Long-term treatment outcomes of patients with non-clear cell renal cell carcinoma

Objective: to analyze factors affecting relapse-free and overall survival of patients with non-metastatic non-clear cell renal cell carcinoma (nccRCC) after surgical treatment.Materials and methods. This study included 279 (13.62 %) nccRCC patients from the database containing information on 2049 patients with localized and locally advanced renal cell carcinoma (RCC) without distant metastases who underwent surgical treatment in the Department of Urologic Oncology, P.A. Herzen Moscow Oncology Research Institute between 2002 and 2018. Gender ratio was 1.36:1 (161 men (57.7 %) and 118 women (42.3 %)). Median follow-up time was 34.5 months (range: 1-141 months). Patients had undergone either radical nephrectomy (n = 117; 41.9 %) or kidney resection (n = 160; 57.4 %) or radiofrequency thermal ablation (n = 2; 0.7 %). Standard (open) transperitoneal approach was used in 135 patients (48.4 %) patients, whereas 144 (51.6 %) patients were operated on via laparoscopic approach. Postoperative histological examination demonstrated that 110 participants (39.4 %) had chromophobe RCC, while 79 (28.3 %) and 63 (22.6 %) individuals had type 1 and type 2 papillary RCC, respectively. Twenty-seven patients were found to have rare or mixed variants of nccRCC (they were excluded from the analysis due to their relatively small number). Patients were diagnosed with the following stages of cancer: рТ1а (n = 129; 46.2 %), pT1b (n = 72; 25.8 %), рТ2а (n = 18; 6.5 %), pT2b (n = 8; 2.9 %), рТ3а (n = 31; 11.1 %), pT3b (n = 4; 1.4 %), рТ4 (n = 1; 0,4 %), and pN+ (n = 16; 5.7 %).Results and conclusion. 13 patients (4.7 %) were diagnosed progressive disease; 9 patients (3.2 %) died due to nccRCC progression. The highest relapse-free and overall survival rates were registered in the patients with type 1 papillary RCC and chromophobe RCC.Spearman's correlation analysis showed a significant correlation between the risk of disease progression and tumor size (R = 0.23; p <0.0001), pT stage (R = 0.24; p = 0.0001), vascular invasion (R = 0.36; p <0.0001), pN+ stage (R = 0.4; p <0.0001), surgical resection margin (R = 0.5; p <0.0001), histological variant (R = 0.14; p = 0.02), and Furman differentiation grade (R = 0.16; p = 0.02). The following factors were found to have an impact on relapse-free survival according to multivariate Cox regression: presence of necrosis (p = 0.04), pT stage (p = 0.03), and vascular invasion (p = 0.08), although the last variable failed to reach statistical significance. Cancer-specific survival was significantly affected by pT stage (p = 0.01) and Furman differentiation grade (p = 0.04). None of the factors demonstrated significant associations with overall survival. Thus, the most significant prognostic factor affecting relapse-free, overall, and cancer-specific survival in nccRCC patients was the pT stage (p <0.05).

GATA3 Is a Useful Immunohistochemical Marker to Differentiate Variants of Renal Tubular Lesions from Different Segments of Renal Tubules

Introduction/Objective GATA3 is found in glomerular mesangial cells, and the distal tubules & collecting ducts in metanephros and eventual kidneys, but not associated with the proximal tubules and loops of Henle. We hypothesize that GATA3 can be used as a marker to identify the origin of tubular differentiation in most renal tumors. Methods/Case Report Ten negative controls and 43 renal mass lesions (RCC, papillary, clear cell papillary, and chromophobe carcinomas, oncocytoma, and polycystic kidney disease). GATA3 nuclear stain was graded as negative (absent stain), equivocal and positive (&lt; 5 and &gt; 5% cells, respectively). Details of their GATA3 nuclear expression was analyzed for identifying their tubular segmental origins. Results (if a Case Study enter NA) In 10 normal renal parenchyma, GATA3 was positive in mesangial cells, distal tubules, and collecting ducts, but was negative in the proximal tubules and loop of Henle. The cystic lining of glomerulocystic renal disease was stained negatively for GATA3 (proximal tubular origin), whereas pediatric and adult variants of polycystic kidney diseases was positive for GATA3 staining (distal tubular origin). 1/10 ten clear cell RCC and papillary RCC showed focal positive GATA3 stain. GATA3 showed weakly positive staining in some oncocytomas (4/11) and some chromophobe RCC (4/11), indicating that they might be derived from the junctional segment between the loop of Henle and the distal tubules. By contrast, all clear cell papillary RCC (distal tubule origin) were diffusely positive. Conclusion Our results indicate that GATA3 is a useful immunohistochemical marker to determine the developmental origin in the specific renal tubular segment for the majority of renal mass lesions. Thus, it may be useful for routine differential diagnosis of these lesions.

Various Histological Types of Renal Cell Carcinoma Associated With Hereditary Papillary Renal Cell Carcinoma (HPRCC): a Case Report

Background: Hereditary papillary renal cell carcinoma (HPRCC) is a rare autosomal dominant disease characterized by the development of multiple and bilateral papillary type I renal cell carcinomas (RCC) and papillary adenomas caused by activating mutations in the MET proto-oncogene. Classically, distinctive histological features of RCC are described according to the familial renal cell carcinoma syndrome. To date, no clear cell RCC has been reported in HPRCC syndrome. Case presentation: We describe the case of a 51-year-old man with a germline MET mutation, who developed numerous papillary tumors but also unexpectedly clear cell renal cell carcinomas. During the follow-up, an adrenal metastasis was observed seven years after the initial diagnosis corresponding to a clear cell RCC metastasis. Using FISH, the metastatic tumor presented a trisomy of chromosomes 7 and 17. These genomic alterations are usually detected in papillary RCC, highlighting the potential link between both histological subtypes of tumors and the HPRCC syndrome.Conclusions: The pathologist must be aware that the presence of a non-papillary RCC associated with numerous papillary tumors should not exclude the diagnostic suspicion of HPRCC and thus to perform a thorough genomic study.

Ιστική μελέτη στην επιθήλιο-μεσεγχυματική μετατροπή σε νεφροκυτταρικό καρκίνωμα

Το φαινόμενο της επιθηλιομεσεγχυματικής μετατροπής είναι η διεργασία κατά την οποία ένα επιθηλιακό κύτταρο αποκτά φαινότυπο μεσεγχυματικού κυττάρου. Η μετατροπή αυτή στον φαινότυπο του επιθηλιακού κυττάρου απαιτεί την δημιουργία ενός νέου μοριακού προγράμματος του επιθηλιακού ιστού με νέες βιοχημικές οδηγίες. Η ΕΜΤ συμμετέχει σε φυσιολογικές καθώς και σε παθολογικές διεργασίες του οργανισμού. Σκοπό της παρούσας ερευνητικής δραστηριότητας αποτέλεσε η διερεύνηση της ανοσοιστοχημικής πρωτεινικής συνέκφρασης των μορίων ε-καντχερίνης και βιμεντίνης σε σειρά καρκινωμάτων νεφρού διάφορης ιστολογικής τυποποίησης και η συσχέτισή τους με τα κλινικοεργαστηριακά χαρακτηριστικά τους γνωρίσματα. Το υλικό αναδύθηκε από την αρχειακή ιστική βάση του Παθολογο-ανατομικού Τμήματος του Γενικού Νοσοκομείου Αθηνών ‘’ΕΛΠΙΣ’’ και αφορούσε σε - εμπεδωμένα σε κύβους παραφίνης – εκατό (n=100) σποραδικά πρωτοπαθή καρκινώματα νεφρού (RCC), προιόντα νεφρεκτομής. Παθολογοανατομικά ταξινομημένα σύμφωνα με τα ιστολογικά κριτήρια της WHO και όσον αφορά τη διαφοροποίηση βαθμονομημένα με το σύστημα κατά Furhman. Τα εξετασθέντα καρκινώματα αφορούσαν σε 75 διαυγοκυτταρικού τύπου (clear cell RCC), 13 θηλώδους τύπου (papillary RCC) και 12 χρωμόφοβου τύπου (chromophobe RCC). Σύμφωνα με τη συνδυασμένη συμβατική και ψηφιακή ανάλυση, υποέκφραση ή απώλεια της έκφρασης της ε-καντχερίνης παρατηρήθηκε σε 52 περιπτώσεις (52%), ενώ οι υπόλοιπες 48 (48%) χαρακτηρίστηκαν από μετρίου εώς ισχυρού βαθμού ανοσοέκφραση. Όσον αφορά τον ιστολογικό τύπο των εξετασθέντων περιστατικών, απώλεια της έκφρασης της ε-καντχερίνης συσχετίσθηκε περισσότερο με τα διαυγοκυτταρικά και θηλώδους τύπου (p=0.001). Ενδιαφέρουσα παρατήρηση αποτελεί ακόμη η προοδευτική απώλεια της έκφραση του μορίου σε σχέση με το βαθμό διαφοροποίησης του νεοπλάσματος κατά ταξινόμηση Fuhrman’s grade classification (p=0.002). Yποέκφραση ή απώλεια της έκφρασης της βιμεντίνης παρατηρήθηκε σε 19 περιπτώσεις (19%), ενώ οι υπόλοιπες 81 (81%) χαρακτηρίστηκαν από μετρίου εώς ισχυρού βαθμού ανοσοέκφραση. Όσον αφορά τον ιστολογικό τύπο των εξετασθέντων περιστατικών, απώλεια της έκφρασης της βιμεντίνης συσχετίσθηκε περισσότερο με τα διαυγοκυτταρικά και θηλώδους τύπου (p=0.001).

Diffusion kurtosis imaging features of renal cell carcinoma: a preliminary study

Objective: To explore the feasibility of diffusion kurtosis imaging (DKI) in differentiating different types of renal cell carcinoma (RCC). Methods: 36 patients with clear cell RCC (CCRCC, low-grade,n = 20 and high-grade, n = 16), 19 with papillary RCC, 11 with chromophobe RCC, and 9 with collecting duct carcinoma (CDC) were examined with DKI technique. b values of 0, 500 and 1000 s/mm2 were adopted. The DKI parameters, i.e., mean diffusivity (MD), mean kurtosis (MK), kurtosis anisotropy (KA), radial kurtosis (RK) and signa-to-noise ration (SNR) of DKI images at different b values were used. Results: The mean SNRs of DKI images at b = 0, 500 and 1000 s/mm2 were 32.8, 14.2 and 9.18, respectively. For MD parameter, a significant higher value was shown in CCRCC than those of papillary RCC, chromophobe RCC and CDC (p < 0.05). In addition, both chromophobe RCC and CDC have larger MD values than papillary RCC (p < 0.05), however, there was no significant differences between chromophobe RCC and CDC (p > 0.05). For MK, KA and RK parameters, a significant higher value was shown in papillary RCC than those of CCRCC, chromophobe RCC and CDC (p < 0.05). Moreover, both chromophobe RCC and CDC have significantly larger values of MK, KA and RK than CCRCC (p < 0.05). Conclusion: Our preliminary study demonstrated significant differences in the DKI parameters between the subtypes of RCCs, given an adequate SNR of DKI images. Advances in knowledge: 1.The MD value is the best parameter to distinguish CCRCC from other RCCs. 2.The MK, KA and RK values are the best parameters to distinguish papillary RCC from other RCCs. 3.DKI is able to provide images with sufficient SNRs in kidney disease.

Papillary Renal Cell Carcinoma in Lynch/Muir-Torre Syndrome with Germline Pathogenic Variant in MSH6 and Molecular Analysis

Lynch syndrome (LS) is an autosomal dominant inherited disorder due to pathogenic variations in the mismatch repair genes, which predisposes to malignancies, most commonly colon and endometrial carcinoma. Muir-Torre syndrome is a subset of LS with cutaneous sebaceous adenoma and keratoacanthoma in addition to the malignancies. Renal cell carcinoma (RCC) in patients with LS is extremely rare. Only 26 cases have been reported and among them, only two cases of papillary RCC. We report a case of synchronous papillary RCC and colonic adenocarcinoma in an 85-year-old male with Lynch/Muir-Torre syndrome. The LS was diagnosed when he presented with multiple sebaceous adenomas and genetic testing showed a pathogenic variant in MSH6 mismatch repair gene. A colonoscopy at that time showed multiple tubular adenomas with high-grade dysplasia. He was lost to follow-up and presented with gastrointestinal bleeding after 20 years. A right colonic mass, and a solid mass in the lower pole of the right kidney, was detected by imaging. Right Colectomy showed a T3N0 mucin-producing adenocarcinoma. Right nephrectomy showed a T3a papillary RCC which was microsatellite stable with MSH6, and KRAS mutation. The 36-month follow-up exams showed additional sebaceous neoplasms, and an absence of metastatic carcinoma. Analysis of the reported cases of RCC in LS show clear cell RCC as the most common type. These tumors showed MLH1 mutation most commonly, unlike the urothelial malignancies in LS which involve MSH2. Among the 4 cases of RCC with MSH6 mutation, three were in females, indicating some gender differences.

Tumor cell PD-L1 expression is a strong predictor of unfavorable prognosis in immune checkpoint therapy-naive clear cell renal cell cancer

Background PD-L1 expression predicts response to immune checkpoint inhibitors in renal cell carcinomas (RCC), but has also been suggested to be linked to poor patient outcome. Methods We analyzed PD-L1 in > 1400 RCC in a tissue microarray format by immunohistochemistry. Results were compared with histological tumor type, parameters of cancer aggressiveness, and intratumoral CD8+ cytotoxic cells. Result At a cut-off level of 5% PD-L1 positive tumor cells, PD-L1 positivity was seen in 6.3% of 633 clear cell RCC (ccRCC), 18.2% of 165 papillary RCC, 18.8% of 64 chromophobe RCC, and 41.7% of 103 oncocytomas. In ccRCC, PD-L1 positivity was significantly linked to high ISUP (p < 0.0001), Fuhrman (p < 0.0001), Thoenes grade (p < 0.0001), distant metastasis (p = 0.0042), short recurrence-free (p < 0.0001), and overall survival (p = 0.0002). Intratumoral CD8+ lymphocytes were more frequent in PD-L1 positive (1055 ± 109) than in PD-L1 negative ccRCC (407 ± 28; p < 0.0001). PD-L positive immune cells were seen in 8.2% of all RCC and 13.9% of papillary RCC. In ccRCC, PD-L1 positive immune cells were linked to high numbers of tumor-infiltrating CD8+ cells (p < 0.0001), high ISUP (p < 0.0001), Fuhrman (p = 0.0027), and Thoenes grade (p < 0.0001), and poor tumor-specific survival (p = 0.0280). Conclusions These data suggest that PD-L1 expression in highly immunogenic RCCs facilitates immune evasion and contributes to cancer aggressiveness.

Clinical utility of FDG PET/CT for primary and recurrent papillary renal cell carcinoma

Purpose Papillary renal cell carcinoma (RCC) is the second most common subtype of RCC, after clear cell RCC. This study aimed to investigate the usefulness of FDG PET/CT in primary and recurrent papillary RCC, and the role of staging FDG PET/CT in predicting survival. Methods A total of 66 patients with histopathologically confirmed papillary RCC who underwent either staging or restaging FDG PET/CT scans (30 had staging scans only, 28 had restaging scans only, 8 had both) were retrospectively included in this study. The sensitivity and specificity of restaging FDG PET/CT for detecting recurrence were assessed by histopathology and/or clinical follow-up as standard reference. Results Staging FDG PET/CT scans were performed in 38 patients, of which 31 (81.5%) showed FDG-positive primary renal lesions. The SUVmax of high-grade (WHO grade 3 and 4) papillary RCCs were significantly higher than that of low-grade (WHO grade 1 and 2) tumors (9.44 ± 6.18 vs 4.83 ± 3.19, P = 0.008). The SUVmax was not significantly different between type 1 and type 2 papillary RCCs (5.71 ± 2.88 vs. 6.99 ± 5.57, P = 0.563). Of the 38 patients, 12 developed disease progression during the follow-up period. Patients with primary tumor SUVmax> 5.85 were associated with significantly shorter progression-free survival (PFS) than those with tumor SUVmax≤5.85 (P = 0.005). Restaging FDG PET/CT scans were performed in 36 patients with suspected recurrent papillary RCCs. FDG PET/CT showed a sensitivity and specificity of 100 and 72.7% for detecting recurrent disease. Comparison of PET/CT scans with CT/MRI imaging was available in 23 patients. FDG PET/CT revealed additional findings in 11 patients, mainly including lymph node and bone metastases. FDG PET/CT findings led to change in management in 5.3% (2/38) of patients in the staging setting and 16.7 (6/36) of patients in the restaging setting. Conclusions FDG PET/CT had a sensitivity of 81.5% for detecting primary papillary RCC, and tumor SUVmax derived from staging FDG PET/CT was a predictor of PFS. In the restaging process of papillary RCC, FDG PET/CT was very effective for detecting recurrent disease.

Detection of a peritumoral pseudocapsule in patients with renal cell carcinoma undergoing robot-assisted partial nephrectomy using enhanced MDCT

To investigate the detection of peritumoral pseudocapsule (PC) using multi-detector row computed tomography (MDCT) for tumors resected by robot-assisted laparoscopic partial nephrectomy (RAPN) for T1 renal cell carcinoma (RCC). Study participants included 206 patients with clinical T1 RCC who underwent RAPN between October 2017 and February 2018. Two radiologists who were blinded to the pathological findings evaluated the computed tomography (CT) images. Radiological diagnosis of a PC was defined by a combination of observations, including a low-attenuation rim between the tumor and renal cortex in the cortico-medullary phase and a high-attenuation rim at the edge of the tumor in the nephrogenic or excretory phase. A PC was detected on CT in 156/206 tumors (76%) and identified by pathology in 182/206 (88%) tumors including 153/166 (92%) clear cell RCC, 13/14 (93%) papillary RCC, and 7/16 (44%) chromophobe RCC. In the whole cohort, CT findings showed a sensitivity of 81.3% (148/182), specificity of 66.7% (16/24), and positive predictive value of 94.9% (148/156). When the data were stratified according to pathological subtypes, MDCT was observed to have a sensitivity of 86.9% (133/153) and specificity of 61.5% (8/13) in clear cell RCC, sensitivity of 38.5% (5/13) and specificity of 100% (1/1) in papillary RCC, and sensitivity of 44.4% (4/7) and specificity of 66.7% (6/9) in chromophobe RCC. A low or high-attenuation rim around the tumor in the cortico-medullary or nephrographic-to-excretory phase indicates a PC of RCC, though the accuracy is not satisfactory even with 64- or 320-detector MDCT.