The Development of Prostate Adenocarcinoma in a Transgender Male to Female Patient: Could Estrogen Therapy Have Played a Role?

BACKGROUND: Prostate adenocarcinoma (PCa) is a rare diagnosis in the male to female transgender (MtFT) population with only a few case reports published in the current medical literature. Long standing beliefs of androgen suppression conferring a protective effect against prostate cancer development have been challenged by the literature citing adenocarcinoma development in the prostate of rodent models following combined estrogen and testosterone treatment. MATERIALS AND METHODS: We herein present a MtFT patient who presented with high grade PCa following 20 years of exogenous estrogen therapy. RESULTS: Immunohistochemical (IHC) localization of estrogen receptor alpha (ER-α) and progesterone receptor (PR) demonstrated positive staining in stromal cells; while, androgen receptor (AR) demonstrated positive staining in malignant glands and weak scattered staining in adjacent stroma. CONCLUSION: This pattern of staining raises concern for a possible contributing role of exogenous estrogen therapy in tumorigenesis. As awareness of gender dysphoria and acceptance of gender reassignment surgery has seen a recent increase, the unique needs of this population must be recognized. Prostate 77:824-828, 2017. © 2017 Wiley Periodicals, Inc.

Matrix stiffness reverses the effect of actomyosin tension on cell proliferation.

The stiffness of the extracellular matrix exerts powerful effects on cell proliferation and differentiation, but the mechanisms transducing matrix stiffness into cellular fate decisions remain poorly understood. Two widely reported responses to matrix stiffening are increases in actomyosin contractility and cell proliferation. To delineate their relationship, we modulated cytoskeletal tension in cells grown across a physiological range of matrix stiffnesses. On both synthetic and naturally derived soft matrices, and across a panel of cell types, we observed a striking reversal of the effect of inhibiting actomyosin contractility, switching from the attenuation of proliferation on rigid substrates to the robust promotion of proliferation on soft matrices. Inhibiting contractility on soft matrices decoupled proliferation from cytoskeletal tension and focal adhesion organization, but not from cell spread area. Our results demonstrate that matrix stiffness and actomyosin contractility converge on cell spreading in an unexpected fashion to control a key aspect of cell fate.

Human neutrophil elastase-mediated goblet cell metaplasia is attenuated in TACE-deficient mice.

Neutrophilic inflammation is associated with chronic airway diseases. It has been observed that human neutrophil elastase (HNE), which is secreted by active neutrophils during inflammation, induces both mucin overproduction and goblet cell metaplasia. Several in vitro studies suggest that tumor necrosis factor-α converting enzyme (TACE) regulates the signaling axis that mediates HNE-induced mucin overproduction; however, it is unknown whether TACE performs a similar function in HNE-induced goblet cell metaplasia in vivo. We conducted this study to determine whether the inactivation of Tace gene expression attenuates HNE-induced goblet cell metaplasia in mice. Deletion of Tace is lethal shortly after birth in mice; therefore, we utilized Tace(flox/flox)R26CreER(+/-) mice and induced conditional deletion of Tace using a tamoxifen injection. Wild-type mice were given tamoxifen to control for its effect. Tace conditional deletion mice and wild-type mice were exposed to HNE via nasal instillation three times at 3-day intervals, and the lungs were harvested on day 11 after initial HNE exposure. Using periodic acid-Schiff staining and MUC5AC immunohistochemical staining to visualize goblet cells in the lungs, we found that HNE induced goblet cell metaplasia in the wild-type mice and that HNE-induced goblet cell metaplasia was significantly attenuated in the Tace conditional deletion mice. These findings suggest that TACE could be a potential target in the treatment of goblet cell metaplasia in patients with chronic airway diseases.

Tissue factor-bearing exosome secretion from human mechanically stimulated bronchial epithelial cells in vitro and in vivo.

BACKGROUND: Tissue factor (TF), a primary initiator of blood coagulation, also plays a pivotal role in angiogenesis. TF expression in the airways is associated with asthma, a disease characterized in part by subepithelial angiogenesis. OBJECTIVES: To determine potential sources of TF and the mechanisms of its availability in the lung microenvironment. METHODS: Normal human bronchial epithelial cells grown in air-liquid interface culture were subjected to a compressive stress of 30 cm H(2)O; this is comparable to that generated in the airway epithelium during bronchoconstriction in asthma. Conditioned media and cells were harvested to measure TF mRNA and TF protein. We also tested bronchoalveolar lavage fluid and airway biopsies from asthmatic patients and healthy controls for TF. RESULTS: TF mRNA was upregulated 2.2-fold after 3 hours of stress compared with unstressed cells. Intracellular and secreted TF proteins were enhanced 1.6-fold and more than 50-fold, respectively, compared with those of control cells after the onset of compression. The amount of TF in the bronchoalveolar lavage fluid from patients with asthma was found at mean concentrations that were 5 times greater than those of healthy controls. Immunohistochemical staining of endobronchial biopsies identified epithelial localization of TF with increased expression in asthma. Exosomes isolated from the conditioned media of normal human bronchial epithelial cells and the bronchoalveolar lavage fluid of asthmatic subjects by ultracentrifugation contained TF. CONCLUSIONS: Our in vitro and in vivo studies show that mechanically stressed bronchial epithelial cells are a source of secreted TF and that exosomes are potentially a key carrier of the TF signal.

Tumor necrosis in radical prostatectomies with high-grade prostate cancer is associated with multiple poor prognostic features and a high prevalence of residual disease.

The Gleason grading system and the recently defined Grade Groups are strong, well-established predictors of outcome in prostate cancer. Each Gleason score, however, is the result of a sum of categories (Gleason patterns or GPs) that are intrinsically heterogeneous, as each individual pattern encompasses several tumor morphologies. Although the prognostic value of specific morphologic components of GP4 has recently been demonstrated, the significance of the different patterns of GP5 is largely unknown. We reviewed 344 consecutive prostatectomies performed at the Hospital of the University of Illinois at Chicago between 2011 and 2016 and selected 56 cases with primary or secondary GP5 with archival material available for review. Subsequently, we sorted the cases according to the presence or absence of tumor necrosis in invasive adenocarcinoma GP5-designated G5 (+N) and G5 (-N), respectively-for comparison of histopathologic and clinical characteristics. The GP5 (+N) group demonstrated higher prevalence of biochemical recurrence (P=.0006) and seminal vesicle invasion (P=.02), with a trend toward a higher frequency of lymph node metastases (P=.07) and multifocal surgical margin involvement (P=.09). Also, G5 (+N) patients showed higher preoperative prostate-specific antigen values (P=.005) and a larger percentage of submitted tissue involved by tumor (P<.0001). Our results show that GP5 with tumor necrosis is associated with poor prognostic histopathologic features and high rates of residual disease after prostatectomy.

Comparison of prostatic adenocarcinoma Gleason 5 and intraductal carcinoma of the prostate with tumor necrosis. A morphometric study.

Intraductal carcinoma of the prostate(IDCP) is defined as a solid or cribriform neoplastic growth confined to ducts and acini, with preservation of the basal cell layer. Since IDCP can often present tumor necrosis (TN), it should be distinguished from Gleason 5 (GP5) invasive adenocarcinoma for staging and clinical purposes. In the present study we reviewed 344 radical prostatectomies performed at our institution and selected all cases with either >5% GP5 or IDCP for assessment of TN on histology slides (n = 59). A total of 19 cases with TN were identified, and morphology, size, location, and histoarchitecture of the lesions with TN were recorded. Subsequently, the corresponding sections were stained with a basal cell immunomarker (P63), and lesions with TN were assigned to IDCP or invasive carcinoma GP5 for comparison. Our results show that a branched shape and size 501-1000 µm are more common in IDCP, while a size >1000 µm and location within 1 mm of the periprostatic soft tissue are significantly more prevalent in invasive adenocarcinoma GP5. These features, however, usually cannot be assessed in core biopsies. In this setting, the utilization of immunohistochemistry is warranted to differentiate IDCP and GP5 with necrosis.

Metastatic intestinal adenocarcinoma to a lymph node involved by follicular lymphoma: The importance of looking beyond the apparent.

Composite tumors consisting of follicular lymphoma (FL) and colorectal or small intestinal adenocarcinoma are exceedingly rare, with only four cases published in the literature, to the best of our knowledge. While in most of these cases the clinical prognosis seems to be determined by the adenocarcinoma, at least one patient has shown rapid and aggressive progression of the FL. Here we report on a 62 year-old male with colonic adenocarcinoma metastatic to a retroperitoneal lymph node involved by FL, which illustrates the importance of carefully examining the histomorphology of lymphoid elements in surgical specimens.

A Rare Case of Epstein-Barr Virus Negative Inflammatory Pseudotumor-like Follicular Dendritic Cell Sarcoma Presenting as a Solitary Colonic Mass in a 53-Year-Old Woman; Case Report and Review of Literature.

Follicular dendritic cell (FDC) sarcoma is a rare neoplasm that occurs predominantly in lymph nodes. One third of FDC sarcomas happens in extranodal sites. There are 2 morphologic variants of this tumor: conventional and inflammatory pseudotumor (IPT)-like. IPT-like FDC sarcomas are reported mostly in females and usually involve the spleen and liver. In all cases of IPT-like FDC sarcoma the Epstein-Barr virus (EBV) was positive by in situ hybridization except one instance. We report a case of 53-year-old woman who presented with abdominal discomfort. Colonoscopy identified a sessile polypoid mass. Microscopically, there was a prominent lymphoplasmacytic infiltrate. Interspersed among the reactive lymphoid cells were large, pleomorphic stromal cells with marked atypia, irregular and multilobed nuclei, and hyperchromatic smudged chromatin. Immunohistochemical studies demonstrated the atypical stromal cells to be strongly positive for CD10 and D2-40, but negative for CD21, CD23, Clusterin, and epidermal growth factor receptor. EBV-encoded mRNA was negative. A diagnosis of IPT-like FDC sarcoma was rendered. To our knowledge, this is the second case of EBV-negative IPT-like FDC sarcoma reported so far in the literature.

Colon cancer presenting as a testicular metastasis.

We report a case of a 43-year-old male who initially presented with intermittent testicular pain as the first sign of metastatic stage IV colon cancer. Physical examination revealed a normal penis, scrotum and testes. Magnetic resonance imaging (MRI) of pelvis showed an irregular 3 cm mass of the spermatic cord and right radical inguinal orchiectomy was performed. The pathological diagnosis was metastatic adenocarcinoma. In conclusion, even though metastases to the testes are rare, they should be considered in clinical practice especially in older men who present with a testicular mass or discomfort.

Ductal Spread Versus High-Grade Prostatic Intraepithelial Neoplasia: A Diagnostic Pitfall.

Ductal spread (DS) of acinar adenocarcinoma of the prostate can lead to an incomplete replacement of the benign epithelium by cancer cells, resulting in a lesion that can be indistinguishable from high-grade prostatic intraepithelial neoplasia (HGPIN). Kovi and colleagues demonstrated 30 years ago that there is a significant association between the presence of DS and local extent of invasive adenocarcinoma, making the distinction between DS and HGPIN clinically relevant. However, despite the existence of certain morphologic features that are suggestive of DS, a definitive differentiation between the aforementioned lesions cannot always be attained.

A 13-Month-Old With Xanthogranulomatous Pyelonephritis With Features of Renal Malakoplakia.

Xanthogranulomatous pyelonephritis is an uncommon chronic inflammatory renal disorder caused by chronic infection with gram-negative bacteria leading to destruction of the renal parenchyma and replacement with foamy lipid-laden macrophages. Renal malakoplakia is another rare form of chronic inflammatory granulomatous disease in the kidney associated with infection usually occurring in adults with immunocompromised status or debilitating disease. It is hallmarked by the finding of foamy histiocytes with distinctive basophilic inclusions (Michaelis-Gutmann bodies). We present a case of a 13-month-old male with history of congenital hydronephrosis who presented with clinical and radiologic findings suggestive of xanthogranulomatous pyelonephritis. However, further pathologic studies revealed the presence of Michaelis-Gutmann bodies, which are pathognomonic for renal malakoplakia. With this case we hope to bring further evidence to support that these two conditions are not mutually exclusive but rather represent two pathologic processes on the same disease spectrum.

A multiwell platform for studying stiffness-dependent cell biology.

Adherent cells are typically cultured on rigid substrates that are orders of magnitude stiffer than their tissue of origin. Here, we describe a method to rapidly fabricate 96 and 384 well platforms for routine screening of cells in tissue-relevant stiffness contexts. Briefly, polyacrylamide (PA) hydrogels are cast in glass-bottom plates, functionalized with collagen, and sterilized for cell culture. The Young's modulus of each substrate can be specified from 0.3 to 55 kPa, with collagen surface density held constant over the stiffness range. Using automated fluorescence microscopy, we captured the morphological variations of 7 cell types cultured across a physiological range of stiffness within a 384 well plate. We performed assays of cell number, proliferation, and apoptosis in 96 wells and resolved distinct profiles of cell growth as a function of stiffness among primary and immortalized cell lines. We found that the stiffness-dependent growth of normal human lung fibroblasts is largely invariant with collagen density, and that differences in their accumulation are amplified by increasing serum concentration. Further, we performed a screen of 18 bioactive small molecules and identified compounds with enhanced or reduced effects on soft versus rigid substrates, including blebbistatin, which abolished the suppression of lung fibroblast growth at 1 kPa. The ability to deploy PA gels in multiwell plates for high throughput analysis of cells in tissue-relevant environments opens new opportunities for the discovery of cellular responses that operate in specific stiffness regimes.

Feedback amplification of fibrosis through matrix stiffening and COX-2 suppression.

Tissue stiffening is a hallmark of fibrotic disorders but has traditionally been regarded as an outcome of fibrosis, not a contributing factor to pathogenesis. In this study, we show that fibrosis induced by bleomycin injury in the murine lung locally increases median tissue stiffness sixfold relative to normal lung parenchyma. Across this pathophysiological stiffness range, cultured lung fibroblasts transition from a surprisingly quiescent state to progressive increases in proliferation and matrix synthesis, accompanied by coordinated decreases in matrix proteolytic gene expression. Increasing matrix stiffness strongly suppresses fibroblast expression of COX-2 (cyclooxygenase-2) and synthesis of prostaglandin E(2) (PGE(2)), an autocrine inhibitor of fibrogenesis. Exogenous PGE(2) or an agonist of the prostanoid EP2 receptor completely counteracts the proliferative and matrix synthetic effects caused by increased stiffness. Together, these results demonstrate a dominant role for normal tissue compliance, acting in part through autocrine PGE(2), in maintaining fibroblast quiescence and reveal a feedback relationship between matrix stiffening, COX-2 suppression, and fibroblast activation that promotes and amplifies progressive fibrosis.