IU Indianapolis ScholarWorks :: Browsing by Author "Eble, John N."

Browsing by Author "Eble, John N."

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Artificial intelligence-based multi-class histopathologic classification of kidney neoplasms
(Elsevier, 2023-02-16) Gondim, Dibson D.; Al-Obaidy, Khaleel I.; Idrees, Muhammad T.; Eble, John N.; Cheng, Liang; Pathology and Laboratory Medicine, School of Medicine
Artificial intelligence (AI)-based techniques are increasingly being explored as an emerging ancillary technique for improving accuracy and reproducibility of histopathological diagnosis. Renal cell carcinoma (RCC) is a malignancy responsible for 2% of cancer deaths worldwide. Given that RCC is a heterogenous disease, accurate histopathological classification is essential to separate aggressive subtypes from indolent ones and benign mimickers. There are early promising results using AI for RCC classification to distinguish between 2 and 3 subtypes of RCC. However, it is not clear how an AI-based model designed for multiple subtypes of RCCs, and benign mimickers would perform which is a scenario closer to the real practice of pathology. A computational model was created using 252 whole slide images (WSI) (clear cell RCC: 56, papillary RCC: 81, chromophobe RCC: 51, clear cell papillary RCC: 39, and, metanephric adenoma: 6). 298,071 patches were used to develop the AI-based image classifier. 298,071 patches (350 × 350-pixel) were used to develop the AI-based image classifier. The model was applied to a secondary dataset and demonstrated that 47/55 (85%) WSIs were correctly classified. This computational model showed excellent results except to distinguish clear cell RCC from clear cell papillary RCC. Further validation using multi-institutional large datasets and prospective studies are needed to determine the potential to translation to clinical practice.
Biphasic Hyalinizing Psammomatous Renal Cell Carcinoma (BHP RCC): A Distinctive Neoplasm Associated with Somatic NF2 Mutations
(Wolters Kluwer, 2020-07) Argani, Pedram; Reuter, Victor E.; Eble, John N.; Vlatkovic, Ljiljana; Yaskiv, Oksana; Swanson, David; Dickson, Brendan C.; Antonescu, Cristina R.; Matoso, Andres; Gagan, Jeffrey; Palsgrove, Doreen N.; Pathology and Laboratory Medicine, School of Medicine
We report 8 cases of a distinctive, previously undescribed renal cell carcinoma associated with somatic mutations in the neurofibromin 2 (NF2) gene. All patients were adults, ranging from 51 to 78 years of age and of cases of known sex 6 of 7 were males. The carcinomas were predominantly unencapsulated, and all had a rounded, nodular interface with the native kidney. The neoplasms were all solid with papillary architecture evident in most cases (7/8), while 1 was only tubular. All cases were biphasic, characterized by larger and smaller carcinoma cells. The smaller cells clustered around basement membrane material similar to the characteristic pattern of the t(6;11) renal cell carcinoma associated with TFEB gene fusions. In 6 of 8 carcinomas, branching nodules of small cells clustered around basement membrane material within larger acini yielding a distinctive glomeruloid pattern. In 6 of 8 carcinomas, the small cells were focally spindle-shaped and unassociated with the basement membrane material. The stroma was sclerotic in all 8 carcinomas, and all 8 contained psammoma bodies that were abundant in 2. In some carcinomas, focal or predominant areas had a less distinctive appearance; 2 had areas that resembled clear cell renal cell carcinoma, 2 had high-grade eosinophilic areas, while 1 had branching tubular architecture that resembled mucinous tubular and spindle cell carcinoma. Two carcinomas demonstrated cellular necrosis. Although we have minimal clinical follow-up, 1 case presented with distant metastasis, progressed and resulted in patient death. While NF2 mutations may be found in other established renal cell carcinoma subtypes (often as secondary genetic alterations), they are potentially the genetic driver of this distinctive entity.
Correcting the Shrinkage Effects of Formalin Fixation and Tissue Processing for Renal Tumors: toward Standardization of Pathological Reporting of Tumor Size
(Ivyspring International Publisher, 2015-07-02) Tran, Thu; Sundaram, Chandru P.; Bahler, Clinton D.; Eble, John N.; Gringon, David J.; Monn, M. Francesca; Simper, Novae B.; Cheng, Liang; Department of Pathology and Laboratory Medicine, IU School of Medicine
Given the importance of correctly staging renal cell carcinomas, specific guidelines should be in place for tumor size measurement. While a standard means of renal tumor measurement has not been established, intuitively, tumor size should be based on fresh measurements. We sought to assess the accuracy of postfixation and microscopic measurements of renal tumor size, as compared to fresh measurements and radiographic size. Thirty-four nephrectomy cases performed by a single surgeon were prospectively measured at different time points. The study cases included 23 clear cell renal cell carcinomas, 6 papillary renal cell carcinomas, and 5 other renal tumors. Radiologic tumors were 12.1% larger in diameter than fresh tumors (P<0.01). Furthermore, fresh specimens were 4.6% larger than formalin-fixed specimens (P<0.01), and postfixation measurements were 7.1% greater than microscopic measurements (P<0.01). The overall mean percentage of shrinkage between fresh and histological specimens was 11.4% (P<0.01). Histological processing would cause a tumor stage shift from pT1b to pT1a for two tumors in this study. The shrinkage effects of formalin fixation and histological processing may result in understaging of renal cell carcinomas. The shrinkage factor should be considered when reporting tumor size.
Diagnostic Criteria for Oncocytic Renal Neoplasms: A Survey of Urologic Pathologists
(Elsevier, 2017-05) Williamson, Sean R.; Gadde, Ramya; Trpkov, Kiril; Hirsch, Michelle S.; Srigley, John R.; Reuter, Victor E.; Cheng, Liang; Kunju, L. Priya; Barod, Ravi; Rogers, Craig G.; Delahunt, Brett; Hes, Ondrej; Eble, John N.; Zhou, Ming; McKenney, Jesse K.; Martignoni, Guido; Fleming, Stewart; Grignon, David J.; Moch, Holger; Gupta, Nilesh S.; Department of Pathology and Laboratory Medicine, IU School of Medicine
Renal oncocytoma and chromophobe renal cell carcinoma have been long recognized as distinct tumors; however, it remains unknown if uniform diagnostic criteria are used to distinguish these tumor types in practice. A survey was distributed to urologic pathologists regarding oncocytic tumors. Responses were received from 17 of 26 invitees. Histologically, more than 1 mitotic figure was regarded as most worrisome (n = 10) or incompatible (n = 6) with oncocytoma diagnosis. Interpretation of focal nuclear wrinkling, focal perinuclear clearing, and multinucleation depended on extent and did not necessarily exclude oncocytoma if minor. Staining techniques most commonly used included the following: cytokeratin 7 (94%), KIT (71%), vimentin (65%), colloidal iron (59%), CD10 (53%), and AMACR (41%). Rare cytokeratin 7–positive cells (≤5%) were regarded as most supportive of oncocytoma, although an extent excluding oncocytoma was not universal. Multiple chromosomal losses were most strongly supportive for chromophobe renal cell carcinoma diagnosis (65%). Less certainty was reported for chromosomal gain or a single loss. For tumors with mixed or inconclusive features, many participants use an intermediate diagnostic category (82%) that does not label the tumor as unequivocally benign or malignant, typically “oncocytic neoplasm” or “tumor” with comment. The term “hybrid tumor” was used variably in several scenarios. A slight majority (65%) report outright diagnosis of oncocytoma in needle biopsies. The morphologic, immunohistochemical, and genetic characteristics that define oncocytic renal tumors remain incompletely understood. Further studies correlating genetics, behavior, and histology are needed to define which tumors truly warrant classification as carcinomas for patient counseling and follow-up strategies.
Distinct clinicopathological features in metanephric adenoma harboring BRAF mutation
(Impact Journals, 2016-07-08) Caliò, Anna; Eble, John N.; Hes, Ondrej; Martignoni, Guido; Harari, Saul E.; Williamson, Sean R.; Brunelli, Matteo; Osunkoya, Adeboye O.; Wang, Lisha; Comperat, Eva; Lopez-Beltran, Antonio; Wang, Mingsheng; Zhang, Shaobo; Curless, Kendra L.; Post, Kristin M.; Chang, Hsim-Yee; Luchini, Claudio; Baldrige, Lee Ann; MacLennan, Gregory T.; Montironi, Rodolfo; Grignon, David J.; Cheng, Liang; Pathology and Laboratory Medicine, School of Medicine
BRAF mutation recently has been reported in metanephric adenoma. We sought to determine the clinical and morphologic features of BRAF-mutated metanephric adenoma and to correlate BRAF mutation with BRAF V600E immunohistochemical staining results. A series of 48 metanephric adenomas and 15 epithelial-predominant nephroblastomas were analyzed for the occurrence of BRAF mutation (BRAF V600E/V600E complex, BRAF V600D, BRAF V600K and BRAF V600R) using the BRAF RGQ PCR kit (Qiagen). Immunohistochemistry was performed using monoclonal mouse antibodies against p16INK4 and VE1 (Spring Bioscience), recognizing the BRAF V600E mutant protein. Forty-one of 48 cases (85%) showed BRAF V600E mutation; none of the other BRAF variants was detected. Of 41 BRAF-mutated metanephric adenomas, 33 showed positive VE1 immunostaining (sensitivity 80%, specificity 100%); in all cases we detected p16INK4 expression regardless of BRAF mutation status. All epithelial-predominant nephroblastomas were BRAF-wild-type and none expressed VE1. The following features were associated with BRAF V600E mutation: older patients (p=0.01), female predominance (p=0.005) and the presence of a predominantly acinar architecture (p=0.003). In summary, BRAF-mutated metanephric adenomas were associated with older age, female predominance, and the presence of a predominant acinar component. A subset (20%) of BRAF-mutated metanephric adenomas was not detected by VE1 immunostaining.
Evidence of a dual histogenetic pathway of sacrococcygeal teratomas
(Wiley, 2017-01) Emerson, Robert E.; Kao, Chia-Sui; Eble, John N.; Grignon, David J.; Wang, Mingsheng; Zhang, Shaobo; Wang, Xiaoyan; Fan, Rong; Masterson, Timothy A.; Roth, Lawrence M.; Cheng, Liang; Department of Pathology and Laboratory Medicine, IU School of Medicine
Aims Sacrococcygeal teratomas are rare tumours that occur most frequently in neonates, although adult cases also occur. The molecular pathogenesis of these tumours and their long-term prognosis is uncertain. We investigated the i(12p) status of a large number of primary sacrococcygeal teratomas in both children and adults, including cases with malignant germ cell tumour elements. Methods and results Fifty-four sacrococcygeal teratoma specimens from 52 patients were identified, and available follow-up information was obtained. Fluorescence in-situ hybridization analysis was performed to identify isochromosome 12p [i(12p)] abnormalities on paraffin blocks of the tumours. Among the 48 paediatric patients, there were 44 teratomas and four tumours with combined teratoma and yolk sac tumour (one of whom also had primitive neuroectodermal tumour). The teratomas included 37 mature teratomas and 11 immature teratomas (four grade 1, two grade 2, and five grade 3). The 44 teratomas lacking a yolk sac tumour component were all negative for i(12p). The four tumours with a yolk sac tumour component were all positive for i(12p). The four adult cases all lacked non-teratomatous germ cell tumour components, immature elements, and i(12p). Follow-up information was available for 32 patients. Two patients with teratoma had recurrence, but were alive with no evidence of disease after long-term follow-up. One patient with combined teratoma and yolk sac tumour had recurrence 7 months after resection. The other patients were alive with no evidence of disease at last follow-up. Conclusions Our data suggest that paediatric sacrococcygeal teratomas should be considered as two distinct groups with divergent histogenetic pathways. The prognosis of these tumours is excellent, despite rare recurrence.
Morphologic Spectrum of Renal Cell Carcinoma, Unclassified: An Analysis of 136 Cases
(Wiley, 2017) Perrino, Carmen M.; Grignon, David J.; Williamson, Sean R.; Idrees, Muhammad T.; Eble, John N.; Cheng, Liang; Department of Pathology and Laboratory Medicine, School of Medicine
Aims Renal cell carcinoma, unclassified (RCCU) is a category that includes a morphologically and biologically heterogeneous group of tumors that are unable to be diagnosed as other well-defined entities. We aim to describe the morphologic findings of tumors within this category and to determine the most frequent morphologic features leading to classification difficulty. Methods and results One hundred and thirty-six cases of RCCU were examined. Patients ranged in age from 23 to 87 years. Seventy-seven patients were men and 59 were women. International Society of Urological Pathology (ISUP) grade was most commonly 3 (n=66), followed by 2 (n=42) and 4 (n=28). Tumor size ranged from 0.6 cm to 24.9 cm. The AJCC pathologic T categories included pT1a (n=50), pT1b (n=14), pT2a (n=7), pT2b (n=4), pT3a (n=50), and pT4 (n=9). Forty-four cases included lymph node(s), of which 41% (n=18) had metastases. Tumors were assessed for a variety of histologic features and assigned to the following morphologic groups: predominantly oncocytoma/chromophobe RCC-like; clear cell RCC-like; papillary RCC-like; collecting duct-like; and pure sarcomatoid differentiation. The majority of the oncocytoma/chromophobe and clear cell RCC-like phenotypes were low stage (pT1 or pT2). The papillary RCC-like, collecting duct-like, and pure sarcomatoid phenotypes were mostly high stage (pT3 or pT4). Conclusions RCCU is a term that encompasses tumors with a variety of morphologic features and a wide biologic spectrum. The most common source of diagnostic difficulty was tumors composed of predominantly eosinophilic cells.
Preservation of Truncal Genomic Alterations in Clear Cell and Papillary Renal Cell Carcinomas with Sarcomatoid Features: An Intra- and Intertumoral, Multifocal Fluorescence in Situ Hybridization Analysis Reveals Limited Genetic Heterogeneity
(Wiley, 2017) Sanfrancesco, Joseph M.; Eble, John N.; Grignon, David J.; Wang, Mingsheng; Zhang, Shaobo; Sundaram, Chandru P.; Idrees, Muhammad T.; Pili, Roberto; Kouba, Erik; Cheng, Liang; Department of Pathology and Laboratory Medicine, School of Medicine
Understanding tumor genomic heterogeneity may offer vital information in an age of targeted therapy for renal cell carcinoma. We sought to investigate hallmark truncal chromosomal alterations between conventional, sarcomatoid, and matched metastatic tumor foci in clear cell and papillary renal cell carcinomas. A retrospective review identified 58 cases including clear cell (CCRCC) and papillary renal cell carcinomas (PRCC). All cases contained sarcomatoid transformation. Additionally, 10 of 58 patients had matched metastatic disease available for analysis. Three separate foci of conventional and sarcomatoid morphologies were analyzed in each tumor using dual color interphase fluorescence in situ hybridization. In the CCRCC cohort, hallmark chromosome 3p deletion was identified in 71% of cases (37/52). Complete concordance of chromosomal status between intratumoral foci in sarcomatoid and conventional foci was 89% and 86%, respectively. Overall chromosome 3p status between matched conventional and sarcomatoid morphologies was identified in 98% of cases (51/52). Hallmark 3p deletion was present in 91% of CCRCC metastatic samples (10/11) and was concordant with the matched primary CCRCC tumor in 91% (10/11). In the PRCC cohort, trisomy 7 and 17 was identified in all six cases (6/6). Complete concordance between intratumoral foci of trisomy 7 and 17 was 83% (5/6). Trisomy 7 and 17 were identified in all metastatic PRCC samples with 100% concordance with the matched primary tumor. These data show the relative preservation of truncal chromosomal abnormalities between conventional and sarcomatoid morphologic as well as matched metastatic settings.
Renal Cell Carcinoma with Angioleiomyoma-Like Stroma and Clear Cell Papillary Renal Cell Carcinoma: Exploring SDHB Protein Immunohistochemistry and the Relationship to Tuberous Sclerosis Complex
(Elsevier, 2017) Williamson, Sean R.; Hornick, Jason L.; Eble, John N.; Gupta, Nilesh S.; Rogers, Craig G.; True, Lawrence; Grignon, David J.; Cheng, Liang; Pathology and Laboratory Medicine, School of Medicine
Renal cell carcinoma (RCC) with angioleiomyoma-like stroma appears to be molecularly distinct from clear cell RCC; however, its relationship to clear cell papillary RCC remains debated. Recent studies have found that similar tumors sometimes occur in patients with tuberous sclerosis complex (TSC), of which one study found unexpectedly negative succinate dehydrogenase (SDH) B immunostaining. We evaluated immunohistochemistry for SDHB in 12 apparently sporadic RCCs with angioleiomyoma-like stroma and correlated with clinical information for stigmata of TSC. Tumors were compared to a group of 16 clear cell papillary RCCs and 6 unclassified tumors with prominent stroma. With exception of 1 unclassified tumor, all exhibited at least focal cytoplasmic staining for SDHB protein, often requiring high magnification and better appreciated with increased antibody concentration. Detailed history information was available for 9/12 patients with smooth muscle-rich tumors, revealing no stigmata of undiagnosed TSC. Electron microscopy performed on 1 of these tumors revealed mitochondria to be very sparse, potentially accounting for the weak immunohistochemical labeling for SDHB protein. Weak SDHB immunostaining may represent another shared feature of RCC with angioleiomyoma-like stroma and clear cell papillary RCC, likely due to sparse mitochondria, strengthening the possible relationship of these entities. Although smooth muscle-rich tumors have been recently reported in patients with TSC, absence of staining in tumors with this pattern may not be specific for TSC. In tumors with pale or clear cytoplasm, immunohistochemical staining for SDHB should be interpreted with caution as evidence of abnormality in the SDH pathway.
Sclerosing TFEB Rearrangement Renal Cell Carcinoma: A Recurring Histologic Pattern
(Elsevier, 2017-04) Williamson, Sean R.; Eble, John N.; Palanisamy, Nallasivam; Department of Pathology and Laboratory Medicine, IU School of Medicine
Renal cell carcinoma with TFEB rearrangement (t[6;11][p21;q13]) was initially recognized to be composed of dual populations of large cells with clear cytoplasm and small cells forming rosettes around hyaline material. With increasing awareness, however, the spectrum of described morphology has been found to be more heterogeneous. We report a 54-year-old woman who underwent partial nephrectomy for a 2.4-cm renal mass, composed of fibrosis, hyalinization, calcification, and ossification and a smaller component of epithelioid cells. Immunohistochemical staining revealed diffuse positivity for cytokeratin AE1/AE3 and PAX8, patchy labeling for melan-A, human melanosome, and cathepsin K, and negative caldesmon, smooth muscle actin, TFE3 protein, carbonic anhydrase IX, CD10, cytokeratin 7, epithelial membrane antigen, and inhibin. Fluorescence in situ hybridization confirmed rearrangement of TFEB and not TFE3. Together with one recent case in another report, our findings suggest that extensive sclerosis and ossification may be a less common recurring histology of TFEB-rearrangement renal cell carcinoma.

Browsing by Author "Eble, John N."

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