Faculty Bibliography

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.

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

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: Traditional pathology reports of prostate biopsy mainly focus on presence of carcinoma but ignore other pathologic findings such as inflammation or hyperplasia. In the era of MRI-ultrasound fusion-targeted prostate biopsy (MRF-TB), where specific MRI regions of interest (ROI) are targeted for biopsy, these benign findings should be reported as they may guide decisions on when to repeat imaging or prostate biopsy. In this study, we reviewed MRF-TB prostate biopsies reported as negative for carcinoma to identify pathologic correlates to visible ROI on prostate MRI. Design: From 2012 to2016, 1595 men underwent a total of 1813 prebiopsy prostate MRI, followed by MRF-TB at our institution. We rereviewed the prostate biopsy cores for all patients with PI-RADS 4 or 5 (PI-RADS 4/5) ROI but had no cancer detected on MRF-TB. Pathologic findings were separated into two groups: significant pathologic findings (SPF, such as inflammation, hyperplasia, ASAP/HGPIN) and no significant pathologic findings (NSPF) with or without cancer in same/adjacent site on systematic biopsy (SB). Patients with repeat MRI and follow-up MRF-TB evaluation. Results: 497 men had PI-RADS 4/5 lesions out of 1595 initial biopsies. Of these 497 men, 101 (20%) had MRF-TB negative for carcinoma. Upon review, 54 had SPF and 47 had NSPF on MRF-TB. Of 54 men with SPF on initial MRF-TB, 31 had repeat MRI, 23 of 31 men downgraded in which 16 had repeat MRF-TB with 1 had cancer detect. The other 8 of 31 men had persistent PI-RADS 4/5 lesions, 3 were detected cancer on repeat MRF-TB. Of 47 men with NSPF on initial MRF-TB, 19 had PCa in the same/ adjacent site on SB and were considered as missed on MRF-TB; of the other 28, 13 underwent repeat MRI. 8 of 13 downgraded with 0 had PCa in the repeat MRF-TB and 5 of 13 men with persistent PI-RADS 4/5 lesions, 3 had PCa detect on repeat MRF-TB. Altogether, 22/47 (47%) of the cases with NSPF in the initial MRF-TB were missed cancer. Conclusions: 1/5 of the target biopsy cases on PI-RADS 4/5 ROI had negative cancer detection. Inflammation, nodular hyperplasia and HGPIN can account for some of the cases, and those were downgraded in followup MRI usually had a negative repeat biopsy. Cases with NSPF on MRF-TB for PI-RADS 4/5 lesions are likely (47%) missed PCa, high likelihood of persistent PI-RADS 4/5 ROI on repeat MRI and PCa detection on repeat biopsy. We suggest pathology findings beside cancer should be reported on MRF-TB biopsy as they can guide decisions on repeat imagine and biopsy

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