cytology and histology of glandular lesions of the uterine ... · cytology and histology of benign...

Cytology and Histology of Benign Glandular Lesions of

the Uterine Cervix

Máire A. Duggan MD, FRCPC,9th

Annual Meeting,

Hong Kong Society of Cytology,Hong Kong,

December 5, 2008

Goal

• Know the key

cytopathologic

and histopathologic

features of usual and

unusual benign glandular lesions of the uterine cervix

Classification

• Benign Lesions– Physiologic– Iatrogenic– Inflammatory– Neoplastic– Metaplastic– Hyperplastic

Cytopathology of Glandular Lesions

• Variable • Confounded if more than one pathology • Diagnoses include

– NILM• Other: BEC; age>/=40 years

– Atypical glandular cells– Adenocarcinoma in situ– Invasive adenocarcinoma

Chhieng. Clin Lab Med. 2003; 23: 633.

Normal endocervical cells Normal endometrial cells

Cell Features Endocervical EndometrialCell size ++ +Cytoplasm Abundant ++ VariableNucleus Oval /elongated Round

DeMay. In: The Pap Test. 2005, 110.

Benign Endometrial Cells (BEC) in a Pap test

• NILM– Menstrual

• Highest frequency: day 1-4• Infrequent after day 14

– Brush artifact of LUS– BEC in Women <40 years

• NILM-OTHER: predictive of pathology– BEC in women >/=40

Ng. Acta Cytol 1974, 18:356, Gondos. Ann Clin Lab Sci 1977; 7: 486,Chang. Gynecol Oncol 2001; 80: 37.

Menstrual EndometriumStromal cells: cytology

Key features•

Bloody background

•

Groups with central stroma and peripheral glandular cells

•

Hyperchromatic spindle cells

Exit ball: Histology

Shimizu. Diagn Cytopathol. 2006; 34: 609.

Exit ball: cytology

Abraded Endometrium

Key features•

Biphasic tissue fragments

•

Packed spindle cells•

Branching tubular glands

De Peralta-Venturino. Diagn Cytopathol 1995;12: 263.

Benign Endometrial Cells in a woman >/=40 years

• Rationale– Post menopausal: 1.7% endometrial carcinoma– Symptomatic: 17% endometrial adenocarcinoma

• Currently controversial– 2-5 fold increase in reporting– 30% increase in endometrial sampling– 1% endometrial pathology (0.8% malignant)– Not cost effective for asymptomatic women– Post menopausal status and symptoms more predictive

Ng. Acta Cytol 1974, 18:356, Kapali. Cancer Cytopathol. 2007; 111:26, Thrall. Cancer Cytopathol. 2005; 105: 207, Beal. Am J Obstet

Gynecol. 2007; 196: 568.

AGUS:Atypical Glandular cells of Undetermined Significance

JNCI Workshop. JAMA 1989; 262: 931. JNCI Workshop. Acta Cytol 1993; 37: 115. Schnatz. Obstet Gynecol 2006; 107:701

AGC: 94 follow up studies

29

11.1

8.50.3

1.22.92.91.40.7

05

101520253035

neoplasm squamous glandular

%

OtherEndom hyperEndom cacervix aiscervix cascclsilhsilall

٠Nuclear atypia > benign < malignant

Terminological Evolution

• Adenocarcinoma in situ (AIS)– Precursor lesion of invasive adenocarcinoma

• Cytologic criteria– High PPV– Excellent reproducibility

• Separate category in TBS 2001• All other AGUS: atypical glandular cells

Solomon. Acta Cytol 1998; 42: 1, Solomon JAMA. 2002; 287: 2114.

AIS: cytologic criteria

• Arrangements– 3D crowded aggregates

• Feathering– Single cells

• Nuclear features– Altered polarity– Oval/elongated shape– Hyperchromasia– Apoptosis– Mitoses

Biscotti. Diagn Cytopathol 1997:17; 326.

Adenocarcinoma In Situ: 3 D aggregates, hyperchromasia

Endocervical cells

Adenocarcinoma In Situ: rosette, feathering, ↑n:c, apoptosis

Adenocarcinoma In Situ: altered polarity, mitoses, strip

AGC: Atypical Glandular Cells• Classified

– Not otherwise specified (NOS)• Endocervical, endometrial, glandular

– Favor neoplastic• Endocervical, endometrial

Solomon JAMA. 2002; 287: 2114, Chhieng . Clin Lan Med 2003; 23:

633, Schnatz. Obstet Gynecol. 2006; 107: 701, Ramsaroop. Diagn Cytopathol2006; 34: 614, Simsir. Cancer Cytopathol. 2003; 99: 323.

Cell FeatureArrangements 3D Aggregates

RosettesStrips

Borders IndistinctCytoplasm Reduced

AGC: cytologic features

Covell. Springer; New York: 2004, 123.

•

Some but not all features present

AGC: cytologic features

Nucleus Feature

Arrangement CrowdedFeatheringPalisading

Size and shape Increased and VariableChromatin Dark

Coarsely granularNucleoli Absent or inconspicuousMitosis Present

•

Some but not all features present


Atypical Endometrial CellsAdditional features

•

Cells in small 3D groups -Hyperchromatic crowded groups (HCG)

•

Vacuolated cytoplasm•

Hyperchromatic nuclei

•

Small nucleoli

Covell. Springer; New York: 2004, 123, DeMay. Am J Clin Pathol 2000; 114 suppl 1: s36.

AGC: Atypical Glandular Cells

• Follow up– colposcopy, endocervical curettage and

endometrial biopsy– HPV testing

• Reproducibility– poor for cell type and diagnosis

• LBC diagnoses more sensitive and higher PPV

AGC: Psammoma Bodies without Atypia

•

Rare occurrence•

Cytology features

•

Psammoma body•

No cells/single layer of benign cells

•

Etiology–

50% benign-50% malignant

Kern. Acta Cytol 1991; 35: 81. Nicklin. Gynecol

Oncol 2001; 83: 6, Zreik. Obstet

Gynaecol

2001; 97: 693.

Benign Lesions: classification

• Physiologic– Arias Stella reaction

• Iatrogenic– Fallopian tube prolapse– Drug/procedure associated

• Inflammatory– IUD

Physiologic: Arias Stella Reaction

• Hormonally associated proliferative atypia of glandular epithelium

• Endometrial glands typically involved• Endocervical glands rarely involved

– 9% hysterectomies from pregnant women• Rarely presents as an abnormal Pap test

Arias Stella. Arch Pathol 1954; 58: 112, Arias Stella. Cancer 1959; 12: 782, Schneider. Acta Cytol 1981; 25: 224..

Histology: Arias Stella Reaction

Key pathology•

Cytoplasmic clearing

•

Nuclear enlargement•

Hobnailed nuclei

•

Hyperchromasia

Cytology:Arias Stella ReactionKey features•

Cells: single/aggregates

• Clear cytoplasm

•

Nuclei: round/oval

•

Variable n:c ratio

•

Chromatin: smudgy, granular

•

Background: inflammatory

Benoit. Diagn Cytopathol 1996; 14: 349.

Arias Stella Reaction: differential diagnosis

• Clear cell adenocarcinoma, HSIL• Clues

– History of current or recent pregnancy– Histology

• Focal lesion, confined to endocervical glands• Absent stromal invasion

– Cytology• Absent diathesis and mitoses• Single cells, groups rare• Navicular cells may be present

Iatrogenic: Fallopian Tube Prolapse

• Rare complication of vaginal hysterectomy• Symptoms

• Dyspareunia• Vaginal bleeding and discharge

• Rarely presents as an abnormal Pap test• Complications: none

Silverberg. Arch Pathol 1974; 97:100.

Fallopian Tube Prolapse

Key pathology•

Inflamed Tubal mucosa

•

Regenerative changes

Fallopian Tube Prolapse

Key features•

Hypercellular smear

•

Inflammatory background •

Sheets and groups of small glandular cells

•

Uniform nuclei.•

Mitoses infrequent

Prolapsed Fallopian Tube: differential diagnosis

• Well differentiated adenocarcinoma• Clues

– Previous hysterectomy for benign disease– Histology

• Absent stromal invasion• Absent cell stratification

– Cytology• Absent blood and diathesis• Absent nuclear variability and mitoses

Iatrogenic: Tamoxifen Therapy

• Small blue cells– Post menopausal women/Tamoxifen– Origin: parabasal or reserve cell

• Differential diagnosis– Metastatic breast carcinoma– Endometrial carcinoma

• Clues– History– Absent diathesis, nuclear variability, mitoses

Small Blue Cell of Tamoxifen Therapy

Key features•

Loose clusters of naked nuclei

•

Smooth nuclear outlines

•

Uniform hyperchromasia

Opjorden. Cancer 2001; 93:23, Yang . Arch Pathol Lab Med 2001; 125:1047.

Inflammatory: IUD Changes

• Variable changes– Type and duration of use

• Endometrium– Chronic endometritis– Regenerative atypia– Squamous and hobnail metaplasia– Gland atrophy and decidualization

Schmidt. Hum Pathol 1982; 13: 878, Buckley. Curr Top Pathol 1994; 86: 307.

Cytology:IUD changes

Actinomyces

Hypermucinatedendocervical cells

Gupta. Acta Cytol 1978; 22: 286.

Psammoma body

IUD cells•

Possibly endometrial

• High N:C•

Multinucleated

• Nucleoli

Benign Lesions: classification

• Metaplastic– Tubal– Tubo-

endometrioid– Oxyphilic– Prostatic

• Neoplastic– Endocervical

polyp– Adenomyoma– Papillary

adenofibroma– Villus adenoma

Neoplastic: Endocervical Polyp

• Most frequent tumor of the cervix• Gross

– Single lesion– Round with a smooth surface– 2-3cm

• Histological Types– Mucosal– Stromal– Vascular

Caroti. Clin Exp Obstet Gynecol. 1988; 15: 108.

Endocervical Polyp

Key pathology•

Fibrovascular core

•

Feeder vessel•

Mucinous epithelium

•

Squamous metaplasia

Endocervical Polyp: Cytology

• Not diagnostic • Benign or atypical cells

– Enlarged cells and nuclei– Multinucleation– Hyperchromasia– Prominent nucleoli

• Inflammation– Pus and blood

• Squamous metaplasia

Ghorab. Diagn Cytopathol 2000; 22: 342.

Metaplasia: Tubo-endometrioid

• Frequent incidental finding– 31% cone/hysterectomy specimens

• Etiology– Idiopathic – Glandular ectopia– Repair reaction: laser, 5fu, xrt– Adenosis: DES

Jonasson . Int J Gynecol Pathol 1992; 11: 89, Robboy. Arch Pathol Lab Med 1977; 101:1, Bernstein . Obstet Gynecol 1993; 81: 896.

Tubo/endometrioid metaplasia

Suh. Int J Gynecol Pathol 1990; 9: 122, Oliva. AJCP 1995; 103: 618.

Key pathology•

Usually confined to inner 1/3 of cervix

• Tubal- ciliated, non ciliated, and peg cells• Endometrioid - non ciliated cells, apical snouts, no peg cells

• Bcl2 positive, p16 focally positive, Ki67<10%

Tubal Metaplasia: cytology

Novotny. Acta Cytol 1992: 36; 1, Robboy. Am J Obstet Gynecol 1981; 140: 579.

Key pathology•

Sheets or single cells

•

Terminal bars/cilia •

Enlarged, polarized nuclei

•

Fine chromatin•

Small nucleoli

•

Rare mitosis •

Clean background

Hyperplastic: pseudoneoplastic

• Microglandular hyperplasia• Endometriosis• Endocervical hyperplasia• Mesonephric hyperplasia• Nabothian

cysts and deep glands

• Tunnel Clusters• Endosalpingioisis

Hyperplasia: Microglandular

• Presentation: incidental or polyp• Frequency: 27% cone/hysterectomy• Progestin relationship unclear• Complications

– Atypical/florid

Leslie. Prog Surg Pathol 1984; 5: 95, Young . AJSP 1989; 13: 50, Witkiewicz. Hum Pathol 2005; 35: 154.

Microglandular Hyperplasia

Key pathology•

Focal/diffuse, superfical/deep proliferation

•

Closely packed small tubular glands•

Mucinous epithelium, reserve cells, squamous metaplasia

•

Mitosis: </=1/10hpf•

Ki67<10%, Negative p16

Microglandular Hyperplasia

Yahr. Diagn Cytopathol 1991: 7; 248

Cytology features•

Sheets of enlarged glandular cells

•

Vacuolated cytoplasm•

Mild nuclear enlargement

•

Fine chromatin •

Small nucleoli

Hyperplasia: Endometriosis• Uncommon• Etiology

– Post conization/implantation• Pap test presentation: rare

– Variable: NILM –

HSIL –

AIS– Absolute diagnosis very difficult

Baker. Int J Gynecol Pathol 1999; 18: 198.

Cervical Endometriosis

Key pathology•

Endometrial glands

•

Endometrial stroma•

No atypia

Endometriosis

Lundeen. Diagn Cytopathol 2002;26:35.

Cytology features•

Cell spindling

•

Cell uniformity•

Absent diathesis

Hyperplasia:Endocervical

• Rare: incidental finding, mucus discharge, mass lesion

• Proliferation confined to inner half of cervix

• Pap test presentation: not reported• 2 Histological types:

– Lobular-pyloric gland metaplasia (PGM)– Diffuse laminar hyperplasia (DLEH)

Nucci. AJSP 1999; 23: 886, Jones. AJSP 1991; 15: 1123.

Lobular Hyperplasia

Hashi. Int J Gynecol Pathol 2006; 25: 187. Nara. Gynecol

Oncol 2007; 106: 289.

Key pathology•

Rounded proliferation ofsmall glands

•

Duct centred•

Pseudocribriform pattern

•

Bland mucinous epithelium

Immunoprofile•

PAS positive

•

p16 positive•

HIK1083 positive•

HPV DNA negative

•

CEA negative

Diffuse Laminar Endocervical Hyperplasia

Key Pathology •

Circumscribe glandular proliferation

•

Chronic inflammatory infiltrate•

Benign endocervical glands

Mesonephric Remnants• Wolffian duct remnants: lateral wall

– 22% adults• Pap test presentation: rare

– Clusters of cuboidal cells• Complications

– Hyperplasia• Proliferation>6mm: diffuse/lobular/ductal

– Occasionally transmural

– Carcinoma

Ferry . AJSP 1990; 14: 1100, Jones. Gynecol Oncol 1993; 49: 41. Hejmadi. Cytopathol 2005; 16: 240.

Mesonephric Hyperplasia

Key pathology•

Small tubular glands

•

No intracellular mucin or glycogen•

PAS positive luminal, colloid like secretion

The EndThank you for your attention

Cytology and Histology of Malignant Glandular Lesions

of the Uterine Cervix

Máire A. Duggan MD, FRCPC,9 th Annual Meeting,

Hong Kong Society of Cytology,Hong Kong,

December 6, 2008

Goal

• Know the key cytopathologic and histopathologic features of usual and unusual malignant glandular lesions of the uterine cervix

Classification

• Malignant Lesions– Premalignant lesions

• Adenocarcinoma in situ: AIS• Endocervical glandular dysplasia: EGD• Stratified mucin producing intraepithelial lesion:

SMILE

– Adenocarcinoma

Glandular Premalignancy

• Precursor lesions of adenocarcinoma– AIS: good evidence– Dysplasia: poor evidence

• AIS incidence: 0.6/100,000– CIN III: x50 more frequent

• AIS prevalence: increasing

AIS: risk factors

• 50% AIS: concomitant SIL• Risk factors similar to SIL• HPV 16 and 18• Multiple sexual partners• OCP• Early onset sexual activity• Low socio-economic status

Zaino. Int J Gynecol Pathol 2002; 21: 314.

AIS: clinical features

• Mean age: 29 years• Symptoms

– None, discharge, abnormal Pap test• Location: 65% T zone• Mostly unifocal• Colposcopy: no specific pattern

AIS

• Frequency: 10% of glandular malignancies• Histological types: not clinically significant

– Mucinous– Intestinal– Adenosquamous

Friedell. Cancer 1953; 6: 887, Schlesinger. Int J Gynecol Pathol 1999;18:1.

- Clear cell- Endometrioid- Ciliated

AIS

Key pathology

• Normal glandular architecture• Decreased mucin• Stratified columnar cells• Hyperchromatic nuclei• Mitoses • Absent stromal invasion

AIS: HPV status and IHC

• HPV DNA– 66% (40-90%) positive– HPV 16 and 18 – Predominance of HPV 18

• Antibody positive– CEA ( 70%) and Steroid receptors– P16 and p53– Ki67: high index (>30%)

• Antibody negative– Vimentin and bcl2

McCluggage. J Clin Pathol 2003; 56: 164.. Wells. Int J Gynecol Pathol 2002;21: 360. Duggan. Int J Gynecol Pathol 1994; 13: 143, Liang. Int J Gynecol Pathol 2007; 26: 71.

AGC and HSIL

• Approximately 16% of AGC in follow up = HSIL

• Reasons– Co-incidental lesions

• AIS and HSIL: 50%

– Glandular mimics• HSIL in endocervical glands

AIS and HSIL: 2 cell types

HSILAIS

HSIL involving endocervical glands

Pattern A

Pattern B

Mattosinho. Acta Cytol 2003; 47: 154. Selvaggi. Acta Cytol 1994:38; 687.

SMILE

• Uncommon lesion• Resembles SIL with full thickness

cytoplasmic vacuolization• Described in association with cervical

adenocarcinoma• Also associated with HSIL, AIS or

squamous cell carcinoma

Park. AJSP. 2000; 24: 1414 McCluggage Pathol 2006; 39: 97.

SMILE

Key pathology• Dysplastic nuclei• Mucin vacuoles• Mitoses

Cytology features• Not reported

Endocervical Dysplasia

• Controversial lesion– No outcome studies

• Alternate terminologies– Low CGIN: UK– Superficial (early) AIS

• Investigation– HPV testing– P16 positive– Steroid receptor positive

Zaino. Int J Gynecol Pathol 2002; 21: 314, Brown. J Clin Pathol 1986; 39: 22, Witkiewicz. AJSP 2005; 29: 1609, Liang. Int J Gynecol Pathol 2007; 26: 71.

Endocervical dysplasia: criteria• Hyperchromatic

nuclei • Occasional mitoses • Minimal stratification• AIS in one gland• Other criteria

• Management – controversial

McCluggage. J Clin Pathol 2003; 56: 164.

Adenocarcinoma: epidemiology

• 20-25% cervical carcinomas• Mean age at presentation

– Microinvasive adenocarcinoma: 39-44 years– Invasive adenocarcinoma: 44-54 years

• Incidence increasing in Canada and elsewhere– 1994-96: 1.83/100,000

• 41% relative increase in 22 years• Higher Pap test false negative rate due to sampling error

Liu. CMAJ 2001; 164: 1, Wang. Cancer 2004; 100: 1035, Herzog. Am J Obstet Gynecol. 2007; Dec: 566 .

Adenocarcinoma: risk factors

• Sexual behavior– Early age of onset of sexual activity– Lifetime number of sexual partners– Early age of first birth and increasing parity

• Oral contraceptives• Obesity and body fat distribution• No association with cigarette smoking

Green. Br J Cancer 2003; 89: 2078, Lacey. Cancer 2003; 98: 814, Castellsague. J NCI. 2006; 98: 303, Berrington de Gonzalez. Int J Cancer. 2007; 120: 885.

Adenocarcinoma: risk factors

• Human Papilloma Virus (odds ratio=81)– 88% HPV DNA positive – Types 16/18 in 82%

• Type 16 predominant in endometrioid and VGA• Type 18=16 or slight predominance in others

• Genetic– Ovarian carcinoma– Peutz Jegher’s syndrome

An. Mod Pathol. 2005 18: 528, Duggan. Hum Pathol 1995; 26: 319, Pirog . Am J Clin Pathol 2000; 157: 1055, Altekruss . Am J Obstet Gynecol 2003; 188: 657, Castellsague. J NCI. 2006; 98: 303.

Adenocarcinoma: classification

• 57% Mucinous• 30% Endometrioid• 11% Clear cell• 2% Rare types

– Minimal deviation – Serous– Mesonephric– Well differentiated villoglandular

Wright. Springer Verlag, 2002.

Classification System Deficiencies

• Variable frequency of endometrioid – 7-50%

• Interobserver agreement– Endocervical, endometrioid, clear cell,

serous: moderate-good– Mixed carcinomas: fair-poor– Villoglandular, adenosquamous: poor

Young. Int J Gynecol Pathol 2002; 21: 212, Alfsen. Gynecol Oncol 2003; 90: 282..

Mucinous Adenocarcinoma

• Synchronous premalignancy– 66% AIS– 16% HSIL

• Synchronous mucinous tumors of ovary and fallopian tube– Primary or metastatic

• 3 morphologic types– Endocervical, intestinal, signet ring

• Pure• Mixed

Wang. Gynecol Oncol. 2006; 103: 541.

Key pathology • Complex racemose glands• Surface and intraluminal papillae• Pale granular cytoplasm• Brisk mitotic activity• Apoptotic bodies

Endocervical adenocarcinoma

Young. Histopathol 2002; 41: 185.

Endocervical adenocarcinoma• Mostly neutral mucin: content variable

– Pas/al blue: red/purple mixed cytoplasmic stain– Mucicarmine: cytoplasmic positivity

• Antibody positive– CEA : cytoplasmic– P16 positive: diffuse and strong

• Antibody negative– Vimentin – Estrogen receptor

Wells. Int J Gynecol Pathol 2002; 21: 360.

CEA

Vimentin

Pas/al blue

Endocervical adenocarcinoma

p16

Cytology:endocervical adenocarcinoma

• Hypercellular smears• Cells

– Single– Sheets– Clusters

• Cell features of AIS• Additional features

– Perinuclear clearing– Macronucleoli– Tumor Diathesis


Intestinal adenocarcinoma

Key pathology• Glands and papillae• Pseudostratified mucin poor cells• Goblet cells

Young and Clement. Histopathol 2002; 41: 185.

Signet ring carcinoma

Key pathology• Signet ring cells• Pure form is rare• Usually mixed with other types


Endometrioid Adenocarcinoma

• Resembles endometrial counterpart• Synchronous premalignancy

– Higher compared to non endometrioid carcinomas• 81% AIS• 54% HSIL

• Difficult to distinguish from mucin poor mucinous carcinomas

• Lower frequency of squamous differentiation• Better prognosis than mucinous carcinoma

Wang. Gynecol Oncol. 2006; 103: 541.

Endometrioid adenocarcinoma

Key pathology• Glandular architecture• Benign squamous differentiation • Stratified, oval nuclei• No cytoplasmic mucin


Endometrioid carcinoma

Cytology features• Similar to mucinous

carcinoma

Clear cell Carcinoma

• DES exposed• Young women• Location

– Ectocervical

• HPV status– Usually negative– Rare cases HPV 31

positive

• Sporadic• Post menopausal

women• Location

– Endo or ectocervical

Waggoner. Obstet Gynecol 1994; 84: 404.

Clear cell Carcinoma


Key pathology• Solid, tubulocystic, papillary• Glycogenated clear cytoplasm• Intracystic mucin• Hobnail cells

Clear cell CarcinomaCytology features• Large cells• Abundant cytoplasm• Round nucleus• Prominent nucleolus

Minimal Deviation Adenocarcinoma

• Rare tumor– 3 types

• Associations– Not HPV related: 1 report of type 16 and 18+– Lobular endocervical hyperplasia (PGM)– AIS with a gastric immunophenotype– Adenoma malignum (AM)

• Mucinous ovarian tumors• SCTAT• Peutz Jeghers Syndrome

Gilks. Am J Surg Pathol 1989; 13: 717, Hart . Int J Gynecol Pathol 2002; 21: 327, Fukishima . Jpn J Clin Oncol 1990 ; 20: 407, Mikami. Mod Pathol. 2004; 17: 962.

–Adenoma malignum–Endometrioid–Clear cell

Adenoma Malignum

• Symptoms – Profuse watery discharge/bleeding

• Difficult on cytology and small biopsies• Cytology features

– Irregular sheets of benign glandular cells– Rare malignant cells with large nucleoli

• Prognosis– Worse than mucinous carcinoma

Voselgang. Diagn Cytopathol 1995; 13: 146.

Adenoma malignum

Key pathology• Atypical glands: shape, size, location• Desmoplasia near outpouchings• Single layer of low grade mucinous cells• Rare gland with malignant cells

Adenoma Malignum versus Normal or Benign Endocervix

Stain Adenoma Malignum Normal or Benign

PAS/Al Blue Mostly red Purple/ violet

HIK1083-PGM + -*

CEA + -

P16 30% + -Alpha SMA Increased + stroma - stromaER - stroma + stroma

*positive staining in lobular hyperplasia

Hayashi. Am J Surg Pathol 2000; 24: 559, Mikami. Mod Pathol 2004; 17: 962. Ischimura. Int J Gynecol Pathol 2001; 20: 220, Mikami. Gynecol Oncol 1999; 74: 501, McCluggage. Pathol 2007; 39: 97.

Adenoma Malignum: Pas Al Blue*

Adenoma Malignum Normal Gland

Hayashi. Am J Surg Pathol. 2000; 24: 559.*ph=2.5

Serous Carcinoma

• Histology similar to ovarian and endometrial counterparts

• Metastatic spread should be excluded• Outcome

– Stage 1 = Stage 1 endocervical adenocarcinoma

– Advanced stage: rapidly fatal

Nofech-Mozes. Int J Gynecol Cancer. 2006; 16 Suppl 1: 286.

Serous carcinoma

Zhou. Am J Surg Pathol 1998; 22:130.

Key pathology• Complex papillary proliferation• Stratification and tufting• High grade nuclei

• P53 positive, CEA negative

Serous Carcinoma

Chang. Cancer 1999; 87: 5.

Cytology features• Single cells• Sheets• Tight balls• Malignant features obvious• Psammoma bodies

Mesonephric carcinoma

• Rare tumor– 30 documented cases

• Arise from mesonephric duct remnants• Gross appearance

– Cervical mass• HPV negative• Outcome

– More indolent than mucinous carcinomaClement. Am J Surg Pathol 1995; 19: 1158, Hart. Int J Gynecol Pathol 2002; 21: 327, Pirog. Am J Pathol 2000; 157: 1055.

Mesonephric carcinoma

Key pathology• Variable pattern: mostly ductal• Retiform, tubular, sex cord, spindle cell • Eosinophilic mucinous secretion• Mesonephric remnants

Mesonephric carcinoma: immunohistochemistry

• Pattern similar to mesonephric remnants• Negative staining

– mCEA, CTK 20, ER/PR• Positive staining

– EMA, CTK 7, CAM 5.2, CD10, Vimentin, Calretinin, Inhibin, p16

• CEA, CD10, and vimentin pattern is controversial

Silver. Am J Surg Pathol 2001; 25: 379, Clement. Am J Surg Pathol 1995; 19: 1158, Ordi. Am J Surg Pathol 2001; 25: 1540 , Tringler. Hum Pathol 2004; 35: 689.

Well Differentiated Villoglandular Adenocarcinoma

• Rare tumor of young women– Average age: 35

• Presentation: vaginal bleeding/exophytic mass• May be mixed with other types of carcinoma• HPV status

– 100% type16/18 positive– Mostly type 16

• Prognosis usually excellentYoung. Cancer 1989; 63: 1773, Jones. Int J Gynecol Pathol 1993; 12: 1. Jones. Int J Gynecol Pathol 2000; 19: 110. Fadare. Virchows Arch 2005; 447: 883.

Well differentiated villoglandular adenocarcinoma

Key pathology• Papillary architecture• Minimal cytological atypia• Minimal stromal invasion• No desmoplasia

Well differentiated villoglandular

adenocarcinoma: cytology• Not specific• Atypical glandular cells

– Papillary fragments– Nuclear crowding– Subtle atypia

• High false negative rate

Chang. Cancer 1999; 87: 5.

Secondary Adenocarcinoma

• Genital tract– Endometrial carcinoma– Ovarian, tubal and peritoneal

• Extragential sites– Rare

• Breast• Colorectal• Gastric

Zaino. Int J Gynecol Pathol 2001; 21: 1, Mazur. Cancer 1984; 53: 1978.

Endometrial carcinoma

• Stage II tumors– IIa: Surface cancerization– IIb: Stromal invasion

• Tumor source– Direct spread– Surface metastases– Embolic

Scurry. Int J Gynecol Oncol 2000; 10: 497.

Stage II endometrial carcinoma: histology

Stage IIa Stage IIb

Endometrial endometrioid carcinoma: cytology

Key Pathology• Watery diathesis• Crowded groups• Prominent nucleoli• Ingested PMNs

Cervical Primary versus Stage II Endometrial Carcinoma

Antibody Cervix Endometrium

ER/PR 83% - 70% +

CEA 86% + 89% -

Vimentin 86% - 59% +

P16 100% + strong/diffuse

30%+Moderate/patchy

Castrillon. Int J Gynecol Pathol 2001; 21: 4, McCluggage. Pathology 2007; 39: 97.

Stage II Endometrial Carcinoma

mCEA Vimentin

p16

El-Mansi. Int J Gynecol Cancer 2006; 16: 1254.

PTEN: tumor suppressor gene• Endometrial carcinoma: somatic mutations

• Expression is diminished• Cervical adenocarcinoma

• Expression retained

Extrauterine genital tract primaries

• Dissemination pathways• Direct spread• Embolic spread• Transtubal migration

Olsen . Obstet Gynecol 2001; 78: 71.

Transtubal migration: serous ovarian carcinoma

Metastatic Breast Carcinoma

• Frequency increasing• longer survival

• Lobular more frequent than ductal• Pap test: rare malignant cells• Histology: isolated metastasis

Ng. Acta Cytol 1974; 18: 108, Hepp. Cancer Invest 1999; 17: 468.

Pap test

Endocervical curettage

Metastatic colonic carcinoma

Lemoine. Cancer 1986; 57: 2002, Nakagami. Jpn J Clin Oncol 1999; 29:640.

Key cytology features• Dirty background• Glandular groups• Palisading of basal nuclei

The End

Thank you for inviting me

1

Benign and Malignant Glandular Lesions of the Uterine Cervix

Máire A. Duggan MD, FRCPC

Hong Kong Society of Cytology Annual Meeting Hong Kong

December 7, 2008

References

Alfsen GC et al. Reproducibility of classification in non-squamous cell carcinomas of the uterine cervix. Gynecol Oncol 2003; 90:282-89.

Altekruss SF et al. Comparison of human papilloma virus genotypes, sexual and reproductive risk factors of cervical adenocarcinoma and squamous cell carcinoma northeastern United States. Am J Obstet Gynecol 2003; 188:657-63.

An HJ et al. Prevalence of human papillomavirus DNA in various histological subtypes of cervical adenocarcinoma: a population based study. Mod Pathol. 2005; 18: 528-34.

Arias-Stella J. A topographic study of uterine epithelial atypia associated with chorionic tissue: demonstration of alteration in the endocervix. Cancer 1959; 12:782-790.

Arias-Stella J. Atypical endometrial changes associated with the presence of chorionic tissue. Arch Pathol 1954; 54: 112-128.

Baker PM et al. Superficial endometriosis of the uterine cervix: a report of 20 cases of a process that may be confused with endocervical glandular dysplasia or adenocarcinoma in situ. Int J Gynecol Pathol 1999; 18:198-205.

Beal HN et al. Endometrial cells identified in cervical cytology in woman ≥40 years of age: criteria for appropriate endometrial evaluation, Am J Obstet Gynecol June 2007; 568.e1 – 568.e6.

Benoit JL, Kini SR. “Arias-Stella Reaction” – like changes in endocervical glandular epithelium in cervical smears during pregnancy and post-partum states. A potential diagnostic pitfall. Diagnostic Cytopathol 1996; 14:349-355.

Bernstein J et al. Development of vaginal adenosis following combined 5-F-U and carbon dioxide laser treatments for diffuse vaginal condylomatosis. Obstet Gynecol 1993; 81:896-898.

Berrington de Gonzales A, and Green J. Comparison of risk factors for invasive squamous cell carcinoma and adenocarcinoma of the cervix: Collaborative reanalysis of individual data on

2

8,097 women with squamous cell carcinoma and 1,374 women with adenocarcinoma from 12 epidemiological studies. Int J Cancer 2007 ;120: 885-91.

Biscotti CV et al. Endocervical adenocarcinoma in situ: an analysis of cellular features. Diagn Cytopathol 1997; 17:326-332.

Brown LJ and Wells M. Cervical glandular atypia associated with squamous intraepithelial lesions: a premalignant lesion? J Clin Pathol 1986; 39:22-28.

Buckley CH. The pathology of intra-uterine contraceptive devices. Curr Top Pathol 1994; 86:307-330.

Caroti S and Siliotti F. Cervical polyps: a colpo-cyto-histological study. Clin Exp Obstet Gynecol 1988; 15:108-115.

Castellsague X et al. Worldwide human papillomavirus etiology of cervical adenocarcinoma and its cofactors: implications for screening and prevention. J Natl Cancer Inst. 2006; 98: 303-15.

Castrillon D et al. Distinction between endometrial and endocervical adenocarcinoma: an immunohistochemical study. Int J Gynecol Pathol 2001; 21:4-10.

Chang A et al. Cytologically benign endometrial cells in the Papanicolaou smears of postmenopausal women. Gynecol Oncol 2001; 80:37-43.

Chang WC et al. Cytologic features of villoglandular adenocarcinoma of the uterine cervix: comparison with typical endocervical adenocarcinoma with a villoglandular component and papillary serous carcinoma. Cancer 1999; 87:5-11.

Chhieng DC and Cangiarella JF. Atypical glandular cells. Clin Lab Med. 2003 Sep;23(3):633-57.

Clement PB et al. Malignant mesonephric neoplasms of the uterine cervix. Am J Surg Pathol 1995; 19:1158-71.

Covell J et al. Epithelial glandular abnormalities. In: The Betheseda System for reporting cervical cytology. Definitions, Criteria and Explanatory Notes. Editors: Solomon D and Nayar R. 2nd edition. Springer Verlag. New York, USA. 2004,141-47.

Covell JL et al. Epithelial abnormalities: glandular. In: The Bethesda System for Reporting Cervical Cytology. Definitions, Criteria and Explanatory notes. 2nd Edition. Editors: Solomon D. and Nayar R. Springer, New York, USA. 2004; 123-156.

de Peralta-Venturino MN et al. Endometrial cells of the "lower uterine segment" (lus) in cervical smears obtained by endocervical brushings: a source of potential diagnostic pitfall. Diagn Cytopathol 1995; 12:263-271.

3

DeMay R. Hyperchromatic crowded groups: pitfalls in Pap smear diagnosis. Am J Clin Pathol 2000; 114, Suppl 1: S36-43.

DeMay R. Cytology of the glandular epithelium. In: The Pap Test. ASCP Press Chicago, USA. 2005; 110-116.

Duggan MA et al. Adenocarcinoma in situ of the endocervix; human papillomavirus determination by dot blot hybridization and polymerase chain reaction amplification. Int J Gynecol Pathol 1993; 13:143-149.

Duggan MA et al. The human papilloma virus status of invasive cervical adenocarcinoma: a clinicopathological and outcome analysis. Hum Pathol 1995; 26: 319-25

El-Mansi MT and Williams AR. Evaluation of PTEN expression in cervical adenocarcinoma by tissue microarray. Int J Gynecol Cancer 2006; 16:1254-60.

Fadare O and Zheng W. Well-differentiated papillary villoglandular adenocarcinoma of the uterine cervix with a focal high-grade component: is there a need for reassessment? Virchows Arch. 2005; 447:883-7.

Ferry JA and Scully RE. Mesonephric Reminants, hyperplasia and neoplasia in the uterine cervix. A study of 49 cases. Am J Surg Pathol 1990; 14:1100-1111.

Friedell G and McKay D. Adenocarcinoma In Situ of the endocervix. Cancer 1953; 6:887-897.

Fukushima N et al. The detection of human papilloma virus (HPV) in a case of minimal deviation adenocarcinoma of the uterine cervix (adenoma malignum) using in situ hybridization. Jpn J Clin Oncol 1990; 20:407-12.

Ghorab Z et al. Endocervical reactive atypia: a histological cytologic study. Diagn Cytopathol 2000; 22:342-346.

Gilks CB et al. Adenoma malignum (minimal deviation adenocarcinoma) of the uterine cervix: a clinico-pathological and immunohistochemical analysis of 26 cases. Am J Surg Pathol 1989; 13:717-29.

Gondos B and King EB. Significance of endometrial cells in cervicovaginal smears. Ann Clin Lab Sci 1977; 7:486-490.

Green J et al. Risk factors for adenocarcinoma and squamous cell carcinoma of the cervix in women aged 20-44 years: the UK national case control study of cervical cancer. Br J Cancer 2003; 89:2078-86.

Gupta P et al. Epithelial atypias associated with intrauterine contraceptive devices (IUD). Acta Cytol 1978; 22:286-291.

4

Hart WR . Symposium Part II. Special types of adenocarcinoma of the uterine cervix. Am J Gynecol Pathol 2002; 21:327-46.

Hashi A et al. p161NK4a overexpression independent of human papillomavirus infection in lobular endocervical glandular hyperplasia. Int J Gynecol Pathol. 2006; 25:187-94.

Hayashi I et al. Reappraisal of orthodox histochemistry for the diagnosis of minimal deviation adenocarcinoma of the cervix. Am J Surg Pathol 2000; 24:559-62.

Hejmadi RK et al. Mesonephric hyperplasia can cause abnormal cervical smears: report of three cases with review of literature. Cytopathology. 2005; 16:240-3.

Hepp HH et al. Breast cancer metastasis to the uterine cervix: analysis of a rare event. Cancer Invest 1999; 17:468-73.

Herzog TJ; Monk BJ Reducing the burden of glandular carcinomas of the uterine cervix, Am J Obstet Gynecol December 2007; 566 – 571 Ischimura T et al. Immunohistochemical expression of gastric mucin and p53 in minimal deviation adenocarcinoma of the uterine cervix. Int J Gynecol Pathol 2001; 20:220-26.

Jonasson JG et al. Tubal metaplasia of the uterine cervix: a prevalence study in patients with gynecologic pathologic findings. Int J Gynecol Pathol. 1992;11:89-95.

Jones MA et al. Diffuse laminar endocervical glandular hyperplasia. Am J Surg Pathol 1991;15:1123-129.

Jones MA et al. Mesonephric reminant Hyperplasia of the Cervix: A clinicopatholgic analysis of 14 cases. Gynecol Oncol 1993; 49:41-47,

Jones MW et al. Well-differentiated villoglandular adenocarcinoma of the uterine cervix. A clinico-pathological study of 24 cases. Am J Gynecol Pathol 1993; 12:1-7.

Jones MW et al. Well-differentiated villoglandular adenocarcinoma of the uterine cervix: oncogene/tumor suppressor gene alterations and human papilloma virus genotyping. Int J Gynecol Pathol 2000; 19:110-17.

Kapali M et al. Routine endometrial sampling of asymptomatic premenopausal women shedding normal endometrial cells in papanicolaou tests is not cost effective. Cancer Cytopathol 2007; 111: 26-33. Kern SB. Prevalence of psammoma bodies in Papanicolaou-stained cervicovaginal smears. Acta Cytol 1991; 35:81-8.

Lacey JV et al. Obesity as a potential risk factor for adenocarcinoma and squamous cell carcinomas of the uterine cervix. Cancer 2003; 89:814-21.

5

Lemoine R et al. Epithelial tumors metastatic to the uterine cervix. Cancer 1986; 57: 2002-05.

Leslie KO and Silverberg SG. Microglandular hyperplasia of the cervix: unusual clinical and pathological presentations and their differential diagnosis. Prog Surg Pathol 1984; 5:95-114.

Liang J et al. Utility of p16INK4a, CEA, Ki67, P53 and ER/PR in the differential diagnosis of benign, premalignant, and malignant glandular lesions of the uterine cervix and their relationship with Silverberg scoring system for endocervical glandular lesions. Int J Gynecol Pathol 2007;26:71-5.

Liu S et al. Cervical Cancer: The increasing incidence of adenocarcinoma and adenosquamous carcinoma in younger women. CMAJ 2001; 164:1-5.

Lundeen SJ et al. Abnormal cervicovaginal smears due to endometriosis: a continuing problem. Diagn Cytopathol 2002; 26:35-40.

Masatoshi Nara et al. Lobular endocervical glandular hyperplasia as a presumed precursor of cervical adenocarcinoma independent of human papillomavirus infection, Gyne Oncol 2007; 106:289 – 298. Mattosinho de Castra Ferraz Mola G et al. Atypical glandular cells of undetermined significance. Cytologic predictive value for glandular involvement in high grade squamous intraepithelial lesions. Acta Cytol 2003; 47:154-158.

Mazur MT et al. Metastases to the female genital tract: analysis of 325 cases. Cancer 1984; 53:1978-84.

McCluggage WG. Endocervical glandular lesions: controversial aspects and ancillary techniques. J Clin Pathol 2003; 56:164-173.

McCluggage WG. Immunohistochemistry as a diagnostic aid in cervical pathology. Pathology 2007; 39:97-111.

Mikami Y et al. Florid endocervical glandular hyperplasia with intestinal and pyloric gland metaplasia: worrisome benign mimic of adenoma malignum. Gynecol Oncol 1999; 74:501-11.

Mikami Y et al. Gastro intestinal immuno phenotype in adenocarcinoma of the uterine cervix and dilated glandular lesions. A possible link between lobular endocervical glandular hyperplasia/pyloric gland metaplasia and adenoma malignum. Mod Pathol 2004; 17:962-72.

Nakagami K et al. Uterine cervix metastasis from rectal carcinoma, a case report and a review of the literature. Jpn J Clin Oncol 1999; 29:640-42.

National Cancer Institute Workshop. The 1988 Bethesda System for reporting cervical/vaginal cytological diagnoses. JAMA. 1989;262:931-4

6

National Cancer Institute Workshop. The Bethesda System for reporting cervical/vaginal cytological diagnoses: revised after the second National Cancer Institute Workshop, April 29-30, 1991.Acta Cytol. 1993; 37;115-24

Ng AB et al. Significance of endometrial cells in the detection of endometrial carcinoma and its precursors. Acta Cytol 1974; 18: 356-61.

Ng AB et al. The cellular manifestations of extra uterine cancer. Acta Cytol 1974; 18:107-17.

Nicklin JL et al. The significance of psammoma bodies in cervical cytology smears. Gynecol Oncol 2001; 83:6-9.

Nieuwenhuizen L et al. Endometrial and endocervical secretion: the search for histochemical differentiation. Anal Quant Cytol Histol 2006; 28:87-96.

Nofech-Mozes S et al. Immunohistochemical characterization of endocervical papillary serous carcinoma. Int J Gynecol Cancer 2006; 16 Suppl 1:286-92.

Novotny DB et al. Tubal metaplasia. a frequent potential pitfall in the cytologic dianosis of glandular dysplasia in cervical smears. Acta Cytol 1992; 36:1-10.

Nucci MR et al. Lobular endocervical glandular hyperplasia, not otherwise specified. Am J Surg Pathol 1999; 23:886-91.

Oliva E et al. Tubal and tubo-endometroid metaplasia of the uterine cervix. Am J Clin Path 1995; 103:618-623.

Olsen TG et al. Primary peritoneal carcinoma presenting on routine Papanicolaou smear. Gynecol Oncol 2000; 78:71-73.

Opjorden SL et al. Small cells in cervical-vaginal smears of patients treated with tamoxifen. Cancer 2001; 93:23-28.

Ordi J et al. Mesonephric adenocarcinoma of the uterine corpus: CD 10 expression as evidence of mesonephric differentiation. Am J Surg Pathol 2001; 25:1540-45.

Park JJ et al. Stratified mucin producing intraepithelial lesions of the cervix: adenosquamous or columnar cell neoplasia? Am J Surg Pathol 2000; 24:1414-1419.

Pirog EC et al. Prevalence of human papilloma virus DNA in different histological subtypes of cervical adenocarcinoma. Am J Pathol 2000; 157:1055-62.

Ramsaroop R and Chu I. Accuracy of diagnosis of atypical glandular cells – conventional and Thinprep. Diagn Cytopathol 2006; 34: 614-9.

Robboy SJ et al. Dysplasia and cytologic findings in 4,589 young women enrolled in diethylstilbestrol-adenosis (DESAD) Project. Am J Obstet Gynecol 1981;140:579-86.

7

Schlesinger C and Silverberg S. Endocervical adenocarcinoma in situ of tubal type and its relation to atypical tubal metaplasia. Int J Gynecol Pathol 1999; 18:1-4.

Schmidt WA. IUDs, inflammation, and infection: assessment after 2 decades of IUD use. Hum Pathol 1982; 13:878-881.

Schnatz PF et al. Clinical significance of atypical glandular cells on cervical cytology. Obstet Gynecol 2006 Mar; 107: 701-8.

Schneider V. Arias-Stella reaction of the endocervix: frequency and location. Acta Cytol 1981;25: 224-228.

Scurry J et al. Histologic study of patterns of cervical involvement in Figo stage II endometrial carcinoma. Int J Gynecol Cancer 2000; 10:497-02.

Selvaggi SM. Cytologic features of squamous cell carcinoma in situ involving endocervial glands in endocervical cytobrush. Acta Cytol 1994; 38:687-692.

Shimizu K et al. Endometrial glandular and stromal breakdown, part 1: cytomorphological appearance. Diagn Cytopathol. 2006; 34:609-13.

Shintaku M et al. Adenocarcinoma of the uterine cervix with choriocarcinomatous and hepatoid differentiation: report of a case. Int J Gynecol Pathol 2000; 19:174-78.

Silver SA et al. Mesonephric adenocarcinomas of the uterine cervix: a study of 11 cases with immunohistochemistry findings. Am J Surg Pathol 2001; 25:379-87.

Silverberg SG and Frable WJ. Prolapse of fallopian tube into vaginal vault after hysterectomy. Histopathology, cytopathology and differential diagnosis. Arch Pathol 1974; 97:100-103.

Simsir A et al. Glandular cell atypia on Papanicolaou smears: interobserver variability in the diagnosis and prediction of cell of origin. Cancer Cytopathol. 2003; 99:323-30.

Solomon D et al. ASCUS and AGUS Criteria. International Academy of Cytology Task Force Summary. Diagnostic cytology towards the 21st century, an international expert conference and tutorial. ACTA Cytol 1998; 42:16-24.

Solomon D et al. The 2001 Bethesda System: Terminology for Reporting Cervical Cytology. JAMA 2002; 287: 2114-2119.

Suh KS and Silverberg SG. Tubal metaplasia of the uterine cervix. Int J Gynecol Pathol 1990; 9:122-128.

Thrall MJ et al. Significance of benign endometrial cells in Papanicolaou tests from women > 40 years. Cancer Cytopathol 2005; 105: 207-216.

8

Tringler B et al. Evaluation of p16 and pRB expression in cervical squamous and glandular neoplasia. Hum Pathol 2004; 35:689-96.

Voselgang PJ et al. Exfoliative cytology of adenoma malignum (minimal deviation adenocarcinoma ) of the uterine cervix. Diagn Cytopathol 1995; 13:146-50.

Waggoner SE et al. Human papilloma virus detection and p53 expression in clear cell adenocarcinoma of the vagina and cervix. Obstet Gynecol 1994; 84:404-08.

Wang SS et al. Cervical cancer and squamous cell carcinoma incidence trends among white women and black women in the United States for 1976 –2000. Cancer 2004; 100:1035-44.

Wang SS et al. Pathological characteristics of cervical adenocarcinoma in a multi-center US-based study. Gynecol Oncol 2006; 103:541-6.

Wells M and Brown LJR. Symposium Part IV. Investigative approaches to endocervical pathology. Int J Gynecol Pathol 2002; 21:360-367.

Witkiewicz A et al. Superficial (early) endocervical adenocarcinoma in situ: a study of 12 cases and comparison to conventional AIS. Am J Surg Pathol. 2005; 29:1609-14.

Witkiewitcz AK et al. Microglandular hyperplasia: a model for the de novo emergence and evolution of endocervical reserve cells. Hum Pathol 2005; 36: 154-161.

Wright TC et al. Carcinoma and other tumors of the cervix. In: Blaustein’s Pathology of the Female Genital Tract. 5th edition. Editor Kurman RJ. Springer, New York, USA. 2002: 325-81.

Yahr LJ and Lee KE. Cytologic findings in microglandular hyperplasia of the cervix. Diagn Cytopathol 1991; 7:248-251.

Yang YJ et al. The small blue cell dilemma associated with tamoxifen therapy. Arch Pathol Lab Med 2001; 125:1047-1050.

Young RH and Clement PB. Endocervical adenocarcinoma and its variants: their morphology and differential diagnosis. Histopathol 2002; 41:185-07.

Young RH and Scully RE. Atypical forms of microglandular hyperplasia of the cervix simulating carcinoma. Am J Surg Pathol 1989; 13:50-56.

Young RH and Scully RE. Invasive adenocarcinoma and related tumors of the uterine cervix. Semin Diagn Pathol 1990; 7: 205-27.

Young RH and Scully RE. Villoglandular papillary adenocarcinoma of the uterine cervix. A Clinicopathological Analysis of 13 Cases. Cancer 1989; 63:1773-79.

Young RH and Scully RE. Uterine carcinomas simulating microglandular hyperplasia. A report of six cases. Am J Surg Pathol 1992; 16:1092-97.

9

Young RH. Simple clefts, complex problems; reflections on glandular lesions of the uterine cervix. J Gynecol Pathol 2002; 21:212-16.

Zaino R. The fruits of our labors. Distinguishing endometrial from endocervical adenocarcinoma. Int J Gynecol Pathol 2001; 21:1-3.

Zaino RJ. Symposium Part 1: Adenocarcinoma In situ, glandular dysplasia, and early invasive adenocarcinoma in situ of the uterine cervix. Int J Gynecol Pathol 2002; 21:314-26.

Zhou C et al. Papillary serous carcinoma of the uterine cervix. a clinico-pathologic study of 17 cases. Am J Surg Pathol 1998; 22:113-20.

Zreik TG and Rutherford TJ. Psammoma bodies in cervicovaginal smears. Obstet Gynecol 2001; 97:693-95.

cytology and histology of glandular lesions of the uterine ... · cytology and histology of benign...

Documents