Andres Matoso

Radical Prostatectomy Findings in Men on Active Surveillance: Variable Findings Dependent on Reason for Surgery and Entry Criteria

PURPOSEnWe studied adverse radical prostatectomy findings in men on an active surveillance program with different entry and exit criteria.nnnMATERIALS AND METHODSnThe study included 80 men with biopsy progression, 33 who opted out for personal reasons and 24 who initially did not meet entry criteria mainly due to increased prostate specific antigen density.nnnRESULTSnOf men who opted out 78.8% had a higher Gleason score of 6 than men who progressed on biopsy (46.2%, p = 0.002) and men with high prostate specific antigen density (45.8%, p = 0.02). Men with high prostate specific antigen density had less organ confined disease than the group that opted out (p <0.006) and a trend compared to the biopsy progression group (p = 0.07). Mean dominant tumor volume was lower in men who opted out than in those with biopsy progression (0.56 vs 1.1 cc, p = 0.03). The incidence of insignificant cancer was higher in men who opted out (48.4%) than in those with biopsy progression (28.4%, p = 0.05) and those with high prostate specific antigen density (20.8%, p = 0.035). There was a higher incidence of anterior tumor in men with high prostate specific antigen density (55.0%) than with biopsy progression (21.3%, p = 0.009) and a trend compared to those who opted out (27.3%, p = 0.06).nnnCONCLUSIONSnThe majority of men with biopsy progression still had tumors with features of curable disease. Men who opted out without biopsy progression had even less adverse findings, which supports counseling men to stay on active surveillance while they meet followup criteria. Men with elevated prostate specific antigen density had more anterior tumors and less organ confined cancer, substantiating that the ideal patients for active surveillance are those who meet all entry criteria.

Clinicopathologic and gene expression analysis of initial biopsies from patients with eosinophilic esophagitis refractory to therapy

Some patients with eosinophilic esophagitis (EoE) do not respond to therapy. The clinicopathologic characteristics and gene expression profile at time of presentation could help predict response to therapy. Refractory EoE was defined as persistence of symptoms and biopsies with histologic features of EoE after 6 months of therapy with proton pump inhibitors and topical corticosteroids. Initial biopsies from refractory EoE patients (n=21), responder to therapy (n=8), patients who relapsed (n=6), and reflux controls (n=24) were studied. RNA was isolated from a subset of cases, and gene expression analysis of 285 genes involved in inflammation was performed using NanoString technology. There was no difference in the presenting symptoms among groups. The number of eosinophils/high-power field among nonresponders was higher (66±15) than responders (39±8; P<.0001) and similar to patients who relapsed (62±11). Six genes were expressed by at least 4-fold compared with reflux at a false discovery rate < 0.05, including overexpression of ALOX15, CCL26, FCER2, RTNLB, and RNASE2, and underexpression of DSG1. EoE patients refractory to therapy or who relapsed showed a trend toward higher ALOX15 expression compared with patients with good response to therapy (364.4- and 425-fold change, P=.097 and P=.07). RTNLB was significantly overexpressed in patients who were refractory to therapy versus those who responded favorably (10-fold versus 3-fold; P<.01). In conclusion, the number of eosinophils/high-power field in the initial biopsy inversely correlates with therapy response. Overexpression of RTNLB in refractory-to-therapy patients and overexpression of ALOX15 and CCL26 suggest that they are critical in the EoE pathogenesis.

Hypomethylation, endogenous retrovirus expression, and interferon signaling in testicular germ cell tumors

Methylation of cytosine residues exerts a critical role in silencing gene transcription. Importantly, DNA methylation patterns are often altered in cancer, with many tumors showing site-specific gain of methylation marks in a background of global hypomethylation (1).nnIn PNAS, Stone et al. (2) show in an ovarian cancer model that treatment with the demethylating agent 5-azacytidine resulted in reexpression of human endogenous retroviruses (HERVs), activation of type I IFN signaling, and increased CD8+ T cells in the tumor microenvironment. These data provide important insights into the role of DNA methylation in suppressing immunogenic pathways and provide additional support for the notion that hypomethylation can resculpt the host antitumor response through derepression of HERV and activation of type I IFN signaling (3, 4).nnWe hypothesized that such elevated HERV expression and type I IFN signaling are also present in tumors that are characterized by constitutive DNA hypomethylation. Seminoma, a type of testicular germ cell tumor (TGCT), provides an opportunity to test this hypothesis. The majority of seminomas are … nn[↵][1]1To whom correspondence may be addressed. Email: mhaffne4{at}jhmi.edu or syegnasu{at}jhmi.edu.nn [1]: #xref-corresp-1-1

Pathologic and Clinical Characteristics of Early Onset Renal Cell Carcinoma

The majority of renal cell carcinomas (RCCs) occur within the 7th decade of life, uncommonly arising in adults ≤46 years. We reviewed the clinicopathologic features of early onset RCC and evaluated the role of immunohistochemistry (IHC) in potentially identifying diagnoses of newly recognized RCC subtypes that may have been previously misclassified. A retrospective review was performed from 2011-2016 for cases of RCC. Early onset RCC was defined as ≤46 years of age. Clinicopathologic findings and hematoxylin and eosin (H&E) slides were reviewed on early onset RCC patients. IHC was performed on all cases previously diagnosed as unclassified or papillary. Clinicopathologic findings were compared to a control group of RCC patients >46 years over the same time period. We identified 98/598 (16.4%) early onset RCCs. The median age in the early onset RCC and control group was 38.4 and 62.8 years, respectively. The early onset RCC group contained 33/96 (34.3%) females and 63/96 (65.6%) males, including 52/96 (54.2%) whites, 39/96 (40.6%) African Americans, 4/96 (4.2%) Hispanics, and 1/96 (1%) Asian. Nonwhites were significantly more likely to develop early onset RCC (P=.004). Early onset RCCs included 52% clear cell, 28.6% papillary, 8.2% unclassified, 5.1% chromophobe, 3.1% clear cell papillary(CCP), and 3 other rare tumors. Six unclassified and 26 papillary RCCs had tissue available for IHC. Two of 6 (33.3%) unclassified RCCs were reclassified (1 CCP, 1 Xp11 translocation). One of 26 (3.8%) papillary RCCs was reclassified as CCP. Early onset RCCs were more likely to occur in nonwhites (P=.004), be lower stage (P=.03), and undergo partial nephrectomy (P=.002). Few unclassified and papillary tumors were reclassified with IHC.

Clinical significance of subtypes of Gleason pattern 4 prostate cancer

Major updates in prostate cancer grading have been adopted in recent times. These include redefinitions of Gleason pattern (GP) 4 architectural variants and reporting of the grade group (GG) system, which divides prostate cancer into five groups that better stratify patients. Still, the GG system uses the GPs 3, 4 or 5 to define each GG. Patients belonging to GG 2, 3 and 4 have increasing amounts of GP 4 in the composition of their tumors. GP4 is a heterogeneous group of morphologic variants that include poorly formed glands, glomeruloid structures, cribriform glands, and fused glands. Recently published studies suggest that the morphologic subtypes of GP 4 have different clinical significance. While the diagnostic reproducibility of poorly formed glands and fused glands is low, glomeruloid structures and cribriform glands are easier to be distinguished from other morphologies. A growing body of evidence suggests that the presence of cribriform glands is associated with an aggressive clinical course compared with other architectural subtypes. The latest 2014 guidelines issued by the International Society of Urologic Pathology recommend that the percentage of GP 4 be reported on needle biopsies and radical prostatectomy (RP) specimens. The data reviewed here invites consideration for the need to report the subtype of GP 4, especially the presence or absence of cribriform glands.

A Role for De Novo Purine Metabolic Enzyme PAICS in Bladder Cancer Progression

Genomic and transcriptome sequencing of bladder cancer (BLCA) has identified multiple molecular alterations during cancer progression. Many of these identified genetic and epigenetic changes play a role in the progression of this disease. Studies have identified molecular subtypes in muscle-invasive bladder cancer (MIBC) with different sensitivities to frontline therapy suggesting the heterogeneity in these tumors and the importance of molecular characterization of MIBC to provide effective treatment. Specifically, it has become increasingly evident, as demonstrated by The Cancer Genome Atlas project, that metabolic enzymes are commonly dysregulated in BLCA. Elevated expression of multiple metabolic enzymes is due to the increased demand from rapidly proliferating BLCA cells requiring extensive nucleotide synthesis. Cancer cells utilize the de novo purine and pyrimidine biosynthetic pathway as a source of their nucleotide needs. In this study, we show that phosphoribosyl aminoimidazole succinocarboxamide synthetase (PAICS), an enzyme involved in de novo purine biosynthetic pathway, is significantly overexpressed in BLCA. Immunohistochemical staining of paraffin-embedded tissue sections showed that PAICS is overexpressed in MIBC. Furthermore, we found that tumor suppressor miR-128 negatively regulated PAICS expression by binding to its 3′-untranslated region. We also found that PAICS induces EMT by positively regulating SNAI1 and by a reduction in E-cadherin expression. Additionally, our in vitro functional studies and in vivo chicken chorioallantoic membrane assay show that PAICS plays a critical role in BLCA cell proliferation, invasion, and tumor growth. Collectively, our data suggest that targeting PAICS may provide a therapeutic option in BLCA.

Spectrum of findings in orchiectomy specimens of persons undergoing gender confirmation surgery

Gender confirmation surgery is increasingly common in persons with gender dysphoria. We describe changes seen in gonads from individuals seeking male-to-female physical adaptation. We studied 99 orchiectomies from 50 persons. The average age was 33 years (range, 21-63 years). Eighty-six (86.8%) of 99 testes were normal in size with an average size of 3.87 cm (range, 3.0-5.5 cm). Thirteen (13.1%) of 99 testes were hypotrophic and measured up to 2.5 cm. Seminiferous tubules were reduced in diameter compared with controls (0.137 mm versus 0.237 mm; P < .001) and showed peritubular fibrosis in 41 (82%) of 50 persons. In 40 (80%) of 50 persons, there was maturation arrest at the spermatogonia level. In 10 (20%) of 50 persons, the seminiferous tubules showed focal spermatids/spermatozoa up to 7 per 10 tubules mixed with partial maturation arrest at primary spermatocytes. Twenty-six (26%) of 99 testes showed seminiferous tubules with rare cells with large nuclei (3× size of Sertoli cells nuclei) and degenerative chromatin (cytomegaly). Leydig cells were absent in 50 (50%), markedly reduced in 30 (30%), and similar to controls (mean, 33/high-power field) in 20 (20%). A subset (20/99; 20%) of testes had epithelial hyperplasia of the proximal epididymis with stratification and micropapillae. There was no germ cell tumor, sex cord stromal tumors, or germ cell neoplasia in situ. In summary, the histologic changes include (1) decreased diameter of seminiferous tubules and expansion of the interstitium, (2) marked hypoplasia of germ cells, (3) rare cytomegaly, (4) hypoplasia or absence of Leydig cells, and (5) epididymal hyperplasia.

Metastatic breast Cancer simulating well-differentiated neuroendocrine neoplasms of visceral organs

A series of metastatic breast carcinoma (MBC) mimicking visceral well-differentiated neuroendocrine neoplasms has not previously been reported. We identified 5 consultation cases originally submitted as neuroendocrine neoplasms in women but that were found to be MBC on subsequent review. All 5 neoplasms demonstrated nested architecture and relatively uniform nuclei. Four patients had a known history of breast cancer (remote in 3 and concurrent in 1), but the metastases (3 liver, 1 lung) labeled for chromogranin and/or synaptophysin, prompting misdiagnosis as neuroendocrine neoplasm. In a fifth case, a liver metastasis in a patient with a known pancreatic endocrine neoplasm was originally thought to be of pancreatic origin; an occult concurrent primary breast cancer (PBC) was subsequently identified as the source. On further immunohistochemistry (IHC), all metastases evaluated were diffusely, strongly positive for estrogen receptor (5/5 cases) and GATA3 (4/4 cases). Three patients had previously received ineffective treatment for neuroendocrine carcinoma. Based on the consultation diagnosis, all 4 patients with follow-up received hormone therapy, which was effective in 3. In a separate tissue microarray cohort of paired PBCs and hematogenous MBCs, chromogranin and/or synaptophysin IHC labeling was typically negative and increased from the PBC to the MBC in only 5% of cases. In conclusion, although neuroendocrine differentiation is uncommon in breast cancer and does not commonly increase in metastases, MBC with neuroendocrine differentiation should be considered in patients with visceral neuroendocrine neoplasms of unknown primary site. Diffuse IHC labeling for estrogen receptor and GATA3 helps establish the correct diagnosis.

Expression of PD-L1, indoleamine 2,3-dioxygenase and the immune microenvironment in gastric adenocarcinoma

The tumour microenvironment is increasingly important in several tumours. We studied the relationship of key players of immune microenvironment with clinicopathological parameters in gastric adenocarcinomas.

Multiparametric MRI findings of granulomatous prostatitis after intravesical bacillus calmette-guérin therapy in a patient undergoing active surveillance

Monitoring prostate cancer (PCa) using multiparametric magnetic resonance imaging (MP-MRI) may have an important role in active surveillance (AS) for low-risk PCa. Benign mimickers of PCa on MP-MRI can falsely raise the level of suspicion for disease progression, triggering earlier biopsy procedures or overtreatment, or both. The granulomatous prostatitis (GP) induced by intravesical bacillus Calmette-Guerin (BCG) therapy for bladder cancer has been recognized as a benign mimicker of PCa on MP-MRI. We present a case of GP induced by intravesical BCG therapy of bladder cancer in a patient with lowrisk PCa managed with AS in whom highly suspicious imaging findings indicating potential disease progression developed on a second surveillance MP-MRI.