Faculty Bibliography

We previously showed that KLF4, a gene highly expressed in murine prostate stem cells, blocks the progression of indolent intraepithelial prostatic lesions into aggressive and rapidly growing tumors. Here, we show that the anti-tumorigenic effect of KLF4 extends to PC3 human prostate cancer cells growing in the bone. We compared KLF4 null cells with cells transduced with a DOX-inducible KLF4 expression system, and find KLF4 function inhibits PC3 growth in monolayer and soft agar cultures. Furthermore, KLF4 null cells proliferate rapidly, forming large, invasive, and osteolytic tumors when injected into mouse femurs, whereas KLF4 re-expression immediately after their intra-femoral inoculation blocks tumor development and preserves a normal bone architecture. KLF4 re-expression in established KLF4 null bone tumors inhibits their osteolytic effects, preventing bone fractures and inducing an osteogenic response with new bone formation. In addition to these profound biological changes, KLF4 also induces a transcriptional shift from an osteolytic program in KLF4 null cells to an osteogenic program. Importantly, bioinformatic analysis shows that genes regulated by KLF4 overlap significantly with those expressed in metastatic prostate cancer patients and in three individual cohorts with bone metastases, strengthening the clinical relevance of the findings in our xenograft model.

Parathyromatosis is a rare but recognized cause of recurrent primary hyperparathyroidism. Initially described in 1975 by Palmer et al.(1), about 40 cases have been described in the literature. Most patients are middle-aged females. A small majority of the cases arise in the context of secondary hyperplasia due to end-stage renal disease.(2) The nature of parathyromatosis is unknown. It may be a low-grade carcinoma, seeding of a prior adenoma, or overgrowths of embryologic rests. Several oncogenes of interest have been identified in parathyroid neoplasms (PRAD1, MEN1, HRPT2, CaSR). (3) A biallelic CDC73/HRPT2 inactivating mutation is known to be present in about 75% of sporadic parathyroid carcinomas and absent in most adenomas. (4) Their possible relationship to parathyromatosis has not been studied. As such, differentiating parathyromatosis from other parathyroid neoplasms is challenging.(5-10) This article is protected by copyright. All rights reserved.

CONTEXT.—/UNASSIGNED:Phosphatase and tensin homolog (PTEN) is a promising prognostic and potentially predictive biomarker in prostate cancer. OBJECTIVE.—/UNASSIGNED:To assess the effects of preanalytic variables on an analytically validated and fully automated PTEN immunohistochemistry assay. DESIGN.—/UNASSIGNED:PTEN immunohistochemistry was performed on Ventana immunostaining systems. In benign prostate tissues, immunostaining intensity across variable conditions was assessed by digital image analysis. In prostate tumor tissues, immunostaining was scored visually. RESULTS.—/UNASSIGNED:Delay of fixation for 4 hours or longer at room temperature or 48 hours or longer at 4°C and duration of formalin fixation did not significantly alter immunostaining intensity. Intensity of staining was highest in 10% formalin compared with other fixatives. Tumor tissues with PTEN loss processed using protocols from 11 academic institutions were all evaluable and scored identically. PTEN immunostaining of needle biopsies where tissue blocks had been stored for less than 10 years was more frequently scored as nonevaluable compared with blocks that had been stored for 10 years or longer. This effect was less evident for radical prostatectomy specimens, where low rates of nonevaluable staining were seen for 23 years or more of storage. Storage of unstained slides for 5 years at room temperature prior to immunostaining resulted in equivalent scoring compared with freshly cut slides. Machine-to-machine variability assessed across 3 Ventana platforms and 2 institutions was negligible in 12 tumors, and platform-to-platform variability was also minor comparing Ventana and Leica instruments across 77 tumors (κ = 0.926). CONCLUSIONS.—/UNASSIGNED:Automated PTEN immunostaining is robust to most preanalytic variables in the prostate and may be performed on prostate tumor tissues subjected to a wide range of preanalytic conditions. These data may help guide assay development if PTEN becomes a key predictive biomarker.

CONTEXT/BACKGROUND:- In Gleason score GS (7) prostate cancers, the quantity of Gleason pattern 4 (GP 4) is an important prognostic factor and influences treatment decisions. Magnetic resonance imaging (MRI)-targeted biopsy has been increasingly used in clinical practice. OBJECTIVE:- To investigate whether MRI-targeted biopsy may detect GS 7 prostate cancer with greater GP 4 quantity, and whether it improves biopsy/radical prostatectomy GS concordance. DESIGN/METHODS:- A total of 243 paired standard and MRI-targeted biopsies with cancer in either standard or targeted or both were studied, 65 of which had subsequent radical prostatectomy. The biopsy findings, including GS and tumor volume, were correlated with the radical prostatectomy findings. RESULTS:- More prostate cancers detected by MRI-targeted biopsy were GS 7 or higher. Mean GP 4 percentage in GS 7 cancers was 31.0% ± 29.3% by MRI-targeted biopsy versus 25.1% ± 29.5% by standard biopsy. A total of 122 of 218 (56.0%) and 96 of 217 (44.2%) prostate cancers diagnosed on targeted biopsy and standard biopsy, respectively, had a GP 4 of 10% or greater ( P = .01). Gleason upgrading was seen in 12 of 59 cases (20.3%) from MRI-targeted biopsy and in 24 of 57 cases (42.1%) from standard biopsy ( P = .01). Gleason upgrading correlated with the biopsy cancer volume inversely and GP 4 of 30% or less in standard biopsy. Such correlation was not found in MRI-targeted biopsy. CONCLUSIONS:- Magnetic resonance imaging-targeted biopsy may detect more aggressive prostate cancers and reduce the risk of Gleason upgrading in radical prostatectomy. This study supports a potential role for MRI-targeted biopsy in the workup of prostate cancer and inclusion of percentage of GP 4 in the prostate biopsy reports.

Objectives: To report a rare recurrent malignant gastrointestinal neuroectodermal tumor in a 36-year-old woman with an upper gastrointestinal obstruction. Clinical History: In January 2017, a 36-year-old female physician with a history of GI tract clear cell sarcoma- like tumor s/p resection (September 2015) had a follow-up PET/CT scan that found a new PDG-avid lesion in the left adnexal region. The TVUS ruled out an adnexal lesion. In September 2017, she presented to the emergency room for abdominal discomfort but no nausea, vomiting fever, or chills. She then underwent laparoscopy small bowel resection with primary anastomosis. Pathologic Findings: The gross specimen showed a segment of small bowel with a thin brown cystic mass (2.9 +/- 2.9 +/- 1.4 cm) arising from the anastomotic site. Sectioning revealed a tan-brown solid and partially cystic mass with thin brown fluid. Microscopy revealed epithelioid and spindle cells arranged in nests and cords, with abundant clear cytoplasm, slightly pleomorphic nuclei with occasionally prominent nucleoli, low mitotic activity, and no necrosis. No positive lymph nodes were identified. Neoplastic cells infiltrated most of the thickness of the gastric wall, sparing the mucosa. Immunohistochemical stains revealed reactivity for S-100 protein and vimentin. Actin, desmin, and CD117 were negative. EWSR1 (22q12) translocation was detected. Final Diagnosis: Recurrent tumor (gastrointestinal-type clear cell sarcoma) similar to a previous one is seen in mesenteric adipose tissue adjacent to the small intestinal anastomotic site. Strong reactivity for neural markers (S-100, SOX10, synatophysin, and vimentin) and negative melanocytic markers (HMB 45, Melanin A) suggest an origin from a gastrointestinal neuroectodermal precursor cell not differentiable along the melanocytic lineage.
Conclusion(s): Malignant gastrointestinal neuroectodermal tumor has frequent local recurrences that are easily misdiagnosed as metastasized melanoma. Clinical history, pathologic morphology, and molecular tests are the best combination for diagnosis

There is a considerable need to identify those individuals with prostate cancer who have indolent disease. We propose that genes that control adult stem cell homeostasis in organs with slow turnover, such as the prostate, control cancer fate. One such gene, KLF4, overexpressed in murine prostate stem cells, regulates their homeostasis, blocks malignant transformation, and controls the self-renewal of tumor-initiating cells. KLF4 loss induces the molecular features of aggressive cancer and converts PIN lesions to invasive sarcomatoid carcinomas; its re-expression in vivo reverses this process. Bioinformatic analysis links these changes to human cancer. KLF4 and its downstream targets make up a gene signature that identifies indolent tumors and predicts recurrence-free survival. This approach may improve prognosis and identify therapeutic targets for advanced cancer.

Background: Urothelial carcinoma of the upper tract (UTUC) is relatively rare. Urine cytology has been used in the diagnosis and surveillance of UTUC but its utility is not well established. Another method of UTUC detection is via endoscopic biopsy which itself can be limited due to inadequate sampling. Our study aims to explore the efficacy of urine cytology alone and in combination with endoscopic biopsy results in detecting UTUC. Design: We searched our pathology database for cases with both urine cytology specimen and subsequent histologic followup including endoscopic biopsies, ureterectomy, nephrectomy or nephroureterectomy over a 10 year period. Urine cytology and biopsies done concurrently or within 6 months follow-up are included in the study and the highest degree of abnormality was selected if multiple specimen available. For cases with both biopsies and surgical specimen diagnoses, the final diagnosis from surgery was used. Results: 154 cases of confirmed UTUC were included in the study. Among them, urine diagnoses of suspicious or positive for malignancy were made in 106 cases (69%): 7 cases were low grade UC (LGUC) and 99 cases were high grade UC (HGUC) upon surgical pathology evaluation. 32/154 cases (21%) were atypical urothelial cells (AUC) on cytology, among which 27 had confirmed HGUC and 5 cases had LGUC on surgical pathology. 16/154 urine cytology cases (10%) were negative: 11/16 had HGUC and 5/16 cases had LGUC in the concurrent or follow-up biopsies or surgery. The sensitivity for abnormal urine cytology was 89.6% for detecting UTUC. We also compared the urine cytology and endoscopic biopsies (within 6 months) in detecting UTUC. There are 62 cases are positive for both methods. Four cases show positive urine but negative biopsy, and 1 with negative urine but positive biopsy (HGUC). The sensitivity for combined urine cytology and biopsy is slightly higher for one method alone. Conclusions: Urine cytology is highly sensitive for detecting UTUCespecially for HGUC. Combining urine cytology and endoscopic biopsy results increases the sensitivity for detecting UTUC and should therefore be recommended for clinical practice

Background: Russell Body Gastritis (RBG) is considered to be a rare histologic finding that has an unclear pathogenesis and an unpredictable clinical outcome. We sought to clarify the frequency and significance of RBG by assessing their associated histology and relationship with the local microbiome. Design: We reviewed all 220 gastric biopsies over a 2-month period at 1 institution for the presence and density of Russell bodies (RB). In biopsies with RB, the quantity of RB was manually counted using light microscopy at 200x magnification in every biopsy level (3068 sections) and the sectional area was estimated using a 1x1 mm grid overlay. RB density was calculated by dividing the total quantity of RB in all sections by the total sectional area. 48 additional patients, which corresponded to an extra 100 histologic biopsies, were consented at the same visit for an extra gastric biopsy for 16S rRNA sequencing, and these microbiome profiles were correlated with the highest RB density per patient. Results: Russell bodies (RB) were frequent in gastric biopsies (43% of all gastritides) and the RB density significantly increased with more severe gastritides (p<0.001, n=320). The gastric microbiome globally differed in beta diversity between RB-positive and RB-negative cases by unweighted and weighted principal component analysis (p=0.03, p=0.007, n=48, respectively). In particular, Helicobacter and Streptococcus were significantly enriched in gastritis with RB and their abundances correlated with RB density (p=0.0002, r=0.51; p=0.009, r=0.37, n=48, respectively). Protonpump inhibitor (PPI) use reduced RB density per unit abundance of Streptococcus (p=0.0021, n=48). H. pylori abundance significantly correlated with RB density and two Streptococcus species (an unclassified Streptococcal species and S. anginosus) significantly correlated with RB density in H. pylori-negative gastritis (p=0.009, n=36, r=0.36; p=0.0025, n=36, r=0.51, respectively). 7 H. pylorinegative patients were followed for 1 year and variation in Streptococcus abundance reflected RB density (p=0.085, n=7). Conclusions: RB are common within the inflamed gastric mucosa and gastritis with RB is associated with Helicobacter and Streptococcus enrichment and consequent global shifts in the gastric microbiome. PPI dampens RB production, presumably through anti-inflammatory effects. Gastritis with RB might represent a reactive humoral response to bacteria within the gastric microbiome. Streptococcus species may influence chronic gastritis

Background: On January 1, 1898, New York City consolidated the five boroughs to create the modern municipal government. This legislation reorganized the borough-based coroner system and death recordkeeping. The previous year, the world-renowned Bellevue Hospital Medical College pathology department lost its morgue in a fire. Among the records saved in the aftermath, recently rediscovered, were log books documenting hundreds of autopsies performed at Bellevue Hospital in 1897. Design: Data from 324 autopsies (n=325, excluding one duplicate entry) performed at Bellevue Hospital between March 16 and December 31, 1897 were collected in a Microsoft Excel 2010 spreadsheet. Each decedent's name, age, race, ethnicity, country of origin, medical division, ward assignment, time of death, time of autopsy, and autopsist(s) were recorded, along with external examination findings, gross findings by organ system, and final anatomic diagnosis. Frequency tables and measures of central tendency were compiled. The final anatomic diagnoses were subcategorized by etiology (chronic disease, malignancy, infectious disease, therapeutic complication, medicolegal, psychiatric). Where possible, patient and physician identifiers were matched to contemporaneous public records, medical journals, and online archives (NYU Health Sciences Library, New York Public Library, National Library of Medicine). Microscope slides and laboratory medicine results were unavailable. Results: Decedents included 222 men, 82 women, and 20 of unknown sex. Age was recorded for 166 adults and 46 children. The adults' average age at death was 42 years (range 19-78 years); children, 17 months (3 days-13 years). The majority (310) were U.S. born, with 11 European-born (Ireland, Germany, Austria, Italy, Sweden), 3 of unknown birthplace. Six U.S.-born were identified as "colored." The combined medical divisions ordered 208 autopsies, and the surgical 21. Other decedents were from the insane pavilion (2), emergency ward (1), prison (1), and found on the street (6). Average turnaround time was 43 hours (1 hour-14 days after death). Thirty-nine autopsies were same-day. Conclusions: The most frequent causes of death in this cohort match those reported by New York State in 1896-8. Average age at death, 42 years, was younger than U.S. life expectancy (46.3 years for men, 48.3 years for women). There was insufficient data to classify decedents' occupations and socioeconomic status. No major diagnostic errors were seen, accounting for changes in nomenclature over time