SMARCA4 / BRG1 -deficient Uterine Neoplasm With Hybrid Adenosarcoma and Carcinoma Features: Expanding the Molecular-morphologic Spectrum of SMARCA4 -driven Gynecologic Malignancies.

SMARCA4 gene encodes BRG1 , a member of the SWItch/sucrose non-fermentable protein family involved in epigenetic transcriptional regulation of important cellular processes. In the uterine corpus, SMARCA4 / BRG1 deficiency is associated with a novel class of undifferentiated uterine sarcomas, characterized by younger age onset, rhabdoid histology, focal phyllodiform architecture, high-risk pathologic findings, and dismal prognosis. Herein, we report a case of a 34-year-old Asian woman with a SMARCA4 / BRG1 -deficient uterine tumor fulfilling the clinicopathologic features of an undifferentiated uterine sarcoma. However, the tumor exhibited several unique features that have not been previously emphasized, including (1) conspicuous phyllodiform architecture recapitulating conventional adenosarcoma, (2) rhabdoid tumor cells forming cords and keratin-positive cohesive epithelial islands, and (3) cooccurrence with a spatially distinct and discrete endometrial complex atypical hyperplasia from the rest of the proliferation. By immunohistochemistry, the tumor cells were diffusely positive for synaptophysin, whereas BRG1 was lost. Pertinent molecular findings included frameshift mutations in the SMARCA4 gene, mutations in histone modification and chromatin remodeling genes, including KMT2C , ARID1B , KAT6A , and NCOR1 , and mutations in Wnt signaling involving APC and CTNNB1 . Copy number gain in MDM2 and CDK4 were also identified. The tumor mutation burden was intermediate (6.8/MB) and it was microsatellite stable. On balance, our case exhibited morphologic and molecular features that overlap with (1) an undifferentiated uterine sarcoma, (2) an adenosarcoma with sarcomatous overgrowth, and (3) a mixed adenosarcoma and undifferentiated endometrial carcinoma. These hybrid features further expand the molecular-morphologic spectrum of SMARCA4 / BRG1 -deficient uterine neoplasms.

Impact of pathologic lymph node-positive renal cell carcinoma on survival in patients without metastasis: Evidence in support of expanding the definition of stage IV kidney cancer.

BACKGROUND: Stage III renal cell carcinoma (RCC) encompasses both lymph node-positive (pT1-3N1M0) and lymph node-negative (pT3N0M0) disease. However, prior institutional studies have indicated that among patients with stage III disease, those with lymph node disease have worse oncologic outcomes and experience survival that is similar to that of patients with American Joint Committee on Cancer (AJCC) stage IV disease. The objective of the current study was to validate these findings using a large, nationally representative sample of patients with kidney cancer. METHODS: Patients with AJCC stage III or stage IV RCC were identified using the National Cancer Data Base (NCDB). Patients were categorized as having lymph node-positive stage III (pT1-3N1M0), lymph node-negative stage III (pT3N0M0), or stage IV metastatic (pT1-3 N0M1) disease. Cox proportional hazards models compared outcomes while adjusting for comorbidities. Kaplan-Meier estimates illustrated relative survival when comparing staging groups. RESULTS: A total of 8988 patients met the inclusion criteria, with 6587 patients classified as having lymph node-negative stage III disease, 2218 as having lymph node-positive stage III disease, and 183 as having stage IV disease. Superior survival was noted among patients with lymph node-negative stage III disease, but similar survival was noted between patients with lymph node-positive stage III and stage IV RCC, with 5-year survival rates of 61.9% (95% confidence interval [95% CI], 60.3%-63.4%), 22.7% (95% CI, 20.6%-24.9%), and 15.6% (95% CI, 11.1%-23.8%), respectively. CONCLUSIONS: Current RCC staging systems group pT1-3N1M0 and pT3N0M0 disease as stage III disease. However, the results of the current validation study suggest the need for further stratification and even placement of patients with pT1-3N1M0 disease into the stage IV category. Staging that accurately reflects oncologic prognosis may help clinicians better counsel and select patients who might derive the most benefit from lymphadenectomy, adjuvant systemic therapy, more rigorous imaging surveillance, and clinical trial participation.

Accuracy of Grading Gleason Score 7 Prostatic Adenocarcinoma on Needle Biopsy: Influence of Percent Pattern 4 and Other Histological Factors.

BACKGROUND: Recognition of Gleason pattern 4 in prostatic needle biopsies is crucial for both prognosis and therapy. Recently, it has been recommended to record percent pattern 4 when Gleason score 7 cancer is the highest grade in a case. METHODS: Four hundred and five prostate needle core biopsies received for a second opinion at our institution from February-June, 2015 were prospectively diagnosed with prostatic adenocarcinoma Gleason score 7 as the highest score on review by a consultant urological pathologist. Percentage of core involvement by cancer, percentage of Gleason pattern 4 per core, distribution of Gleason pattern 4 (clustered, scattered), morphology of pattern 4 (cribriform, non-cribriform), and whether the cancer was continuous or discontinuous were recorded. RESULTS: Better agreement was noted between the consultant and referring pathologists when pattern 4 was clustered as opposed to dispersed in biopsies (P = 0.009). The percentage of core involvement by cancer, morphology of pattern 4, and continuity of cancer did not affect the agreement between the consultant and referring pathologists. There was a trend (P = 0.06) for better agreement based on the percent of pattern 4. CONCLUSIONS: When pattern 4 is scattered amongst pattern 3 as opposed to being discrete foci, there is less interobserver reproducibility in grading Gleason score 7 cancer, and in this setting pathologists should consider obtaining second opinions either internally within their group or externally. Prostate 77: 681-685, 2017. © 2017 Wiley Periodicals, Inc.

Chromosomal abnormalities of high-grade mucinous tubular and spindle cell carcinoma of the kidney.

AIMS: Mucinous tubular and spindle cell carcinoma (MTSC) of the kidney is a distinct entity characterized by bland tightly packed elongated tubules and spindle cells with low nucleolar grade in a basophilic mucinous stroma. Several case studies have reported MTSC with high-grade features and have brought into question whether they represented MTSC or a variant of papillary renal cell carcinoma. METHODS AND RESULTS: We searched our pathology database and identified seven cases: six MTSC with high International Society of Urological Pathology (ISUP) nucleolar grade and one MTSC with overall low nucleolar grade but extensive necrosis. DNA samples were extracted from paraffin blocks and analysed using a single nucleotide polymorphism (SNP) array platform. Six of seven patients were female, aged between 46 and 82 years. Tumour sizes ranged from 3 to 7.5 cm. One case showed involvement of renal sinus fat and a second case showed involvement of the perinephric fat. All cases shared common chromosomal abnormalities observed with the more typical MTSC, with monosomy of chromosomes 1, 4, 6, 8, 9, 13, 14, 15 and 22. Trisomy of chromosomes 7, 17 and loss of Y chromosome were not observed in any of the cases. None of the patients showed evidence of recurrence or metastasis. DISCUSSION: The molecular analysis performed in this study supports that MTSC of the kidney can have high nucleolar grade or extensive necrosis, and that they are not papillary renal cell carcinoma. We support modifying the definition of MTSC to include those with higher nucleolar grade.

Detailed analysis of patients with metastasis to the prostatic anterior fat pad lymph nodes: a multi-institutional study.

PURPOSE: Lymph nodes in the prostatic anterior fat pad rarely harbor metastatic disease. Therefore, the characteristics of patients with prostatic anterior fat pad lymph node metastasis are not well described in the literature. We identified the perioperative characteristics and assessed the clinical outcomes of patients with prostatic anterior fat pad lymph node metastasis. MATERIALS AND METHODS: At 8 tertiary care centers a total of 4,261 patients underwent complete removal and pathological analysis of the prostatic anterior fat pad. We describe preoperative and pathological characteristics, and clinical management and outcomes in patients with metastatic disease to the prostatic anterior fat pad. RESULTS: Metastatic disease to the prostatic anterior fat pad lymph nodes was detected in 40 patients (0.94%), of whom 37 (92.5%) had intermediate or high risk features preoperatively. Most patients with prostatic anterior fat pad metastases underwent concomitant pelvic lymph node dissection, and adjuvant therapy with radiation, androgen ablation and/or chemotherapy. A total of 27 patients (67.5%) with prostatic anterior fat pad metastatic disease were up-staged as a result of prostatic anterior fat pad pathological analysis, of whom 14 (51.8%) remained free of biochemical recurrence with observation and/or definitive adjuvant/salvage therapy. CONCLUSIONS: Most patients with prostatic anterior fat pad metastatic disease had intermediate to high risk features preoperatively. In some patients with such lymph node metastasis removing these lymph nodes resulted in prolonged biochemical recurrence-free survival. Therefore, we recommend that the prostatic anterior fat pad be removed in all patients undergoing radical prostatectomy. However, pathological analysis of the prostatic anterior fat pad may be limited to patients with intermediate to high risk oncological features preoperatively.

Heterogeneity of foam cell biogenesis across diseases.

Foam cells are dysfunctional, lipid-laden macrophages associated with chronic inflammation of infectious and non-infectious origin. For decades, the paradigm underlying foam cell biology has been based on atherogenesis, a disease in which macrophages are cholesterol-enriched. Our previous work showed that foam cells in tuberculous lung lesions surprisingly accumulate triglycerides, suggesting multiple modalities of foam cell biogenesis. In the present study, we used matrix-assisted laser desorption/ionization mass spectrometry imaging to assess the spatial distribution of storage lipids relative to foam-cell-rich areas in murine lungs infected with the fungal pathogen Cryptococcus neoformans and in human papillary renal cell carcinoma resection tissues. We also analyzed neutral lipid content and the transcriptional program of lipid-laden macrophages generated under corresponding in vitro conditions. The in vivo data were consistent with in vitro findings showing that C. neoformans-infected macrophages accumulated triglycerides, while macrophages exposed to human renal cell carcinoma-conditioned medium accumulated both triglycerides and cholesterol. Moreover, macrophage transcriptome analyses provided evidence for condition-specific metabolic remodeling. The in vitro data also showed that although both Mycobacterium tuberculosis and C. neoformans infections induced triglyceride accumulation in macrophages, they did so by different molecular mechanisms, as evidenced by different sensitivity of lipid accumulation to the drug rapamycin and the characteristics of macrophage transcriptome remodeling. Collectively, these data demonstrate that the mechanisms of foam cell formation are specific to the disease microenvironment. Since foam cells have been regarded as targets of pharmacological intervention in several diseases, recognizing that their formation is disease-specific opens new research directions of biomedical significance.

Underreporting of SMARCB1 alteration by clinical sequencing: Integrative patho-genomic analysis captured SMARCB1/INI-1 deficiency in a vulvar yolk sac tumor.

•SMARCB1/INI1-deficient gynecologic tumors are rare and clinically aggressive. A subset shows primitive yolk sac tumor features.•Due to technical limitation of next generation sequencing (NGS) and interlaboratory variability in sequencing methodologies and analytical pipelines, SMARCB1 deficiency caused by somatic copy number variations (SCNV) may be underreported by NGS.•To improve identification of SMARCB1/INI1-deficient neoplasm, we propose the following strategy: First, careful pathology slide review and detection of rhabdoid cells should raise the possibility of SMARCB1/INI1 deficiency. Second, INI1 IHC is a useful complementary test to exclude clinical suspicion of SMARCB1 deficiency in the context of negative molecular reporting. Third, knowledge of potential underreporting of SMARCB1 mutation would avoid underdiagnosis.

Chromophobe Renal Cell Carcinoma with Sarcomatoid Differentiation.

Chromophobe renal cell carcinoma (chRCC) is one of the less common types of kidney cancer and generally portends a more favorable prognosis. RCC with sarcomatoid differentiation has a more aggressive clinical course with poor outcomes. Four cases of chRCC with varying degrees of sarcomatoid differentiation were retrospectively reviewed at our institution, and clinicopathologic data as well as clinical courses were reported. Patients with higher degrees of sarcomatoid differentiation and larger tumors at presentation generally had and worse overall survival. chRCC with sarcomatoid differentiation portends a poor prognosis with limited data on systemic treatment options for metastatic disease.

Pulmonary tumor thrombotic microangiopathy with cor pulmonale due to desmoplastic small round cell tumor.

A 12-year-old boy presented acutely after an episode of syncope with perioral cyanosis. He died 19 hours after admission due to cor pulmonale as a complication of metastatic desmoplastic small round cell tumor in the lungs with associated tumor thrombotic microangiopathy.

Establishment of a whole slide imaging-based frozen section service at a cancer center.

Background: In recent years, there has been a surge of interest in clinical digital pathology (DP). Hardware and software platforms have matured and become more affordable, and advances in artificial intelligence promise to transform the practice of pathology. At our institution, we are launching a stepwise process of DP adoption which will eventually encompass our entire workflow. Out of necessity, we began by establishing a whole slide imaging (WSI)-based frozen section service. Methods: We proceeded in a systematic manner by first assembling a team of key stakeholders. We carefully evaluated the various options for digitizing frozen sections before deciding that a WSI-based solution made the most sense for us. We used a formalized evaluation system to quantify performance metrics that were relevant to us. After deciding on a WSI-based system, we likewise carefully considered the various whole slide scanners and digital slide management systems available before making decisions. Results: During formal evaluation by pathologists, the WSI-based system outperformed competing platforms. Although implementation was relatively complex, we have been happy with the results and have noticed significant improvements in our frozen section turnaround time. Our users have been happy with the slide management system, which we plan on utilizing in future DP efforts. Conclusions: There are various options for digitizing frozen section slides. Although WSI-based systems are more complex and expensive than some alternatives, they perform well and may make sense for institutions with a pre-existing or planned larger DP infrastructure.

Inflammatory Hibernoma of the Renal Hilum Mimicking a Renal Pelvis Tumor.

We report on an enhancing, heterogenous renal pelvis mass growing over 2 years which was found to be a benign hibernoma with inflammatory and lipomatous features originating from the renal hilum. To our knowledge, this is the first case reported on a hibernoma compressing on the renal pelvis and second case of a hibernoma with the inflammatory variant.

Massive Malignant Epithelioid Angiomyolipoma of the Kidney.

Renal angiomyolipomas (AMLs) are a subset of perivascular epithelioid cell neoplasms (PEComas) that are associated with tuberous sclerosis complex (TSC). Epithelioid angiomyolipomas (EAMLs) are a rare variant of AML with more aggressive propensities. EAMLs with malignant potential can be difficult to distinguish from relatively benign AMLs and other renal tumors. Although there are no established criteria for predicting EAML malignancy, there are proposed histologic parameters that are associated with higher tumor risk. EAML can be treated with surgical resection as well as mTOR inhibitors. Here, we present a unique case of a patient with a 36-cm renal EAML metastatic to the lungs that was treated with complete surgical resection of the primary lesion and mTOR inhibition.

Renal Cell Carcinoma with Testicular Metastases: A Case Report and Review of the Literature.

Renal cell carcinoma (RCC) metastases to the testicle are an extremely rare clinical entity. Here, we describe the case of a man with metastatic RCC who developed a new testicular mass. Pathologic analysis after surgical removal of this testicle confirmed the diagnosis of metastatic RCC. This report highlights the unique diagnostic and therapeutic challenges associated with such a disease process.

An Expandable Informatics Framework for Enhancing Central Cancer Registries with Digital Pathology Specimens, Computational Imaging Tools, and Advanced Mining Capabilities.

BACKGROUND: Population-based state cancer registries are an authoritative source for cancer statistics in the United States. They routinely collect a variety of data, including patient demographics, primary tumor site, stage at diagnosis, first course of treatment, and survival, on every cancer case that is reported across all U.S. states and territories. The goal of our project is to enrich NCI's Surveillance, Epidemiology, and End Results (SEER) registry data with high-quality population-based biospecimen data in the form of digital pathology, machine-learning-based classifications, and quantitative histopathology imaging feature sets (referred to here as Pathomics features). MATERIALS AND METHODS: As part of the project, the underlying informatics infrastructure was designed, tested, and implemented through close collaboration with several participating SEER registries to ensure consistency with registry processes, computational scalability, and ability to support creation of population cohorts that span multiple sites. Utilizing computational imaging algorithms and methods to both generate indices and search for matches makes it possible to reduce inter- and intra-observer inconsistencies and to improve the objectivity with which large image repositories are interrogated. RESULTS: Our team has created and continues to expand a well-curated repository of high-quality digitized pathology images corresponding to subjects whose data are routinely collected by the collaborating registries. Our team has systematically deployed and tested key, visual analytic methods to facilitate automated creation of population cohorts for epidemiological studies and tools to support visualization of feature clusters and evaluation of whole-slide images. As part of these efforts, we are developing and optimizing advanced search and matching algorithms to facilitate automated, content-based retrieval of digitized specimens based on their underlying image features and staining characteristics. CONCLUSION: To meet the challenges of this project, we established the analytic pipelines, methods, and workflows to support the expansion and management of a growing repository of high-quality digitized pathology and information-rich, population cohorts containing objective imaging and clinical attributes to facilitate studies that seek to discriminate among different subtypes of disease, stratify patient populations, and perform comparisons of tumor characteristics within and across patient cohorts. We have also successfully developed a suite of tools based on a deep-learning method to perform quantitative characterizations of tumor regions, assess infiltrating lymphocyte distributions, and generate objective nuclear feature measurements. As part of these efforts, our team has implemented reliable methods that enable investigators to systematically search through large repositories to automatically retrieve digitized pathology specimens and correlated clinical data based on their computational signatures.

Ovarian transposition and metachronous ovarian metastasis in a premenopausal colorectal carcinoma patient: a case report.

Colon cancer has a high incidence of metastasis, with an estimated 0.8-7.4% of colorectal adenocarcinoma (CRC) cases metastasizing to the ovary. The role of prophylactic bilateral oophorectomy in CRC is contested in the literature, particularly in premenopausal patients. Further, it is unclear if prophylactic removal of the contralateral ovary is indicated in cases of direct involvement of one ovary to reduce recurrence. Facing a lack of evidence for survival benefit, hormonal complications, and sterilization, some choose to pursue fertility sparing options. For female patients interested in additional pregnancies, the ovaries can be surgically relocated in a prophylactic procedure known as ovarian transposition; as even small doses of radiation to the ovary can effectively sterilize women in their 30 s. We present a case of a 29-year-old female who underwent ovarian transposition of the right ovary before initiating chemoradiation for primary left sided colon adenocarcinoma with direct invasion of the left ovary. Months later, she presented to the emergency department (ED) with abdominal pain suspicious for ovarian torsion. On restaging computerized tomography (CT), she was diagnosed with symptomatic right ovarian metastasis in the transposed ovary, requiring reoperation and oophorectomy. For this patient, and for others facing critical decisions about ovarian preservation in advanced colorectal cancer, the question remains how to balance fertility concerns with optimal minimization of metastasis and recurrence.

Fourteen-Core Systematic Biopsy That Includes Two Anterior Cores in Men With PI-RADS Lesion ≥ 3 is Comparable With Magnetic Resonance Imaging-ultrasound Fusion Biopsy in Detecting Clinically Significant Prostate Cancer: A Single-institution Experience.

INTRODUCTION: Magnetic resonance imaging (MRI)-ultrasound fusion targeted prostate biopsy (FB) has been advocated by many experts as a replacement for the standard template biopsy. Herein, we compared pathology results and cancer detection rates of FB with our standard 14-core systematic prostate biopsy (SB) that includes 2 anterior cores. MATERIALS AND METHODS: One hundred two men with elevated prostate-specific antigen and suspicious lesions on multiparametric MRI, Prostate Imaging Reporting And Data System (PI-RADS) v2 score ≥ 3, underwent FB. Each target lesion was biopsied 3 times; our SB was performed concurrently. Biopsy results were compared for overall and clinically significant (cs), defined as Gleason score ≥ 7, cancer detection. RESULTS: Fifty-two percent of patients had positive biopsy results, and of those, 44 had cs prostate cancer (PCa). The overall detection rates for FB and SB were 39% and 50%, respectively, and there was no statistical difference in the detection rate of csPCa detection rate (P = .42). Of 17 patients diagnosed with a high-risk PCa, defined as Gleason score ≥ 8, SB identified 15, whereas FB identified 10. Within the SB group, 21 had positive anterior core biopsies, of which 11 were cs. CONCLUSION: Expanding the standard template prostate biopsies to include 2 anterior horn sampling may be just as effective as FB in men with PI-RADS lesion ≥ 3, thereby mitigating the increased cost associated with FB.

The role of chromodomain helicase DNA binding protein 1 (CHD1) in promoting an invasive prostate cancer phenotype.

BACKGROUND: Prostate cancer (PCa) phenotypes vary from indolent to aggressive. Molecular subtyping may be useful in predicting aggressive cancers and directing therapy. One such subtype involving deletions of chromodomain helicase DNA binding protein 1 (CHD1), a tumor suppressor gene, are found in 10-26% of PCa tumors. In this study, we evaluate the functional cellular effects that follow CHD1 deletion. METHODS: CHD1 was knocked out (KO) in the non-tumorigenic, human papillomavirus 16 (HPV16)-immortalized prostate epithelial cell line, RWPE-1, using CRISPR/Cas9. In vitro assays such as T7 endonuclease assay, western blot, and sequencing were undertaken to characterize the CHD1 KO clones. Morphologic and functional assays for cell adhesion and viability were performed. To study expression of extracellular matrix (ECM) and adhesion molecules, a real-time (RT) profiler assay was performed using RWPE-1 parental, non-target cells (NT2) and CHD1 KO cells. RESULT: Compared to parental RWPE-1 and non-target cells (NT2), the CHD1 KO cells had a smaller, rounder morphology and were less adherent under routine culture conditions. Compared to parental cells, CHD1 KO cells showed a reduction in ECM and adhesion molecules as well as a greater proportion of viable suspension cells when cultured on standard tissue culture plates and on plates coated with laminin, fibronectin or collagen I. CHD1 KO cells showed a decrease in the expression of secreted protein acidic and rich in cysteine (SPARC), matrix metalloproteinase 2 (MMP2), integrin subunit alpha 2 (ITGA2), integrin subunit alpha 5 (ITGA5), integrin subunit alpha 6 (ITGA6), fibronectin (FN1), laminin subunit beta-3 precursor (LAMB3), collagen, tenascin and vitronectin as compared to parental and NT2 cells. CONCLUSION: These data suggest that in erythroblast transformation specific (ETS) fusion-negative, phosphatase and tensin homolog (PTEN) wildtype PCa, deletion of CHD1 alters cell-cell and cell-matrix adhesion dynamics, suggesting an important role for CHD1 in the development and progression of PCa.

A Giant Childhood Mesenteric Lipoblastoma With Extensive Maturation.

Abdominal lipoblastomas are uncommon soft tissue tumors in children and rarely arise from the mesentery. Due to intraabdominal location and slow growth, these masses can go unnoticed for long periods of time and often found on surgical exploration. We present a case of a 12-year-old male with years of abdominal distension accompanied by new onset early satiety that was found to have an intra-abdominal mass. He underwent an exploratory laparotomy revealing a large 33 x 27 x 15 cm rubbery mesenteric mass displacing the entire intra-abdominal contents, connected by a single vascular pedicle and encasing a loop of small intestine. The mass was resected and the patient did well without signs of recurrence. Histology confirmed the presence of mature adipocytes but on further cytogenetic analysis, a translocation between chromosomes 2 and 8 at the 12q arm was detected, which is often associated with lipoblastomas. This case represents the one of the largest mesenteric lipoblastomas that matured extensively to lipoma-like histology at the time of surgical resection.