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.

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.

Background & Objectives: Ciliated muconodular papillary tumour (CPMT) is a rare benign lesion, which occurs in the periphery of the lung and is characterised by papillary architecture, intra-alveolar mucin and the presence of non-atypical ciliated-columnar, basal and mucous cells. Since its introduction in 2002 by Ishikawa et al, this entity counts a few reports in the literature, which have primarily occurred in East Asia. Although not in the 2015WHO classification, CPMT represents a frank neoplastic process, harbouring genetic alterations including BRAF and EGFR mutations. The goal of this study was to characterise the clinicopathologic features of CPMT diagnosed at a tertiaty care institution in the U.S.
Method(s): Nine cases with characteristic features of classic and nonclassic CPMT from New York University Tisch Hospital and Bellevue Hospital from 2016 to 2019 were identified. Clinical and pathologic data were reviewed.
Result(s): CPMTs were identified in 3 Male and 6 Female patients, whose age ranged from 47 to 82 years old. The lesions were predominantly found in the right lung and had a median size of 6 mm. Six (6) cases represented classic CPMTs, while 3 cases lacked the full spectrum of CPMT diagnostic features, and were classified as non-classic CPMTs. While in 7 cases, surgical resection was performed due to radiologic diagnosis of a peripheral nodule, in 2 cases, small CPMTs were incidental findings in resections performed for a dominant lesion, which was either adenocarcinoma, non-mucinous type (case 2) or atypical carcinoid (case 8). All lesions showed the characteristic immunohistochemical TTF-1 stain of columnar cells and p63 or p40 stain of basal cells. Two out of four (2/4) cases stained for BRAF-V600E showed uniform staining of all 3 cellular components of the lesion. The data are summarized on Table 1.
Conclusion(s): CPMTs although infrequent are now increasingly recognized and their incidence appears higher than reported in western literature. Interestingly, this self-limited tumour shares similar driver mutations with lung adenocarcinoma. Further studies will include a comprehensive immunohistochemical and molecular characterization of these nine cases and comparison with morphologically similar non-neoplastic processes, like bronchiolar metaplasia