Cytology and Histology of Glandular Lesions - Hong Kong Society of ...

Cytology and Histology of
Benign Glandular Lesions of
the Uterine Cervix
Máire A. Duggan MD, FRCPC,
9 th
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

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

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 Endometrial
Cell size ++ +
Cytoplasm Abundant ++ Variable
Nucleus Oval /elongated Round
DeMay. In: The Pap Test. 2005, 110.

Benign Endometrial Cells
• NILM
– Menstrual
(BEC) in a Pap test
• Highest frequency: day 1-4
• Infrequent after day 14
– Brush artifact of LUS
– BEC in Women /=40
Ng. Acta Cytol 1974, 18:356, Gondos. Ann Clin Lab Sci 1977; 7: 486,Chang. Gynecol Oncol 2001; 80: 37.

Exit ball: cytology
Menstrual Endometrium
Key features
•
Stromal cells: cytology
Bloody background
• Groups with central stroma and peripheral
glandular cells
• Hyperchromatic spindle cells
Exit ball: Histology
Shimizu. Diagn Cytopathol. 2006; 34: 609.

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
%
35
30
25
20
15
10
5
0
Undetermined Significance
٠Nuclear atypia > benign < malignant
29
AGC: 94 follow up studies
0.3
8.5
11.1
JNCI Workshop. JAMA 1989; 262: 931. JNCI Workshop. Acta Cytol 1993; 37: 115. Schnatz. Obstet
Gynecol 2006; 107:701
1.4 0.7
2.9
2.9
1.2
neoplasm squamous glandular
Other
Endom hyper
Endom ca
cervix ais
cervix ca
scc
lsil
hsil
all

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.

•
AGC: cytologic features
Some but not all features present
Cell Feature
Arrangements 3D Aggregates
Rosettes
Strips
Borders Indistinct
Cytoplasm Reduced
Covell. Springer; New York: 2004, 123.

AGC: cytologic features
•
Some but not all features present
Nucleus Feature
Arrangement Crowded
Feathering
Palisading
Size and shape Increased and Variable
Chromatin Dark
Coarsely granular
Nucleoli Absent or inconspicuous
Mitosis Present
Covell. Springer; New York: 2004, 123.

Atypical Endometrial Cells
Additional 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 Reaction
Key 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.

Key pathology
•
Inflamed Tubal mucosa
• Regenerative changes
Fallopian Tube Prolapse

Key features
•
Fallopian Tube
Prolapse
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
IUD cells
• Possibly endometrial
•High N:C
• Multinucleated
•Nucleoli
Actinomyces
Hypermucinated
endocervical cells
Psammoma body
Gupta. Acta Cytol 1978; 22: 286.

Benign Lesions: classification
• Neoplastic
– Endocervical
polyp
– Adenomyoma
– Papillary
adenofibroma
– Villus adenoma
• Metaplastic
– Tubal
– Tuboendometrioid
– Oxyphilic
– Prostatic

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.

Key pathology
•
Fibrovascular core
• Feeder vessel
• Mucinous epithelium
• Squamous metaplasia
Endocervical Polyp

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
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

Key pathology
• Sheets or single cells
• Terminal bars/cilia
• Enlarged, polarized nuclei
• Fine chromatin
• Small nucleoli
• Rare mitosis
• Clean background
Tubal Metaplasia:
cytology
Novotny. Acta Cytol 1992: 36; 1, Robboy. Am J Obstet Gynecol 1981; 140: 579.

Hyperplastic: pseudoneoplastic
• Microglandular hyperplasia
• Endometriosis
• Endocervical hyperplasia
• Mesonephric hyperplasia
• Nabothian
• Tunnel Clusters
• Endosalpingioisis
cysts and deep glands

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:

Cytology features
• Sheets of enlarged glandular cells
• Vacuolated cytoplasm
• Mild nuclear enlargement
• Fine chromatin
• Small nucleoli
Microglandular
Hyperplasia
Yahr. Diagn Cytopathol 1991: 7; 248

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

Cytology features
• Cell spindling
• Cell uniformity
• Absent diathesis
Endometriosis
Lundeen. Diagn Cytopathol 2002;26:35.

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
Key pathology
• Rounded proliferation of
small glands
• Duct centred
• Pseudocribriform pattern
• Bland mucinous epithelium
Immunoprofile
• PAS positive
• p16 positive
• HIK1083 positive
• HPV DNA negative
• CEA negative
Hashi. Int J Gynecol Pathol 2006; 25: 187. Nara. Gynecol Oncol 2007; 106: 289.

Key Pathology
•
Diffuse Laminar
Endocervical Hyperplasia
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 End
Thank 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

• Malignant Lesions
Classification
– 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
- Clear cell
- Endometrioid
- Ciliated
Friedell. Cancer 1953; 6: 887, Schlesinger. Int J Gynecol Pathol 1999;18:1.

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
AIS and HSIL: 2 cell types
HSIL

Pattern A
Pattern B
HSIL involving
endocervical glands
Mattosinho. Acta Cytol 2003; 47: 154.
Selvaggi. Acta Cytol 1994:38; 687.

• Uncommon lesion
SMILE
• 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.

Key pathology
• Dysplastic nuclei
• Mucin vacuoles
•Mitoses
SMILE
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%
• Genetic
• Type 16 predominant in endometrioid and VGA
• Type 18=16 or slight predominance in others
– 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.

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

Endocervical adenocarcinoma
Pas/al blue
Vimentin
CEA
p16

Cytology:endocervical
adenocarcinoma
• Hypercellular smears
• Cells
– Single
– Sheets
– Clusters
• Cell features of AIS
• Additional features
– Perinuclear clearing
– Macronucleoli
– Tumor Diathesis
Covell. Springer; New York: 2004, 141.

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
Young. Histopathol 2002; 41: 185.

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
Young. Histopathol 2002; 41: 185.

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.

Young. Histopathol 2002; 41: 185.
Clear cell Carcinoma
Key pathology
• Solid, tubulocystic, papillary
• Glycogenated clear cytoplasm
• Intracystic mucin
• Hobnail cells

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

• Rare tumor
– 3 types
• Associations
Minimal Deviation
Adenocarcinoma
–Adenoma malignum
–Endometrioid
–Clear cell
– 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
• 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 - stroma
ER - 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.

*ph=2.5
Adenoma Malignum: Pas Al Blue*
Adenoma Malignum Normal Gland
Hayashi. Am J Surg Pathol. 2000; 24: 559.

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
Key pathology
• Complex papillary proliferation
• Stratification and tufting
• High grade nuclei
• P53 positive, CEA negative
Zhou. Am J Surg Pathol 1998; 22:130.

Serous Carcinoma
Cytology features
• Single cells
• Sheets
• Tight balls
• Malignant features obvious
• Psammoma bodies
Chang. Cancer 1999; 87: 5.

Mesonephric carcinoma
• Rare tumor
– 30 documented cases
• Arise from mesonephric duct remnants
• Gross appearance
– Cervical mass
• HPV negative
• Outcome
– More indolent than mucinous carcinoma
Clement. 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 excellent
Young. 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 IIa
Stage II endometrial
carcinoma: histology
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
PTEN: tumor suppressor gene
• Endometrial carcinoma: somatic mutations
• Expression is diminished
• Cervical adenocarcinoma
• Expression retained
p16
El-Mansi. Int J Gynecol Cancer 2006; 16: 1254.

Extrauterine genital tract primaries
Transtubal migration:
serous ovarian carcinoma
• Dissemination pathways
• Direct spread
• Embolic spread
• Transtubal migration
Olsen . Obstet Gynecol 2001; 78: 71.

Metastatic Breast
Carcinoma
Pap test
Endocervical curettage
• 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.

Metastatic colonic carcinoma
Key cytology features
• Dirty background
• Glandular groups
• Palisading of basal nuclei
Lemoine. Cancer 1986; 57: 2002, Nakagami. Jpn J Clin Oncol 1999; 29:640.

The End
Thank you for inviting me

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
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