The Use of Lurbinectedin for the Treatment of Small Cell and Neuroendocrine Carcinoma of the Prostate.

INTRODUCTION: Lurbinectedin is FDA approved for treatment of metastatic small cell lung cancer (SCLC) following progression on or after platinum-based chemotherapy. Prostatic small cell or neuroendocrine carcinoma (SC/NEPC) behaves like SCLC; however, no safety or efficacy data for lurbinectedin in SC/NEPC exists. PATIENTS AND METHODS: All SC/NEPC patients treated with lurbinectedin across 4 academic oncology centers were identified. Baseline patient data and lurbinectedin outcomes including radiographic responses (complete response [CR], partial response [PR], stable disease [SD], progressive disease [PD]), progression free survival (PFS), overall survival (OS), and treatment-related adverse events (trAEs) were described. Clinical benefit rate (CBR) included CR, PR, or SD on imaging. Descriptive statistics were performed. RESULTS: At first lurbinectedin dose, all 18 patients had metastatic disease. Median age was 63.5 (Range: 53-84), number of prior systemic therapies was 4 (Range: 2-7), and lurbinectedin cycles completed was 5 (Range: 1-10). ADT was administered during lurbinectedin treatment in 9/18 patients. CBR was 9/16 (56%). The most common trAEs were fatigue and anemia. Median OS and PFS were 6.01 (0.23-16.69) and 3.35 (0.16-7.79) months. CONCLUSIONS: Lurbinectedin showed modest but significant clinical benefit in some patients with SC/NEPC and demonstrated an acceptable toxicity profile with no hospitalizations from trAEs. SC/NEPC is an aggressive disease with a poor prognosis for which more treatment options are needed. Evidence for subsequent treatments after platinum-based chemotherapy is lacking. Lurbinectedin is an active treatment option for SC/NEPC; however, larger confirmatory studies are needed.

Single nucleotide polymorphism (SNP) chromosomal microarray as a diagnostic tool for mucinous tubular and spindle cell carcinoma: A validation study.

Mucinous tubular and spindle cell carcinoma (MTSCC) shows significant overlap with papillary renal cell carcinoma (PRCC), and harbor recurrent copy-number alterations (CNA). We evaluated 16 RCC with features suggestive of MTSCC using chromosomal microarrays. The cohort was comprised of 8 females and males, each, with an age range of 33-79 years (median, 59), and a tumor size range of 3.4-15.5 cm (median, 5.0). Half the tumors were high-grade (8/16, 50%) with features such as necrosis, marked cytologic atypia, and sarcomatoid differentiation, and 5/16 (31%) were high stage (≥pT3a). Three (of 16, 19%) cases had a predominant (>95%) spindle cell component, whereas 5/16 (31%) were composed of a predominant (>95%) epithelial component. Most cases (12/16, 75%) exhibited a myxoid background and/or extravasated mucin, at least focally. Twelve (of 16, 75%) cases demonstrated CNA diagnostic of MTSCC (losses of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22). In addition, 2 high-grade tumors showed loss of CDKN2A/B, and gain of 1q, respectively, both of which are associated with aggressive behavior. Three (of 16, 19%) cases, demonstrated nonspecific CNA, and did not meet diagnostic criteria for established RCC subtypes. One (of 16, 6%) low-grade epithelial predominant tumor (biopsy) demonstrated characteristic gains of 7, 17, and loss of Y, diagnostic of PRCC. MTSCC can be a morphologically heterogenous tumor. Our study validates the detection of characteristic chromosomal CNA for diagnostic use that may be useful in challenging cases with unusual spindle cell or epithelial predominant features, as well as in high-grade tumors.

Extensive intratumor regional epigenetic heterogeneity in clear cell renal cell carcinoma targets kidney enhancers and is associated with poor outcome.

BACKGROUND: Clear cell renal cell cancer (ccRCC), the 8th leading cause of cancer-related death in the US, is challenging to treat due to high level intratumoral heterogeneity (ITH) and the paucity of druggable driver mutations. CcRCC is unusual for its high frequency of epigenetic regulator mutations, such as the SETD2 histone H3 lysine 36 trimethylase (H3K36me3), and low frequency of traditional cancer driver mutations. In this work, we examined epigenetic level ITH and defined its relationships with pathologic features, aspects of tumor biology, and SETD2 mutations. RESULTS: A multi-region sampling approach coupled with EPIC DNA methylation arrays was conducted on a cohort of normal kidney and ccRCC. ITH was assessed using DNA methylation (5mC) and CNV-based entropy and Euclidian distances. We found elevated 5mC heterogeneity and entropy in ccRCC relative to normal kidney. Variable CpGs are highly enriched in enhancer regions. Using intra-class correlation coefficient analysis, we identified CpGs that segregate tumor regions according to clinical phenotypes related to tumor aggressiveness. SETD2 wild-type tumors overall possess greater 5mC and copy number ITH than SETD2 mutant tumor regions, suggesting SETD2 loss contributes to a distinct epigenome. Finally, coupling our regional data with TCGA, we identified a 5mC signature that links regions within a primary tumor with metastatic potential. CONCLUSION: Taken together, our results reveal marked levels of epigenetic ITH in ccRCC that are linked to clinically relevant tumor phenotypes and could translate into novel epigenetic biomarkers.

Incidentally Discovered Right Atrial Mass: A Rare and Unexpected Etiology.

Primary cardiac sarcoma is a rare type of intracardiac mass. This report describes a patient with atrial flutter who had a new right atrial mass incidentally discovered on transesophageal echocardiography. A thrombus was suspected based on radiographic appearance, but there was minimal change with anticoagulation. The mass was resected and found to be an undifferentiated pleomorphic cardiac sarcoma, an uncommon sub-type within the already rare category of primary cardiac neoplasms. This report highlights the importance of considering primary malignancy and thoroughly correlating radiographic and clinical evidence during the diagnostic workup of patients with intracardiac masses.

Reprint of: lessons from histopathologic examination of nephrectomy specimens in patients with tuberous sclerosis complex: cysts, angiomyolipomas & renal cell carcinoma.

Renal manifestations in patients with tuberous sclerosis complex (TSC) include cysts, angiomyolipoma, and renal cell carcinoma. Unlike many hereditary predisposition syndromes, the spectrum of renal tumors in TSC patients (including both angiomyolipoma and renal cell carcinoma) is broad, with significant morphologic heterogeneity. An improved understanding of histopathologic findings in TSC patients and associated clinicopathologic correlates has significant implications not just in establishing a diagnosis of TSC, but also in the recognition of sporadic tumors occurring secondary to somatic alterations of TSC1/TSC2/MTOR pathway genes and accurate prognostication. In this review, we have discussed issues relevant to clinical management based on histopathologic findings in nephrectomy specimens from patients with TSC. This includes discussions related to screening for TSC, diagnosis of PKD1/TSC2 contiguous gene deletion syndrome, the morphologic spectrum of angiomyolipoma and renal epithelium-derived neoplasia, including the risk of disease progression.

Urinary Bladder Masses, Rare Subtypes, and Masslike Lesions: Radiologic-Pathologic Correlation.

Urinary bladder masses are commonly encountered in clinical practice, with 95% arising from the epithelial layer and rarer tumors arising from the lamina propria, muscularis propria, serosa, and adventitia. The extent of neoplastic invasion into these bladder layers is assessed with multimodality imaging, and the MRI-based Vesical Imaging Reporting and Data System is increasingly used to aid tumor staging. Given the multiple layers and cell lineages, a diverse array of pathologic entities can arise from the urinary bladder, and distinguishing among benign, malignant, and nonneoplastic entities is not reliably feasible in most cases. Pathologic assessment remains the standard of care for classification of bladder masses. Although urothelial carcinoma accounts for most urinary bladder malignancies in the United States, several histopathologic entities exist, including squamous cell carcinoma, adenocarcinoma, melanoma, and neuroendocrine tumors. Furthermore, there are variant histopathologic subtypes of urothelial carcinoma (eg, the plasmacytoid variant), which are often aggressive. Atypical benign bladder masses are diverse and can have inflammatory or iatrogenic causes and mimic malignancy. © RSNA, 2022 Online supplemental material is available for this article.

Molecular and Immunophenotypic Correlates of Metastatic Epithelioid Angiomyolipoma Include Alterations of TP53, RB1, and ATRX.

CONTEXT.­: Epithelioid angiomyolipomas (eAMLs) are rare tumors of the kidney that occur in patients with tuberous sclerosis complex or in a sporadic setting; a subset of these tumors exhibit metastatic behavior. OBJECTIVE.­: To analyze molecular profiling data to identify pathogenic alterations in rare cases of metastatic eAML, and to identify immunohistochemistry (IHC)-based surrogate markers. DESIGN.­: Molecular profiling data from the American Association for Cancer Research GENIE registry was accessed for 23 patients with angiomyolipomas, and 9 of 16 patients with eAMLs in our institutional registry were evaluated with next-generation sequencing. IHC was performed to screen for alterations of P53, RB, and ATRX for all 16 institutional cases. RESULTS.­: Combined alterations of 5 tumor-suppressor genes (TP53, ATRX, RB1, APC, and NF1) were identified using next-generation sequencing in 7 of 8 (88%) patients with metastatic disease compared to a single patient with nonmetastatic disease (RB1 variant of uncertain significance; 1 of 24, 4%). No cases with abnormal IHC results were identified in 11 patients with nonmetastatic disease compared to 3 of 5 patients with metastatic disease. CONCLUSIONS.­: Our results show that the majority of metastatic eAMLs have mutations of 5 tumor-suppressor genes (TP53, ATRX, RB1, APC, and NF1), while these are rare in patients with nonmetastatic disease. Furthermore, IHC for P53, RB, and ATRX may serve as a screen for a subset of these alterations in resource-limited settings. These findings, if validated in larger data sets, have the potential to predict metastatic behavior in eAMLs.

Lessons from histopathologic examination of nephrectomy specimens in patients with tuberous sclerosis complex: cysts, angiomyolipomas, and renal cell carcinoma.

Renal manifestations in patients with tuberous sclerosis complex (TSC) include cysts, angiomyolipoma, and renal cell carcinoma. Unlike many hereditary predisposition syndromes, the spectrum of renal tumors in TSC patients (including both angiomyolipoma and renal cell carcinoma) is broad, with significant morphologic heterogeneity. An improved understanding of histopathologic findings in TSC patients and associated clinicopathologic correlates has significant implications not just in establishing a diagnosis of TSC, but also in the recognition of sporadic tumors occurring secondary to somatic alterations of TSC1/TSC2/MTOR pathway genes and accurate prognostication. In this review, we have discussed issues relevant to clinical management based on histopathologic findings in nephrectomy specimens from patients with TSC. This includes discussions related to screening for TSC, diagnosis of PKD1/TSC2 contiguous gene deletion syndrome, the morphologic spectrum of angiomyolipoma and renal epithelium-derived neoplasia, including the risk of disease progression.

Immunohistochemical expression of renin and GATA3 help distinguish juxtaglomerular cell tumors from renal glomus tumors.

Juxtaglomerular cell tumors and glomus tumors both arise from perivascular mesenchymal cells. Juxtaglomerular cells are specialized renin-secreting myoendocrine cells in the afferent arterioles adjacent to glomeruli, and juxtaglomerular tumors derived from these cells are therefore unique to the kidney. In contrast, glomus tumors have been described at numerous anatomic sites and may show significant morphologic and immunophenotypic overlap with juxtaglomerular tumors when occurring in the kidney. Although ultrastructural studies and immunohistochemistry for renin may distinguish these entities, these diagnostic modalities are often unavailable in routine clinical practice. Herein, we studied the clinicopathologic features of a large series of juxtaglomerular tumors (n = 15) and glomus tumors of the kidney (n = 9) to identify features helpful in their separation, including immunohistochemistry for smooth muscle actin (SMA), CD34, collagen IV, CD117, GATA3, synaptophysin, and renin. Markers such as SMA (juxtaglomerular tumors: 12/13, 92%; glomus tumors: 9/9, 100%), CD34 (juxtaglomerular tumors: 14/14, 100%; glomus tumors: 7/9, 78%), and collagen IV (juxtaglomerular tumors: 5/6, 83%; glomus tumors: 3/3, 100%) were not helpful in separating these entities. In contrast to prior reports, all juxtaglomerular tumors were CD117 negative (0/12, 0%), as were glomus tumors (0/5, 0%). Our results show that juxtaglomerular tumors have a younger age at presentation (median age: 27 years), female predilection, and frequently exhibit diffuse positivity for renin (10/10, 100%) and GATA3 (7/9, 78%), in contrast to glomus tumors (median age: 51 years; renin: 0/6, 0%; GATA3: 0/6, 0%). These findings may be helpful in distinguishing these tumors when they exhibit significant morphologic overlap.

Variation in Lymph Node Yield After Radical Cystectomy.

OBJECTIVES: To test the hypothesis that lymph node yield will vary by pathology assistant (PA) in patients undergoing radical cystectomy (RC) with pelvic lymph node dissection (PLND). METHODS: This is a single-institution retrospective review that included patients who underwent an RC with PLND for bladder cancer from January 1, 2007, to January 1, 2018. Predicted mean lymph node counts were generated using multivariable regression analysis. RESULTS: In a total of 430 patients who underwent RC with PLND, the median lymph node count (interquartile range) was 15.0 (11.0-21.0). The frequency of the limits of lymphadenectomy was as follows: external iliac, internal iliac, and obturator (true pelvis) (33.3%); true pelvis plus common iliac to the level of the aortic bifurcation (47.9%); and inferior mesenteric artery (18.8%). On descriptive analysis, there were differences in lymph node yield when evaluating the following variables: level of dissection, clinical stage, neoadjuvant chemotherapy, surgical approach, surgeon, pathologist, and PA (P < .05). On multivariable analysis, adjusted lymph node counts varied between surgeons, pathologists, clinical stage, and level of dissection but not by PA (P = .18). CONCLUSIONS: Lymph node yield after RC varies on several known levels, including surgeon, extent of lymphadenectomy, clinical stage, and pathologist. This study found no significant variation in lymph node yield according to PA.

Identification of DNA methylation signatures associated with poor outcome in lower-risk Stage, Size, Grade and Necrosis (SSIGN) score clear cell renal cell cancer.

BACKGROUND: Despite using prognostic algorithms and standard surveillance guidelines, 17% of patients initially diagnosed with low risk clear cell renal cell carcinoma (ccRCC) ultimately relapse and die of recurrent disease, indicating additional molecular parameters are needed for improved prognosis. RESULTS: To address the gap in ccRCC prognostication in the lower risk population, we performed a genome-wide analysis for methylation signatures capable of distinguishing recurrent and non-recurrent ccRCCs within the subgroup classified as 'low risk' by the Mayo Clinic Stage, Size, Grade, and Necrosis score (SSIGN 0-3). This approach revealed that recurrent patients have globally hypermethylated tumors and differ in methylation significantly at 5929 CpGs. Differentially methylated CpGs (DMCpGs) were enriched in regulatory regions and genes modulating cell growth and invasion. A subset of DMCpGs stratified low SSIGN groups into high and low risk of recurrence in independent data sets, indicating that DNA methylation enhances the prognostic power of the SSIGN score. CONCLUSIONS: This study reports a global DNA hypermethylation in tumors of recurrent ccRCC patients. Furthermore, DMCpGs were capable of discriminating between aggressive and less aggressive tumors, in addition to SSIGN score. Therefore, DNA methylation presents itself as a potentially strong biomarker to further improve prognostic power in patients with low risk SSIGN score (0-3).

Added Benefit and Risk of an Additional Biopsy or Targeting With Contrast-Enhanced Ultrasound for Patients With Renal Transplants.

OBJECTIVES: To determine whether renal transplant diagnoses substantially change when 2 biopsy sites are chosen and whether contrast-enhanced ultrasound (CEUS) has value for targeting the second site. METHODS: We prospectively enrolled 40 patients undergoing ultrasound-guided renal transplant biopsy within 2 years of transplant: 20, surveillance; and 20, for cause. A CEUS examination was performed to identify cortical regions with subjectively altered flow. One biopsy was performed at the operator-preferred (primary) site regardless of CEUS findings. Another biopsy was done at a second location, either targeted to an area in which CEUS perfusion findings differed from the primary site (targeted) or at a random location (secondary) if no other area differed. Specimens were randomly labeled A or B; pathologists were blinded to the CEUS result and biopsy location. Location-specific CEUS assessments were recorded. Pathologic results were compared, including acute and chronic Banff scores and any new findings from the targeted or secondary biopsy. RESULTS: Forty patients were enrolled between January 2016 and December 2018. No location-specific pathologic differences correlated with differences in CEUS assessments. The second biopsy provided additional information that changed management in 4 of 40 patients (10.0% [95% confidence interval, 2.8%-23.7%]). Major bleeding complications occurred in 3 of 40 (7.5%) patients. CONCLUSIONS: Contrast-enhanced ultrasound targeting was not useful. Major bleeding complications were higher than expected, possibly due to the additional biopsy away from the operator-preferred location. Obtaining a second renal transplant biopsy from a substantially different area than the initial operator-preferred location provided additional clinically useful information in 10% of patients.

The Clinical Implication of Incidental Prostatic Amyloidosis.

OBJECTIVE: To describe the clinicopathologic features of patients with incidental prostatic amyloidosis. PATIENTS AND METHODS: We queried the genitourinary pathology database at Mayo Clinic Arizona for prostate specimens which showed amyloid deposits. Congo red stain was used for the diagnosis of amyloidosis and amyloid subtype was performed analysis using Liquid chromatography tandem mass spectrometry. We reviewed the patient's medical charts for past or subsequent diagnosis of systemic amyloidosis and clinical course. RESULTS: Prostatic amyloidosis was identified in 7 patients between 2008-2018. Median age was 79 years (range 69-84) and median follow-up was 5 years (range 0-11). Benign prostate tissue was found in 4 patients, and prostate cancer was diagnosed in 3 patients. Amyloid subtyping was available in 6 patients and was consistent with Amyloid transthyretin Amyloidosis. Liquid chromatography tandem mass spectrometry did not detect an amino acid sequence abnormality in the transthyretin protein in any of the patients. Five of 6 patients were diagnosed with cardiac amyloidosis, which preceded and followed the diagnosis of prostatic amyloidosis in 1 and 4 patients, respectively. Of these 4 patients, 2 were diagnosed immediately and as a consequence of the diagnosis of prostatic amyloidosis, and the remaining 2 3 and 4 years later. CONCLUSION: Incidental prostatic amyloidosis should prompt systemic and cardiac evaluation for amyloidosis. In patients with suspected cardiac amyloidosis, prior prostate specimens should be reviewed for the presence of amyloidosis.

Behavior of blood plasma glycan features in bladder cancer.

Despite systemic therapy and cystectomy, bladder cancer is characterized by a high recurrence rate. Serum glycomics represents a promising source of prognostic markers for monitoring patients. Our approach, which we refer to as "glycan node analysis", constitutes the first example of molecularly "bottom-up" glycomics. It is based on a global glycan methylation analysis procedure that is applied to whole blood plasma/serum. The approach detects and quantifies partially methylated alditol acetates arising from unique glycan features such as α2-6 sialylation, ß1-4 branching, and core fucosylation that have been pooled together from across all intact glycans within a sample into a single GC-MS chromatographic peak. We applied this method to 122 plasma samples from former and current bladder cancer patients (n = 72 former cancer patients with currently no evidence of disease (NED); n = 38 non-muscle invasive bladder cancer (NMIBC) patients; and n = 12 muscle invasive bladder cancer (MIBC) patients) along with plasma from 30 certifiably healthy living kidney donors. Markers for α2-6 sialylation, ß1-4 branching, ß1-6 branching, and outer-arm fucosylation were able to separate current and former (NED) cases from certifiably healthy controls (ROC curve c-statistics ~ 0.80); but NED, NMIBC, and MIBC were not distinguished from one another. Based on the unexpectedly high levels of these glycan nodes in the NED patients, we hypothesized that recurrence of this disease could be predicted by some of the elevated glycan features. Indeed, α2-6 sialylation and ß1-6 branching were able to predict recurrence from the NED state using a Cox proportional hazards regression model adjusted for age, gender, and time from cancer. The levels of these two glycan features were correlated to C-reactive protein concentration, an inflammation marker and known prognostic indicator for bladder cancer, further strengthening the link between inflammation and abnormal plasma protein glycosylation.

A Study of Combination Bicalutamide and Raloxifene for Patients With Castration-Resistant Prostate Cancer.

BACKGROUND: Prostate tissue expresses 2 estrogen receptor (ER) isoforms, ER-α and ER-ß, and estrogen-based therapies have shown activity in preclinical studies. Raloxifene, a selective ER modulator, has inhibited the growth of prostate cancer xenograft models and was tested in a phase II trial of castration-resistant prostate cancer (CRPC), with some patients achieving stable disease. However, no studies have examined the safety of the combination of bicalutamide plus raloxifene for CRPC. Therefore, we investigated the safety of treatment with bicalutamide plus raloxifene in patients with CRPC in an initial study. MATERIALS AND METHODS: We conducted a study to evaluate the toxicity (primary endpoint) of the combination of bicalutamide (50 mg) and raloxifene (60 mg) in 28-day cycles (maximum, 6 cycles) in men with progressive CRPC. The secondary endpoint, quality of life (QOL), was assessed by patients using a 6-item linear analog self-assessment or hormonal domain scale of the Expanded Prostate Cancer Index Composite. RESULTS: We enrolled 18 patients with CRPC in the study to evaluate the safety of, and patient assessment of QOL (mental, physical, social, emotional, and spiritual) with, bicalutamide plus raloxifene therapy. No grade 3 or 4 adverse events occurred. None of the 18 patients required dose reductions. The patient assessment of QOL showed no statistically significant changes after 2 treatment cycles. The median progression-free survival with bicalutamide plus raloxifene was 1.9 months (95% confidence interval, 1.8-2.8 months). CONCLUSION: The results of the present study have shown that bicalutamide/raloxifene treatment is well tolerated. However, limited clinical activity occurred in men with CRPC who had previously undergone secondary hormonal therapy or chemotherapy.