Cervix
Last revised 9 July 2010
Last major update February 2006
Copyright © 2003-2009, PathologyOutlines.com, Inc.
Reviewed by Dr. Branko Perunovic (see Reviewers Page)
See also Cervix-cytology, Uterus
Cervix: embryology, normal anatomy, normal histology, metaplasia
Inflammation: inflammation-general, actinomycosis, amebiasis, bacterial vaginosis, Candida/fungi, Chagas’ disease, chlamydia, chronic cervicitis, CMV, Enterobius, granuloma inguinale, granulomas, herpes, pseudolymphoma, Schistosomiasis, syphilis, Trichomonas, tuberculosis, vasculitis, Wuchereria
Benign/non-neoplastic lesions: adenomyoma, adenosis, Arias-Stella reaction, atrophy, atypical polypoid adenomyoma, blue nevus, cervical pregnancy, decidual nodule, decidual reaction, diffuse laminar endocervical glandular hyperplasia, ectopic tissue/heterotopia, endocervical polyp, endometrial polyp, endometriosis, endosalpingiosis, florid deep glands, glial polyp, hemangioma, inflammatory pseudotumor, inverted urothelial papilloma, leiomyoma, lipoleiomyoma, lobular endocervical hyperplasia, melanosis, mesonephric papilloma, mesonephric rests, mesonephric hyperplasia, microglandular hyperplasia, myofibroblastoma, Nabothian cysts, necrobiotic granulomas, neurofibroma, pagetoid dyskeratosis, papillary adenofibroma, papillary endocervicitis, placental site nodule, post-operative spindle cell nodule, pseudosarcomatous fibroepithelial stromal polyps, pyogenic granuloma, rhabdomyoma, squamous papilloma, traumatic neuroma, tunnel clusters
Premalignant/preinvasive lesions: HPV, condyloma, atypical squamous lesion, SIL-general, LSIL/CIN I, HSIL/CIN II, HSIL/CINIII, SIL variants, endocervical glandular atypia/dysplasia, adenocarcinoma in situ, radiation atypia, stratified mucin producing intraepithelial lesions
Carcinoma: WHO classification, squamous cell and variants, microinvasive squamous cell, adenocarcinoma and variants, microinvasive adenocarcinoma, adenoid basal, adenoid cystic, adenosquamous, basaloid squamous cell, carcinoid, clear cell, endometrioid, epithelioid trophoblastic tumor, glassy cell, large cell neuroendocrine, lymphoepithelioma-like, mesonephric adenocarcinoma, metastases to cervix, minimal deviation adenocarcinoma, mixed, serous papillary adenocarcinoma, small cell, spindle cell, urothelial, verrucous, villoglandular papillary adenocarcinoma, warty
Sarcoma/lymphoma/other: adenosarcoma, aggressive angiomyxoma, alveolar soft parts sarcoma, Ewing’s sarcoma/PNET, granulocytic sarcoma, leiomyosarcoma, lymphoma, malignant mixed mullerian tumor, melanoma, other (case reports), plasmacytoma, rhabdomyosarcoma, stromal sarcoma, teratoma, Wilm’s tumor, yolk sac tumor
Miscellaneous: procedures, grossing, staging of cervical carcinoma, features to report
Go to Cervix-cytology
AJCC Cancer Staging Manual (7th ed)
American Journal of Clinical Pathology (AJCP), August 1975 to February 2006
American Journal of Surgical Pathology (AJSP), March 1977 to January 2006
Archives of Pathology and Laboratory Medicine (Archives), June 1976 to January 2006
Human Pathology (Hum Path), May 1974 to January 2006
Modern Pathology (Mod Path), March 1988 to January 2006
Kurman: Tumors of the Cervix, Vagina, and Vulva (AFIP, 3rd Series, Vol 4)
Rosai, J: Ackerman’s Surgical Pathology (9th Ed); Mosby, 2004
Sternberg,
S: Diagnostic Surgical Pathology (4th Ed); Lippincott Williams & Wilkins,
2004
Website: Histopathology and cytopathology
of the Uterine Cervix – Digital Atlas
Journal search terms: cervix, cervicovaginal
Please refer to these primary references for more detailed discussions and photographs
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
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
Drawings: local anatomy; microanatomy; saggital section of local anatomy #1; #2; uterus, cervix and vagina #1; #2; vasculature
Gross: nulliparous cervix; endocervical canal
References: ASCCP
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
Drawings: location of glandular and squamous epithelium
Gross images: squamocolumnar junction
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Micro images: ectocervix (H&E, stains, EM); normal nonkeratinizing squamous epithelium #1; #2; #3; #4
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transformation zone #1-various images; #2; #3
endocervix (H&E, stains, EM); endocervix #1; #2; #3; #4; #5; infoldings resemble glands; endocervical canal (whole mount); normal exocervix; squamocolumnar junction; cervical myometrium #1; #2; myometrium and adventitia; prepubertal squamous epithelium shows only basal and parabasal cells with no maturation
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Virtual slides: normal cervix
Cytology: see Cervix-cytology
References: ASCCP
Defined as change in differentiation pathway to which the stem cell progeny commit
Not neoplastic
Micro images: osseous and cartilaginous metaplasia
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
Micro images: (1) with sebaceous glands; (2) figure 1: cervix covered by keratinized squamous epithelium with prominent granular cell layer; 2: stroma has mature sebaceous glands; 3: sebaceous cells are surrounded by epithelial cells
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
Cytology: see Cervix-cytology
Micro images: immature squamous metaplasia; with mild atypia
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
Cytology: see Cervix-cytology
Micro images: various images; early metaplasia; involving clefts; with cytoplasmic vacuoles
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)
Cytology: see Cervix-cytology
Micro images: tubal metaplasia #1; #2; #3; #4; #5 (bcl2+)
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
Cytology: see Cervix-cytology
Micro images: urothelial metaplasia #1; #2; #3; #4 (serotonin+); transitional metaplasia and atrophy after androgen treatment #1; #2
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
Micro images: reactive (inflammatory) atypia #1 (various images-mainly ectocervix); #2-endocervix; #3-transformation zone
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
Cytology: see Cervix-cytology
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
Micro images: various images (not cervix), figures 1-5; clusters of trophozoites (liver)
See Cervix-cytology
See Cervix-cytology
Case reports: HIV+ patient (Hum Path 2000;31:120)
Cytology: See Cervix-cytology
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
Cytology: see Cervix-cytology
Positive stains: immunocytochemistry can detect organisms
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
Micro images: chronic cervicitis; various images; ectocervicitis; endocervicitis
Cytology: See Cervix-cytology
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
Micro images: intracytoplasmic inclusions #1 (endocervical cells); #2 (endothelial cells); CMV+ glands and stroma; associated acute inflammatory infiltrate; intracytoplasmic vacuoles within endocervical glandular cells; fibrin thrombi within small vessels; not cervix - lung #1 (Giemsa stain); #2; kidney; pancreas; brain
Cytology: See Cervix-cytology
Cytology: See Cervix-cytology
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)
Cytology: See Cervix-cytology
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)
Micro images: (1) xanthogranuloma (ceroid granuloma); (2) A: PAS+; B: Perls’ iron stain+; C: Ziehl-Neelsen (acid fast)+; D: Schmorl’s reagent (melanin)+
Cytology: See Cervix-cytology
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
Cytology: see Cervix-cytology
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)
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
Micro images: dense lymphoid infiltrate with germinal centers
Cytology: see Cervix-cytology
Positive stains: polyclonal
References: Int J Gynecol Pathol 1985;4:289, Eur J Obstet Gynecol Reprod Biol 2001;97:235
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)
Micro images: S. haematobium; S. mansoni in ectocervix; figure 1/2: calcified eggs; 3: terminal spine; various images (rectal mass)
Cytology: see Cervix-cytology
References: Acta Trop 2001;79:193.
May form primary chancre at cervix
May produce a mass suggestive of invasive carcinoma (AJCP 1995;104:643)
Due to Treponema pallidum infection
Micro images: #1-umbilical cord; #2; dermal lesion with abundant plasma cells; dermal lesion with anti-T. pallidum immunostain
Cytology: see Cervix-cytology
References: eMedicine
Cytology: see Cervix-cytology
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
Micro images: various images; granulomas with giant cells; acid-fast bacilli #1; #2 (lung)
Cytology: see Cervix-cytology
Positive stains: usually acid-fast
Vasculitis of any type affecting the female genital tract is usually an isolated finding (only 10% have systemic disease, Int J Gynecol Path 2000;19:258)
Isolated polyarteritis nodosa of female genital tract is rare - either giant cell type in post-menopausal women in any part of female genital tract or PAN-type in younger women affecting cervix (Mod Path 1994;7:610)
Case reports: Case of the Week #91
Micro images: isolated polyarteritis nodosa - image #1; #2; #3
References: Int J Gynecol Path 1998;17:193
Wuchereria bancrofti microfilariasis
Cytology: see Cervix-cytology
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
Cytology: see Cervix-cytology
Positive stains: PAS+ neutral mucin, Ki-67+ (up to 20%), focal CEA
DD: minimal deviation adenocarcinoma (invasive glands, focal atypia, desmoplastic stroma)
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)
Micro images: various images
Cytology: see Cervix-cytology
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
Micro images: complex glands resembling late secretory enometrium but with cervical stroma; nuclear enlargement and hyperchromasia
endometrium (not cervix) - pregnant patient
Cytology: see Cervix-cytology
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
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
Cytology: see Cervix-cytology
Micro images: atrophy
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)
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
Gross images: uterine tumor - polypoid mass (arrow)
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
Micro images: uterine tumor - atypical complex glandular hyperplasia, smooth muscle stroma and morules #1; #2; #3; #4; #5; #6; #7
Cytology: see Cervix-cytology
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
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
Micro images: pigment containing nevus cells in cervical stroma #1; #2
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
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)
Micro images: villi within cervical stroma
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
Micro images: decidualized stromal cells
Negative stains: keratin
DD: non-keratinizing squamous cell carcinoma, placental-site nodule
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
Micro images: various images; ectopic decidual deposits in lymph nodes
Cytology: see Cervix-cytology
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 #1), AJSP 2006;30:209 (#2)
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
Gross images: polyp #1; #2; #3
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
Micro images: whole mount; various images
Cytology: see Cervix-cytology
DD: superficial cervicovaginal myofibroblastoma
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)
Micro images: not necessarily cervix - endometrial polyp #1; #2; #3
Cytology: see Cervix-cytology
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
Gross images: Cervical Endometriosis #2
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
Micro images: various images; endometriosis
Cytology: see Cervix-cytology
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
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)
Micro images: not necessarily cervix - glands
lined by tubal type epithelium #1; #2
Cytology: see Cervix-cytology
DD: extraovarian serous cystadenoma
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
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), overgrowth of teratoma, ectopic glial tissue or neoplastia of mullerian origin
Case reports: Case of the Week #135
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, no mitotic figures
Micro images: polypoid mass of glia below endocervical surface (AFIP)
case of the week - #1; #2; #3; #4; #5; GFAP
Positive stains: PTAH (fibrillary processes), GFAP (astrocytic cells and stroma, Gynecol Oncol 1985;21:385)
Capillary or cavernous
Arteriovenous malformations may also be present in cervix, due to surgery or as part of larger pelvic vascular abnormality
Micro images: cavernous hemangioma #1; #2
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
Micro images: other sites - prostate; spleen; breast
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
Micro images: bladder - inverted papilloma #1; #2; #3; basaloid appearance; with squamous metaplasia
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
Gross images: leiomyoma (arrows at tumor)
Micro: resembles uterine leiomyoma; often prominent thick walled blood vessels; may have mitotic figures below ulcerated areas
Micro images: spindled cells; spindled cells in streaming pattern
Cytology: see Cervix-cytology
Micro images: contributed by Dr. Asmaa Gaber Abdou, Menofiya University, Egypt - image #1; #2; #3; #4
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
Micro images: various images
Cytology: see Cervix-Cytology
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)
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
Micro images: various images and immunostains;
borderline vaginal tumor in above case history - papillary tumor with various epithelial types; focal atypia due to stratification, pleomorphism and atypical mitotic figure
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
Micro images: clusters of mesonephric tubules surround a branching duct; mesonephric remnants with hyaline secretion; cells are cuboidal with a distinct basement membrane; complex and deep duct with focal squamous metaplasia; CD10+
Cytology: see Cervix-Cytology
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; no back to back glandular crowding, no nuclear atypia, no angiolymphatic invasion, no perineural invasion
Micro images: marked tubular proliferation but with lobular architecture; more nuclear variation than in mesonephric rests; bland glands deep in cervical stroma #1; #2; large ducts deep in stroma with tufting
Cytology: see Cervix-Cytology
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
Micro images: dense glands but no atypia; solid pattern #1; #2; possible involvement by HSIL
Cytology: see Cervix-cytology
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)
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
Micro images - breast: (1) epithelioid type #1; #2; #3; CD34+; (5) figure 1: sharply circumscribed tumor with fibrous pseudocapsule; 2: composed of bland spindle cells in collagenous or myxoid stroma; 3A: CD34+; 3B: bcl2+; 4: desmin+ (focal)
Cytology: see Cervix-cytology
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
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
Gross images: in situ #1; #2; Nabothian cysts #1 (arrows); #2; #3; various images
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
Micro images: cyst with flattened epithelium #1; #2
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
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)
Micro images: plexiform neurofibroma; figure 2
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
Micro images: glandular epithelium and connective tissue proliferation; adenofibroma-not necessarily from cervix
DD: endocervical polyps (not branching, no stromal proliferation), adenosarcoma (increased mitotic figures in stroma and stromal atypia)
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
Micro images: nodule just below surface with sparsely cellular stroma; cytoplasmic vacuoles and nuclear enlargement; HLA-G+ (not necessarily cervix)
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
Micro images: bladder tumor
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 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)
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
Micro images: various images
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
Micro images: various images and stains; kidney #1; #2; various cardiac tumors
Positive stains: desmin, myoglobin, myoD1, myogenin
DD: rhabdomyosarcoma
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
Micro images: squamous epithelium overlying fibrovascular papillae; not cervix - respiratory squamous papilloma; GE junction
Cytology: see Cervix-cytology
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)
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
Micro images: oral cavity
Positive stains: S100
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
Micro images: tunnel clusters (type B) with sharp circumscription #1; #2; #3 with dense secretion
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 2006;20:253)
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
Cytology: see Cervix-cytology
Micro images:
HPV immunostains - normal cervix has some HPV background staining; cervical condyloma is HPV+; LSIL/CIN1; HSIL/CIN2; HSIL/CIN3; carcinoma
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)
Molecular images: various HPV detection schemes
EM: intranuclear crystalline or filamentous inclusions
z 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)
Micro images: various images #1; #2; #3; spiked excrescences; cervical condyloma is HPV+
Cytology: see Cervix-cytology
Molecular: HPV 6 or 11 in 70-90% of cases, HPV 16 is occasionally seen and associated with high grade cytologic atypia
References: eMedicine
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
Micro images: papillary immature metaplasia; p16 negative (page 2)
Cytology: see Cervix-cytology
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
Micro: reactive atypia - normal architecture and polarity; prominent nucleoli
Cytology: see Cervix-cytology
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
Micro images: image1; image2; colposcopy, cytology and histology
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
Cytology: see Cervix-cytology
Drawings/micro images: SIL diagram #1; #2; classification systems
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 if 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; prominent nucleoli suggests reactive changes
Cytology: see Cervix-cytology
Micro images: various images; LSIL merging into HSIL; koilocytosis #1; #2; #3 with markedly enlarged bizarre nuclei; #4; Cdc6 and MIB-1 (figures C, D)
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
Micro images: various images; H&E #1; #2; #3; #4
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)
Gross images: colposcopic image #1; #2
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
Micro images: various images #1; #2; #3; #4; #5; #6; #7; #8; #9; involvement of endocervical glands; at squamocolumnar junction; LSIL merging into HSIL; Cdc6, MIB-1 (figures E, F)
Virtual slides: high grade SIL #1; #2
Cytology: see Cervix-cytology
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
Keratinizing SIL of cervix
See Cervix-cytology
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)
In United Kingdom, use terminology of CGIN - cervical glandular intraepithelial 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
Cytology: see Cervix-cytology
Micro images: reactive glandular atypia #1; #2; low grade intraepithelial neoplasia/dysplasia; glandular dysplasia-various images; glandular dysplasia #1; #2
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
In United Kingdom, overlaps with high grade CGIN (cervical glandular intraepithelial neoplasia)
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
Cytology: see Cervix-cytology
Micro images: various images #1; #2; endocervical type #1; #2; #3; #4; #5; #6; endometrioid type #1; #2; #3; #4; #5; intestinal type; adenosquamous type #1; #2; with HSIL-#1; #2; #3; Cdc6, MIB-1 (figures A, B); adenocarcinoma in situ; #2; #3; #4 - with HSIL; #5 - with HSIL; biopsy
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
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
Cytology: see Cervix-cytology
Micro images: radiation atypia #1; #2; #3
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
Micro images: resembles HSIL but with abundant mucin
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
References: IARC/WHO
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 (