GATA3 as a valuable marker to distinguish clear cell papillary renal cell carcinomas from morphologic mimics

doi:10.1016/j.humpath.2017.06.016

Human Pathology

Volume 66, August 2017, Pages 152-158

https://doi.org/10.1016/j.humpath.2017.06.016 Get rights and content

Highlights

•
GATA3 immunoreactivity is present in 74% of clear cell papillary renal cell carcinomas (CCPRCC).
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None of the more aggressive morphologic mimics or CCPRCC showed immunoreactivity for GATA3.
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The sensitivity and specificity of GATA3 for diagnosing CCPRCC are 76% and 100%, respectively.
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GATA3 positivity in CCPRCC suggests a potential origin of this neoplasm in the distal nephron.

Summary

Clear cell papillary renal cell carcinoma (CCPRCC) is a low-grade, indolent neoplasm with no reported cases of death from disease or metastasis. These lesions can show clinical, morphologic, and immunophenotypic overlap with several aggressive forms of renal cell carcinoma (RCC), including clear cell RCC, translocation RCC, and papillary RCC with cytoplasmic clearing. Given the difference in behavior, it is important to reliably separate these entities. We retrospectively reviewed 47 tumors from 45 patients with morphologic features of CCPRCC. All cases were stained against cytokeratin 7 (CK7), carbonic anhydrase IX (CAIX), and GATA3. Cases inconsistent with CCPRCC were reclassified. In addition, we stained tissue microarrays with 103 typical clear cell RCCs and 62 papillary RCCs, each in triplicate. Twenty-five cases were morphologically and immunophenotypically consistent with CCPRCC; all of them showed diffuse CK7 expression and cup-like reactivity with CAIX. Of these, 19 (76%) showed strong nuclear reactivity for GATA3. Although some non-CCPRCC neoplasms showed at least partial CK7/CAIX coexpression, none were immunopositive for GATA3. All background normal kidneys studied showed GATA3 expression in the distal tubules, collecting ducts, and retention cysts of the distal nephron. On follow-up, none of the patients with CCPRCC had recurrences or metastasis. Sensitivity and specificity for GATA3 staining in the diagnosis of CCPRCC were 76% and 100%, with positive and negative predictive values of 100% and 74%. In conclusion, GATA3 is specific and sensitive for CCPRCC and can be used for accurate distinction from its main mimickers. Coexpression of GATA3 and CK7 in most CCPRCC provides evidence of their origin from distal nephron.

Introduction

Clear cell papillary renal cell carcinoma (CCPRCC) is a recently described, relatively uncommon renal neoplasm characterized by an indolent biological behavior, with a tendency to locally recur, but no documented cases of aggressive behavior or metastatic disease [1]. Although originally described in individuals with end-stage renal disease (ESRD), it has been also seen in otherwise healthy kidneys [1], [2], [3]. Its typical morphologic features are those of a well-circumscribed lesion composed of tubules and papillary structures lined by cuboidal to columnar cells with clear cytoplasm and low-grade nuclei showing characteristic linear alignment with apical distribution resembling endometrium in secretory phase or “piano keys”.

The most important morphologic differential diagnoses of CCPRCC are low-grade clear cell renal cell carcinoma (CCRCC), papillary renal cell carcinoma (PRCC) with prominent cytoplasmic clearing, and MiTF/TFE-family translocation-associated carcinomas, which can be very aggressive neoplasms with a tendency to metastasize even several years from the original time of diagnosis. Therefore, accurately distinguishing between indolent CCPRCC and these more aggressive tumors is of vital importance in terms of treatment and long-term prognosis [4]. In cases in which the morphologic features are not clear to distinguish CCPRCC from these more aggressive neoplasms, combined immunoreactivity with cytokeratin 7 (CK7) and carbonic anhydrase IX (CAIX), along with negativity for TFE3, P504S, and CD10, can aid in the recognition of CCPRCC [5], [6]. However, there is significant overlap between the morphologic and immunophenotypic features of CCPRCC and other recently described subtypes of RCC, including those characterized by monosomy 8 and/or TCEB1 loss, renal adenomyomatous tumors (RATs), tuberous-sclerosis associated RCCs, and unclassified RCC. This constitutes an important diagnostic pitfall, which can lead to unnecessarily aggressive treatment [6], [7].

Given the indolent (and possibly completely benign) nature and wide clinical and morphologic differential diagnosis of CCPRCC, it is of utmost importance to accurately diagnose these tumors to prevent unnecessary therapy as well as to provide patients and clinicians with adequate prognostic information. In this study, we evaluate the utility of GATA3, a widely expressed transcription factor that is crucial to the development of the collecting system [8], as an immunohistochemical marker for the diagnosis of CCPRCC and in contrast to those entities in its differential diagnosis.

Section snippets

Case selection

With prior approval from the institutional review boards from both institutions, records from the Anatomic Pathology Laboratory Information Systems were reviewed, identifying 47 tumors with histologic features suggestive of CCPRCC (ie, low-grade neoplasms with a tubulopapillary architecture, abundant clear cytoplasm, and apically oriented nuclei) in 24 resection specimens and 1 needle core biopsy. Cases with the morphologic features of CCPRCC that also showed positive membranous and cytoplasmic

Results

Forty-seven cases were identified in 45 different patients, of which 25 (in 24 patients) were morphologically and immunophenotypically consistent with CCPRCC, including 1 patient with synchronous bilateral CCPRCC. The remaining 22 cases were reclassified as follows: 8 CCRCCs with prominent fibromuscular stroma or CCPRCC-like; 3 monosomy 8–associated RCCs; 3 PRCCs, including 2 with cytoplasmic clearing; 1 acquired cystic renal disease RCC; and 6 low-grade CCRCC. One patient had coexisting CCPRCC

Discussion

Immunohistochemical studies have been a fundamental tool in the distinction of renal cell neoplasms, particularly those with significant overlap in their morphologic features. In the case of CCPRCCs, it is of utmost prognostic and therapeutic importance to distinguish these lesions from more aggressive malignant neoplasms. Since its recognition as a distinct entity, diffuse CK7 positivity and cup-like staining for CAIX have been used to make this distinction [3], [10]. However, other entities

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Clear cell papillary renal cell carcinoma and renal angiomyoadenomatous tumor—two variants of a morphologic, Immunohistochemical and genetic distinct entity of renal cell carcinoma
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In summary, PRNRP can be differentiated by its specific morphological characteristics and IHC findings. GATA3 is expressed in the distal tubule epithelium and collecting system, which suggests that PRNRP may originate there [26,27]. GATA3 expression is rarely positive in renal epithelial tumors, while it is expressed diffusely and consistently in the nucleus of PRNRP cells.
Papillary renal neoplasm with reverse polarity (PRNRP) is a newly defined entity with distinct histomorphology and recurrent KRAS mutation. In this study, we aimed to identify and analyze the clinicopathological, immunohistochemical (IHC), and molecular features of PRNRP in our center and to evaluate its differential diagnosis with other tumors with which it is easily confused: clear cell papillary renal cell carcinoma (CCPRCC), oncocytic papillary renal cell carcinoma (OPRCC), and papillary renal cell carcinoma type 1 (PRCC1). Nephrectomy specimens of PRNRP (n = 15), CCPRCC (n = 11), and OPRCC (n = 12) were retrieved from our pathology archives. We also selected typical cases of PRCC1 (n = 15) as a control group. PRNRP accounted for 3.05% (15/492) of all PRCC cases at our center. The median follow-up period was 41.3 months. All PRNRP cases were pT1N0M0, and only one involved recurrence (1 year after surgery). IHC analysis showed diffuse staining of CK7, EMA, and GATA3 but weak or negative staining of CD10, CD117, p504s, and vimentin in the PRNRP samples and distinctive IHC features in the other three tumor types. KRAS mutation was detected in 4/10 PRNRP cases. Among the 40 most commonly mutated genes identified, 5 (BCLAF1, PDE4DIP, NCOR1, PARP4, and PABPC1) have actionable alterations. Our study supports the suggestion that PRNRP is an entity distinct from CCPRCC, OPRCC, and PRCC1.
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At present, GATA binding protein 3 (GATA-3) is the most frequently used diagnostic immunohistochemical (IHC) marker for breast carcinoma (BC). However, it is not specific and has very low sensitivity for triple-negative BC (TNBC). SRY-box transcription factor 10 (SOX-10) and trichorhinophalangeal syndrome type 1 (TRPS-1) have been suggested for inclusion in the diagnostic workup of TNBC. TRPS-1 has not been established in cytology specimens as a diagnostic IHC marker for metastatic BC (MBC). Hence, in the present study we evaluated the utility of TRPS-1 in diagnosing MBC in cytology specimens.
MBC cases diagnosed on cytology specimens from January to October 2020 were included in the present study. Only cases with hormonal status available and ≥20 tumor cells on cell blocks were included in the study. The cell blocks were assessed for TRPS-1, GATA-3, and SOX-10 IHC marker positivity (intensity and percentage of tumor cells). The results were correlated with the specimen type (fine needle aspiration [FNA] versus body fluid) and various BC prognostic subgroups.
We analyzed 61 cases, including 33 body fluid and 28 FNA (13 lymph node, 10 bone, 2 liver, 2 soft tissue, and 1 lung) specimens. TRPS-1 had 97.2% positivity in ER/PR+ (estrogen receptor/progesterone receptor-positive) MBC compared with GATA-3, which had 100% positivity in the same group. TRPS-1 showed high positivity in 35 of 37 cases (94.6%) and intermediate positivity in 1 (2.6%) and was negative/low positive in 1 case (2.7%). In contrast, GATA-3 showed high positivity for all 37 cases (100%). SOX-10 showed positivity in only 1 of 37 cases (2.7%), with intermediate positivity. In the HER2+ (human epidermal growth factor receptor 2-positive) group, TRPS-1 showed high positivity in 5 of 7 cases (71.4%), intermediate positivity in 1 case (14.3%), and negativity in 1 case (14.3%). However, GATA-3 showed high positivity in 6 of 7 cases (85.7%) and negative/low positivity in 1 case (14.3%). SOX-10 was negative in all 7 cases. In TNBC, TRPS-1 showed high positivity in 16 of 17 cases (94%) and intermediate positivity in 1 (5.9%), and GATA-3 showed high positivity in 9 (53%), intermediate positivity in 2 (11.8%), and low positive/negative in 6 of the 17 cases (35.3%). TRPS-1 expression was significantly higher than GATA-3 expression for the number of positive cases (P = 0.07), mean percentage of positive tumor cells (P = 0.005), and intensity of reactivity (P = 0.005). SOX-10 expression was present in only 5 of 17 cases (29%), with a mean percentage of positivity in the tumor cells of 26.5% and intensity of 0.8. No differences were found in the IHC results between the different specimen types (FNA versus fluid) in any group.
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GATA3 has been reported to be positive in clear cell papillary renal cell carcinoma and papillary renal neoplasm with reverse polarity. However, its features in high-grade RCC remain unclear. Despite the emergence of novel renal entities, FH-deficient RCC remains one of the most aggressive renal neoplasms. The diagnosis is mainly based on the loss of FH at the protein level. Previous studies have shown that inclusion-like nuclei, multiple architectural patterns, FH loss, and 2SC positivity can differentiate FH-deficient RCC from other RCC. In some FH-deficient RCC cases, FH is normally expressed and is difficult to diagnose. This study included 11 FH-deficient RCC, and GATA3 showed different expression in seven cases. However, 147 papillary renal cell carcinomas were included, and GATA3 expression was negative. A comparison of clinicopathological aspects between 11 FH-deficient RCC and 30 high-grade PRCC showed statistical significance in age, size, multiple architectural patterns, inclusion-like nuclei, and prognosis. However, PRCC exhibited similar characteristics. CK7, GATA3, and FH profiles were also statistically significant. Different chromosomal alterations were found in FH-deficient RCC, and chromosomal alterations were not different between FH-deficient RCC and PRCC. GATA3 was positive in 33 % (7/21) of collecting duct carcinomas and negative in other high-grade renal neoplasms. GATA3 is negative in PRCC, but can be positive in FH-deficient RCC and collecting duct carcinoma. GATA3 expression may indicate a worse outcome in high-grade RCC with papillary architecture. We recommend GATA3 IHC for the differential diagnosis and prognostic assessment of high-grade RCC with papillary architecture.
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^☆: Presented in an abstract form at the annual meeting of the United States and Canadian Academy of Pathology, San Antonio, TX, March 4-10, 2017.

^☆☆: Disclosures: None.

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Original contributionGATA3 as a valuable marker to distinguish clear cell papillary renal cell carcinomas from morphologic mimics☆,☆☆

Highlights

Summary

Introduction

Section snippets

Case selection

Results

Discussion

Urol Oncol

Mod Pathol

Kidney Int

Pathology

Hum Pathol

Spectrum of epithelial neoplasms in end-stage renal disease: an experience from 66 tumor-bearing kidneys with emphasis on histologic patterns distinct from those in sporadic adult renal neoplasia

Am J Surg Pathol

Clear-cell papillary renal cell carcinoma: 24 cases of a distinct low-grade renal tumour and a comparative genomic hybridization array study of seven cases

Histopathology

Clear cell renal cell carcinoma with borderline features of clear cell papillary renal cell carcinoma: combined morphologic, Immunohistochemical, and cytogenetic analysis

Am J Surg Pathol

Clear cell papillary renal cell carcinoma and renal angiomyoadenomatous tumor—two variants of a morphologic, Immunohistochemical and genetic distinct entity of renal cell carcinoma

Am J Surg Pathol

Original contribution
GATA3 as a valuable marker to distinguish clear cell papillary renal cell carcinomas from morphologic mimics☆,☆☆