Cytology and Histology of Glandular Lesions of the Uterine Cervix

Transcription

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
Cell Features
Cell size
Cytoplasm
Nucleus
Normal endometrial cells
Endocervical
++
Abundant ++
Oval /elongated
Endometrial
+
Variable
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 Endometrium
Exit ball: cytology
Stromal cells: cytology
Exit ball: Histology
Key features
• Bloody background
• Groups with central stroma and peripheral
glandular cells
• Hyperchromatic spindle cells
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
Undetermined Significance
٠Nuclear atypia > benign < malignant
AGC: 94 follow up studies
%
35
30
25
20
15
29
10
5
0.3
8.5
11.1
0.7
1.4
2.9
2.9
1.2
squamous
glandular
0
neoplasm
Other
Endom hyper
Endom ca
cervix ais
cervix ca
scc
lsil
hsil
all
JNCI Workshop. JAMA 1989; 262: 931. JNCI Workshop. Acta Cytol 1993; 37: 115. Schnatz. Obstet
Gynecol 2006; 107:701
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
rosette, feathering, ↑n:c, apoptosis
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
Borders
3D Aggregates
Rosettes
Strips
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
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.
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 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
Hypermucinated
endocervical cells
IUD cells
• Possibly endometrial
• High N:C
• Multinucleated
• Nucleoli
Psammoma body
Actinomyces
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.
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
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%
Suh. Int J Gynecol Pathol 1990; 9: 122, Oliva. AJCP 1995; 103: 618.
Tubal Metaplasia:
cytology
Key pathology
• Sheets or single cells
• Terminal bars/cilia
• Enlarged, polarized nuclei
• Fine chromatin
• Small nucleoli
• Rare mitosis
• Clean background
Novotny. Acta Cytol 1992: 36; 1, Robboy. Am J Obstet Gynecol 1981; 140: 579.
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
Cytology features
• Sheets of enlarged glandular cells
• Vacuolated cytoplasm
• Mild nuclear enlargement
• Fine chromatin
• Small nucleoli
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
Endometriosis
Cytology features
• Cell spindling
• Cell uniformity
• Absent diathesis
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.
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 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
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
- Clear cell
– Intestinal
– Adenosquamous
- 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
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
AIS
HSIL
Pattern A
HSIL involving
endocervical glands
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
Cytology features
• Dysplastic nuclei
• Mucin vacuoles
• Mitoses
• 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.
Endocervical adenocarcinoma
Key pathology
• Complex racemose glands
• Surface and intraluminal papillae
• Pale granular cytoplasm
• Brisk mitotic activity
• Apoptotic bodies
Young. Histopathol 2002; 41: 185.
• 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.
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
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
• Sporadic
• Young women
• Location
• Post menopausal
women
• Location
– Ectocervical
• HPV status
– Endo or ectocervical
– Usually negative
– Rare cases HPV 31
positive
Waggoner. Obstet Gynecol 1994; 84: 404.
Key pathology
• Solid, tubulocystic, papillary
• Glycogenated clear cytoplasm
• Intracystic mucin
• Hobnail cells
Cytology features
• Large cells
• Abundant cytoplasm
• Round nucleus
• Prominent nucleolus
Minimal Deviation
Adenocarcinoma
• Rare tumor
–Adenoma malignum
– 3 types
–Endometrioid
–Clear cell
• 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
• 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
Alpha SMA
30% +
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.
Adenoma Malignum: Pas Al Blue*
Adenoma Malignum
Normal Gland
*ph=2.5
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 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
PTEN: tumor suppressor gene
• Endometrial
carcinoma: somatic mutations
• Expression is diminished
• Cervical adenocarcinoma
• Expression retained
El-Mansi. Int J Gynecol Cancer 2006; 16: 1254.
Extrauterine genital tract primaries
• Dissemination pathways
• Direct spread
• Embolic spread
• Transtubal migration
Transtubal migration:
serous ovarian carcinoma
Olsen . Obstet Gynecol 2001; 78: 71.
Metastatic Breast
Carcinoma
Endocervical curettage
Pap test
• 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
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
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Cytology and Histology of Glandular Lesions of the Uterine Cervix

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