Recent Advances in Gynecologic, Urologic, and

Soft Tissue Pathology. Timisoara, June 2-4, 2013

DIAGNOSTIC PROBLEMS
IN GLANDULAR LESIONS
OF THE UTERINE CERVIX
Esther Oliva
Massachusetts General Hospital
eoliva@partners.org

ADENOCARCINOMA IN SITU (AIS)

Typically begins at the squamocolumnar junction
Concomitant high-grade squamous dysplasia in
approximately 50% of cases
High-risk HPVs frequently found
< 20% skip lesions
10 to 20 % of cervical adenocarcinomas

Sharp transition

AIS: Normal architecture preserved

Nuclear enlargement, coarse chromatin, small single or multiple

nucleoli, increased mitotic activity, and +/- nuclear stratification
involving part or all of the surface and/or glandular epithelium

Hanging mitoses

APOPTOTIC BODIES
Significant correlation
between apoptotic bodies
and mitotic figures
Seen in adenocarcinoma in
situ and all types of invasive
adenocarcinoma except in
adenoma malignum
May be seen in cervical
endometriosis
Differential diagnosis with
intraepithelial lymphocytes

LOBULAR
ARCHITECTURE

Replacement of pre-existing glands

Endocervical glands may have a complex growth pattern

ADENOCARCINOMA IN SITU:
SUBTYPES
Endocervical
Endometrioid
Tubal
Intestinal
Adenosquamous

Mucin depletion

ADENOCARCINOMA IN SITU,
INTESTINAL TYPE

PANETH CELLS

Less obvious cytologic atypia, mitoses and apoptosis

MIXED AIS

Intestinal-Type Endocervical Adenocarcinoma In

Situ: An Immunophenotypically Distinct Subset of
AIS Affecting Older Women
Howitt BE, et al , Am J Surg Pathol 2013;37:625
TO REMEMBER:
- Occurs in older age group (44.5 vs 32.6 years)
- Rarely pancreatobiliary/gastric epithelium if few
goblet cells in adjacent conventional AIS
- Subset (4/13) show variable p16 and Ki67 staining
- Not as frequently HPV 16 or 33 positive (6/9)
when compared to conventional AIS
- CDX2 + and p53 -

STRATIFIED MUCINOUS INTRAEPITHELIAL LESION

(SMILE)

ADENOCARCINOMA IN SITU
Differential Diagnosis

Reactive glandular atypia

High-grade squamous dysplasia involving glands
Endometriosis
Tubal metaplasia
Mesonephric hyperplasia
Radiation induced atypia
Invasive adenocarcinoma

GLANDULAR ATYPIA = REACTIVE

HIGH-GRADE SQUAMOUS DYSPLASIA

INVOLVING GLANDS

S
C
C
In situ
M
I
M
I
C
K
I
N
G

p63 may be helpful

A
I
S

CERVICAL ENDOMETRIOSIS
Two major categories:
- Superficial: Related to previous trauma
No association with endometriosis
elsewhere
- Deep: Associated with pelvic endometriosis

ENDOMETRIOSIS

AIS

CERVICAL ENDOMETRIOSIS WITH ATYPIA

ENDOMETRIOSIS

DIFFERENTIAL FEATURES
EMOS
AIS
Abnormal Pap smear
+
+
Endometrial stroma
+
Stromal hemorrhage
+
Nuclear pseudostratif
+
+
Mitotic figures
-/+ (also stroma) +
Apoptotic bodies
-/+
+
Squamous dysplasia
+
p16 positivity
Focal
Diffuse

TUBAL METAPLASIA
MIMICKING ADENOCARCINOMA IN SITU

TUBAL METAPLASIA
Frequent finding
More common in hysterectomy specimens than
cone biopsies
Typically in upper endocervix and deep glands
No association with other pathologic conditions
Frequent confusion with endocervical gland
neoplasia on biopsy and Pap smears

TUBAL METAPLASIA

Atypia

ENDOMETRIOID
CILIATED CARCINOMA

TUBAL-TYPE AIS

AIS
MIB 1
ProExC
p16
CEA (M)
Bcl-2
Vim
ER
PAX2

> 30%
+ (>50% cells)
+ (D)
+ (CP)
-/+ (F)
-

AIS

Ki-67

TEM/EMOS
< 10%
+ (<10% cells)
-/+ (F)
-/+ (Lum)
+
+
+ (D)
+

TEM

p16

TUBOENDOMETRIOD METAPLASIA

Bcl-2

Vim

MESONEPHRIC HYPERPLASIA

Also PAX2 positive

p16

Ki67

AIS

CD10
AR
Calretinin
Vim
CEA (m)
ER
PR
p16
PAX2
PAX8

MESONEPHRIC
LESIONS

+
+
-/+
+/+
+

+ (L)
+/+/+/-/+
+
+

RADIATION INDUCED ATYPIA

EARLY INVASIVE ADENOCARCINOMA

Pathologic definition

Presence of stromal invasion with

effacement of the normal glandular
architecture with tumor extending beyond
the deepest normal crypt
Diagnosis cannot be made on biopsy alone
stor AG. Int J Gynecol Pathol 2000;19:29-38

Obliteration of crypts

Extension beyond nx glands

EARLY INVASIVE ADENOCARCINOMA

Cytologically malignant
glands surrounded by
desmoplastic and/or
inflammatory response
Individual cells or fragmented
/ incomplete glands lined by
cytologically malignant cells

EARLY INVASIVE ADENOCARCINOMA

stor AG, Int J Gynecol Pathol 2000;19:29-38

IN 20% OF CASES IT IS NOT

POSSIBLE TO DISTINGUISH
BETWEEN ADENOCARCINOMA IN
SITU AND EARLY INVASIVE
ADENOCARCINOMA

INVASIVE OR IN SITU?

AIS vs ADENOCARCINOMA
WITH EXPANSILE GROWTH

LOOK AT AND COMPARE TO THE

ARCHITECTURE OF THE NONNEOPLASTIC ENDOCERVICAL GLANDS

I
N
V
A
S
I
V
E
A
D
E
N
O
C
A

I
N
V
A
S
I
V
E
A
D
E
N
O
C
A
OVARIAN METASTASES

ENDOCERVICAL ADCA WITH PROMINENT

ENDOMYOMETRIAL INVOLVEMENT
ENDOCERVIX

p16

ENDOMETRIUM

PgR

Yemelyanova A et al, Am J Surg Pathol 2009;33:914

CERVICAL ADENOCARCINOMA (WHO)

Mucinous
- Endocervical
- Intestinal
- Signet-ring cell
- Minimal deviation
- Villoglandular
Endometrioid
Clear cell
Serous
Mesonephric
Adenoid basal/adenoid cystic
Neuroendocrine tumors

ADENOMA MALIGNUM

(Minimal Deviation Adenocarcinoma)

1-10% of cervical adenocarcinomas
Nonspecific presenting symptoms; mucoid vaginal
discharge in a minority of patients
Association with Peutz-Jeghers syndrome and sex
cord tumors with annular tubules
Most tumors HPV negative
Loss of heterozygosity at 19p13.3
Poor prognosis; only 50% of patients with
stage I alive at 2 years after initial diagnosis

ADENOMA
MALIGNUM
(Minimal
deviation
endocervical
adenoca)

ADENOMA MALIGNUM

ADENOMA MALIGNUM WITH DECEPTIVE APPEARANCE

ADENOMA MALIGNUM
(Minimal Deviation Adenocarcinoma)
Differential Diagnosis
Deep endocervical glands and Nabothian cysts
Lobular endocervical gland hyperplasia or pyloric
gland metaplasia
Endocervical hyperplasia, NOS
Tunnel clusters
Cervical adenomyoma
Endocervicosis

LOBULAR ENDOCERVICAL GLAND HYPERPLASIA

LOBULAR ENDOCERVICAL GLAND HYPERPLASIA

DIFFERENTIAL FEATURES
Mucous discharge
Mass
Demarcation
Wall involvement
Lobulation
Cytologic atypia

LEGH
+/-/+
Present
< 50%
+
minimal

Stromal response

absent

AM
+/+
Absent
>> 50%
prominent
(at least focally)
present

CEA

Precursor lesion ?
Lobular
Endocervical Gland
Hyperplasia;
typical/atypical

Adenoma
malignum

Common features:
- Proximal location in the cervical canal
- Pyloric metaplasia (Neutral mucin-MUC6/HIK1083/PAS+)
- ER - No clear relation to high-risk HPV (p16 frequently -)

Is LEGH a cancerous precursor of AM?:

a comparative molecular-genetic and
immunohistochemical study
Kawauchi S et al, Am J Surg Pathol 2008

LEGH (15)
Gastric muc
+
3q gains
3/14*
1p losses
2/14*
HPV
-

AM (16)
+
5/11
4/11
-

MAC (15)
4/9
6/9
13/15 +

* Correlated with degree of atypia in hyperplastic comp

LOBULAR ENDOCERVICAL GLAND HYPERPLASIA

with SEVERE CYTOLOGIC ATYPIA

CERVICAL TYPE ADENOMYOMA

Mostly problematic in small specimens

LOBULATION

NO STROMAL RESPONSE

NO CYTOLOGIC ATYPIA

WELL-DIFFERENTIATED
VILLOGLANDULAR ADENOCARCINOMA
Occurs at a younger age (average 35 yrs)
than cervical adenocarcinomas in general
In the series reported by Kurman and
colleagues 62% of patients had a history
of oral contraceptive use
If pure it has an excellent prognosis

VILLOGLANDULAR ADENOCARCINOMA:
Diagnosis
It is very important to evaluate the

cytologic features and the

advancing front of the tumor in
order to exclude the presence of a
conventional adenocarcinoma

WELL-DIFFERENTIATED
VILLOGANDULAR ADENOCARCINOMA
Differential Diagnosis
Papillary endocervicitis
Mullerian papilloma
Villous adenoma
Papillary adenofibroma
Conventional endocervical adenoca with
prominent exophytic papillary growth
Serous carcinoma

METASTATIC SEROUS CA

ADENOCA, USUAL TYPE,

with PAPILLAE

CLEAR CELL CARCINOMA

Biphasic age distribution
1/3 associated with in utero exposure to
diethylstilbestrol (DES) and non-steroidal
estrogen before the 18th week of gestation
Frequent coexistence with vaginal adenosis,
and less commonly transverse vaginal or
cervical ridges
2/3 not associated with DES

CLEAR CELL
CARCINOMA
Typical architectural patterns

CLEAR CELL CARCINOMA

Differential Diagnosis
Arias-Stella reaction
Microglandular hyperplasia
Squamous cell carcinoma with prominent
clear cells
Yolk sac tumor
Alveolar soft part sarcoma

ARIAS STELLA REACTION

DIFFERENTIAL FEATURES
AS
Pregnancy/OC
Incidental finding
Preserved architecture
Glandular involvement
Intranuclear inclusions
Prominent nuclei
Mitotic activity

+
+
+
+
+
Absent

CCC
+
Present

M
I
C
R
O
G
L
A
N
D
U
L
A
R
H

SOLID MICROGLANDULAR HYPERPLASIA

SIGNET RING CELLS

Tubular/Solid
Hyalinized stroma
Cytoplasm
Atypia
Mitoses/10HPFs
Invasive growth

MGH

CCC

+/+
Mucin
Absent
1
Absent

+
+
Glycogen
Present
Frequent
Present

MICROGLANDULAR HYPERPLASIA vs
MGH-LIKE CARCINOMA
Features favoring adenocarcinoma:
Postmenopausal age
Absence of typical areas of MGH
Cytologic atypia greater than expected in MGH
Increased mitotic activity (> 1 mitoses/10HPFs)
High MIB-1 index

MESONEPHRIC
CARCINOMA

Tubular growth

MESONEPHRIC CARCINOMA

Spindle growth

Papillary growth

MESONEPHRIC CARCINOMA
Differential Diagnosis
Mesonephric hyperplasia
Cervical AIS
Cervical endometrioid adenocarcinoma
Uterine tumor resembling ovarian sexcord tumor
Endometrioid carcinoma from corpus
extending to cervix

Diffuse Mesonephric Hyperplasia

Tips: No complex architecture, minimal cytologic atypia and

mitotic activity and absent stromal response

ENDOMETRIOID CA EXTENDING TO CERVIX

SIMULATING MESONEPHRIC HYPERPLASIA

THANK YOU!

UNUSUAL ENDOCERVICAL CARCINOMAS

p16
MD (3)
0
Gastric (9)
1
CCC (11)
5
Serous (4)
2
Mesonephric (3) 0

p53
1
5
1
1
0

CEAm
3
8
2
3
0

HPV
0
1
0
0
0