Cervix
Last revised 19 April 2011
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, 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
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)
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 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
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
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), 30 year old woman with HSIL on pap smear (Case of Week #202)
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 (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
Gross images: barrel shaped cervix; ulcerative tumor; stage I tumor; tumor extending to vagina; stage IV tumor with bladder extension #1; #2; invading lower uterine segment; squamous tumor
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)
May have HSIL / CIN3 like growth pattern (Int J Gynecol Cancer 2000;10:95)
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
Cytology: see Cervix-cytology
Drawings: evolution of invasive carcinoma from SIL; lymphatic pathways of spread
Micro images: various images; invasive tumor #1; #2; #3; central keratinization; resembling clear cell carcinoma; margin involvement; Cdc6, MIB-1 (figures G, H);
Images contributed by Frank Melgoza MD and Mai Gui MD PhD, UC Irvine, California (USA): squamous cell carcinoma #1; #2
Grading: well differentiated with prominent keratin pearl; moderately differentiated with invasion by nests and single cells; poorly differentiated spindled tumor with focal keratinization; poorly differentiated with markedly pleomorphic nuclei
Virtual slides: squamous cell carcinoma #1; #2; #3
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
EM images: tumor cell in intratumoral vessel
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, 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
Micro images: central cystic degeneration; multiple keratin pearls
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%)
Gross images: #1
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
Micro images: nonkeratinizing tumor #1; #2; #3; #4
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
Micro images: papillae covered by atypical basal cells #1; #2; focal squamous differentiation; infiltration of stroma
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 invasive carcinoma” (WHO), “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 (invasive depth of 3 mm or less; no wider than 7 mm) and Ia2 (invasive depth of more than 3 mm but not more than 5 mm; no wider than 7 mm), IARC
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
Cytology: see Cervix-cytology
Micro images: various images #1; #2; irregularly shaped tongues of squamous epithelium with loose fibroblastic stroma #1; #2 with differentiated overlying squamous epithelium; #3; #4; small invasive bud; individual cell keratinization of invasive cells; measuring depth of invasion; suggestive of angiolymphatic invasion; angiolymphatic invasion confirmed by factor VIII related antigen immunostain; HSIL with focal necrosis and nearby angiolymphatic invasion
Virtual slides: early invasive carcinoma
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;101:346), 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 (for classical adenocarcinoma, not variants; not universally accepted):
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
Cytology: see Cervix-cytology
Micro images: various images; poorly defined glands lined by malignant cells; malignant glands with necrotic debris #1; #2; #3; poorly differentiated tumor #1; #2
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; stains may be helpful - negative or focal/superficial for CEA and mucin; 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: 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
Micro images: well differentiated tumor composed of endocervical type cells; colloid type with clusters of tumor cells floating in mucin
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)
Micro images: intestinal type cells #1; #2; #3; A: H&E; B: CDX2-; C: CK7+; D: CEA+; E: CK20-; metastatic colonic adenocarcinoma is CDX2+
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
Cytology: see Cervix-cytology
Micro images: signet-ring type tumor cells; A: H&E, B: CDX2-, C: CK7+, D: CEA+, E: CK20-
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; in some cases, unequivocal invasion may be difficult to identify
Cytology: see Cervix-cytology
Micro images: various images; malignant gland with desmoplasia; complex / labyrinthine pattern of malignant epithelium; buds of early stromal invasion
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
Gross images: small polypoid lesion (arrow)
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)
Cytology: see Cervix-cytology
Micro images: tumor lower right corner, also HSIL; top-microcysts with peripheral palisading and squamous differentiation of small basaloid cells with scant cytoplasm and hyperchromatic nuclei, bottom-true lumina may be present; top-CK17+, bottom-CK18+; figure 1: nests of basaloid cells with overlying HSIL; 2: central squamous differentiation with microcysts, plus nests of small basaloid cells with scant cytoplasm and hyperchromatic nuclei; various images (figures 1-4); nests of basaloid cells infiltrating the stroma; squamous differentiation and microcyst formation; squamous differentiation
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
Gross images: contributed by Dr. Ihab Hosny, Ohio - image #1; #2
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
Micro images: cribriform architecture and basement membrane material #1; #2; #3; figure 1: friable and ulcerated cervical mass, 2: cribriform islands of basaloid cells with peripheral palisading, high N/C ratio and scant mitotic activity; 3: focal solid pattern; 4: infiltrating cords of cells within basement membrane-like material
contributed by Dr. Ihab Hosny, Ohio: image #1; #2; #3; #4; #5; #6; vascular invasion; actin #1; #2; CEA #1; #2; EMA; high molecular weight keratin #1; #2; S100
other sites: esophagus; salivary gland-various images as part of case history
Cytology: see Cervix-cytology
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
Cytology: see Cervix-cytology
Micro images: various images; poorly formed glands and squamous components #1 (arrows); #2; #3
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
Micro images: oral cavity; skin
DD: adenoid basal carcinoma, adenoid cystic carcinoma
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
Micro images: ribbons of tumor cells; glandular features; cords and glands of tumor cells
other sites - kidney; small intestine
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)
Micro images: various images and stains; atypical carcinoid tumor; chromogranin+ atypical carcinoid tumor
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
Cytology: see Cervix-cytology
Micro images: various images; clear cell carcinoma #1; #2; #3; tubulocystic pattern; approaching mesonephric remnants; vaginal tumor
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)
EM images: clear cell carcinoma
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
Micro images: branching glands whose cells lack mucin; stratified epithelium, cells have scant granular cytoplasm and no mucin #1; #2; uterus, not necessarily cervix - endometrioid adenocarcinoma #1; #2; #3 (invasive patterns)
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)
Gross images: expansile mass with fleshy cut surface
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
Micro images: various images; uterine tumor with coexisting choriocarcinoma
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
Gross images: bulky exophytic mass
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
Micro images: various images; sheets of cells with abundant lightly stained cytoplasm; cells have distinct cell border and prominent nucleoli; nests of glassy cells separated by eosinophil laden stroma; eosinophils infiltrating into nests; focal glandular differentiation
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
Micro images: trabecular pattern with mitotic activity; with adenocarcinoma in situ; metastatic to bone marrow; keratin+ (MNF116) in paranuclear dot-like pattern; synaptophysin+
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)
Molecular images: HPV16+ by ISH
EM images: pseudorosette
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
Cytology: see Cervix-cytology
Micro images: syncytial pattern of cells with prominent nucleoli, atypical mitotic figure; H&E and stains; CD45+ infiltrating lymphocytes
vagina - well circumscribed tumor; large epithelioid cells with prominent nucleoli in inflammatory background
bladder - image#1; #2; AE1-AE3 positive
lung - various images
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
Micro images: figure 1: 3 cm polypoid mass; 2: prominent tubule formation; 3: stroma shows minimal desmoplasia; 4: CD10+
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
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
Cytology: see Cervix-cytology
Micro images: breast carcinoma metastatic to cervix (AFIP)
contributed by Dr. Mowafak Hamodat, Eastern Health of Newfoundland and Labrador, St. John’s, Canada - #1; #2; #3; #4; ER; PR; GCDFP-15
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
Cytology: see Cervix-cytology
Micro images: endocervical type; malignant cells merging with normal endocervical cells; nonspecific type #1; #2; endometrioid-type glands deep in cervix #1; #2; #3; various images
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
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
Cytology: see Cervix-cytology
Micro images: H&E and p53; uterus, not necessarily cervix - image
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
Cytology: see Cervix-cytology
Micro images: sheets of small cells with scant cytoplasm and hyperchromatic nuclei #1; #2; H&E
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, metastatic carcinoma (lung or other sites)
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
Micro images: bladder #1; #2
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
Cytology: see Cervix-cytology
Micro images: renal pelvis; bladder
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
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 Gynaecol Oncol 1999;20:35), with pelvic abscess and abdominal wall fistula (Gynecol Oncol 1999;74:115)
Treatment: usually hysterectomy; radiation may induce anaplastic transformation
Gross: large, warty lesion resembling condyloma; cut surface shows sharply circumscribed deep margin
Micro: well differentiated squamous cell carcinoma with a polypoid growth pattern (but no fibrovascular cores) expanding the underlying stroma instead of involving crypts; blunt pattern of invasion, with minimal nuclear atypia at epithelial-stromal interface; may be exophytic and endophytic; may have intense inflammatory infiltrate; no/rare mitotic figures; no koilocytosis
Cytology: see Cervix-cytology
Micro images: various images; squamous cells with central keratinization but no fibrovascular cores; bland epithelium with at most mild atypia; pushing margin; other sites - penis #1; #2; vulva
DD: condyloma accuminatum (more delicate architecture, distinct fibrovascular cores), squamous cell carcinoma with papillary growth pattern (usually has finger-like invasive tongues, marked nuclear atypia), warty / condylomatous carcinoma (prominent cytoplasmic halos around tumor cells)
Villoglandular papillary adenocarcinoma of cervix
Rare
Excellent prognosis only if pure; must examine carefully for squamous differentiation or other growth patterns (Eur J Obstet Gynecol Reprod Biol 1999;87:183); limit diagnosis to cases with minimal atypia and no other types of carcinoma
Metastases reported only rarely
Often in women age 40 years or less
Case reports: recurrent tumor and metastases (Tohoku J Exp Med 2004;202:305), with nodal metastases (Gynecol Oncol 2004;92:64)
Treatment: surgery (conservative to allow future pregnancy, Gynecol Oncol 2006;101:168, Gynecol Oncol 2001;81:310), chemotherapy
Gross: exophytic polypoid lesion
Micro: very well differentiated papillary adenocarcinoma; surface papillae with complex branching lined by endocervical, endometrial or intestinal type epithelium with mild to moderate atypia; may resemble villous adenoma of colon; mean 43 mitotic figures/10 HPF, often angiolymphatic invasion; no desmoplasia; usually associated with adenocarcinoma in situ or SIL; may be deeply invasive and extend to endometrium
Cytology: see Cervix-cytology
Micro images: tumor extends throughout most of cervix; papillary fibrovascular cores lined by mildly atypical epithelium #1; #2; #3; adjacent area of higher grade adenocarcinoma
Positive stains: HPV
DD: implant from endometrial tumor (Int J Gynecol Cancer 2002;12:308), other papillary carcinomas (smaller and thinner papillae, form a more complex lattice), hyperplastic and reactive glands (no invasion, cells not cytologically malignant)
References: Cancer 1989;63:1773, Mod Path 2000;13:261
Warty (condylomatous) carcinoma of cervix
Very rare variant of invasive squamous cell carcinoma; more common in vulva
May be less aggressive than well differentiated squamous carcinoma
Gross: often feathery and thin surface (Pathol Res Pract 1998;194:713)
Micro: striking condylomatous or warty appearance, although deep margin is similar to classic squamous cell carcinoma; often koilocytotic atypia
Cytology: see Cervix-cytology
Molecular: HPV+ (often different HPVs)
Sarcoma/lymphoma/other
Also called Mullerian adenosarcoma
More common in endometrium
Often in adolescents
Good prognosis if no myometrial invasion, bland histology and no sarcomatous overgrowth (Oncol Rep 1998;5:939)
Median survival is 4 years; 40% recur
Case reports: involving cervix, ovary and pelvic peritoneum (Philipp J Obstet Gynecol 1998;22:87), with heterologous elements (Gynecol Oncol 2002;84:161), presenting as 6 cm cervical polyp (Pathol Int 1998;48:649), with ovarian sex cord-like differentiation (Cancer 1986;57:1197), rhabdomyomatous variant (Int J Gynecol Pathol 1985;4:146), resembling embryonal rhabdomyosarcoma (Cancer 1976;37:1725)
Treatment: hysterectomy
Gross: broad based or sessile polypoid mass
Micro: biphasic; papillary stromal fronds lined by epithelium form leaf-like processes that protrude into cysts and cleft-like spaces distributed within the stroma, similar to breast phyllodes tumors; malignant stroma resembles stromal sarcoma, or less often, has rhabdomyoblasts or heterologous elements (bone, cartilage, skeletal muscle, fat, occasionally smooth muscle); usually stroma has 2+ MF/10 HPF; periglandular accentuation or cuffing of stroma; may have sex cord differentiation; glandular component may be endocervical, ciliated, eosinophilic or endometrioid
Micro images: phyllodes tumor-like pattern #1; #2 (more cellular than adenofibroma); uterus, not necessarily cervix - with dilated glands
Positive stains: muscle specific actin, desmin, ER
EM: stromal cells resemble endometrial stromal cells
DD: rhabdomyosarcoma
References: Hum Path 1981;12:579
With sarcomatous overgrowth
Rare aggressive variant
Case reports: 37 year old with clinical endocervical polyp (Int J Gynecol Cancer 2004;14:1024)
Micro: obvious high grade sarcoma in addition to low grade stroma
Aggressive angiomyxoma of cervix
First described in female pelvis in 1983 (AJSP 1983;7:463)
Very rarely reported in cervix
Usually large, bulky mass of deep soft tissue of pelvicoperineal region of young adult women and men
High risk of local recurrence, but only rare metastases (Hum Path 2003;34:1072)
Gross: gelatinous, up to 60 x 20 cm, locally infiltrative
Micro: bland-appearing myofibroblastic tumor composed of scanty spindled and stellate cells in loose stromal matrix with collagen fibrils, prominent vasculature including thick walled vessels; may infiltrate locally; no/rare mitotic figures, no atypia
Micro images: not necessarily cervix - bland hypocellular mesenchymal tumor #1; #2; #3; vulva
Positive stains: vimentin, desmin, muscle-specific actin, smooth muscle actin; variable CD13, factor XIIIa, ER and PR
Negative stains: keratin, S100
Molecular: rearrangement of HMGIC gene
EM: myofibroblastic features
DD: myxoma, myxoid liposarcoma, botyroid rhabdomyosarcoma, myxoid MFH, nerve sheath myxoma
References: Hum Path 1985;16:621
Alveolar soft parts sarcoma of cervix
Very rare
Usually ages 30 to 40 years
Associated with abnormal uterine bleeding
Patients often do well, but may die of metastatic disease
Case reports: 35 year old woman (Archives 1989;113:1179), incidental tumor in 39 year old woman (Int J Gynecol Pathol 2005;24:131), 8 year old girl (Acta Pathol Jpn 1993;43:204)
Gross: solid, mean 4 cm (range 1-10 cm); irregular, circumscribed, friable nodule
Micro: well circumscribed tumor with loss of central cohesion causing a pseudoalveolar pattern; nests are separated by thin-walled, sinusoidal vascular spaces; cells are large with distinct cell borders, resembling gemistocytic astrocytes; contain PAS+ diastase resistant intracytoplasmic crystals; small nuclei with prominent nucleoli
Micro images: nests of tumor cells with PAS+ crystals #1; #2
Positive stains: neuron-specific enolase, S100, TFE3 (nuclear staining); reticulin highlights alveolar pattern; also desmin, myoglobin, HHF35
Negative stains: GFAP, S100 (usually)
Molecular: t(X;17)(p11;q25) - TFE3-ASPL fusion transcript
EM: rhomboid, rod-shaped or spicular crystals with a regular lattice pattern and electron dense secretory granules; crystals consist of filaments 6 nm in diameter, arranged in parallel arrays with periodicity of 10 nm; basal lamina surrounds groups of tumor cells with prominent mitochondria, glycogen and lipid
DD: metastatic renal cell carcinoma, clear cell carcinoma (often papillary or cystic with hobnail cells, cytoplasm is more clear, may have focal PAS+ areas in cytoplasm, but diastase sensitive), paraganglia (solid nests of neuroendocrine cells surrounded by S100+ sustentacular cells; negative for muscle markers, no PAS+ diastase resistant crystals)
References: Mod Path 1989;2:676
Ewing sarcoma / PNET of cervix
Extremely rare, <20 cases reported
May present as abnormal uterine bleeding
May have similar prognostic factors as other sites (5 year survival of 70% with chemotherapy), although limited number of cases
Case reports: presenting with abnormal uterine bleeding (Archives 2001;125:1389), 21 year old woman (Gynecol Oncol 2005;98:516), 36 year old woman with necrotic and hemorrhagic mass (Int J Gynecol Pathol 1998;17:83)
Treatment: surgery and chemotherapy
Gross: may be necrotic and hemorrhagic
Micro: diffuse sheets of small round cells with scant cytoplasm, hyperchromatic and vesicular nuclei, indistinct nucleoli
Cytology: see Cervix-cytology
Micro image: H&E; not necessarily cervix - PAS+ glycogen; CD99+
Positive stains: CD99, PAS, neuron-specific enolase
Negative stains: keratin, CD45, chromogranin, synaptophysin
Molecular: t(11:22)(q24,q12) - EWS/FLI1 fusion transcript
EM: large glycogen pools in cytoplasm, few cytoplasmic organelles, rare neurosecretory granules, no cell projections
DD: neuroendocrine neoplasms, endometrial carcinoma, melanoma, lymphoma, endometrial stromal sarcoma, metastatic carcinoma
Granulocytic sarcoma of cervix
Also called chloroma (due to green appearance)
Soft tissue masses of AML blasts
Rare, must consider possibility of this diagnosis to arrive at correct diagnosis
Usually presents with vaginal bleeding; rarely is initial manifestation of AML (Cancer 1977;40:3030, J Obstet Gynaecol Res 1997;23:261)
Two year survival is 6% for all sites, no patients live 5 years
Case reports: 33 year old woman with large cervical mass (Gynecol Oncol 2005;98:493); relapses in cervix - after bone marrow transplantation (Int J Gynecol Cancer 2004;14:553), after remission (Acta Cytol 1999;43:1124); in a child (J Pediatr Hematol Oncol 1996;18:311), relapse with abdominal tumor
Micro: diffuse, cords or pseudoacinar growth patterns; often sclerosis; composed of primitive myeloid blasts
Micro images: various images (uterus, not necessarily cervix); H&E; (a) left - alpha-1-antitrypsin+; (b) right - chloroacetate esterase+; thoracic lesion-various images
Positive stains: chloroacetate esterase, lysozyme, myeloperoxidase, CD68, CD43, CD45
EM images: P-early promyelocyte, L-late stage granulocyte, MY-myofibroblast; detail of promyelocyte - A is primary or azurophilic granule; other granules have irregular or partially extracted contents
DD: diffuse large B cell lymphoma, inflammatory conditions
References: AJSP 1997;21:1156, Gynecol Oncol 1992;46:128; J Clin Pathol 1989;42:483
Rare; <100 cases reported; but most common primary sarcoma of cervix
May develop in cervical stump after subtotal hysterectomy (Ginekol Pol 2002;73:613)
To diagnose cervical primary, must exclude tumors of lower uterine segment
Peri- and postmenopausal women ages 40 to 60 years
Commonly presents with abnormal vaginal bleeding, abdominopelvic pain and a palpable cervical mass
Poor prognosis (Cancer 1973;31:1176)
Case reports: Case of the Week #92, epithelioid tumors (Gynecol Oncol 2005;97:957, Gynecol Oncol 2003;91:636), with endometrial adenocarcinoma and cervical squamous cell carcinoma (Gynecol Oncol 2001;82:400), xanthomatous tumor (Int J Gynecol Pathol 1998;17:89), 10 kg tumor (Gynecol Oncol 1998;69:169)
Gross: large (up to 12 cm), polypoid, soft, with irregular outline; may thicken and expand cervical canal; often hemorrhage and necrosis
Gross images: tumor attached by short pedicle #1; #2-sagittal section
Micro: interlacing fascicles of smooth muscle cells with large, atypical, hyperchromatic nuclei; 5+ mitotic figures/10 HPF; may have osteoclast-like giant cells, epithelioid, myxoid or xanthomatous features
Cytology: see Cervix-cytology
Micro images: interlacing fascicles #1; #2; various images; large pleomorphic nuclei #1; #2; muscle specific actin; smooth muscle actin; uterus-not necessarily cervix - leiomyosarcoma #1; #2; #3 with bizarre giant cells; #4
Positive stains: actin, desmin
References: Diagn Pathol 2006;18:30
Primaries are rare in cervix (<100 cases reported)
Mean age approximately 40 years; range 20’s to 80’s
Usually present with abnormal uterine or vaginal bleeding; may have negative cervical smear or be reported as SIL
Most cases present with stage IE disease (Am J Obstet Gynecol 2005;193:866)
Usually diffuse large B cell lymphoma or follicular lymphoma (Mod Path 2000;13:19)
5 year survival: 83% in low stage tumors, 29% in high stage tumors
Should confirm with immunostains to rule out other unusual tumors and to classify
Case reports: MALT lymphoma presenting as endocervical polyp (Archives 2001;125:537), NK lymphoma #1 (Archives 2000;124:1510); #2 with relapse in cervix (Leuk Lymphoma 2002;43:203), Burkitt’s lymphoma with HSIL (Pathol Res Pract 2005;201:521), two patients with cervical CLL/SLL and squamous cell carcinoma (Gynecol Oncol 2004;92:974), relapse of T-ALL in cervix and uterine corpus (Ann Diagn Pathol 2002;6:125)
diffuse large B cell lymphoma - 3 patients requiring repeat biopsy for diagnosis (Eur J Gynaecol Oncol 2005;26:36); spindle cell variant (Int J Gynecol Pathol 2003;22:289), diffuse large B cell lymphoma and follicular lymphoma at biopsy but HSIL by pap smear (Gynecol Oncol 2005;98:484)
Gross: diffuse enlargement of cervix (barrel-shaped), or polypoid mass with fish-flesh appearance; soft, gray-white
Micro: tumor cells infiltrate stroma without destroying glandular or squamous epithelium
Cytology: see Cervix-cytology
Micro images: diffuse large B cell lymphoma #1; #2; #3; #4; #5 (CD20+); marginal zone lymphoma; high grade MALT presenting as endocervical polyp; NK lymphoma
DD: lymphoid follicles of chronic cervicitis, infectious mononucleosis or other reactive changes (polymorphic infiltrate with plasma cells and neutrophils, Gynecol Oncol 2005;99:481, Eur J Obstet Gynecol Reprod Biol 2001;97:235), granulocytic sarcoma (positive for myeloperoxidase, lysozyme, CD68, negative for lymphocytic markers)
References: AJSP 2005;29:1512 (gynecologic lymphomas)
Malignant mixed Mullerian tumor (MMMT) of cervix
Also called malignant mixed mesodermal tumor or carcinosarcoma (if homologous)
Rare, < 100 reported cases, less common than leiomyosarcoma
Most tumors of cervix are extensions from endometrium; may be secondary to radiation therapy for cervical squamous cell carcinoma
Mean age 50 to 65 years, range 12 to 93 years
Often confined to uterus at presentation, with better prognosis
Case reports: with adenoid cystic carcinoma component (AJSP 1995;19:229, Int J Gynecol Pathol 1998;17:91, Eur J Gynaecol Oncol 2000;21:292), with coexisting adenoid basal carcinoma (Int J Gynecol Pathol 2002;21:186), with neuroendocrine differentiation (Int J Gynecol Cancer 2002;12:223), with osteosarcomatous component (J Obstet Gynaecol Res 2005;31:404), initially interpreted as high grade sarcoma (Hum Path 1988;19:605), after subtotal hysterectomy (Gynecol Oncol 1997;67:322), heterologous tumor arising in cervical stump due to hysterectomy for benign disease (Gynecol Oncol 1983;16:422), tumor in 12 year old girl (Eur J Gynaecol Oncol 1988;9:365)
Treatment: usually hysterectomy with or without radiation therapy or chemotherapy (Gynecol Oncol 2005;97:442)
Gross: polypoid mass with variable necrosis
Micro: may resemble uterine tumor; neoplastic epithelial and mesenchymal components; usually accompanied by high grade squamous intraepithelial lesion; invasive epithelial component may be adenoid basal, adenoid cystic, basaloid squamous cell or keratinizing squamous cell, but is usually NOT adenocarcinoma
Sarcomatous component usually homologous resembling fibrosarcoma or endometrial stromal sarcoma, often with prominent myxoid change (Int J Gynecol Pathol 1998;17:211); heterologous component is usually rhabdomyosarcoma, present in 50%; also chondrosarcoma, liposarcoma
Cytology: see Cervix-cytology
Positive stains: both components - EMA, keratin, vimentin (most); sarcomatous component - muscle specific actin or smooth muscle actin, desmin
Molecular: HPV DNA positive in 8/8 cases (AJSP 2001;25:338)
DD: squamous cell carcinoma with sarcoma-like stroma
Rare; <100 cases reported; more common in vulva and vagina
Usually presents with vaginal bleeding
Poor prognosis with historical 5 year survival of 40% with stage I disease (Gynecol Oncol 1989;32:375, Zhonghua Fu Chan Ke Za Zhi 2005;40:183)
Case reports: 39 year old woman with vaginal bleeding (Indian J Cancer 2005;42:201), 67 year old woman with vaginal bleeding (Anticancer Res 2003;23:1063), 63 year old woman with S100 negative tumor (Int J Gynecol Pathol 1999;18:265), 33 year old Japanese woman with clear cell variant (Gynecol Oncol 2001;80:409), after radiation for cervical squamous cell carcinoma (Clin Oncol (R Coll Radiol) 2000;12:234)
Gross: gray-blue-black nodule
Gross images: melanoma of vagina with extension into cervix
Micro: often small cell and spindle cell variants; junctional activity present in <50%, variable melanin pigment; stromal infiltration by malignant cells.
Cytology: see Cervix-cytology
Micro images: small cell variant (common in vagina); epithelioid cells; prominent junctional activity; vaginal melanoma extending into cervix; various images in advanced tumor
Positive stains: S100, HMB45, vimentin, Ki-67 (high percentage)
Negative stains: keratin, CD45, ER, PR
DD: metastatic melanoma (usually from vulva or vagina, no junctional change in cervix)
Other tumors of cervix (case reports)
PEComas: large study with 2 cases in cervix (AJSP 2005;29:1558)
Undifferentiated carcinoma: HPV+ stroma (Hum Path 1999;30:483)
Rare in cervix
Case reports: 38 year old woman (Acta Obstet Gynecol Scand 1989;68:279)
Cytology: see Cervix-cytology
Micro images: H&E and stains
DD: reactive plasmacytosis (Geburtshilfe Frauenheilkd 1983;43:40)
Rhabdomyosarcoma (embryonal) of cervix
Rhabdomyosarcomas are divided into embryonal, botyroid (subtype of embryonal), alveolar or pleomorphic (anaplastic) subtypes
Embryonal type is most common; occurs in children; more common in vagina than cervix
Cases in older women often contain cartilage and have better prognosis
Case reports: embryonal rhabdomyosarcoma - pediatric heterologous tumors in sisters (Gynecol Oncol 2005;99:742), 19 year old with tumor in cervical polyp (Gynecol Oncol 2004;95:243), 13 year old girl with anaplastic (pleomorphic) subtype (Arch Gynecol Obstet 2004;270:278), 17 year old woman with botyroid subtype and recurrence after excision and chemotherapy (Acta Cytol ;43:475), 46 year old woman with botyroid subtype (Int J Gynecol Pathol 2004;23:78)
other types - 39 year old woman with alveolar rhabdomyosarcoma (Gynecol Oncol 2003;91:623)
Treatment: minor surgery plus chemotherapy may be recommended for stage I disease (Eur J Pediatr 2004;163:452, Br J Cancer 1999;80:403)
Gross: botyroid cases have protrusion of grape-like masses (due to edema and myxoid stroma) from cervix into vagina; surface is glistening and translucent
Gross images: embryonal rhabdomyosarcoma with gray surface and hemorrhage; bladder tumor with polypoid masses
Micro: botyroid - polypoid mass of rhabdomyoblasts at different maturational stages covered by attenuated epithelium; resembles vaginal tumor; often cambium layer beneath cervical epithelium in botyroid cases; often loose myxoid stroma, surface ulceration; may have cartilage in older women; variable mitotic rate
In young children, tumor cells may lack marked atypia and may blend in with normal, immature, cellular stroma
Micro images: embryonal rhabdomyosarcoma-various images; cambian layer and edematous stroma; edematous stroma; cambian layer (vaginal botyroid tumor); tadpole and strap cells; cross striations
Cytology: see Cervix-cytology
Positive stains: in young children, focal staining for desmin, muscle-specific actin, smooth muscle actin, myoD1 and WT1, although not specific (Pediatr Dev Pathol 2005;8:427)
DD: yolk sac tumor, adenosarcoma (fibrous stroma so no grape-like clusters, no edematous, leaf-like pattern resembling phyllodes tumor), edematous mesodermal polyp (adult women, small, soft fleshy protuberances up to 1.5 cm, stroma is uniform, no cambium layer, no rhabdomyoblasts, may have widely scattered atypical stromal cells)
References: Radiographics 1997;17;919
Usually post-menopausal women (mean 54 years, range 29 to 72 years)
Usually represents extension from uterine corpus; may arise from cervical endometriosis
Poor prognosis unless low grade
Case reports: uterine tumor presenting as cervical polyp (Ann Diagn Pathol 2005;9:101), polypoid tumor with heterologous elements (Eur J Obstet Gynecol Reprod Biol 2000;88:103), after hormonal therapy for breast cancer (Gynecol Oncol 2000;79:120), Gynecol Oncol 1985;22:105
Micro: sheets of spindle-shaped cells with minimal cytoplasm and high mitotic activity; resembles endometrial stromal sarcoma but without prominent vessels
Micro images - uterus - H&E; H&E, CD10+, ER+, PR+
Cytology: see Cervix-cytology
Positive stains: reticulin (outlines each cell)
DD: small cell carcinoma, lymphoma
Teratoma of cervix
Very uncommon
Usually mature elements with benign behavior
Case reports: with lymphoid hyperplasia (Pathol Int 2003;53:327), with pulmonary differentiation (Archives 1995;119:848), HIV+ patient with squamous cell carcinoma arising in teratoma (Gynecol Oncol 1996;60:475), immature teratoma in 13 year old girl (Eur J Gynaecol Oncol 1990;11:37), mature cystic teratoma (Asia Oceania J Obstet Gynaecol 1990;16:363), with extensive surface ulceration (Archives 2003;127:759)
Gross: polypoid lesion of cervix
Micro: mature squamous epithelium resembling skin with sebaceous glands and hair; also bone, cartilage, lymphoid tissue, choroid plexus and ganglion cells; immature elements are very rare
Micro images: epidermal elements and fat; endocervical cystic gland, nerve tissue, cartilage (arrow); figure 1: squamous epithelium and adipose tissue; 2: mature neural tissue; 3: cartilage
DD: epidermal metaplasia (only ectodermal derivatives), fetal remnants implantation (can differentiate with DNA typing), mixed mullerian tumor, perforation of cystic ovarian teratoma
Very rare in cervix (<10 reported cases)
Case reports: 13 year old with polypoid vaginal mass producing bleeding (Archives 1985;109:371), 13 year old girl with 7 cm tumor (Gynecol Oncol 2000;76:107), 12 year old girl with large vaginal mass (J Pediatr Hematol Oncol 1999;21:548), 11 year old girl with cervical polyp (Int J Gynecol Pathol 1998;17:277)
Gross: gray, solid, rubbery to gelatinous
Micro: triphasic with blastema, epithelial areas and mesenchyme
Micro images: kidney - triphasic tumor #1; #2
DD: MMMT (no glomeruloid differentiation, no tubules, has adenocarcinoma)
Also called endodermal sinus tumor
More common in vagina; some arise in both areas
Usually girls 1-2 years old with blood-tinged vaginal discharge and variably elevated serum alpha-fetoprotein
Case reports: 6 month old girl with tumor of vagina and cervix (Pediatr Radiol 1993;23:57), Indian J Cancer 1996;33:43
Treatment: surgery and chemotherapy
Gross: partially eroded, pedunculated, soft and friable
Micro: reticular (net-like), solid and festoon (string or garland) patterns are most common; usually Schiller-Duval bodies (central blood vessel surrounded by primitive cells)
Micro images: microcystic pattern; festoon pattern with Schiller-Duval bodies
Miscellaneous
Fractional curettage: separate sampling from the endocervical and endometrial cavities during the same procedure; the endocervical specimen should be obtained first; purpose is to distinguish endocervical extension of an endometrial carcinoma from isolated tumor fragments in endocervical specimen
This procedure may be replaced by hysteroscopy
Trachelectomy: excise cervix but preserve uterine corpus (Radiographics 2005;25:41)
Diagrams: trachelectomy technique
Grossing of cervical specimens
Note: see Uterus chapter for grossing of hysterectomy specimens
Specimen should be oriented by the surgeon (either directly showing pathologist or by labeling with a stitch or ink mark)
All tissue submitted should be examined (check the container and lid carefully)
Describe the number and size of pieces and any gross abnormalities
Describe gross tumor location, size, depth of invasion, extension to margins or adjacent organs
Submit labeled specimens separately
Cone biopsies: ink deep margin, orient by quadrants, fixation for 3 hours may be helpful; then section by quadrant, and within each quadrant at 1-3 mm intervals
Sections should be along plane of endocervical canal, and include epithelium in each section
Diagrams: hysterectomy specimen; grossing diagrams
Many patients are treated with radiation therapy, and never undergo surgical-pathologic staging
Thus, AJCC prefers clinical staging (FIGO staging) of all patients for uniformity
Clinical stage should be determined prior to start of definitive therapy, and not be altered because of subsequent findings once treatment has started
Pathologic findings should be recorded as pT, pN or pM, but should not change the clinical staging
In AJCC 7th edition, TNM has changed to reflect FIGO 2008
Primary tumor and FIGO stage
TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
Tis: Carcinoma in situ (preinvasive carcinoma)
T1 (FIGO I): Cervical carcinoma confined to uterus (extension to corpus should be disregarded)
T1a (FIGO IA): Invasive carcinoma diagnosed only by microscopy (i.e. no macroscopically visible); stromal invasion has a maximum depth of 5.0 mm measured from the base of the epithelium and a horizontal spread of 7.0 mm or less; vascular space involvement (venous or lymphatic) does not affect classification
T1a1 (FIGO IA1): Measured stromal invasion 3.0 mm or less in depth and 7.0 mm or less in horizontal spread
T1a2 (FIGO IA2): Measured stromal invasion more than 3.0 mm and not more than 5.0 mm in depth with a horizontal spread 7.0 mm or less
T1b (FIGO IB): Clinically visible lesion confined to the cervix or microscopic lesion greater than T1a (FIGO IA2)
T1b1 (FIGO IB1): Clinically visible lesion 4.0 cm or less in greatest dimension
T1b2 (FIGO IB2): Clinically visible lesion more than 4.0 cm in greatest dimension
T2 (FIGO II): Cervical carcinoma invades beyond uterus but not to pelvic wall or to lower third of vagina
T2a (FIGO IIA): Tumor without parametrial invasion
T2a1 (FIGO IIA1): Clinically visible lesion 4.0 cm or less in greatest dimension
T2a 2(FIGO IIA2): Clinically visible lesion more than 4.0 cm in greatest dimension
T2b (FIGO IIB): Tumor with parametrial invasion
T3 (FIGO III): Tumor extends to pelvic wall or involves lower third of vagina, or causes hydronephrosis or non-functioning kidney
T3a (FIGO IIIA): Tumor involves lower third of vagina, no extension to pelvic wall
T3b (FIGO IIIB): Tumor extends to pelvic wall or causes hydronephrosis or non-functioning kidney
T4 (FIGO IVA): Tumor invades mucosa of bladder or rectum, or extends beyond true pelvis (bullous edema is not sufficient to classify a tumor as T4)
Note: all macroscopically visible lesions - even with only superficial invasion - are at least pT1b (FIGO IB)
Regional lymph nodes (N)
NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1 (FIGO IIIB): Regional lymph node metastasis
Note: Specify number of nodes examined and number positive
Distant Metastasis (M)
M0: No distant metastasis
M1 (FIGO IVB): Distant metastasis (including peritoneal spread, involvement of supraclavicular, mediastinal or paraaortic lymph nodes, lung, liver or bone)
Stage grouping
Stage 0: T1s N0 M0
Stage I: T1 N0 M0
Stage IA: T1a N0 M0
Stage IA1: T1a1 N0 M0
Stage IA2: T1a2 N0 M0
Stage IB: T1b N0 M0
Stage IB1: T1b1 N0 M0
Stage IB2: T1b2 N0 M0
Stage II: T2 N0 M0
Stage IIA: T2a N0 M0
Stage IIA1: T2a1 N0 M0
Stage IIA2: T2a2 N0 M0
Stage IIB: T2b N0 M0
Stage III: T3 N0 M0
Stage IIIA: T3a N0 M0
Stage IIIB: T1-T3 N1 M0 or T3b any N M0
Stage IVA: T4 any N M0
Stage IVB: M1
Drawings: cervix staging diagram (upper row); WHO reference for FIGO staging; National Cancer Institute (USA) reference for staging
Features of cervical tumors to report
Cone biopsy
Macroscopic tumor site (quadrant: either 12-3, 3-6, 6-9 or 9-12 o’clock or right superior/inferior, left inferior/superior or not specified)
Tumor size (one dimension required, two or three recommended)
Histologic tumor type (WHO)
Tumor grade
Depth of invasion (mm) - measure from most superficial epithelial-stromal interface of the adjacent intraepithelial process
Width (horizontal extent) of tumor (mm)
Endocervical margin - involved by invasive carcinoma (specify location, focal or diffuse) or __ mm from closest invasive carcinoma
Endocervical margin - involved or not involved by intraepithelial neoplasia (specify grade)
Exocervical margin - involved by invasive carcinoma (specify location, focal or diffuse) or __ mm from closest invasive carcinoma
Exocervical margin - involved or not involved by intraepithelial neoplasia (specify grade)
Deep margin - involved by invasive carcinoma (specify location, focal or diffuse) or __ mm from closest invasive carcinoma
Deep margin - involved or not involved by intraepithelial neoplasia (specify grade)
Cone biopsy-optional features to report
Whether tumor width is continuous tumor or multiple small foci
Additional pathologic findings: koilocytosis, inflammation, glandular atypia or dysplasia, other
Angiolymphatic invasion: present, not present, indeterminate
Colpectomy, Hysterectomy or Pelvic Exenteration
Specimen type
Other organs present
Macroscopic tumor site (quadrant: either 12-3, 3-6, 6-9 or 9-12 o’clock or right superior/inferior, left inferior/superior or not specified)
Tumor size (one dimension required, two or three recommended)
Histologic tumor type (WHO)
Tumor grade
Depth of invasion (mm)
pTNM / FIGO staging
Margins (specify for all) - involved by invasive carcinoma (specify location) or __ mm from closest invasive carcinoma
Distal margin - involved or not involved by carcinoma in situ
Colpectomy, Hysterectomy or Pelvic Exenteration-optional features to report
Presence of carcinoma in situ at margins other than distal margin
Angiolymphatic invasion: present, not present, indeterminate
Presence of tumor in other organs
Additional pathologic findings: intraepithelial neoplasia, glandular atypia or dysplasia, koilocytosis, inflammation, other
Sample templates: Michigan Cancer Consortium (PDF file), University of Michigan
References: Archives 1999;123:55, Mod Path 2000;13:1029
End of Cervix chapter
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