GATA3 immunohistochemical expression in invasive urothelial carcinoma

doi:10.1016/j.urolonc.2016.04.016

Urologic Oncology: Seminars and Original Investigations

Volume 34, Issue 10, October 2016, Pages 432.e9-432.e13

https://doi.org/10.1016/j.urolonc.2016.04.016 Get rights and content

Abstract

Introduction

GATA binding protein 3 (GATA3) is a transcription factor, which belongs to a distinct family of tumor suppressor genes. It is involved in human cancer cell growth and differentiation, and plays an important role in cell proliferation and apoptosis. Although, its expression has been reported in various cancers, there are limited data in genitourinary malignancies. Recent studies found GATA3 to be a sensitive marker for urothelial carcinoma (UC) and associated with prognostic pathologic features. Its level of expression was found to be an independent factor predicting cancer recurrence.

Methods and materials

In this article, immunohistochemical evaluation of GATA3 expression in genitourinary malignancies (invasive UC, renal cell carcinoma, and prostatic adenocarcinomas) was performed.

Results

GATA3 was positive in 56/79 (70.8%) of invasive UC, and was negative in all renal cell carcinoma and prostatic adenocarcinomas. The pattern of GATA3 staining, when positive, was intensely nuclear within the clusters of malignant cells. No cytoplasmic staining was noted. Negative controls were all negative. High GATA3 expression was associated with larger tumor size in invasive UC (3.19 cm vs. 1.65 cm, P = 0.01). GATA3 expression did not correlate with other clinicopathologic parameters in UC.

Conclusions

This data suggest that GATA3 is a sensitive marker in confirming invasive UC, and may be helpful in differentiating it from metastatic tumors of renal and prostatic origin. Furthermore, strong GATA3 expression was noted to have an effect on tumor size in patients with UC.

Introduction

Morphology of invasive high-grade urothelial carcinoma (UC) is not always specific and may demonstrate an appearance that overlaps with other invasive carcinomas. Given this morphologic overlap of high-grade UC with other high-grade metastatic tumors like prostatic adenocarcinoma and squamous cell carcinoma (SCC), immunohistochemistry (IHC) is helpful in the assessment of a high-grade carcinoma of the genitourinary (GU) tract when the primary site is not certain.

GATA3 (GATA binding protein 3 to DNA sequence [A/T] GATA [A/G]) is a transacting T-cell specific transcription factor, which is encoded by the GATA3 gene, and plays an important role in endothelial cell biology [1], [2]. It has 2 zinc fingers at the carboxyl terminus and belongs to a distinct family of tumor genes that has tumor suppressor function. GATA3 has an important role in promoting cell proliferation and differentiation in many tissues and cell types such as T lymphocytes, thymocytes, luminal glandular epithelial cells of the mammary gland, sympathetic nervous system, and in hair follicles of the skin [3], [4], [5]. It has been found to be a critical regulator of tumor differentiation and its loss underlies the onset of tumor dissemination with an expanding GATA3-negative tumor cell population [6].

GATA3 overexpression has been reported in different cancers such as breast and colorectal carcinoma, and it is associated with malignant progression in those cancers [5], [7]. A recent study revealed that GATA3 positivity in bladder small cell carcinoma is of potential value in differentiating small cell carcinomas of prostate origin from those of bladder origin. It also indicates that GATA3 expression in a small subset of lung small cell carcinoma should be taken into consideration in assigning site of origin in advanced small cell carcinoma cases [8]. Another study showed high GATA3 expression in fine needle aspirates from 25 cases of metastatic high-grade UC [9]. The study highlights that GATA3 has high sensitivity and specificity for detection of metastatic UC, and thus may play an important role in diagnosing metastatic UC in cell blocks samples. In other studies, its infrequent expression has been reported to be a strong and independent predictor and prognostic factor of tumor grade, differentiation, metastasis as well as clinical outcome in various human carcinomas such as gastric adenocarcinoma [10], [11].

GATA3 IHC has been useful in the identification of metastatic tumors such as breast carcinoma [5]; published data on its expression in UCs are increasing [12], [13]. In our current study, we evaluated the expression of GATA3 as a tumor marker in the diagnosis of UC and its differentiation from other GU cancers. In addition, we correlate this immunohistochemical analysis of GATA3 expression with clinicopathologic parameters and survival in patients with UC.

Section snippets

Study group

The study group was composed of 175 GU tumors from patients diagnosed at Emory University Hospital between 2000 and 2013 with tissue available in tissue microarrays (TMAs). The anatomic sites and number of cases of the represented tumors included the following: invasive UC (79); renal cell carcinoma (48); and prostatic adenocarcinoma (48). Malignant melanomas (27) were used as negative controls. TMAs were constructed using two 1.0 mm tissue cores from each neoplasm and were immunostained for

Results

The study included 175 GU tumors, of which 79 were high-grade, high-stage muscle-invasive urothelial, 48 renal cell, and 48 prostatic adenocarcinomas. Table 1 shows the IHC profile for GATA3, PAX8, and PSA in urothelial, renal, and prostatic carcinomas. GATA3 was>20% nuclear positive and Q-score was high (200–300) in 56/79 (70.8%) of UCs, with high sensitivity and specificity (sensitivity 70.8%, specificity 100%, positive predictive values 100%, and negative predictive values 54%) (Table 2);

Discussion

Distinguishing high-grade poorly differentiated UC from other carcinomas such as renal and prostatic can be challenging because of morphologic overlap. Other differential diagnoses that can be considered in the diagnosis of high-grade UC include metastatic SCC of the uterine cervix or anal canal. Pathologists are often confronted with this challenging diagnostic situation, and therefore IHC that can distinguish urothelial from renal and prostatic carcinomas can be useful. Recently, a study on

References (17)

M. Yamashita et al.
Essential role of GATA3 for the maintenance of type 2 helper T (Th2) cytokine production and chromatin remodeling at the Th2 cytokine gene loci
J Biol Chem
(2004)
J.B. Burch
Regulation of GATA gene expression during vertebrate development
Semin Cell Dev Biol
(2005)
D.G. Davis et al.
GATA-3 and FOXA1 expression is useful to differentiate breast carcinoma from other carcinomas
Hum Pathol
(2016)
H. Kouros-Mehr et al.
GATA-3 links tumor differentiation and dissemination in a luminal breast cancer model
Cancer Cell
(2008)
S.M. Bezerra et al.
GATA3 expression in small cell carcinoma of bladder and prostate and its potential role in determining primary tumor origin
Hum Pathol
(2014)
G.P. Paner et al.
Immunohistochemical evaluation of novel and traditional markers associated with urothelial differentiation in a spectrum of variants of urothelial carcinoma of the urinary bladder
Hum Pathol
(2014)
V. Joulin et al.
A T-cell specific TCR delta DNA binding protein is a member of the human GATA family
EMBO J
(1991)
M.L. Asselin-Labat et al.
Gata-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation
Nat Cell Biol
(2007)

There are more references available in the full text version of this article.

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GATA3 expression loss is linked to stage progression but is unrelated to prognosis in muscle-invasive urothelial carcinoma of the bladder
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However, 10 previous studies analyzing the prognostic role of GATA3 expression in a series of 39–145 pT2-4 urothelial carcinomas by IHC have also failed to show unequivocal evidence for a clinically relevant prognostic impact of GATA3 immunostaining [11–15,17–19,23,29]. Although 5 studies showed a worse prognosis for GATA3 negative than for GATA3 positive cases [11–15], there were 4 studies that did not find a significant link between GATA3 positivity and the clinical course of disease [17–19,29] and 1 study even described a better prognosis for GATA3 negative cancers [23]. Given the absence of an association of GATA3 positivity with OS in our data set, we consider it likely that the significant link of high GATA3 expression with lymph nodes metastasis, vascular and lymphovascular infiltration may represent a statistical alpha error accumulation by multiple testing.
The transcription factor GATA binding protein 3 (GATA3) is commonly used in surgical pathology as a diagnostic marker to distinguish urothelial carcinomas from other cancer entities. However, the clinical relevance of GATA3 expression in urothelial bladder cancer is not completely clarified. In this study, we investigated GATA3 immunostaining on 2710 urothelial bladder carcinomas on a tissue microarray platform by using two different antibodies to better understand its impact in relation to pathological parameters of disease progression and patient outcome. Nuclear GATA3 immunostaining was regularly seen in normal urothelium and found in 74%/82% of interpretable urothelial neoplasms depending on the antibody used. Within pTa tumors, the rate of GATA3 positive tumors decreased with advancing grade. GATA3 positivity was seen in 98.6%/99.8% of pTaG2 low-grade, 98.6%/100% of pTaG2 high-grade, and 94.9%/99.2% of pTaG3 high-grade tumors (P = .0002). As compared to pTa tumors, GATA3 positivity was markedly less common in muscle-invasive urothelial carcinoma (59.9%/71.6%; P < .0001). Within pT2-4 cancers, high-level GATA3 immunostaining was associated with the presence of lymph node metastasis (P = .0034), and blood vessel (P = .0290) or lymphatic invasion (P = .0005) but unrelated to pT stage. GATA3 immunostaining results for both antibodies were not associated with overall survival in 586 patients treated by cystectomy for pT2-4 urothelial carcinoma. The results of our study identify GATA3 expression as a frequent event in noninvasive urothelial carcinomas with favorable tumor features. Loss of GATA3 immunostaining is linked with muscle-invasive disease but is largely unrelated to pathological parameters and patient prognosis.
Napsin A is a highly sensitive marker for nephrogenic adenoma: an immunohistochemical study with a specificity test in genitourinary tumors
2020, Human Pathology
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Assuming a less-than-perfect specificity for PAX8 in diagnosing nephrogenic adenoma, the addition of napsin A (another highly sensitive and specific marker) is a useful adjunct in diagnosing these lesions. Conversely, although the transcription factor GATA3 is often used as a confirmatory marker for classic urothelial carcinomas, it has been found to be negative in up to 30% of invasive urothelial carcinomas [33–36] and is thus inadequate for favoring urothelial carcinoma over nephrogenic adenoma [20]. In our study, positive GATA3 staining was seen in 25 of 43 (58%) nephrogenic adenomas.
Nephrogenic adenomas are uncommon benign lesions that are typically cytologically bland, but degenerative and reactive changes may make it difficult to distinguish these lesions from malignant entities, such as urothelial carcinoma and prostatic adenocarcinoma. In this study, we explored whether napsin A, a sensitive marker for lung adenocarcinoma, may also have a role in distinguishing nephrogenic adenoma from other genitourinary lesions. Immunohistochemically, napsin A was expressed in all 43 nephrogenic adenomas (bladder: 38, prostatic urethra: 4, and ureter: 1; mean positive tumor cells: 72%, median: 80%, range: 15–100%) and showed regional variability in its expression pattern with a bias toward surface architectures (flat, papillary) compared with stromal architectures (tubular/glandular, microcystic). We also compared napsin A with other markers including PAX8, GATA3, p63, and 34BE12. Although napsin A matched PAX8 in terms of its sensitivity for nephrogenic adenoma (100%), napsin A stained a lower percentage of tumor cells than PAX8 (72% vs 99%, respectively, P = 1.0 × 10⁻⁵). P63 was negative in all nephrogenic adenomas, whereas GATA3 showed variable staining in 25 cases (58%). All 43 nephrogenic adenomas showed variable 34BE12 staining. Finally, we profiled napsin A expression among 401 genitourinary tumors on tissue microarrays (n = 308) and full tissue blocks (N = 93) and observed napsin A positivity in 37 tumors (9%), which included urothelial carcinomas with the glandular/microcystic component differentiation (in the glandular/microcystic component in 4/6), bladder adenocarcinomas (primary: 4/4 and metastatic: 3/3), urinary tract clear-cell carcinomas (primary: 8/9, metastatic uterine primary: 1/1), and some renal tumors (17/174). All 81 pure urothelial carcinomas and 53 prostatic acinar adenocarcinomas were negative for napsin A. Our study indicates that napsin A is a highly sensitive marker for nephrogenic adenoma and can serve as a useful addition in immunohistochemical panels seeking to distinguish it from pure urothelial carcinoma and prostatic acinar adenocarcinoma but not clear-cell carcinoma or urothelial carcinoma with glandular differentiation.
Prognostic stratification of muscle invasive urothelial carcinomas using limited immunohistochemical panel of Gata3 and cytokeratins 5/6, 14 and 20
2019, Annals of Diagnostic Pathology
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Loss of Gata3 is more common in MIBCs as compared to NMIBCs and in high grade as compared to low grade urothelial carcinomas [36]. Gata3 loss has been correlated with worsened prognosis in urothelial carcinomas of the upper urinary tract [38]; however prognostic significance of Gata3 loss in MIBCs is controversial with one study reporting a positive association between Gata3 positivity and increased tumor size [39] and another finding frequent tumor progression in Gata3-positive MIBCs [36]. Our study for the first time demonstrates that Gata3 loss in MIBCs increased the risk of death five-fold independent of stage, age, and histology.
Genomic studies have delineated distinct molecular subgroups of urothelial carcinomas whose prognostic impact extends beyond traditional stage and grade groupings. The ‘basal’ subgroup shows increased gene expression levels of KRT5, KRT6, and KRT14 and low expression levels of GATA binding protein 3, and is associated with an extremely poor outcome. Identification of this subset is necessary for improved patient management and research on targeted therapies. We aimed to assess the prognostic utility of immunohistochemistry (IHC) for basal markers: cytokeratin 5/6 (CK5/6) and 14 (CK14), and luminal markers: cytokeratin 20 (CK20) and Gata3 in muscle invasive urothelial carcinomas (MIBC).
Study was of retrospective design (2014‐2017). All chemotherapy naïve patients of MIBC undergoing radical cystectomy were included. IHC was performed on formalin fixed paraffin-embedded whole tumor sections.
Among 40 cases of MIBC included, 45% (18/40) were positive for one or both basal markers, 37.5% (15/40) were positive for one or both luminal markers, while 15% (6/40) were positive for both basal and luminal markers. One case did not express any of the four markers. MIBCs expressing only basal markers presented at an advanced stage with frequent squamous differentiation and showed a trend towards shorter overall survival. Gata3+ MIBCs showed the best outcome irrespective of expression of other markers, while CK14+/Gata3- MIBCs were associated with worst outcomes. Gata3-/CK14- MIBCs showed intermediate survival outcomes. CK5/6, CK20 and p53 expression did not significantly correlate with outcome.
IHC for Gata-3 and CK14 stratified MIBC into distinct prognostic subsets.
Prolonged Remission of Upper Urinary Tract Urothelial Carcinoma With Prominent Choriocarcinomatous Differentiation: A Case Report
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However, renal metastasis of testicular choriocarcinomas is extremely rare. In the present case, the absence of isochromosome 12p (a specific marker of germ-cell tumors15), positive immunoreactivity for GATA-3 (a relatively specific marker for urothelial carcinoma16), and presence of a concurrent stage Ta high-grade noninvasive papillary urothelial carcinoma of the bladder (suggestive of field cancerization or seeding of cancer cells17) all pointed toward a diagnosis of urothelial carcinoma with choriocarcinomatous differentiation. Ideally, such tumors should be treated with chemotherapy before nephroureterectomy, similar to other high-grade upper tract urothelial malignancies18 and to choriocarcinoma in women.19
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Diagnostic and Prognostic Roles of GATA3 Immunohistochemistry in Urothelial Carcinoma
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Original articleGATA3 immunohistochemical expression in invasive urothelial carcinoma

Abstract

Introduction

Methods and materials

Results

Conclusions

Introduction

Section snippets

Study group

Results

Discussion

J Biol Chem

Semin Cell Dev Biol

Hum Pathol

Cancer Cell

Hum Pathol

Hum Pathol

A T-cell specific TCR delta DNA binding protein is a member of the human GATA family

EMBO J

Gata-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation

Nat Cell Biol

Original article
GATA3 immunohistochemical expression in invasive urothelial carcinoma