuclear membrane; also poor staining or fixation makes it resemble glassy cell carcinoma)

References: Archives 1982;106:250

Large cell neuroendocrine carcinoma of cervix

Rare (<1% of cervical carcinomas)

Mean age 34 years, range 21 to 62 years

Presents with abnormal Pap smear or vaginal bleeding

Aggressive behavior, similar to lung counterpart, with early metastases to regional lymph nodes and liver, lung, bone and brain (Int J Gynecol Pathol 2003;22:226)

Median survival < 2 years

Case reports: Japanese woman with 3q amplification in tumor (Hum Path 2005;36:1096), with HSIL (Pathology 1999;31:158), with small cell component (Gynecol Oncol 1998;68:69),presenting as carcinomatous meningitis, with well differentiated adenocarcinoma

Micro: defined as moderate to severe nuclear atypia, neuroendocrine differentiation with cells larger than typical small cell carcinoma; insular, trabecular, glandular and solid growth patterns; usually eosinophilic cytoplasmic granules, >10 MF/10 HPF and extensive necrosis; angiolymphatic invasion; often with adjacent adenocarcinoma in situ

Positive stains: keratin (MNF116) in paranuclear dot-like pattern; chromogranin or synaptophysin, vascular endothelial growth factor (Int J Gynecol Cancer 2005;15:646), HepPar1 (J Clin Pathol 2004;57:48), alpha fetoprotein (Acta Cytol 2003;47:799)

Negative stains: HER2 (usually), ER and PR (usually)

Molecular: HPV16 and HPV18 are usually present (J Clin Pathol 2002;55:108)

DD: atypical carcinoid tumor, poorly differentiated carcinoma

References: AJSP 1997;21:905

Lymphoepithelioma-like carcinoma of cervix

Resembles nasopharyngeal counterpart

Usually younger patients than squamous cell carcinoma of cervix

Uncommon, usually EBV+ in Asian patients (Cancer 1997;80:91); EBV- in non-Asian patients (Archives 2002;126:1501)

Usually low stage at diagnosis; better outcome than usual squamous cell carcinoma of cervix

Case reports: 21 year old black woman, EBV- (AJCP 1993;99:195), 44 year old white woman in Netherlands, EBV- but HPV+ (Gynecol Oncol 2005;97:716), EBV- but HPV+ cases (Hum Path 2001;32:135), positive for beta-hCG (Int J Gynecol Pathol 2000;19:179)

Gross: usually exophytic

Micro: syncytium of large tumor cells with eosinophilic cytoplasm, vesicular nuclei, prominent nucleoli; prominent lymphoplasmacytic infiltration with T lymphocytes; pushing margins; no glandular or squamous differentiation

Positive stains: AE1-AE3, EMA, HPV, p63, p53, MIB-1; variable beta-hCG, focal HER2

Negative stains: lymphoid markers (stain infiltrating lymphocytes only), bcl2, ER, PR

Molecular: may have EBV false positives due to EBV+ lymphocytes (Neoplasma 2003;50:8); HPV negative, SV40 negative

DD: glassy cell carcinoma with lymphocytic infiltrate, poorly differentiated squamous cell carcinoma

References: AJSP 1985;9:883, Archives 2000;124:746

Mesonephric adenocarcinoma of cervix

Very rare; <50 cases reported

Arise from remnants of mesonephric (Wolffian) ducts, which form epididymis and vas deferens in males and persist in females as rete ovarii, paraoophoron and Gartner’s duct

Mean age 52 years, range 35 to 72 years

Usually presents with abnormal vaginal bleeding, stage IB disease; some are higher stage and aggressive

Adjacent to areas of mesonephric hyperplasia

Appears to arise from “lower zone” of Wolffian system, in contrast to female adnexal tumors of probable Wolffian origin (upper zone)

Immunophenotype resembles mesonephric remnants of cervix and vagina (EMA+, CK7+, ER-, PR-, AJSP 2001;25:379)

May have better prognosis than mullerian counterparts (AJSP 2004;28:601)

Case reports: 47 year old woman with pelvic pain (Archives 2004;128:1179), 18 month old girl (Int J Gynaecol Obstet 1988;26:137), 55 year old with postmenopausal bleeding

Gross: often along lateral cervix within fibromuscular stroma

Micro: small tubules or ducts (most common), also retiform, solid, sex-cord like and spindled; glands may be endometrioid; may have eosinophilic secretions seen in mesonephric rests; often lined by cuboidal or low columnar cells with malignant nuclei but no intracytoplasmic mucin; mild to moderate nuclear atypia; usually adjacent hyperplastic mesonephric remnants; surface epithelium is not involved; desmoplastic stroma is not prominent

Positive stains: AE1/AE3, CAM5.2, CK1, CK7, EMA (100%), calretinin (88%), vimentin (70%), CD10 (AJSP 2003;27:178), androgen receptor (33%), inhibin (30%, focal), Ki-67 (15%)

Negative stains: CK20, ER, PR, CEA

DD:

mesonephric hyperplasia - usually incidental finding with lobular and noninfiltrative patterns, minimal atypia, minimal mitotic activity, no solid/ductal patterns, no angiolymphatic invasion, no necrotic luminal debris

endometrioid adenocarcinoma - usually high grade, involves surface epithelium and deep cervical stroma, no mesonephric hyperplasia, ER+, PR+, CEA+, vimentin-

malignant mixed mullerian tumor - high grade atypia, distinct demarcation between glandular and stromal components

clear cell carcinoma of mullerian origin - often associated with DES exposure; tubulocytic or papillary pattern with clear and hobnail cells

References: AJSP 1995;19:1158

Metastases to cervix

Extragenital tumors more commonly metastasize to ovary and vagina than cervix

Usually from ovary, breast, colon (Archives 2003;127:1586), stomach, kidney; evidence of widespread disease is usually present

Direct extension from endometrial primary tumor is also common (particularly poorly differentiated adenocarcinoma)

Often involves cervical stroma and NOT surface epithelium or endocervical glands

Rarely due to metastatic mucinous carcinoma of appendix

Case reports: 19 year old girl with renal cell carcinoma metastasis (Gynecol Oncol 2005;99:232), gastric carcinoma (Int J Gynecol Cancer 2003;13:555), breast carcinoma patients on tamoxifen (Eur J Gynaecol Oncol 1999;20:416, Eur J Obstet Gynecol Reprod Biol 1999;83:57), signet ring breast metastases (Gynecol Oncol 1998;71:461)

Micro: usually no in situ component; extensive angiolymphatic invasion is present, even in small and superficial lesions

Minimal deviation adenocarcinoma of cervix

Also called adenoma malignum

1% of endocervical adenocarcinomas

Usually sporadic, but also associated with Peutz-Jeghers syndrome (rare, autosomal dominant disorder of hamartomatous polyposis in GI tract, mucocutaneous pigmentation and predisposition to benign and malignant GI, breast, ovary, cervix and testicular tumors; due to STK11 gene)

Usually HPV negative (Mod Path 1998;11:11, Mod Path 2005;18:528, Int J Gynecol Pathol 2005;24:296)

Often missed by small cervical biopsies; lack of diagnostic consensus between pathologists (Pathol Int 2003;53:440)

May be identified during endometrial ablation (J Am Assoc Gynecol Laparosc 2003;10:119)

Ages 34 to 42 years in one study

May have worse prognosis due to difficulty of diagnosis / discovery at higher stage with nodal involvement

Case reports: patient with Peutz-Jeghers syndrome (Gynecol Oncol 2004;92:337), with cystic lesions >10 cm causing bladder obstruction (Gynecol Oncol 2002;84:339)

Gross: barrel-shaped cervix (diffusely enlarged)

Micro: very well differentiated glands (usually endocervical-type) with cystic dilation; glands are variable in shape or size with irregular or claw-shaped outlines; malignant due to distorted glands with irregular outlines deep in cervix, focal stromal response; 50% have small foci with a moderate/poorly differentiated focus; often has cilia or apical snouts; often has mitotic figures; often glands are close to thick-walled vessels (within thickness of vessel wall, Int J Gynecol Pathol 2005;24:125); may have vascular or perineural invasion; rarely has endometrioid histology

Positive stains: PAS-Alcian blue 2.5 (red/neutral mucin), HIK1073 (GI phenotype, 75%, Mod Path 2004;17:962), periglandular smooth muscle actin+ stroma (Histopathology 2005;46:130), CEA (variable)

Negative stains: high iron diamine-Alcian blue 2.5 (acid mucin), p53, CD10, calretinin

Molecular: often mutations in STK11 gene (Lab Invest 2003;83:35)

EM: may have gastric phenotypes (Ultrastruct Pathol 1999;23:375)

DD: adenofibroma (may extend throughout cervix and into upper vagina wall; has dense periglandular fibrosis, Int J Gynecol Cancer 1995;5:236), diffuse laminar endocervical glandular hyperplasia (AJSP 1991;15:1123), endocervical type adenomyoma (APMIS 2001;109:546), endocervicosis (outer cervix and paracervical connective tissue, presence of uninvolved zone of cervical wall between endocervicosis and normal endocervical glands, Int J Gynecol Pathol 2000;19:322), endosalpingiosis (rarely presents as a mass, AJSP 1999;23:166), florid deep glands (bland inactive appearing cells), lobular endocervical glandular hyperplasia (noninvasive proliferation of endocervical glandular cells in lobular arrangement without any irregular stromal infiltration, desmoplasia or focal malignant features, Pathol Int 2005;55:412, AJSP 1999;23:886), microglandular hyperplasia (different morphology; CEA negative), pseudoinfiltrative tubal metaplasia of the endocervix associated with in utero DES exposure (Int J Gynecol Pathol 2005;24:391), tunnel clusters (little variation in size, shape and depth of glands)

References: AJSP 1993;17:660 (early study), AJSP 2000;24:559 (mucin stains), AJSP 1989;13:717 (analysis of 26 cases), Mod Path 2000;13:261

Mixed carcinoma of cervix

At least 10% of two components - adenosquamous carcinoma is described above; MMMT is described below

Includes squamous, adenocarcinoma and urothelial carcinoma

References and case reports are listed separately under each component

Serous papillary adenocarcinoma of cervix

Rare, resembles serous papillary carcinoma of ovary or endometrium

Metastasizes to pelvic and periaortic lymph nodes

Stage 1 tumors have similar outcome as other cervical adenocarcinomas; aggressive behavior if supradiaphragmatic metastases

In young women, may be focal component of conventional adenocarcinoma; HPV positive

In menopausal women, may be drop metastasis from endometrial or upper genital tract tumor; HPV negative

Case reports: familial tumors of cervix, ovary and peritoneum (Gynecol Oncol 1998;70:289)

Gross: resembles endocervical adenocarcinoma

Micro: papillary proliferation of pleomorphic epithelial cells with complex papillary architecture on fibrovascular cores, exhibiting epithelial stratification and tufting; cells have protruding apical cytoplasm, moderate/severe nuclear atypia and nuclear pleomorphism; frequent mitotic activity; papillary cores often have intense inflammatory infiltrate; often mixed with another adenocarcinoma, frequently low grade villoglandular; psammoma bodies common

Positive stains: CA-125 (75%), CEA (50%), p53 (40%)

DD: extension / metastatic ovarian or uterine tumors

References: AJSP 1998;22:113, Mod Path 1992;5:426

Small cell (neuroendocrine / undifferentiated) carcinoma of cervix

Rare (2-5% of invasive cervical carcinomas); clinically aggressive with rapid metastases; frequently presents with parametrial invasion and pelvic lymph node metastases

Similar age as squamous cell carcinoma (mean 43 years, range 23 to 63 years)

Associated with HPV-18 (AJSP 1991;15:28, Int J Gynecol Pathol 2004;23:366); occasionally associated with Cushing syndrome or symptoms of other peptide hormones

Coexisting SIL is rare; endocrine cell hyperplasia may be a precursor lesion

5 year survival is 30-40%; relapse in 2/3 at median 8 months (Gynecol Oncol 2004;93:27), poor prognostic factors are smoking and high stage (Cancer 2003;97:568), focal glandular differentiation does not affect prognosis

Case reports: with syndrome of inappropriate antidiuretic syndrome (Mod Path 1996;9:397), 27 year old woman (AJCP 1992;97:516), cervical polyp with rapid growth during pregnancy (Gynecol Oncol 2001;81:117), G-CSF producing tumor (Diagn Cytopathol 2000;23:269)

Amphicrine carcinoma: small cell carcinoma combined with squamous cell carcinoma or adenocarcinoma

Treatment: radical hysterectomy with bilateral lymphadenectomy, radiation therapy and chemotherapy

Gross: may be ulcerative and infiltrative; often barrel shaped cervix

Micro: loose aggregates of uniform small cells with indistinct cell borders, scant cytoplasm, hyperchromatic nuclei with fine granular chromatin, nuclear molding, indistinct nucleoli, extensive mitotic activity, single cell necrosis; may form sheets with small acini resembling rosettes; necrosis common; vascular invasion in 9%; resembles counterpart in lung; patterns include insular (solid nests / islands of cells with peripheral palisading and retraction of stroma), perivascular and thick trabeculae with serpiginous (wavy) growth; variable amyloid deposition; may have minor (<10%) component of glandular or squamous differentiation; often no associated inflammation

well differentiated pattern: organoid arrangement with insular, trabecular, glandular or spindle patterns

Positive stains: note - small cell carcinoma is a morphologic diagnosis regardless of stain results; NSE (80%), chromogranin (60%), synaptophysin (70%), serotonin, CEA, p16 (AJSP 2004;28:901; Hum Path 2003;34:778), S100, keratin (variable); CD56 is sensitive but not specific (Int J Gynecol Pathol 2005;24:113); variable TTF1

Negative stains: CK20, Rb, p53, p63, CD117/c-kit (Mod Path 2004;17:732)

Molecular: frequent loss of heterozygosity at 3p and 11p

EM: cells are tightly packed with close apposition of cell membranes; dense core secretory granules

DD: small cell squamous cell carcinoma (well defined nests similar to large cell nonkeratinizing squamous cell carcinoma), carcinoid tumor

References: AJSP 1988;12:684, Mod Path 1991;4:586, Int J Gynecol Cancer 2005;15:295, Ann Diagn Pathol 2002;6:345

Spindle cell carcinoma of cervix

Also called sarcomatoid carcinoma

Similar to upper aerodigestive tract counterpart

Mean age 48 years, range 29 to 76 years

Aggressive; tumors often recur and cause death (Gynecol Oncol 2003;90:23)

Case reports: death after stage I disease (Eur J Gynaecol Oncol 2000;21:287),

Micro: poorly differentiated squamous cell carcinoma with spindle-shaped cells; often osteoclast-like giant cells

Positive stains: keratin, p63, vimentin; often HPV, smooth muscle actin

DD: MMMT (spindle cell component is malignant)

Urothelial carcinoma of cervix

Also called transitional cell carcinoma

Rare; resembles counterpart in bladder (AJSP 1995;19:1138)

Often presents at advanced clinical stage

May represent subgroup of squamous cell carcinoma

Case reports: complicated by pyometra (pus in uterine cavity, Indian J Pathol Microbiol 2004;47:71), mixed with adenocarcinoma (Pathol Int 2004;54:63, Int J Gynecol Pathol 2003;22:220)

Micro: often exophytic, may have inverted pattern

Positive stains: CK7

Negative stains: CK20

Molecular: often HPV16+ (Gynecol Oncol 1999;74:361, Cancer 1998;83:521)

DD: papillary lesions of cervix, inverted urothelial papilloma

References: AJSP 1995;19:1138

Verrucous carcinoma of cervix

Rare; diagnosis of exclusion

More common in vulva

Diagnosis is difficult with superficial biopsies

Invades locally (may extend into endometrial cavity), and up to 50% recur, but metastases are unlikely

One paper claims that HPV+ cases are better classified as SIL, giant condyloma or invasive squamous cell carcinoma (Can J Surg 1993;36:147)

Case reports: tumors in cervix and vagina (Gynecol Oncol 2003;90:478), multiple small recurrent tumors 13 years later in retroperitoneal space (Oncol Rep 2000;7:1079), 32 year old woman with endometrial involvement, hysterectomy and brachytherapy (Eur J Gynaec