Introduction: Defining the origin of metastatic cancer is crucial for establishing an optimal treatment strategy, especially when obtaining sufficient tissue from secondary malignancies is limited. While cytological examination is often used in this diagnostic setting, morphologic analysis alone often fails to differentiate metastases derived from the breast from other primaries. The hormone receptor, human epidermal growth factor receptor-2, gross cystic disease fluid protein 15, and mammaglobin immunohistochemistry are often used to diagnose metastatic breast cancer. However, their effectiveness decreases in estrogen receptor (ER)-negative breast cancers, including the triple-negative breast cancer (TNBC) subtype. Methods: We conducted a comprehensive evaluation of GATA-binding protein 3 (GATA-3), trichorhinophalangeal syndrome type 1 (TRPS-1), and Matrix Gla Protein (MGP) immunochemistry across 140 effusion cytology specimens with metastatic adenocarcinoma derived from various primaries, including the breast, colon, pancreaticobiliary, lung, tubo-ovarian, and stomach. Results: The expression rates of these immunomarkers were significantly higher in metastatic cancers originating from the breast than other primaries. In TNBC, TRPS-1 (80.00%) and MGP (65.00%) exhibited higher positivity rates compared to GATA-3 (40.00%). Additionally, our data suggest that an immunohistochemical panel comprising MGP, GATA-3, and TRPS-1 significantly enhances the detection of metastatic breast cancer in effusion cytology specimens, including TNBC in particular. When considering dual-marker positivity, the diagnostic accuracy was found to be 89.29% across all breast cancer subtypes and 92.93% for TNBC. Conclusions: MGP appears to be a robust marker for identifying metastatic breast cancer in malignant effusions, especially TNBC. MGP notably enhances diagnostic accuracy when incorporated together with GATA-3 and TRPS-1 in an immunohistochemical panel.

1.
Doxtader
EE
,
Chute
DJ
.
Evaluation of carcinoma of unknown primary on cytologic specimens
.
Surg Pathol Clin
.
2018
;
11
(
3
):
545
62
.
2.
Greco
FA
.
Cancer of unknown primary site: improved patient management with molecular and immunohistochemical diagnosis
.
Am Soc Clin Oncol Educ Book
.
2013
;
33
:
175
81
.
3.
Hainsworth
JD
,
Rubin
MS
,
Spigel
DR
,
Boccia
RV
,
Raby
S
,
Quinn
R
, et al
.
Molecular gene expression profiling to predict the tissue of origin and direct site-specific therapy in patients with carcinoma of unknown primary site: a prospective trial of the sarah cannon research institute
.
J Clin Orthod
.
2013
;
31
(
2
):
217
23
.
4.
Cheson
BD
.
Clinical utility of body fluid analyses
.
Clin Lab Med
.
1985
;
5
(
2
):
195
208
.
5.
Kushwaha
R
,
Shashikala
P
,
Hiremath
S
,
Basavaraj
HG
.
Cells in pleural fluid and their value in differential diagnosis
.
J Cytol
.
2008
;
25
(
4
):
138
.
6.
Gupta
DK
,
Mooney
EE
,
Layfield
LJ
.
Fine-needle aspiration cytology: a survey of current utilization in relationship to hospital size, surgical pathology volume, and institution type
.
Diagn Cytopathol
.
2000
;
23
(
1
):
59
65
.
7.
Goyal
A
.
Recent advances and researches in the field of fine needle aspiration cytopathology
. In:
Advances in fine needle aspiration cytopathology
.
IntechOpen
;
2023
.
8.
Selves
J
,
Long-Mira
E
,
Mathieu
M-C
,
Rochaix
P
,
Ilié
M
.
Immunohistochemistry for diagnosis of metastatic carcinomas of unknown primary site
.
Cancers
.
2018
;
10
(
4
):
108
.
9.
Apffelstaedt
JP
,
Van Zyl
JA
,
Muller
AG
.
Breast cancer complicated by pleural effusion: patient characteristics and results of surgical management
.
J Surg Oncol
.
1995
;
58
(
3
):
173
5
.
10.
Penz
E
,
Watt
KN
,
Hergott
CA
,
Rahman
NM
,
Psallidas
I
.
Management of malignant pleural effusion: challenges and solutions
.
Cancer Manag Res
.
2017
;
9
:
229
41
.
11.
Chen
R
,
Qarmali
M
,
Siegal
GP
,
Wei
S
.
Receptor conversion in metastatic breast cancer: analysis of 390 cases from a single institution
.
Mod Pathol
.
2020
;
33
(
12
):
2499
506
.
12.
Yan
Z
,
Gidley
J
,
Horton
D
,
Roberson
J
,
Eltoum
IE
,
Chhieng
DC
.
Diagnostic utility of mammaglobin and GCDFP‐15 in the identification of metastatic breast carcinoma in fluid specimens
.
Diagn Cytopathol
.
2009
;
37
(
7
):
475
8
.
13.
Utility of GATA3 immunohistochemistry for diagnosis of metastatic breast carcinoma in cytology specimens - braxton - 2015 - diagnostic Cytopathology
.
Wiley Online Library
. [Internet]. [cited 2024 Mar 2]. Available from: https://onlinelibrary.wiley.com/doi/10.1002/dc.23206
14.
Huo
L
,
Zhang
J
,
Gilcrease
MZ
,
Gong
Y
,
Wu
Y
,
Zhang
H
, et al
.
Gross cystic disease fluid protein-15 and mammaglobin A expression determined by immunohistochemistry is of limited utility in triple-negative breast cancer
.
Histopathology
.
2013
;
62
(
2
):
267
74
.
15.
Huo
L
,
Gong
Y
,
Guo
M
,
Gilcrease
MZ
,
Wu
Y
,
Zhang
H
, et al
.
GATA-binding protein 3 enhances the utility of gross cystic disease fluid protein-15 and mammaglobin A in triple-negative breast cancer by immunohistochemistry
.
Histopathology
.
2015
;
67
(
2
):
245
54
.
16.
Abdelwahed
M
,
Yurtsever
N
,
Savant
D
,
Karam
P
,
Gimenez
C
,
Das
K
, et al
.
Utility of TRPS-1 immunohistochemistry in diagnosis of metastatic breast carcinoma in cytology specimens
.
J Am Soc Cytopathol
.
2022
;
11
(
6
):
345
51
.
17.
Yoon
EC
,
Wang
G
,
Parkinson
B
,
Huo
L
,
Peng
Y
,
Wang
J
, et al
.
TRPS1, GATA3, and SOX10 expression in triple-negative breast carcinoma
.
Hum Pathol
.
2022
;
125
:
97
107
.
18.
Ai
D
,
Yao
J
,
Yang
F
,
Huo
L
,
Chen
H
,
Lu
W
, et al
.
TRPS1: a highly sensitive and specific marker for breast carcinoma, especially for triple-negative breast cancer
.
Mod Pathol
.
2021
;
34
(
4
):
710
9
.
19.
Du
T
,
Pan
L
,
Zheng
C
,
Chen
K
,
Yang
Y
,
Chen
J
, et al
.
Matrix Gla protein (MGP), GATA3, and TRPS1: a novel diagnostic panel to determine breast origin
.
Breast Cancer Res
.
2022
;
24
(
1
):
70
.
20.
Hammond
MEH
,
Hayes
DF
,
Dowsett
M
,
Allred
DC
,
Hagerty
KL
,
Badve
S
, et al
.
American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer
.
Arch Pathol Lab Med
.
2010
;
134
(
6
):
907
22
.
21.
Allison
KH
,
Hammond
MEH
,
Dowsett
M
,
McKernin
SE
,
Carey
LA
,
Fitzgibbons
PL
, et al
.
Estrogen and progesterone receptor testing in breast cancer: ASCO/CAP guideline update
.
J Clin Oncol
.
2020
;
38
(
12
):
1346
66
.
22.
Wolff
AC
,
Hammond
MEH
,
Hicks
DG
,
Dowsett
M
,
McShane
LM
,
Allison
KH
, et al
.
Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update
.
J Clin Oncol
.
2013
;
31
(
31
):
3997
4013
.
23.
Wolff
AC
,
Hammond
MEH
,
Allison
KH
,
Harvey
BE
,
Mangu
PB
,
Bartlett
JMS
, et al
.
Human epidermal growth factor receptor 2 testing in breast cancer: American society of clinical oncology/college of American Pathologists clinical practice guideline focused update
.
J Clin Oncol
.
2018
;
36
(
20
):
2105
22
.
24.
Jain
D
,
Mathur
SR
,
Iyer
VK
.
Cell blocks in cytopathology: a review of preparative methods, utility in diagnosis and role in ancillary studies
.
Cytopathology
.
2014
;
25
(
6
):
356
71
.
25.
Clark
BZ
,
Beriwal
S
,
Dabbs
DJ
,
Bhargava
R
.
Semiquantitative GATA-3 immunoreactivity in breast, bladder, gynecologic tract, and other cytokeratin 7-positive carcinomas
.
Am J Clin Pathol
.
2014
;
142
(
1
):
64
71
.
26.
Miettinen
M
,
McCue
PA
,
Sarlomo-Rikala
M
,
Rys
J
,
Czapiewski
P
,
Wazny
K
, et al
.
GATA3: a multispecific but potentially useful marker in surgical pathology: a systematic analysis of 2500 epithelial and nonepithelial tumors
.
Am J Surg Pathol
.
2014
;
38
(
1
):
13
22
.
27.
Byrne
DJ
,
Deb
S
,
Takano
EA
,
Fox
SB
.
GATA3 expression in triple‐negative breast cancers
.
Histopathology
.
2017
;
71
(
1
):
63
71
.
28.
Sangoi
AR
,
Shrestha
B
,
Yang
G
,
Mego
O
,
Beck
AH
.
The novel marker GATA3 is significantly more sensitive than traditional markers mammaglobin and GCDFP15 for identifying breast cancer in surgical and cytology specimens of metastatic and matched primary tumors
.
Appl Immunohistochem Mol Morphol
.
2016
;
24
(
4
):
229
37
.
29.
Gong
C
,
Zou
J
,
Zhang
M
,
Zhang
J
,
Xu
S
,
Zhu
S
, et al
.
Upregulation of MGP by HOXC8 promotes the proliferation, migration, and EMT processes of triple‐negative breast cancer
.
Mol Carcinog
.
2019
;
58
(
10
):
1863
75
.
30.
Fischer
S
,
Asa
SL
.
Application of immunohistochemistry to thyroid neoplasms
.
Arch Pathol Lab Med
.
2008
;
132
(
3
):
359
72
.
31.
Baloch
Z
,
Mete
O
,
Asa
SL
.
Immunohistochemical biomarkers in thyroid pathology
.
Endocr Pathol
.
2018
;
29
(
2
):
91
112
.
32.
Kakar
S
,
Gown
AM
,
Goodman
ZD
,
Ferrell
LD
.
Best practices in diagnostic immunohistochemistry: hepatocellular carcinoma versus metastatic neoplasms
.
Arch Pathol Lab Med
.
2007
;
131
(
11
):
1648
54
.
33.
Liu
H
.
Application of immunohistochemistry in breast pathology: a review and update
.
Arch Pathol Lab Med
.
2014
;
138
(
12
):
1629
42
.
34.
Park
S-Y
,
Kim
B-H
,
Kim
J-H
,
Lee
S
,
Kang
GH
.
Panels of immunohistochemical markers help determine primary sites of metastatic adenocarcinoma
.
Arch Pathol Lab Med
.
2007
;
131
(
10
):
1561
7
.
35.
El Hag
M
,
Schmidt
L
,
Roh
M
,
Michael
CW
.
Utility of TTF-1 and Napsin-A in the work-up of malignant effusions
.
Diagn Cytopathol
.
2016
;
44
(
4
):
299
304
.
36.
Nikas
IP
,
Lim
S
,
Im
S-A
,
Lee
K-H
,
Lee
D-W
,
Lee
H
, et al
.
Discrepancies in hormone receptor and HER2 expression between malignant serous effusions and paired tissues from primary or recurrent breast cancers
.
Pathobiology
.
2023
;
91
(
3
):
169
79
.
You do not currently have access to this content.