H2Bub1 loss is an early contributor to clear cell ovarian cancer progression.

Epigenetic aberrations, including posttranslational modifications of core histones, are major contributors to cancer. Here, we define the status of histone H2B monoubiquitylation (H2Bub1) in clear cell ovarian carcinoma (CCOC), low-grade serous carcinoma, and endometrioid carcinomas. We report that clear cell carcinomas exhibited profound loss, with nearly all cases showing low or negative H2Bub1 expression. Moreover, we found that H2Bub1 loss occurred in endometriosis and atypical endometriosis, which are established precursors to CCOCs. To examine whether dysregulation of a specific E3 ligase contributes to the loss of H2Bub1, we explored expression of ring finger protein 40 (RNF40), ARID1A, and UBR7 in the same case cohort. Loss of RNF40 was significantly and profoundly correlated with loss of H2Bub1. Using genome-wide DNA methylation profiles of 230 patients with CCOC, we identified hypermethylation of RNF40 in CCOC as a likely mechanism underlying the loss of H2Bub1. Finally, we demonstrated that H2Bub1 depletion promoted cell proliferation and clonogenicity in an endometriosis cell line. Collectively, our results indicate that H2Bub1 plays a tumor-suppressive role in CCOCs and that its loss contributes to disease progression.

Placental Site Trophoblastic Tumor in Mediastinal Recurrence of Mixed Germ Cell Tumor of the Testis: Report of a Case and Review of the Literature.

We present a rare case of a 42-year-old man diagnosed with a placental site trophoblastic tumor in combination with teratoma in a mediastinal recurrence of a testicular germ cell tumor post-orchiectomy and chemotherapy. To the best of our knowledge, this is the eighth case of placental site trophoblastic tumor in a male reported so far in the English literature. The purpose of this case report is to add data to the existing literature, review the literature, discuss the differential diagnoses with emphasis on morphologic and immunohistochemical differences between trophoblastic tumors, and highlight the management implications of a correct diagnosis.

Practical Scientific Writing and Publishing in Anatomic Pathology.

OBJECTIVES: To develop a structured, introductory curriculum in scientific writing and publishing for residents in anatomic pathology. METHODS: We assessed the need for this curriculum by using an online questionnaire sent to anatomic pathology residents in our program and tailored content to address areas of least familiarity. The curriculum consisted of 4 virtual lectures delivered by select experts in the field. Curriculum evaluation was assessed through a postcurriculum questionnaire. RESULTS: In total, 27 of 31 (87%) residents responded to the initial questionnaire. The major educational need was identified in the following topics: "responsibilities of a corresponding author"; "selecting a journal for publication"; "editor's approach to evaluating a manuscript"; "correspondence with editors and reviewers"; and "open access, cost and increasing exposure to manuscript." Eight residents participated in at least 3 of 4 lectures and completed the pre- and postcurriculum survey. The postcurriculum survey demonstrated statistically significant interval increases in familiarity with 7 of 18 topics, and the leading increases were noted in topics of most significant educational need. CONCLUSIONS: Development of novel curricula is vital to the ever-changing landscape of pathology resident education. This study proposes a generalizable algorithmic approach to assessing new areas of educational need and effectively addressing them through targeted curricula.

Subcategorization of T1 Bladder Cancer on Biopsy and Transurethral Resection Specimens for Predicting Progression.

CONTEXT.­: Despite continued surveillance and intravesical therapy, a significant subset of patients with lamina propria-invasive bladder cancer (T1) will progress to muscle-invasive disease or metastases. OBJECTIVE.­: To analyze the value of pathologic subcategorization of T1 disease in predicting progression. DESIGN.­: Six substaging methods were applied to a retrospective cohort of 73 patients, with pT1 urothelial carcinoma diagnosed on biopsy/transurethral resection. Additionally, the immunohistochemistry for GATA3 and cytokeratin 5/6 (CK5/6) was performed to study the prognostic value of stratifying T1 cancers into luminal or basal phenotypes. RESULTS.­: On follow-up (mean, 46 months), 21 patients (29%) experienced at least 1 recurrence without progression, and 16 (22%) had progression to muscle-invasive disease and/or distant metastasis. No differences were noted between progressors and nonprogressors with regard to sex, age, treatment status, medical history, tumor grade, and presence of carcinoma in situ. Substaging using depth of invasion (cutoff ≥1.4 mm), largest invasive focus (≥3.6 mm), aggregate linear length of invasion (≥8.9 mm), and number of invasive foci (≥3 foci) correlated significantly with progression and reduced progression-free survival, whereas invasion into muscularis mucosa or vascular plexus, or focal versus extensive invasion (focal when ≤2 foci, each <1 mm) failed. Patients with luminal tumors had higher incidence of progression than those with nonluminal tumors (27% versus 11%), although the difference was statistically insignificant (P = .14). CONCLUSIONS.­: Substaging of T1 bladder cancers should be attempted in pathology reports. Quantifying the number of invasive foci (≥3) and/or measuring the largest contiguous focus of invasive carcinoma (≥3.6 mm) are practical tools for prognostic substaging of T1 cancers.

Intra-Tumoral Nerve-Tracing in a Novel Syngeneic Model of High-Grade Serous Ovarian Carcinoma.

Dense tumor innervation is associated with enhanced cancer progression and poor prognosis. We observed innervation in breast, prostate, pancreatic, lung, liver, ovarian, and colon cancers. Defining innervation in high-grade serous ovarian carcinoma (HGSOC) was a focus since sensory innervation was observed whereas the normal tissue contains predominantly sympathetic input. The origin, specific nerve type, and the mechanisms promoting innervation and driving nerve-cancer cell communications in ovarian cancer remain largely unknown. The technique of neuro-tracing enhances the study of tumor innervation by offering a means for identification and mapping of nerve sources that may directly and indirectly affect the tumor microenvironment. Here, we establish a murine model of HGSOC and utilize image-guided microinjections of retrograde neuro-tracer to label tumor-infiltrating peripheral neurons, mapping their source and circuitry. We show that regional sensory neurons innervate HGSOC tumors. Interestingly, the axons within the tumor trace back to local dorsal root ganglia as well as jugular-nodose ganglia. Further manipulations of these tumor projecting neurons may define the neuronal contributions in tumor growth, invasion, metastasis, and responses to therapeutics.

Autophagy in tumor suppression and cancer therapy.

Autophagy is a stress-induced cell survival program whereby cells under metabolic, proteotoxic, or other stress remove dysfunctional organelles and/or misfolded/polyubiquitylated proteins by shuttling them via specialized structures called autophagosomes to the lysosome for degradation. The end result is the release of free amino acids and metabolites for use in cell survival. For tumor cells, autophagy is a double-edged sword: autophagy genes are frequently mono-allelically deleted, silenced, or mutated in human tumors, resulting in an environment of increased oxidative stress that is conducive to DNA damage, genomic instability, and tumor progression. As such, autophagy is tumor suppressive. In contrast, it is important to note that although tumor cells have reduced levels of autophagy, they do not eliminate this pathway completely. Furthermore, the exposure of tumor cells to an environment of increased metabolic and other stresses renders them reliant on basal autophagy for survival. Therefore, autophagy inhibition is an active avenue for the identification of novel anti-cancer therapies. Not surprisingly, the field of autophagy and cancer has experienced an explosion of research in the past 10 years. This review covers the basic mechanisms of autophagy, discusses its role in tumor suppression and cancer therapy, and posits emerging questions for the future.