Nephrectomy Specimens Research Articles

Renal oncocytoma with adverse pathologic features: a clinical and pathologic study of 50 cases.

Renal oncocytoma is the most common benign epithelial renal neoplasm. Several adverse features that would typically increase the stage of renal cell carcinomas are not uncommon in renal oncocytoma, including perinephric, sinus fat, or renal vein invasion. Herein, we report the largest single institutional series of renal oncocytoma with adverse pathologic features. The cohort comprised 50 patients, 38 were men (76%) and 12 were women (24%), with a mean age of 68 years (range, 50-87 years). All cases were diagnosed on nephrectomy specimens. No laterality predilection was noted. The tumors ranged in size from 1.5-15.7 cm (mean, 5.3 cm). Adverse pathologic features included perinephric fat invasion (n = 25; 50%), renal sinus fat invasion (n = 9; 18%), and renal vein invasion (n = 5; 10%). More than one adverse feature was seen in 11 tumors (22%). All tumors showed diffuse reactions to KIT (n = 40; 100%) and cyclin D1 (n = 27; 100%). Keratin 7 highlighted rare (<5%) scattered cells, as well as entrapped renal tubules (n = 21; 100%). Reaction to DOG1 was patchy in three tumors (n = 27; 11%) while reactions to vimentin (n = 31) and Hale colloidal iron special stain (n = 30) were negative. On follow-up, no tumor recurrence or metastasis was observed over a follow-up range of 1-144 months (mean, 54 months; median, 60 months). Our data suggest that adverse pathologic features in renal oncocytoma do not alter their benign course.

Characterization of the Peritumoral Atrophic Band and Nonneoplastic Renal Parenchyma in Radical Nephrectomy Specimens.

Pathologic evaluation of nonneoplastic renal parenchyma in nephrectomy specimens is important for identifying chronic kidney disease and diabetic nephropathy, but increasing utilization of partial nephrectomies has led to less-sampled nonneoplastic parenchyma. The sampled tissue is often composed predominantly of the peritumoral atrophic band (PAB) directly adjacent to the tumor. We sought to determine the characteristics of the PAB and whether it could be used to reliably assess kidney pathology, including diabetic nephropathy. We investigated 59 radical nephrectomies to determine the PAB characteristics, whether the PAB is representative of distant nonneoplastic parenchyma, and if diabetic nephropathy could be reliably detected in the PAB. Mesangial sclerosis was detected within the PAB in 100% of cases with mesangial sclerosis in the distant parenchyma. Eighty percent had a history of diabetes. The PAB exhibited increased glomerular sclerosis (51% vs 13%, P < .001) and interstitial fibrosis and tubular atrophy (83% vs 13%, P < .001) compared with distant parenchyma. Diabetic nephropathy can be reliably detected in the PAB, which is important in partial nephrectomies or renal mass biopsies without ample distant renal parenchyma. The degree of glomerular and tubulointerstitial scarring within the PAB does not reflect the overall degree of chronic kidney disease.

Renal cell carcinoma in native nephrectomy specimens of autosomal dominant polycystic kidney disease (ADPKD) patients with end-stage renal disease: Findings from an Australian transplant center

Objectives: The aim of this study was to present a contemporary review of renal cell carcinoma (RCC) in native nephrectomy (NN) specimens of patients with autosomal dominant polycystic kidney disease (ADPKD) and end-stage renal disease (ESRD). Materials (patients) and methods: A retrospective review of all ADPKD patients who underwent NN from 1 October 2010 to 31 July 2019 was performed. Data was collected on demographics, length of time on renal replacement therapy, indications for surgery, perioperative details, and histology. Results: In total, 32 NNs were performed in our study period with 12.5% ( n=4) histologically diagnosed with RCC, consisting of 75% ( n=3) Type 1 papillary RCC (p RCC) and 25% ( n=1) clear cell RCC. Average age of ADPKD patients with ESRD diagnosed with RCC was 67±5.9 years. Average time on dialysis for RCC and non-RCC patients was 35.75±46.28 and 22.04±24.33 months, respectively. We did not find a significant correlation between the diagnosis of RCC and time on dialysis. Conclusion: Our contemporary series shows a significant proportion of ADPKD patients with ESRD undergoing NN have RCC. Compared to previously published datasets, our patients are older, and selective to those with very large kidneys and lesions suspicious for RCC. While there may be a role in imaging native kidneys with ADPKD to rule out suspicious lesions, it must be balanced against the cost, radiation exposure, and potential harm from an increased rate of nephrectomy that may ensue for suspicious lesions found on screening. Level of evidence: Not applicable for this multicentre audit.

Improving Renal Tumor Biopsy Prognostication With BAP1 Analyses.

Active surveillance of small renal masses highlights the need for accurate prognostication of biopsies. To comprehensively evaluate the accuracy of biopsies in assessing known prognostic parameters including histologic subtype by comparison with subsequent nephrectomy samples. We retrospectively identified patients at University of Texas Southwestern Medical Center, Dallas, Texas, who had a biopsy for a renal mass between 2004-2018. Biopsy samples were evaluated for known prognostic factors such as tumor grade, necrosis, sarcomatoid/rhabdoid change, and BRCA1-associated protein-1 (BAP1) status, which we previously showed is an independent prognostic factor for clear cell renal cell carcinoma. Accuracy was determined by comparison with subsequent analyses of nephrectomy specimens. Statistical analyses were performed to assess biopsy accuracy and correlation with tumor size and pathologic stage. From 805 biopsies with a diagnosis of renal neoplasm, 178 had subsequent resection of the biopsied tumor. Concordance rate for histologic subtype was 96.9% (κ [w], 0.90; 95% CI, 0.82-0.99) and excellent for small renal masses (98.8%; κ [w], 0.97; 95% CI, 0.90-1). Amongst the prognostic variables evaluated, BAP1 immunohistochemistry in clear cell renal cell carcinoma had the highest agreement (94.8%; κ [w], 0.83; 95% CI, 0.66-0.99). The presence of 1 or more aggressive features (grade 3-4, tumor necrosis, BAP1 loss, sarcomatoid/rhabdoid change) in a biopsy significantly correlated with pT stage (P = .004). Biopsy analyses showed high accuracy for subtyping renal tumors, but it underestimated several poor prognostic features. Addition of BAP1 for clear cell renal cell carcinoma may increase prognostic accuracy. If validated, routine incorporation of BAP1 immunohistochemistry in clear cell renal cell carcinoma biopsies may refine prognosis and aid in the selection of patients for active surveillance.

Cyto-KIK: A phase II trial of cytoreductive surgery in kidney cancer plus immunotherapy (nivolumab) and targeted kinase inhibition (cabozantinib).

TPS4598 Background: Despite recent therapeutic advancements in metastatic renal cell carcinoma (mRCC), only 5-10% of patients will achieve a complete response (CR) to therapy. Cytoreductive nephrectomy removes a large portion of the tumor which may be a source of immunosuppression driven by tumor cell-intrinsic factors in the tumor microenvironment. A pre-clinical orthotopic mouse model of aggressive metastatic triple negative breast cancer showed that neoadjuvant anti-PD-1 checkpoint inhibition generated enhanced and sustained antitumor immune responses with improved survival compared to adjuvant therapy (Liu J et al. Cancer Discov. 2016:1382). Clinical validation of improved outcomes with neoadjuvant compared to adjuvant immune checkpoint inhibitors has been demonstrated in trials for patients with non-small cell lung cancer, advanced melanoma, and recurrent glioblastoma (Forde, P.M., et al. N Engl J Med. 2018:1976; Amaria, R.N., et al Nat Med. 2018:1649; Cloughesy T.F., et al. Nat Med 2019:477). Recent data from a phase III trial in subjects with untreated mRCC, demonstrated the superiority of combination cabozantinib and nivolumab over sunitinib and established a new standard of care for mRCC (Choueiri T.K., et al. Annals of Onc, 2020;31 (suppl; abstr 6960). We hypothesize that if tumor specific immune responses to immunotherapy are greatest prior to nephrectomy, then treatment with nivolumab (nivo) and cabozantinib (cabo) prior to cytoreductive nephrectomy will lead to maximal peripheral and intra-tumoral specific immune responses and higher rates of CR during the course of treatment. Methods: This is an open label phase II, multicenter clinical trial of combination nivo and cabo prior to cytoreductive nephrectomy in patients with mRCC (NCT04322955). 48 treatment- naïve subjects with radiological or histological diagnosis of mRCC will be enrolled with the primary endpoint of CR rate according to RECIST version 1.1. Subjects will receive cabo (40mg) daily and nivo (480mg) every 4 weeks for 12 weeks prior to nephrectomy and a 3+3 design will be used to evaluate the safety of the interval (21 or 14 days) between the discontinuation of cabo and nephrectomy. Post-operatively, subjects will resume treatment with cabo and nivo until evidence of disease progression. Secondary endpoints include median size reduction of the primary tumor, response rate, PFS, OS, and surgical outcomes using the Clavien-Dindo classification system. Tissue based assays will quantify treatment related changes in the renal tumor microenvironment through polychromatic immunofluorescence, single cell RNA sequencing of the biopsy and nephrectomy specimen, and multiplex assessment of circulating serum cytokines. Dynamic contrast-enhanced MRI will be performed in a subset of subjects to assess radiologic correlates of response. The study is currently open to enrollment. Clinical trial information: NCT04322955.

INITIAL STUDY OF THE SELECTION OF THE TYPE OF INCISION FOR THE SPECIMEN EXTRACTION AFTER A LAPAROSCOPIC NEPHRECTOMY: PFANNENSTIEL INCISION

Abstract INTRODUCTION The transverse hypogastric Pfannenstiel incision is one of the possibilities for specimen extraction after a laparoscopic nephrectomy. Its advantages include low morbidity and a favorable cosmetic result. MATERIAL AND METHODS Retrospective and comparative observational study of 105 patients who underwent nephrectomy in our center. Group 1: renal extraction through Pfannenstiel incision. Group 2: renal extraction using other techniques. The presence of infection, incisional hernia and pain (visual analogue scale-VAS) was evaluated in each patient. Additionally, a telephone survey was conducted on the cosmetic results. RESULTS 105 patients: 68 group 1 (Pfannenstiel incision) and 37 group 2 (other incisions). The median size of the nephrectomy specimen was 14 cm (group 1 15cm, group 2 13cm). 27 patients (26%) had pain in the area of the hypogastric incision in the early postoperative period with a median on the VAS scale of 4 (16 group 1 vs 11 group 2). 3 patients (2.8%) presented incisional hernia (0 group 1 vs 3 group 2). 3 patients presented wound infection (0 group 1 vs 3 group 2). 70% of the patients in group 1 (48/68) answered the survey on cosmetic satisfaction: 93% were satisfied with the scar and its location. 49% of the patients in group 2 (18/37) answered the survey on cosmetic satisfaction: 83% were satisfied with the scar and its location. CONCLUSIONS The Pfannenstiel incision is a valid and safe alternative for laparoscopic nephrectomy specimen extraction with a favorable complication and cosmetic profile compared to other common techniques for nephrectomy specimen extraction.

Needle tract seeding in renal tumor biopsies: experience from a single institution

BackgroundPercutaneous needle biopsy of renal masses has been increasingly utilized to aid the diagnosis and guide management. It is generally considered as a safe procedure. However, tumor seeding along the needle tract, one of the complications, theoretically poses potential risk of tumor spread by seeded malignant cells. Prior studies on the frequency of needle tract seeding in renal tumor biopsies are limited and clinical significance of biopsy-associated tumor seeding remains largely controversial.MethodsHere we investigated the frequencies of biopsy needle tract tumor seeding at our institution by reviewing the histology of renal cell carcinoma nephrectomy specimens with a prior biopsy within the last seventeen years. Biopsy site changes were recognized as a combination of foreign body reaction, hemosiderin deposition, fibrosis and fat necrosis. The histologic evidence of needle tract tumor seeding was identified as clusters of tumor cells embedded in perinephric tissue spatially associated with the biopsy site. In addition, association between parameters of biopsy techniques and tumor seeding were investigated.ResultsWe observed needle tract tumor seeding to perinephric tissue in six out of ninety-eight (6 %) renal cell carcinoma cases including clear cell renal cell carcinoma, papillary renal cell carcinoma, chromophobe, and clear cell papillary renal cell carcinoma. The needle tract tumor seeding was exclusively observed in papillary renal cell carcinomas (6/28, 21 %) that were unifocal, small-sized (≤ 4 cm), confined to the kidney and had type 1 features. No recurrence or metastasis was observed in the papillary renal cell carcinoma cases with tumor seeding or the stage-matched cases without tumor seeding.ConclusionsOur study demonstrated a higher than reported frequency of needle tract tumor seeding. Effective communication between pathologists and clinicians as well as documentation of tumor seeding is recommended. Further studies with a larger patient cohort and longer follow up to evaluate the impact of needle tract tumor seeding on long term prognosis are needed. This may also help reach a consensus on appropriate pathologic staging of renal cell carcinoma when the only site of perinephric fat invasion is within a biopsy needle tract.

HISTOPATHOLOGICAL STUDY OF TUMOURS AND TUMOUR LIKE LESIONS OF KIDNEY AND RENAL PELVIS

Background : Tumour and tumour like lesions of kidney and renal pelvis include a wide spectrum of entities. Renal neoplasms occurs both in adults and in children, with few rare tumours and account for 1% to 2% of all body cancers. Majority of which are RCC. Tumour and tumour like lesions of kidney and renal pelvis may present with nonspecic clinical manifestations, incidental ndings on radiology or at autopsy, may present with the classical triad of ank pain, haematuria and abdominal mass or can be asymptomatic. Hence histopathological examination is essential for the diagnosis of renal neoplasms. Material and method : It is retrospective study (July 2003 to June 2013) for a period of 10 years. Histopathological features of 38 tumours and tumour like lesions of the kidney and renal pelvis were analysed.Out of 38 cases, 27 were nephrectomy specimens and 11 were renal biopsies The histopathological reports and clinical details were collected and corresponding slides were reviewed. Tumours are classied according to WHO classication 2016. Results: The present study included 38 cases of tumour and tumour like lesions of kidney and renal pelvis. Histopathological evaluation revealed malignant neoplasms in 27 (71.05%) cases, benign neoplasm in 5 (13.15%) cases and tumour like lesions in 6 (15.79%) cases.Among malignant tumours, clear cell RCC was the most frequent tumour in our study observed in 13 (86.67%) cases. Overall higher numbers of tumours and tumourth th like lesions of kidney and renal pelvis were seen in the rst decade of life followed by 4 to 5 decade of life in our study with a male predominance having M:F ratio of 1.23:1. Conclusion: Malignant tumours outnumbered the benign tumours. Most of the malignant, benign and tumour like lesions present with similar clinical features hence histopathology remains the gold standard method.

More than ancillary records: clinical implications of renal pathology examination in tumor nephrectomy specimens

BackgroundNephrectomy is the management of choice for the treatment of renal tumors. Surgical pathologists primarily focus on tumor diagnosis and investigations relating to prognosis or therapy. Pathological changes in non-neoplastic tissue may, however, be relevant for further management and should be thoroughly assessed.MethodsHere, we examined the non-neoplastic renal parenchyma in 206 tumor nephrectomy specimens for the presence of glomerular, tubulo-interstitial, or vascular lesions, and correlated them with clinical parameters and outcome of renal function.ResultsWe analyzed 188 malignant and 18 benign or pseudo-tumorous lesions. The most common tumor type was clear cell renal cell carcinoma (CCRCC, n = 106) followed by papillary or urothelial carcinomas (n = 25). Renal pathology examination revealed the presence of kidney disease in 39 cases (18.9%). Glomerulonephritis was found in 15 cases (7.3%), and the most frequent was IgA nephropathy (n = 6; 2.9%). Vasculitis was found in two cases (0.9%). In 15 cases we found tubulo-interstitial nephritis, and in 9 severe diabetic or hypertensive nephropathy. Partial nephrectomy was not linked to better eGFR at follow-up. Age, vascular nephropathy, glomerular scarring and interstitial fibrosis were the leading independent negative factors influencing eGFR at time of surgery, whereas proteinuria was associated with reduced eGFR at 1 year.ConclusionOur large study population indicates a high incidence of renal diseases potentially relevant for the postoperative management of patients with renal neoplasia. Consistent and systematic reporting of non-neoplastic renal pathology in tumor nephrectomy specimens should therefore be mandatory.

Clinicopathological and molecular characterisation of papillary renal neoplasm with reverse polarity and its renal papillary adenoma analogue.

Papillary renal neoplasm with reverse polarity (PRNRP) is a newly defined entity with distinct histomorphology and recurrent KRAS mutation. It has been estimated to constitute 4% of previously diagnosed papillary renal cell carcinoma (PRCC). Renal papillary adenoma (PA) is suggested to be the precursor of PRCC. This study aimed to investigate the association between PRNRP and PA, particularly the morphologically similar type D PA. Nephrectomy specimens of PRCC and PA from our 10-year pathology archives were retrieved and reviewed. GATA3 immunohistochemistry and RAS/BRAF testing were performed in all cases reclassified as PRNRP and all PAs with sufficient materials. Overall, PRNRP accounted for 9.1% (10 of 110) of PRCC and there was no recurrence/metastasis with a mean follow-up period of 39months. Three novel morphological features were described, including clear cell change, mast cell infiltration and metaplastic ossification. Nine of the 10 PRNRPs showed diffuse and strong GATA3 expression and KRAS missense mutations at codon 12. One case exhibited moderate GATA3 staining on 80% of the tumour cells and RAS/BRAF wild-type. In a total of 73 PAs, 11 were classified as type D. GATA3 expression was significantly more frequent in type D versus non-type D PAs (100 versus 35%, P<0.01). KRAS missense mutations were identified in six of eight (75%) of the type D PAs but none of the 18 non-type D PAs. Type D PA was different from other types of PA and represented an analogue or a small-sized PRNRP for their identical morphology, immunophenotype and molecular signature.

Observational Histopathological Analysis of Renal Lesions in Nephrectomy Specimens

Aim: This observational retrospective study was initiated to perform histopathological spectrum analysis of renal lesions from resected nephrectomy specimens. Materials and Methods: This was a retrospective observational study. Over a span of 4 years a total of 62 nephrectomy cases who underwent nephrectomy in a tertiary health care center and specimens were received from the surgical Department of the Hospital were analysed. Microscopic and gross features of the specimen were studied. Result: 12(19%) nephrectomy specimens out of 62 were malignant and 50 (81%) were benign. The mean age of patients from whom specimen were collected was 44.16 ± 29.8 years. 34 (54.9%) were Chronic Pyelonephritis cases, some associated with hydronephrosis and others with calculi. Out of 12 total malignant lesions 8 cases (12.9%) constituted as renal cell carcinoma. Among children commonest malignant tumour was Wilm’s tumour. Among the clinical presentation most common was flank pain in 17 (53.1%) cases followed by fever and burning micturition. Conclusion: In current study as compared to the benign tumours, malignant renal tumours far outnumbered. In paediatric age group most common malignancy was the Wilms tumour. Most common histomorphological diagnosis was Chronic Pyelonephritis and among the malignant lesions commonest were Renal Cell Carcinoma. Keywords: Nephrectomy, Histopathology, Chronic Pyelonephritis, Wilm’s tumour, Renal Cell Carcinoma.

LOCALIZATION OF NATRIURETIC PEPTIDE RECEPTORS IN HUMAN KIDNEY TISSUE

Objective: Subsequent to partial and total nephrectomy, the remaining kidney tissue compensates by functional adaption. The glomerular filtration rate (GFR) and the renal blood flow increases. The post-nephrectomy GFR increases rapidly (as early as 8 h) from 50% up to 65–80% compared to pre-nephrectomy. The molecular mechanism is still unexplained. We hypothesized that the cardiac hormones atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) could mediate this response and thus, that their receptors would be expressed in the human kidney preglomerular vasculature, both in smooth muscle and in endothelial cells. This study was conducted to localize the Natriuretic Peptide Receptor A (NPRA) and C (NPRC) at mRNA and protein level in human kidney tissue. Design and method: The localization of the receptors was investigated by; 1) determining vascular reactivity ex vivo in human intrarenal arteries in response to ANP and BNP; 2) microdissection of vessels and glomeruli from nephrectomy specimens followed by polymerase chain reaction (PCR); 3) immunohistochemistry and fluorescence analyses of fixed-paraffin embedded kidney sections and 4) RNAscope detection of mRNA in tissue sections. Results: ANP and BNP caused relaxation of K+-precontracted human arteries. NPRC mRNA was uniformly present in all arteries whereas NPRB was not detected and NPRA was seemingly less abundant in microvessels NPRC. Both NPRA and -C were observed in isolated glomeruli by PCR. NPRA was associated with glomeruli, glomerular podocytes and parietal layer of Bowman's capsule but not mesangial cells. Arteries, arterioles and vasa recta displayed uniform immunolabeling associated with endothelium across sex and age of the patients whereas vascular smooth muscle cells were more faintly and non-uniformly labeled. NPRA was detected in both the descending and ascending vasa recta. No labeling of tubular compartment for NPRA was seen. NPRB was not detected in human kidney tissue. By RNAscope on kidney sections, NPRC was observed in glomeruli but also in proximal tubules and collecting ducts. Conclusions: We conclude that functional NPRA and NPRC are located in human renal tissue, both NPRA and -C are found in the vasculature and could be involved in the acute increase of the GFR following nephrectomy.

Invited Commentary: Infiltrative Growth Pattern in Renal Malignancy-A Clue to Diagnosis and Prognosis.

Invited Commentary: Infiltrative Growth Pattern in Renal Malignancy-A Clue to Diagnosis and Prognosis.

Phase II trial of cytoreductive surgery in kidney cancer plus immunotherapy (nivolumab) and targeted kinase inhibition (cabozantinib) (Cyto-KIK).

TPS371 Background: Despite recent therapeutic advancements in metastatic renal cell carcinoma (mRCC), only 5-10% of patients will achieve a complete response (CR) to therapy. Cytoreductive nephrectomy removes a large portion of the tumor which may be a source of immunosuppression driven by tumor cell-intrinsic factors in the tumor microenvironment. A pre-clinical orthotopic mouse model of aggressive metastatic triple negative breast cancer showed that neoadjuvant anti-PD-1 checkpoint inhibition generated enhanced and sustained antitumor immune responses with improved survival compared to adjuvant therapy (Liu J et al. Cancer Discov. 2016:1382). Clinical validation of improved outcomes with neoadjuvant compared to adjuvant immune checkpoint inhibitors has been demonstrated in trials for patients with non-small cell lung cancer, advanced melanoma, and recurrent glioblastoma (Forde, P.M., et al. N Engl J Med. 2018:1976; Amaria, R.N., et al Nat Med. 2018:1649; Cloughesy T.F., et al. Nat Med 2019:477). Recent data from a phase III trial in subjects with untreated mRCC, demonstrated the superiority of combination cabozantinib and nivolumab over sunitinib and established a new standard of care for mRCC (Choueiri T.K., et al. Annals of Onc, 2020;31 (suppl; abstr 6960). We hypothesize that if tumor specific immune responses to immunotherapy are greatest prior to nephrectomy, then treatment with nivolumab (nivo) and cabozantinib (cabo) prior to cytoreductive nephrectomy will lead to maximal peripheral and intra-tumoral specific immune responses and higher rates of CR during the course of treatment. Methods: This is an open label phase II, multicenter clinical trial of combination nivo and cabo prior to cytoreductive nephrectomy in patients with mRCC (NCT04322955). 48 treatment- naïve subjects with radiological or histological diagnosis of mRCC will be enrolled with the primary endpoint of CR rate according to RECIST version 1.1. Subjects will receive cabo (40mg) daily and nivo (480mg) every 4 weeks for 12 weeks prior to nephrectomy and a 3+3 design will be used to evaluate the safety of the interval (21 or 14 days) between the discontinuation of cabo and nephrectomy. Post-operatively, subjects will resume treatment with cabo and nivo until evidence of disease progression. Secondary endpoints include median size reduction of the primary tumor, response rate, PFS, OS, and surgical outcomes using the Clavien-Dindo classification system. Tissue based assays will quantify treatment related changes in the renal tumor microenvironment through polychromatic immunofluorescence, single cell RNA sequencing of the biopsy and nephrectomy specimen, and multiplex assessment of circulating serum cytokines. Dynamic contrast-enhanced MRI will be performed in a subset of subjects to assess radiologic correlates of response. The study is currently open to enrollment. Clinical trial information: AAAS6927 .

A phase II study of sitravatinib (Sitra) in combination with nivolumab (Nivo) in patients (Pts) undergoing nephrectomy for locally-advanced clear cell renal cell carcinoma (accRCC).

312 Background: Sitra is a spectrum-selective receptor tyrosine kinase inhibitor (TKI) that targets TAM receptors (TYRO3, AXL, MERTK), VEGFR2, c-Kit, and MET. These receptors regulate several immune suppressive cell types in the tumor microenvironment, including M2-polarized macrophages, MDSCs, and T regulatory cells, which are implicated in resistance to checkpoint inhibitors. ccRCC is characterized by upregulation of VEGF and overexpression of MET and AXL. Sitra may combine effectively with immune checkpoint inhibition to augment antitumor activity in ccRCC. About 39% of patients with accRCC who receive surgery with curative intent relapse representing an unmet need in this setting. Together these data support the evaluation of neoadjuvant sitra with nivo in accRCC. Methods: This phase II study (NCT03680521) evaluated sitra and nivo in pts with locally- advanced ccRCC who were candidates for curative nephrectomy. Single-agent sitra (120 mg) was administered daily (QD) for 2 weeks, with nivo (240 mg intravenously Q2W) added to sitra for 4-6 weeks. A plan for potential dose de-escalation was implemented using a modified toxicity probability interval method with a maximum toxicity of 20% at the tolerated dose. Pts underwent pathology/tissue evaluation at 3 timepoints: biopsy prior to treatment, biopsy prior to the addition of nivo, and nephrectomy specimen evaluation at time of nephrectomy. The primary endpoint was objective response (RECIST 1.1); secondary endpoints included safety, PK, and correlative immune effects (selected protein and gene expression and immune cell populations). Results: A total of 20 pts were evaluated for safety (95% had T3 or higher stage tumors, 65% with baseline hypertension). Dose-limiting toxicities (DLTs) led to a dose de-escalation, resulting in 7 pts treated at 120 mg QD sitra and 13 pts treated at 80 mg QD. DLTs included grade 3 (Gr3) hypertension (n=6); deep vein thrombosis and pulmonary embolism (Gr3) were observed in 1 additional pt. Median duration of sitra treatment was 6.3 weeks at the 80 mg dose and 7.1 weeks at the 120 mg dose. With a median follow-up of 9.4 months after initiation of systemic therapy, no pts have relapsed. In 17 pts evaluable for efficacy, the investigator-assessed confirmed ORR was 11.8%, including 2 PRs (33.3% ORR in pts who received 120 mg sitra). No pts experienced progressive disease while on therapy. Median DFS was not reached. There was 1 delayed surgery due to nivo-related thyroiditis that resolved. Reported TRAEs: Gr1/Gr2 in 55% of pts (dysphonia 50%, fatigue 45%, diarrhea 40%, hypertension 30%, increased ALT 30%), Gr3 in 45% of pts (hypertension 30%). There were no Gr4/Gr5 TRAEs. Correlative blood and tissue analyses will be presented. Conclusions: The combination of sitra and nivo is clinically active with a manageable safety profile as a neoadjuvant therapy for accRCC. Clinical trial information: NCT03680521 .

Accuracy of Subclassification and Grading of Renal Tumors on Fine Needle Aspiration Cytology Alone

Background: Fine needle aspiration (FNA) of renal masses can distinguish between benign and malignant neoplasms in 73–94% of cases. Previous studies suggested the correct subclassification of renal cell carcinomas (RCCs) by cytomorphology can be achieved in up to 80% of cases. However, as RCCs become increasingly subclassified by molecular signatures, correct subclassification based on cytology alone is increasingly difficult. Design: Two FNA passes (2 stained with Diff-Quik® and 2 with the Papanicolaou method) were performed on all fresh nephrectomy specimens for a 1-year period. There were 30 cases in this study, with 29 primary renal tumors and 1 case of metastatic lung adenocarcinoma. Each case was assigned a random number and came with 2 slides (1 from each staining method). Eight cytopathologists were asked to provide a diagnosis and the World Health Organization/International Society of Urological Pathology (WHO/ISUP) grading if applicable. Fleiss’ Kappa and Cohen’s Kappa equations were used to look at inter-rater variability. Results: When compared to the surgical pathology diagnosis, the average percent correct diagnosis for all cytopathologist was 35%. Chromophobe RCCs had the best average percent accuracy at 72% followed by clearcell RCC at 48%. Average accuracy for grading RCCs was 40%. Inter-rater variability among the cytopathologists for all RCC diagnoses was fair with a Fleiss’ Kappa coefficient of 0.28. For the WHO/ISUP grade, the weighted coefficient for each pathologist ranged from 0.11 to 0.45, ranging from fair to moderate, respectively. Conclusions: Renal tumors are difficult to classify on cytopathology alone. Core needle biopsy and ancillary studies are necessary if diagnosis will change management.

Evaluation of Non-Neoplastic Pathology in Tumour Nephrectomy Specimens

Evaluation of Non-Neoplastic Pathology in Tumour Nephrectomy Specimens

Role of routine nephrectomy for non-functioning kidneys due to genitourinary tuberculosis: Data from an Indian subcontinent

Objective: To evaluate the role of routine nephrectomy for tuberculous non-functioning kidney (TNFK) after receiving anti-tubercular therapy (ATT) by demonstrating whether live tubercle bacilli persist in nephrectomy specimens after treatment or not. Materials and methods: Patients with TNFK who underwent nephrectomy after completion of at least 6 months of ATT were included in this prospective cohort study. We sent tissue/pus from a nephrectomy specimen for acid-fast bacilli (AFB) staining, polymerase chain reaction (PCR) and culture to look for live bacilli. Bacilli were considered alive only if AFB culture was positive. Results: Twenty-four patients underwent nephrectomy for TNFK between April 2015 and October 2017 (18 laparoscopic and 6 open nephrectomy). Laparoscopic nephrectomy was associated with lower blood loss (225 ml versus 408 ml, p = 0.0003) and shorter hospital stay (3 versus 3.8 days, p = 0.06) compared with open nephrectomy; however, mean operative time and overall complications were similar. Eight specimens were AFB smear and/or tuberculosis PCR positive, out of which three showed viable bacilli upon culture. Drug sensitivity testing showed multi-drug resistant strain in all three patients who were treated with second-line ATT. Conclusion: It is preferable to do routine nephrectomy for TNFKs as they are more likely to harbour live bacilli and lead to disease recurrence. Viability testing for AFB must be performed on all operated specimens to identify drug resistant bacilli so that patients may be treated with second-line therapy if required. Level of evidence: 4.

Morphological findings in frozen non-neoplastic kidney tissues of patients with kidney cancer from large-scale multicentric studies on renal cancer

There are unexplained geographical variations in the incidence of kidney cancer with the high rates reported in Baltic countries, as well as eastern and central Europe. Having access to a large and well-annotated collection of “tumor/non-tumor” pairs of kidney cancer patients from the Czech Republic, Romania, Serbia, UK, and Russia, we aimed to analyze the morphology of non-neoplastic renal tissue in nephrectomy specimens. By applying digital pathology, we performed a microscopic examination of 1012 frozen non-neoplastic kidney tissues from patients with renal cell carcinoma. Four components of renal parenchyma were evaluated and scored for the intensity of interstitial inflammation and fibrosis, tubular atrophy, glomerulosclerosis, and arterial wall thickening, globally called chronic renal parenchymal changes. Moderate or severe changes were observed in 54 (5.3%) of patients with predominance of occurrence in Romania (OR = 2.67, CI 1.07–6.67) and Serbia (OR = 4.37, CI 1.20–15.96) in reference to those from Russia. Further adjustment for comorbidities, tumor characteristics, and stage did not change risk estimates. In multinomial regression model, relative probability of non-glomerular changes was 5.22 times higher for Romania and Serbia compared to Russia. Our findings show that the frequency of chronic renal parenchymal changes, with the predominance of chronic interstitial nephritis pattern, in kidney cancer patients varies by country, significantly more frequent in countries located in central and southeastern Europe where the incidence of kidney cancer has been reported to be moderate to high. The observed association between these pathological features and living in certain geographic areas requires a larger population-based study to confirm this association on a large scale.

A histopathological review of nephrectomy specimens with an emphasis on pathological assessment of prognostic indicators in malignant lesions

Introduction and Aim: Various non-neoplastic and neoplastic lesions occur in the kidney. Pathological assessment of gross and microscopic features in nephrectomy specimens is essential for diagnosis and predicts the prognosis in malignant tumours.&#x0D; Materials and Methods: Case records of 46 nephrectomy specimens received between two-year periods were retrieved. Detailed gross and histopathological and immunohistochemical features were studied, and malignant tumours were analysed using CAP protocol.&#x0D; Results: Out of 46 nephrectomy specimens, 17 were non-neoplastic and 29 neoplastic. Males constituted 32 cases and females 14 cases. The commonest non-neoplastic kidney lesion was chronic pyelonephritis with hydronephrosis (29%). The mixed epithelial and stromal tumour was the frequently encountered benign tumour (50%). Renal cell carcinoma was the most common malignant tumour in adults (70%) and Wilms tumour in children (4%).&#x0D; Conclusion: Histopathological examination of nephrectomy specimens helps in diagnosing, staging, and planning the management.