Alexander Sankin

TCEB1-mutated renal cell carcinoma: a distinct genomic and morphological subtype

Integrated sequencing analysis identified a group of tumors among clear cell renal cell carcinomas characterized by hotspot mutations in TCEB1 (a gene that contributes to the VHL complex to ubiquitinate hypoxia-inducible factor). We analyzed 11 tumors from two distinct cohorts with TCEB1 mutations along with an expanded cohort to assess whether these should be considered an entity distinct from clear cell renal cell carcinoma and clear cell papillary renal cell carcinoma. All tumors were characterized by hotspot mutations in TCEB1 Y79C/S/F/N or A100P. Morphological and immunohistochemical characteristics of the tumors were assessed by two experienced genitourinary pathologists. Clinical and pathological variables, copy number alterations, mutations, and expression signatures were compared with a cohort of TCEB1 wild-type tumors. All TCEB1-mutated tumors were VHL and PBRM1 wild type and contained distinct copy number profiles including loss of heterozygosity of chromosome 8, the location of TCEB1 (8q21.11). All tumors lacked the clear cell renal cell carcinoma signature 3p loss and contained distinct gene expression signatures. None of the clear cell papillary tumors harbored TCEB1 mutations. Pathologically, all TCEB1-mutated tumors shared characteristic features including thick fibromuscular bands transecting the tumor, pure clear cell cytology frequently with cells showing voluminous cytoplasm, and clear cell renal cell carcinoma-like acinar areas associated with infolding tubular and focally papillary architecture. The presence of voluminous cytoplasm, absence of luminal polarization of tumor nuclei, and lack of extensive cup-like distribution of carbonic anhydrase-IX expression distinguish it from clear cell papillary carcinoma. None of the patients developed metastases at last follow-up (median 48 months). In sum, TCEB1-mutated renal cell carcinoma is a distinct entity with recurrent hotspot mutations, specific copy number alterations, pathway activation, and characteristic morphological features. Further clinical follow-up is needed to determine whether these tumors are more indolent compared with the conventional clear cell renal cell carcinoma.

Metastatic Non-Clear Cell Renal Cell Carcinoma: An Evidence Based Review of Current Treatment Strategies

Much progress has been made in the treatment of metastatic renal cell carcinoma (RCC) over the last decade, with the development of agents that block the vascular endothelial growth factor (VEGF) pathway or the mammalian target of rapamycin (mTOR) pathway. The incorporation of these agents into treatment algorithms has been the result of carefully conducted clinical trials leading to Food and Drug Administration (FDA) approval and subsequent adoption as the current standard of care. These trials, however, were dominated by patients with clear cell renal cell carcinoma (ccRCC), and little data are currently available on the treatment of non-clear cell renal cell carcinoma (nccRCC). nccRCC encompasses a biologically heterogeneous group of kidney tumors that portend very diverse prognoses and responses to therapy. This review is a pathway based approach that highlights the current systemic treatment strategies for metastatic nccRCC.

Subcentimeter Pulmonary Nodules are Not Associated with Disease Progression in Patients with Renal Cell Carcinoma

PURPOSE Renal cell carcinoma most commonly metastasizes to the lung. Indeterminate pulmonary nodules develop preoperatively in half of the patients with localized renal cell carcinoma but clinical significance remains poorly defined. We determined whether the presence of indeterminate pulmonary nodules, or nodule size or number is associated with renal cell carcinoma outcomes. MATERIALS AND METHODS We reviewed data on 1,102 patients with renal cell carcinoma in whom chest computerized tomography was done within 6 months before nephrectomy from 2002 to 2012. Patients with metastatic disease at presentation, benign tumors, pulmonary nodules greater than 2 cm or concurrent pulmonary disease were excluded, leaving 748 available for analysis. Study outcomes included lung metastasis, any distant metastasis or death from renal cell carcinoma. Cox proportional hazards models were used to assess whether the presence of indeterminate pulmonary nodules, or nodule size or number was associated with outcomes. Models were evaluated by comparing discrimination using the Harrell c-index. RESULTS Indeterminate pulmonary nodules were present in 382 of 748 patients (51%). Median followup was 4.1 years (IQR 2.2-6.1). The presence of indeterminate pulmonary nodules was not associated with distant metastasis or death from kidney cancer. However, compared to subcm indeterminate pulmonary nodules the nodules greater than 1 cm were associated with metastatic disease after adjusting for tumor histology, stage and size (HR 2.48, 95% CI 1.08-5.68, p = 0.031). The outcome c-index increased slightly after adding nodule size to a predictive model adjusted for tumor characteristics. CONCLUSIONS No evidence in the current study suggested that indeterminate pulmonary nodules less than 1 cm are associated with renal cell carcinoma progression, although large nodules significantly predicted metastatic disease. Patients with subcm indeterminate pulmonary nodules would be unlikely to benefit from extensive postoperative chest imaging surveillance, which should be reserved for patients with nodules greater than 1 cm.

Validation and genomic interrogation of the MET variant rs11762213 as a predictor of adverse outcomes in clear cell renal cell carcinoma

The exonic single‐nucleotide variant rs11762213 located in the MET oncogene has recently been identified as a prognostic marker in clear cell renal cell carcinoma (ccRCC). This finding was validated with The Cancer Genome Atlas (TCGA) cohort, and the biologic implications were explored.

Pathological Stage T3a Significantly Increases Disease Recurrence across All Tumor Sizes in Renal Cell Carcinoma

PURPOSE Tumor size and stage are important prognostic parameters in renal cell carcinoma. While pathological stage T1 and T2 are defined by size alone, the presence of certain intrinsic features can up stage a tumor to pathological stage T3a regardless of size. We investigate the effect of pathological tumor stage on the relationship between tumor size and risk of disease recurrence. MATERIALS AND METHODS Data were reviewed on patients who underwent nephrectomy at our institution between 2006 and 2013 to identify all those with pathological stage T1, T2 and T3a tumors. A proportional hazards Cox model was built with time to recurrence as outcome, and pathological stage and tumor size as covariates. An interaction term for stage and tumor size was included. RESULTS The final cohort included 1,809 patients. On multivariable analysis, when adjusted for tumor size, patients with pT3a tumors had a greater risk of tumor recurrence compared to those with pT1/T2 tumors (HR 3.70; 95% CI 2.31, 5.92; p <0.0001). The risk of disease recurrence increased more rapidly as tumor size increased only with the presence of perinephric fat invasion (p=0.006). CONCLUSIONS Using the AJCC 2010 staging criteria we validated pathological stage T3a as a poor prognostic factor in renal cell carcinoma regardless of tumor size. Our results also demonstrated an increased rate of risk of recurrence with perinephric fat invasion. Given this increased risk of recurrence, even in tumors less than 4 cm, closer surveillance is warranted in such cases and the role of perinephric involvement necessitates further investigation.

Factors That Affect Proportional Glomerular Filtration Rate After Minimally Invasive Partial Nephrectomy

BACKGROUND AND PURPOSE Several factors have been shown to impact the overall glomerular filtration (GFR) rate after partial nephrectomy. Change in overall GFR, however, does not necessarily reflect the impact of these factors on the operated kidney. Using preoperative and postoperative renal scintigraphy, we sought to assess the impact of patient, tumor, and operative factors on GFR of the affected kidney (proportional GFR). PATIENTS AND METHODS We identified 73 patients who underwent minimally invasive partial nephrectomy with preoperative and postoperative renal scans from two institutions. Patient, tumor, and operative characteristics were recorded. We used multiple linear regression to determine the patient and clinical factors predictive of postoperative proportional GFR in the operated kidney. We tested for an interaction between preoperative proportional GFR and nephrometry score and ischemia. We further fitted two separate linear models to compare the proportion of variance (R(2)) explained by ischemia time in change in renal function in the operated kidney with the change in renal function in both kidneys. RESULTS Surgical parameters (procedure approach, ischemia time, and estimated blood loss) and preoperative proportional GFR were significantly associated with postoperative proportional GFR. Preoperative proportional GFR (β=5.93, 95% confidence interval [CI]: 3.88, 7.97, P<0.0005) and procedure approach (β=8.67, 95% CI: 4.50, 12.80, P<0.0005) were strongly associated with outcome while ischemia time (β=-1.80, 95% CI: -3.48, -0.11, P=0.04) and estimated blood loss (β=-1.15, 95% CI: -0.29, -0.01, P=0.04) just reached statistical significance. The interaction term between preoperative proportional GFR and nephrometry score or ischemia time was not statistically significant (nephrometry, P=0.2 continuous or P=0.6 categorical, and ischemia, P=0.7, respectively). CONCLUSION Lower preoperative proportional GFR, longer ischemia times, and higher blood loss all negatively impact postoperative proportional GFR while tumor complexity as gauged by morphometry scoring does not. Larger studies are needed to determine whether renal scintigraphy is a more accurate method of measuring the impact of the ischemia time on postoperative proportional GFR.

Oncological Outcomes of Sequential Intravesical Gemcitabine and Docetaxel in Patients with Non-Muscle Invasive Bladder Cancer

Background: Bacillus Calmette-Guérin (BCG) unresponsive/relapsing patients with non-muscle invasive bladder cancer (NMIBC) who prefer bladder preservation over radical cystectomy (RC) or those who do not qualify for surgery may be offered intravesical therapies. Gemcitabine (GEM) combined with Docetaxel (DOCE) has been offered at Johns Hopkins Hospital (JHH). Objective: To evaluate experience with GEM/DOCE, to confirm safety of the regimen, to identify populations that may benefit most, and to consider the appropriate endpoints for judging efficacy of second line therapies. Methods: Thirty-three patients who received full induction GEM/DOCE since 2011, per the protocol adapted from U. Iowa, were identified and characterized. Multivariable logistic regression was used to determine factors associated with recurrence. Cox proportional hazard models evaluated risk factors for disease-free survival (DFS) and high-grade recurrence-free survival (HG-RFS). Results: There were no serious adverse effects of therapy. Across all patients, median follow-up time was 18.6 months with a median DFS of 6.5 months, 42% 1-year, and 24% 2-year DFS. Median HG-RFS was 17.1 months with 56% 1-year and 42% 2-year HG-RFS. Among patients initially presenting with HG-NMIBC, 46% (13/28) had HG recurrence. BCG unresponsive/relapsing patients (N = 25) displayed 49% 1-year HG-RFS and 34% 2-year HG-RFS. In total, there were 5 LG and 16 HG recurrences, with 5 progressions and 8 cystectomies among these. Conclusions: GEM/DOCE is a well-tolerated therapy that deserves further study as an alternative to immediate RC for highly selected patients with HG-NMIBC. BCG naïve patients responded more effectively than BCG unresponsive/relapsing patients. As anticipated, GEM/DOCE efficacy was improved for HG only patients.

Surgical Treatment of Tumors Involving Kidneys With Fusion Anomalies: A Contemporary Series.

OBJECTIVE To report a contemporary series of surgically treated patients with tumors involving kidneys with fusion anomalies. MATERIALS AND METHODS We retrospectively reviewed the medical records of all 10 patients treated at a single tertiary care institution for tumors involving kidneys with fusion anomalies between the years 2000 and 2015. One patient, diagnosed with lymphoma, did not undergo surgical treatment and was therefore excluded. Data regarding patient, tumor, and treatment characteristics were collected and described. RESULTS The study cohort included 7 male and 2 female patients, at a median age of 52 years. Seven patients underwent open partial nephrectomy. Nephroureterectomy was performed on 2 patients; 1 open and 1 laparoscopic. All patients had localized disease at diagnosis. Tumor histologies were renal cell carcinoma in 5 patients, renal oncocytoma in 1 patient, urothelial carcinoma in 2 patients, and a well-differentiated liposarcoma involving the kidney in 1 patient. Accessory blood vessels were identified in 8 of 9 patients. Median estimated blood loss was 300 mL (interquartile range: 150-1000). Four patients had postoperative complications, including 3 major (Clavien grade ≥ 3) and 3 minor (Clavien grade ≤ 2) complications. During a median follow-up of 19.2 months (interquartile range: 3-34.8), 1 patient with urothelial carcinoma developed a bladder recurrence. None of the patients developed new-onset chronic kidney disease during the early postoperative period. CONCLUSION Localized renal cortical tumors in kidneys with fusion anomalies may be treated with partial nephrectomy; however, complication rates are relatively high. Preoperative imaging of the blood vessels is necessary, as most patients have an accessory blood supply.

MP58-14 USING T CELL RECEPTOR SEQUENCING TO CHARACTERIZE THE HOST IMMUNE RESPONSE IN UROTHELIAL CARCINOMA

INTRODUCTION AND OBJECTIVES: High T cell receptor (TCR) repertoire clonality is associated with clinical response to immune checkpoint blockade in bladder cancer (Funt et al ASCO 2016). We hypothesized that T cell repertoire is more clonal in tumors than in benign inflammation. METHODS: After obtaining IRB approval, we prospectively identified n1⁄412 patients with bladder lesions at Montefiore Medical Center undergoing transurethral resection. Specimens were collected at time of transurethral resection and frozen and stored at -80C. DNA was extracted and high throughput DNA sequencing of the CDR3 region of the TCR beta chain using the immunoSEQ assay (Adaptive Biotechnologies) was performed. T cell fraction, clonal dominance, and maximum frequency of TCR clone were assessed. RESULTS: There was an even distribution of specimens across all pathologic stages: 3/12 were T0, 3/12 were Ta, 3/12 were T1, and 3/ 12 were T2 or greater. The median number of productive TCR rearrangements sequenced in each sample in urothelial carcinoma specimens (UCþ) and benign (UC-) specimens was 5,569 and 25,872 respectively. The median number of unique TCR rearrangements sequenced in UCþ and UCspecimens was 3,069 and 9,680, respectively. The median tumor infiltrating lymphocyte (TIL) percentage in UCþ and UCspecimens was 2% and 12%, respectively. The UCþ specimens demonstrated clonality as evidenced by identification of a specific T cell clone being present in up to 17% of the total TIL pool; in contrast, the frequency of the max T cell clone was 2% in UCspecimens (Figure 1). CONCLUSIONS: Primary urothelial tumors contain clonally expanded T cell populations that are not present in benign urothelial inflammation. These data support the hypothesis that bladder tumors induce an antigen driven immunogenic host response, in contrast to the benign inflammatory response, which does not appear to demonstrate any T cell clonal dominance. Future studies should be aimed to validate these results and to identify which tumor derived antigens are of clinical significance.

Synchronous Bone Metastasis from Multiple Myeloma and Prostate Adenocarcinoma as Initial Presentation of Coexistent Malignancies

The radiographic appearance of bone metastases is usually determined by tumor histology and can be osteolytic, osteoblastic, or mixed. We present a patient with coexistent bone metastasis from multiple myeloma and prostate adenocarcinoma who exhibited synchronous bone involvement of both histologies within the same bone lesion, a rare phenomenon that has not been previously reported and led to atypical radiographic findings. The radiograph of a 71-year-old man with thigh swelling and pain demonstrated a lytic femoral lesion. Magnetic resonance imaging (MRI) confirmed a destructive process, but showed coexistent metaphyseal sclerosis. Multiple myeloma was suspected by demonstration of monoclonal gammopathy and confirmed by computed tomography (CT)-guided biopsy. Incidentally, CT demonstrated areas of sclerosis corresponding to T2 hypointensity on MRI. Further studies revealed osteoblastic spinal metastasis, prostate enhancement on CT and prostate-specific antigen (PSA) level of 90 ng/mL, concerning for concomitant prostate neoplasm. After endoprosthetic reconstruction, pathology of the femur identified both plasma cell neoplasm and metastatic prostate adenocarcinoma. An association between prostate cancer and multiple myeloma is hypothesized due to tumor microenvironment similarities and possible common genetic variations, however, coexisting bone metastases have never been reported. This unusual finding explains the discrepant imaging features in our patient and is evidenced that certain clinical situations merit contemplation of atypical presentations of common malignancies even if this leads to additional testing.