Exploring the Relationship between E-Cadherin and ß-Catenin Cell Adhesion Proteins and Periacinar Retraction Clefting in Prostatic Adenocarcinoma.

BACKGROUND: Periacinar retraction clefts represent a histopathological criterion supporting the diagnosis of prostatic adenocarcinoma. The origin of these clefts in prostatic adenocarcinoma remains unclear. Exploring the established functions of E-cadherin and ß-catenin as intercellular adhesion proteins, and aiming to elucidate the origin of periacinar retraction clefting, we conducted a correlation study between the immunohistochemical expression of E-cadherin and ß-catenin and the presence of periacinar retraction clefts in prostatic adenocarcinoma. METHODS: We examined 53 cases of morphologically diagnosed prostatic adenocarcinoma, assessing both the neoplastic and adjacent nonneoplastic prostatic tissues for the existence and degree of periacinar retraction clefts. Additionally, we analyzed the immunohistochemical expression of E-cadherin and ß-catenin proteins in prostatic tissue and explored their correlation with periacinar retraction clefts, and Gleason score, Grade Group, preoperative serum prostate specific-antigen (sPSA) levels, surgical margin status, and Tumor, Node, Metastasis (TNM) stage in prostatic adenocarcinoma. RESULTS: Our study confirms that periacinar retraction clefting is significantly more extensive in prostatic adenocarcinoma than in nonneoplastic prostatic tissue (p < 0.001). We report a decreased expression of E-cadherin and ß-catenin immunostaining in prostatic adenocarcinoma and a negative correlation with Gleason score and Grade Group. Periacinar retraction clefting positively correlated with E-cadherin and ß-catenin ((rho = 0.350; p = 0.010) and (rho = 0.340; p = 0.012)) immunostaining in prostatic adenocarcinoma. CONCLUSIONS: Periacinar retraction clefts stand out as a dependable criterion in the diagnosis of prostatic adenocarcinoma. E-cadherin and ß-catenin proteins are potential markers indicative of tumor progression and invasiveness in prostatic adenocarcinoma. Our discovery of a positive correlation between immunostaining of E-cadherin and ß-catenin proteins and periacinar retraction clefts in prostatic adenocarcinoma aligns with the notion that periacinar retraction clefting is more characteristic of Gleason Grade3 pattern in prostatic adenocarcinomas, whereas the immunohistochemical expression of E-cadherin and ß-catenin shows a decrease with increasing histopathological tumor grade.

Probing milk extracellular vesicles for intestinal delivery of RNA therapies.

BACKGROUND: Oral delivery remains unattainable for nucleic acid therapies. Many nanoparticle-based drug delivery systems have been investigated for this, but most suffer from poor gut stability, poor mucus diffusion and/or inefficient epithelial uptake. Extracellular vesicles from bovine milk (mEVs) possess desirable characteristics for oral delivery of nucleic acid therapies since they both survive digestion and traverse the intestinal mucosa. RESULTS: Using novel tools, we comprehensively examine the intestinal delivery of mEVs, probing whether they could be used as, or inform the design of, nanoparticles for oral nucleic acid therapies. We show that mEVs efficiently translocate across the Caco-2 intestinal model, which is not compromised by treatment with simulated intestinal fluids. For the first time, we also demonstrate transport of mEVs in novel 3D 'apical-out' and monolayer-based human intestinal epithelial organoids (IEOs). Importantly, mEVs loaded with small interfering RNA (siRNA) induced (glyceraldehyde 3-phosphate dehydrogenase, GAPDH) gene silencing in macrophages. Using inflammatory bowel disease (IBD) as an example application, we show that administration of anti-tumour necrosis factor alpha (TNFα) siRNA-loaded mEVs reduced inflammation in a IBD rat model. CONCLUSIONS: Together, this work demonstrates that mEVs could either act as natural and safe systems for oral delivery or nucleic acid therapies, or inform the design of synthetic systems for such application.

Clear cell renal cell carcinoma with prominent microvascular hyperplasia: Morphologic, immunohistochemical and molecular-genetic analysis of 7 sporadic cases.

Clear cell renal cell carcinoma (CCRCC) is well known for intratumor heterogeneity. An accurate mapping of the tumor is crucial for assessing prognosis, and perhaps this can be linked to potential success/failure of targeted therapies. We assembled a cohort of 7 CCRCCs with prominent vasculature and microvascular hyperplasia (ccRCCPV), resembling those seen in high grade gliomas. A control group of classic CCRCC with no variant morphologies was also included. Both groups were analyzed for clinicopathologic, morphologic, immunohistochemical, and molecular genetic features. No statistically significant differences in mRNA expression of studied genes between the two groups were found. Using NGS panel Trusight Oncology 500 (TSO500), only one clinically significant gene mutation, VHL c.263G > A, p. (Trp88Ter), was found. TMB (Tumor Mutation Burden) and MSI (MicroSatellite Instability) were low, and no copy number variations (CNVs) were detected in the study cohort. Prominent microvascular hyperplasia in CCRCC is a rare phenomenon. From molecular genetic point of view, these tumors do not appear to be different from classic CCRCC. Prognostically, they also demonstrated similar clinical behaviors.

Clear cell renal cell carcinoma with Paneth-like cells: Clinicopathologic, morphologic, immunohistochemical, ultrastructural, and molecular analysis of 13 cases.

Clear cell renal cell carcinoma (CRCC) is well known for its intratumoral heterogeneity. Paneth-like cells (PLC) have been reported in variable organs (i.e., hepatobiliary, genitourinary, and female genital tract). In genitourinary system, it is possible to find PLCs in epididymis, urinary bladder and prostate. The objective of this study was to assess PLC in CRCCs 13 CRCCs with prominent PLC (CRCCPLC) were selected out of 1378 CRCCs in our registry. The tumors were analyzed using morphologic, immunohistochemical, ultrastructural, and molecular genetic methods. CRCCPLCs were mostly of low histologic grade (12/13). Immunohistochemical profile was compatible with classic CRCC. PLC constituted 10 to-70% of the tumor volume (mean 17.7%, median 10%). PLCs did not express neuroendocrine markers (chromogranin, synaptophysin, CD56, INSM-1). Ultrastructurally, PLCs were filled by membrane bounded vesicles of various sizes and were compatible with secretory type of cells. VHL mutation was found in 9/9 cases, and LOH3p was found in 6/8 analyzable cases. Conclusions: PLC morphology can variably be present in "classic" CRCC, even in a substantial proportion. Ultrastructurally, PLCs have all attributes of secretory cells. Preliminary follow up data showed that these tumors may not be associated with aggressive clinical behavior.

hGH and GHR expression in large cell neuroendocrine carcinoma of the colon and rectum.

Large cell neuroendocrine carcinoma (LCNEC) is an aggressive neoplasm with a low frequency of occurrence in the digestive tract. We present a series of eight patients diagnosed with LCNEC of the colon and rectum. Grossly, tumors were presented as endophytic/ulcerative, annular and polypoid masses, with a gray-white color and necrosis in most cases. Histologically, they were high-grade tumors composed of large cells of organoid, nesting, trabecular, rosette-like and palisading patterns, with a high mitotic rate. Tumors were immunoreactive for neuroendocrine markers, including chromogranin A (2/8), synaptophysin (7/8), and neuron-specific enolase (8/8). Moreover, we analyzed the expression of growth hormone (hGH) and growth hormone receptor (GHR) in colorectal LCNECs and six tumors were immunoreactive for hGH, while five tumors were immunoreactive for GHR. To our knowledge hGH and GHR expression has not been previously analyzed in colorectal LCNEC. Their overexpression suggests a role of hGH and GHR in the development of colorectal LCNEC.

Invasive ductal carcinoma within fibroadenoma: a case report.

INTRODUCTION: Fibroadenoma is the most common benign tumor of the female breast with the highest incidence before age 30. Fibroadenoma may be associated with fibrocystic changes, proliferative epithelial changes, and extremely rarely, with non-invasive and invasive cancer. CASE PRESENTATION: We present a rare case of a 39 years old female with invasive ductal carcinoma arising within fibroadenoma. CONCLUSION: There is a low percentage of fibroadenomas harboring carcinoma; however, all breast lumps should be seriously managed; extirpation and histological examination is recommended.