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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.

Objectives To compare the performance of the rabbit monoclonal antihuman CD246 antibody (D5F3 clone) with the established ALK1 clone for immunohistochemical assessment of anaplastic large cell lymphoma (ALCL). Methods Archival cases of ALCL (n = 27) were assessed immunohistochemically by use of ALK1 and D5F3 clones under standard Clinical Laboratory Improvement Amendments–compliant conditions. The intensity of cytoplasmic staining (0 = none; 1 = faint; 2 = moderate; 3+ = strong) and proportion of neoplastic cells (0%, 50%) were evaluated and compared with clinical ALK break-apart fluorescence in situ hybridization (FISH) assays. Results Nine ALCL specimens were positive for ALK expression by ALK1 staining (33%; 1 = 1+; 0 = 2+; 8 = 3+), while 14 were positive by D5F3 staining (48%; 3 = 1+; 1 = 2+; 10 = 3+). Across the cohort, D5F3 staining showed a significantly greater proportion of cells staining positive (P = .02) and greater intensity (P = .03). Of 3 cases positive for D5F3 only with FISH results, none showed rearrangements, although 1 showed copy number gains at the ALK locus in a subset of cells. Conclusions Overall, D5F3 showed greater stain intensity and proportion staining than ALK1 in ALK-positive ALCL cases, which is especially helpful in limited samples. Caution and consideration of orthogonal ALK testing types is recommended, especially for cases with weak or focal staining.

EWS-FLI1 increases BCL-2 expression in EWFT.

Video 2 from PLK1 Induces Chromosomal Instability and Overrides Cell-Cycle Checkpoints to Drive Tumorigenesis

Video 4 B from PLK1 Induces Chromosomal Instability and Overrides Cell-Cycle Checkpoints to Drive Tumorigenesis

supplemental figures and methods

Purpose:It was recently demonstrated that the EWSR1-FLI1 t(11;22)(q24;12) translocation contributes to the hypersensitivity of Ewing sarcoma to PARP inhibitors, prompting clinical evaluation of olaparib in a cohort of heavily pretreated Ewing sarcoma tumors. Unfortunately, olaparib activity was disappointing, suggesting an underappreciated resistance mechanism to PARP inhibition in patients with Ewing sarcoma. We sought to elucidate the resistance factors to PARP inhibitor therapy in Ewing sarcoma and identify a rational drug combination capable of rescuing PARP inhibitor activity.Experimental Design:We employed a pair of cell lines derived from the same patient with Ewing sarcoma prior to and following chemotherapy, a panel of Ewing sarcoma cell lines, and several patient-derived xenograft (PDX) and cell line xenograft models.Results:We found olaparib sensitivity was diminished following chemotherapy. The matched cell line pair revealed increased expression of the antiapoptotic protein BCL-2 in the chemotherapy-resistant cells, conferring apoptotic resistance to olaparib. Resistance to olaparib was maintained in this chemotherapy-resistant model in vivo, whereas the addition of the BCL-2/XL inhibitor navitoclax led to tumor growth inhibition. In 2 PDXs, olaparib and navitoclax were minimally effective as monotherapy, yet induced dramatic tumor growth inhibition when dosed in combination. We found that EWS-FLI1 increases BCL-2 expression; however, inhibition of BCL-2 alone by venetoclax is insufficient to sensitize Ewing sarcoma cells to olaparib, revealing a dual necessity for BCL-2 and BCL-XL in Ewing sarcoma survival.Conclusions:These data reveal BCL-2 and BCL-XL act together to drive olaparib resistance in Ewing sarcoma and reveal a novel, rational combination therapy that may be put forward for clinical trial testing.

Figure legends for Supplementary Figures S1-S8.

full scan WB

Video 1 from PLK1 Induces Chromosomal Instability and Overrides Cell-Cycle Checkpoints to Drive Tumorigenesis

Video 3 from PLK1 Induces Chromosomal Instability and Overrides Cell-Cycle Checkpoints to Drive Tumorigenesis

PDF file - 90K

Hypoxia drives malignant progression in part by promoting accumulation of the oncogenic transcription factor hypoxia inducible factor–1α (HIF-1α) in tumor cells. Tumor aggressiveness also relates to elevation of the cancer stem cell–associated membrane protein CD24, which has been causally implicated in tumor formation and metastasis in experimental models. Here, we link these two elements by showing that hypoxia induces CD24 expression through a functional hypoxia responsive element in the CD24 promoter. HIF-1α overexpression induced CD24 mRNA and protein under normoxic conditions, with this effect traced to a recruitment of endogenous HIF-1α to the CD24 promoter. Short hairpin RNA–mediated attenuation of HIF-1α or CD24 expression reduced cancer cell survival in vitro and in vivo at the levels of primary and metastatic tumor growth. CD24 overexpression in HIF-1α–depleted cancer cells rescued this decrease, whereas HIF-1α overexpression in CD24-depleted cells did not. Analysis of clinical tumor specimens revealed a correlation between HIF-1α and CD24 levels and an association of their coexpression to decreased patient survival. Our results establish a mechanistic linkage between 2 critically important molecules in cancer, identifying CD24 as a critical HIF-1α transcriptional target and biologic effector, strengthening the rationale to target CD24 for cancer therapy. Cancer Res; 72(21); 5600–12. ©2012 AACR.

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PDF file - 25K, Detail of the gene signature of Ral-dependent transcription and molecular concepts

PDF file - 158K, Evaluation of CD24 and HIF1a expression in response to hypoxia and Deferoxamine in human bladder and prostate cancer cells

PDF file - 68K, Quantitation of visible lung for metastases after tail vein inoculation of UMUC-3 cell lines

PDF file - 88K, Western blot and ChIP for HIF-1beta in human bladder cancer cells

PDF file - 890K, Effects of CD24 and HIF1a depletion on in vitro and in vivo growth and metastasis of bladder and prostate cancer cells

PDF file - 860K, Comparison of immunohistochemical evaluation of Ral paralog expression and mRNA Ral expression signature in human tumors as a function of patient outcome

PDF file - 93K, Activity and expression of Ral paralogs in human cancer tissues and cell lines and listing of the genes composing the Ral expression signature used to stratify patients in our study

PDF file - 45K, The CD24 promoter cloned from human prostate and bladder cells

PDF file - 44K, Transcriptional signatures of Ral GTPase are associated with aggressive clinicopathologic characteristics in human cancer

Supplementary Figures S1-S4; Supplementary Table S1.

This paper investigates the accuracy of deriving the composite optical constants of binary mixtures from only the complex indices of refraction of the neat materials. These optical constants enable the reflectance spectra of the binary mixtures to be modeled for multiple scenarios (

The Genitourinary Pathology Society (GUPS) reviewed recent advances in renal neoplasia, particularly post-2016 World Health Organization (WHO) classification, to provide an update on existing entities, including diagnostic criteria, molecular correlates, and updated nomenclature. Key prognostic features for clear cell renal cell carcinoma (RCC) remain WHO/ISUP grade, AJCC/pTNM stage, coagulative necrosis, and rhabdoid and sarcomatoid differentiation. Accrual of subclonal genetic alterations in clear cell RCC including SETD2, PBRM1, BAP1, loss of chromosome 14q and 9p are associated with variable prognosis, patterns of metastasis, and vulnerability to therapies. Recent National Comprehensive Cancer Network (NCCN) guidelines increasingly adopt immunotherapeutic agents in advanced RCC, including RCC with rhabdoid and sarcomatoid changes. Papillary RCC subtyping is no longer recommended, as WHO/ISUP grade and tumor architecture better predict outcome. New papillary RCC variants/patterns include biphasic, solid, Warthin-like, and papillary renal neoplasm with reverse polarity. For tumors with 'borderline' features between oncocytoma and chromophobe RCC, a term "oncocytic renal neoplasm of low malignant potential, not further classified" is proposed. Clear cell papillary RCC may warrant reclassification as a tumor of low malignant potential. Tubulocystic RCC should only be diagnosed when morphologically pure. MiTF family translocation RCCs exhibit varied morphologic patterns and fusion partners. TFEB-amplified RCC occurs in older patients and is associated with more aggressive behavior. Acquired cystic disease (ACD) RCC-like cysts are likely precursors of ACD-RCC. The diagnosis of renal medullary carcinoma requires a negative SMARCB1 (INI-1) expression and sickle cell trait/disease. Mucinous tubular and spindle cell carcinoma (MTSCC) can be distinguished from papillary RCC with overlapping morphology by losses of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22. MTSCC with adverse histologic features shows frequent CDKN2A/2B (9p) deletions. BRAF mutations unify the metanephric family of tumors. The term "fumarate hydratase deficient RCC" ("FH-deficient RCC") is preferred over "hereditary leiomyomatosis and RCC syndrome-associated RCC". A low threshold for FH, 2SC, and SDHB immunohistochemistry is recommended in difficult to classify RCCs, particularly those with eosinophilic morphology, occurring in younger patients. Current evidence does not support existence of a unique tumor subtype occurring after chemotherapy/radiation in early childhood.

We report a novel NIPBL-NACC1 gene fusion in a rare primary hepatic neoplasm previously described as the "cholangioblastic variant of intrahepatic cholangiocarcinoma." The 2 index cases were identified within our consultation files as morphologically distinctive primary hepatic neoplasms in a 24-year-old female and a 54-year-old male. The neoplasms each demonstrated varied architecture, including trabecular, organoid, microcystic/follicular, and infiltrative glandular patterns, and biphasic cytology with large, polygonal eosinophilic cells and smaller basophilic cells. The neoplasms had a distinctive immunoprofile characterized by diffuse labeling for inhibin, and patchy labeling for neuroendocrine markers (chromogranin and synaptophysin) and biliary marker cytokeratin 19. RNA sequencing of both cases demonstrated an identical fusion of NIBPL exon 8 to NACC1 exon 2, which was further confirmed by break-apart fluorescence in situ hybridization assay for each gene. Review of a tissue microarray including 123 cases originally diagnosed as well-differentiated neuroendocrine neoplasm at one of our hospitals resulted in identification of a third case with similar morphology and immunophenotype in a 52-year-old male, and break-apart fluorescence in situ hybridization probes confirmed rearrangement of both NIPBL and NACC1. Review of The Cancer Genome Atlas (TCGA) sequencing data and digital images from 36 intrahepatic cholangiocarcinomas (http://www.cbioportal.org) revealed one additional case with the same gene fusion and the same characteristic solid, trabecular, and follicular/microcystic architectures and biphasic cytology as seen in our genetically confirmed cases. The NIPBL-NACC1 fusion represents the third type of gene fusion identified in intrahepatic cholangiocarcinoma, and correlates with a distinctive morphology described herein.

Since the discovery of association of SMARCB1 mutations with malignant rhabdoid tumors and renal medullary carcinoma, mutations in genes of the SWI/SNF chromatin remodeling complex have been increasingly identified across a diverse spectrum of neoplasms. As a group, SWI/SNF complex subunit mutations are now recognized to be the second most frequent type of mutations across tumors. SMARCB1 mutations were originally reported in malignant rhabdoid tumors of the kidney and thought to be pathognomonic for this tumor. However, more broadly, recognition of typical rhabdoid cytomorphology and SMARCB1 mutations beyond rhabdoid tumors has changed our understanding of the pathobiology of these tumors. While mutations of SWI/SNF complex are diagnostic of rhabdoid tumors and renal medullary carcinoma, their clinical relevance extends to potential prognostic and predictive utility in other tumors as well. Beyond SMARCB1, the PBRM1 and ARID1A genes are the most frequently altered members of the SWI/SNF complex in genitourinary neoplasms, especially in clear cell renal cell carcinoma and urothelial carcinoma. In this review, we provide an overview of alterations in the SWI/SNF complex encountered in genitourinary neoplasms and discuss their increasing clinical importance.

Polo-like kinase 1 (PLK1) is an essential cell-cycle regulator that is frequently overexpressed in various human cancers. To determine whether Plk1 overexpression drives tumorigenesis, we established transgenic mouse lines that ubiquitously express increased levels of Plk1. High Plk1 levels were a driving force for different types of spontaneous tumors. Increased Plk1 levels resulted in multiple defects in mitosis and cytokinesis, supernumerary centrosomes, and compromised cell-cycle checkpoints, allowing accumulation of chromosomal instability (CIN), which resulted in aneuploidy and tumor formation. Clinically, higher expression of PLK1 positively associated with an increase in genome-wide copy-number alterations in multiple human cancers. This study provides in vivo evidence that aberrant expression of PLK1 triggers CIN and tumorigenesis and highlights potential therapeutic opportunities for CIN-positive cancers. Significance: These findings establish roles for PLK1 as a potent proto-oncogene and a CIN gene and provide insights for the development of effective treatment regimens across PLK1-overexpressing and CIN-positive cancers.

Classification of the putative flat preneoplastic and neoplastic lesions of the urothelium with features subthreshold for urothelial carcinoma in situ remains a challenging, indeed, vexing problem in diagnostic surgical pathology. This area, subtending lesions including flat urothelial hyperplasia, urothelial dysplasia, and atypia of unknown significance, has struggled under evolving classifications, changing criteria, and limited clinical actionability, all confounded by the recognized lack of diagnostic reproducibility. Herein, we review the state of the literature around these lesions, reviewing contemporary criteria and definitions, assessing the arguments in favor and against of retaining hyperplasia, dysplasia, and atypia of unknown significance as diagnostic entities. We clarify the intent of the original definitions for dysplasia as a lesion felt to be clearly neoplastic but with morphologic features that fall short of the threshold of urothelial carcinoma in situ. While several pathologists, including some experts in the field, conflate the term dysplasia with urothelial atypia of unknown significance, the latter is defined as a descriptive diagnosis term to express diagnostic uncertainty of a lesion of whether it is clearly reactive or neoplastic. Both molecular studies and clinical needs are considered, as we outline our approach on diagnosing each of these lesions in clinical practice. Recommendations are made to guide consistency and interoperability in future scholarship, and the place of these lesions in context of evolving trends in the field is considered.

This paper updates recent work to populate spectral databases for (near-) infrared sensing of solids in different modalities including passive and active sensing of minerals, ores and other mining chemicals and minerals.

Aims Verruciform xanthoma (VX) is an uncommon lesion, seen in the oral mucosa and rarely occurring at cutaneous genital sites. Reports of exceptional VX presentations dominate the literature; herein, we assess the clinical and histological features of a cohort of routine, consecutive cases. Methods and results Clinicopathological features of genital VXs from four academic centres were reviewed. A cohort of 25 lesions from 24 patients (22 male, two female; median age = 62 years), occurred on the scrotum (84%), penis (8%) and perineum/vulva (8%). VX was never suspected clinically; considerations ranged from fibroepithelial polyps to squamous cell carcinoma. Classic diagnostic criteria were present at least focally in each lesion, including verrucous architecture, prominent wedge-shaped parakeratosis extending between exophytic epidermal projections and neutrophils in the stratum corneum. Xanthomatous cells were present in all cases, but scattered to rare in 24%. Conclusions Consecutive genital VXs reliably exhibited classic histopathological features, although the essential finding of xanthomatous cells may be scarce. Our comparison to meta-analyses of published cases found relatively fewer penile and vulvar examples. Additionally, the median age was older than in published series, which have emphasised syndromic associations.

ObjectivesUniversal screening of upper tract urothelial carcinoma (UTUC) for Lynch syndrome by mismatch repair (MMR) protein immunohistochemistry (IHC) has been recommended by some investigators. Herein, we assess this recommendation retrospectively by simulating its performance on a retrospective, unselected cohort of UTUCs, with comparison to the established setting of colorectal and endometrial adenocarcinoma.MethodsWe assessed for complete loss of MMR protein (MLH1, MSH2, MSH6, and PMS2) IHC in 74 consecutive cases of UTUC and then tabulated clinical and pathologic factors. MMR findings from same-institution colorectal and endometrial adenocarcinomas were tabulated for comparison.ResultsWe observed loss of at least one MMR protein in 12% in our UTUC cohort (three MSH2/MSH6, three MSH6 only, one MLH1/PMS2, and two PMS2 only). Of these nine cases (seven males, two females, median age 67 years, five associated with colorectal adenocarcinoma), at least three (4% of the overall cohort) proved to be Lynch syndrome. Overall, MMR loss in UTUC was comparable to colorectal (11%; 50 of 471 cases) and endometrial (12%; 12 of 101 cases) adenocarcinomas.ConclusionsThe rate of MMR loss observed in UTUC was comparable to that in the established setting of colorectal and endometrial adenocarcinomas, supporting universal UTUC screening at our institution and others.

Objectives Superficial pleomorphic liposarcoma (PL) has a favorable prognosis compared to deeply seated PL. Given developments in the classification of lipomatous neoplasms, we reappraised a series of cases. Methods Retrospective clinicopathologic evaluation and genome-wide single-nucleotide polymorphism (SNP) microarray studies were performed for cases previously designated superficial PL. Results Four cases were identified (age, 48-70 years). Two were dermally confined, whereas two were superficial subcutaneous; no recurrences or metastases were reported. Tumors demonstrated pleomorphic spindled morphology with variable cellularity. Multivacuolated atypical lipoblasts were focal in 3 and abundant in 1. Dermal tumors demonstrated atypical cells within sclerotic collagen. Genome-wide SNP microarray studies revealed consistent gains and losses, including losses at the 13q14.2 locus encompassing RB1 and DLEU2 and deletion/disruption of the TP53 locus. Although subcutaneous examples showed genomic changes similar to deep PL, the dermal examples showed fewer genetic alterations, including changes reported in the spectrum of atypical spindle cell/pleomorphic lipomatous tumors (ASPLT). All lacked MDM2 amplification. Conclusions Careful integration of histologic and genetic features may improve classification of lipomatous neoplasms with atypia, allowing reclassification of some superficial PL as ASPLT.

Ancillary testing with immunohistochemistry has shown recent promise in the workup of equivocal bladder lesions. We read with interest the recent findings of Alston et al., who assessed the diagnostic utility of alpha-methylacyl-CoA racemase (AMACR) in comparison to cytokeratin 20 (CK20) in evaluation of atypia in challenging flat urothelial lesions in the differential between carcinoma in situ (CIS) and reactive atypia. AMACR was reported to be a somewhat more specific but less sensitive marker for CIS than CK20, though showing weaker intensity. Spurred by their report, with the knowledge that we had consistently and consecutively performed AMACR, CK20, and p53 on flat urothelial lesions challenging enough to reach intradepartmental consensus, we performed a retrospective review. Similarly, we found that AMACR was less sensitive (80%) and more specific (100%) than CK20, with the same caveat of less staining intensity. Additionally, our p53 review identified a significant rate (~ 27%) of equivocal/non-informative findings. Taken together, our experience in this consecutive cohort confirms the impression of Alston et al. regarding the utility and challenges of AMACR use, while highlighting challenges with p53, which we plan to use more sparingly prospectively.

To compare the performance of the rabbit monoclonal antihuman CD246 antibody (D5F3 clone) with the established ALK1 clone for immunohistochemical assessment of anaplastic large cell lymphoma (ALCL).Archival cases of ALCL (n = 27) were assessed immunohistochemically by use of ALK1 and D5F3 clones under standard Clinical Laboratory Improvement Amendments-compliant conditions. The intensity of cytoplasmic staining (0 = none; 1 = faint; 2 = moderate; 3+ = strong) and proportion of neoplastic cells (0%,5%, 5%-50%,50%) were evaluated and compared with clinical ALK break-apart fluorescence in situ hybridization (FISH) assays.Nine ALCL specimens were positive for ALK expression by ALK1 staining (33%; 1 = 1+; 0 = 2+; 8 = 3+), while 14 were positive by D5F3 staining (48%; 3 = 1+; 1 = 2+; 10 = 3+). Across the cohort, D5F3 staining showed a significantly greater proportion of cells staining positive (P = .02) and greater intensity (P = .03). Of 3 cases positive for D5F3 only with FISH results, none showed rearrangements, although 1 showed copy number gains at the ALK locus in a subset of cells.Overall, D5F3 showed greater stain intensity and proportion staining than ALK1 in ALK-positive ALCL cases, which is especially helpful in limited samples. Caution and consideration of orthogonal ALK testing types is recommended, especially for cases with weak or focal staining.

Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is typically considered a high-grade, aggressive subtype of RCC that frequently arises in the setting of hereditary leiomyomatosis-renal cell carcinoma (HLRCC) syndrome. Increasing experience with HLRCC-associated RCC and FH-deficient RCC has resulted in recognition of tumors with lower grade morphologic features, overlapping with those of succinate dehydrogenase-deficient RCC and other low-grade oncocytic tumors. In this review article, we report a previously unpublished case that was recently encountered in our practice and review cases in the current literature with an aim of getting a better understanding of these oncocytic tumors and their morphologic spectrum. The 13 cases reviewed were approximately equally distributed across males and females, occurred at a younger age, and were more frequently seen in the right kidney, with both unifocal and multifocal presentations. While most presented an exclusive, low-grade oncocytic morphology, in 4 cases they were associated with either separate high-grade tumors, or as a secondary pattern in an otherwise conventional high-grade FH-deficient RCC. Loss of FH and 2 succinyl cysteine (2SC) positivity by immunohistochemistry supported their diagnosis, and are recommended to be performed alongside CD117, CK7, and CK20 in to aid classification in challenging oncocytic tumors. When occurring in isolation, these tumors are distinctive from their high-grade counterparts, with no reported adverse outcomes in cases reported thus far. As such, accurate diagnosis of this low-grade pattern among FH-deficient RCCs is worthwhile not only due to its association with HLRCC and need of genetic counseling and surveillance, but also due to more favorable prognosis. Finally, increasing experience with the low-grade end of the morphologic spectrum of FH deficient RCC reiterates that not all tumors of this subtype of RCC have a uniformly aggressive outcome.