PD-L1 instead of PD-1 status is associated with the clinical features in human primary prostate tumors.

Immunotherapy targeting programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) has shown efficacy in a variety of solid tumors. However, prostate cancer has often been a non-responder to anti-PD-1/PD-L1 therapies. The objective of this study was to determine PD-1 and PD-L1 expression status and its correlation with clinical features of the patients. A total of 279 patients who underwent radical prostatectomy for prostate cancer were included in this study. PD-1 and PD-L1 expression in primary prostate tumors was detected using immunohistochemical staining. Analyses were made between PD-1/PD-L1 status and patients' age, ethnicity, body mass index (BMI), diabetes mellitus, tumor stage, lymph node metastasis, prostate-specific antigen (PSA), Gleason score, grade group, and survival. We found that 6.5 (standard deviation 14.3; range 0-161.6) tumor-infiltrating lymphocytes per high power field were positive for PD-1 staining and 50/279 (17.9%) tumors were positive for PD-L1 staining. PD-L1-positive tumors had significantly more PD-1-positive lymphocytes than PD-L1-negative tumors. The number of PD-1-positive lymphocytes was not correlated with any clinical features except that patients with diabetes had significantly less PD-1-positive lymphocytes than patients without diabetes. In contrast, more PD-L1-positive tumors were found in older patients (≥ 65 years), obese patients (BMI ≥ 30), and patients with advanced tumor stage, lymph node metastasis, and high Gleason score. Neither PD-1 nor PD-L1 status was correlated with ethnicity, PSA, or survival. Our findings suggest that PD-L1 instead of PD-1 status is associated with the clinical features in human primary prostate tumors.

Obesity, age, ethnicity, and clinical features of prostate cancer patients.

Approximately 36.5% of the U.S. adults (≥ 20 years old) are obese. Obesity has been associated with type 2 diabetes mellitus, cardiovascular disease, stroke, and several types of cancer. The present study included 1788 prostate cancer patients who were treated with radical prostatectomy at the Ochsner Health System, New Orleans, Louisiana, from January, 2001 to March, 2016. The patient's medical records were retrospectively reviewed. Body mass index (BMI), age, ethnicity (Caucasians versus African Americans), clinical stage, Gleason score, and prostate-specific antigen (PSA) levels were retrieved. The relative risk of the patients was stratified into low risk and high risk groups. Associative analyses found that BMI was associated with age, clinical stage, Gleason score, but not ethnicity, PSA levels, or the relative risk in this cohort. Age was associated with ethnicity, clinical stage, Gleason score, and PSA levels, as well as the relative risk. Ethnicity was associated with Gleason score and PSA levels as well as the relative risk, but not clinical stage. These findings suggest that obesity is associated with advanced prostate cancer with stage T3 or Gleason score ≥ 7 diseases, and age and ethnicity are important factors that are associated with the clinical features of prostate cancer patients.

Hyperinsulinemia enhances interleukin-17-induced inflammation to promote prostate cancer development in obese mice through inhibiting glycogen synthase kinase 3-mediated phosphorylation and degradation of interleukin-17 receptor.

Interleukin-17 (IL-17) plays important roles in inflammation, autoimmune diseases, and some cancers. Obese people are in a chronic inflammatory state with increased serum levels of IL-17, insulin, and insulin-like growth factor 1 (IGF1). How these factors contribute to the chronic inflammatory status that promotes development of aggressive prostate cancer in obese men is largely unknown. We found that, in obese mice, hyperinsulinemia enhanced IL-17-induced expression of downstream proinflammatory genes with increased levels of IL-17 receptor A (IL-17RA), resulting in development of more invasive prostate cancer. Glycogen synthase kinase 3 (GSK3) constitutively bound to and phosphorylated IL-17RA at T780, leading to ubiquitination and proteasome-mediated degradation of IL-17RA, thus inhibiting IL-17-mediated inflammation. IL-17RA phosphorylation was reduced, while the IL-17RA levels were increased in the proliferative human prostate cancer cells compared to the normal cells. Insulin and IGF1 enhanced IL-17-induced inflammatory responses through suppressing GSK3, which was shown in the cultured cell lines in vitro and obese mouse models of prostate cancer in vivo. These findings reveal a mechanism underlying the intensified inflammation in obesity and obesity-associated development of aggressive prostate cancer, suggesting that targeting GSK3 may be a potential therapeutic approach to suppress IL-17-mediated inflammation in the prevention and treatment of prostate cancer, particularly in obese men.

Interleukin-17 promotes development of castration-resistant prostate cancer potentially through creating an immunotolerant and pro-angiogenic tumor microenvironment.

BACKGROUND: Interleukin-17 (IL-17) has been demonstrated to promote formation and growth of hormone-naïve prostate adenocarcinoma in mice. IL-17's role in development of castration-resistant prostate cancer is unknown. In the present study, we investigated IL-17's role in castration-resistant prostate cancer in a mouse model. METHODS: IL-17 receptor C (IL-17RC) deficient mice were interbred with Pten conditional mutant mice to produce RC(+) mice that maintained IL-17RC expression and RC(-) mice that were IL-17RC deficient. Male RC(+) and RC(-) mice were Pten-null and were castrated at 16 weeks of age when invasive prostate cancer had already formed. At 30 weeks of age, all male mice were analyzed for the prostate phenotypes. RESULTS: RC(-) mice displayed prostates that were smaller than RC(+) mice. Approximately 23% of prostatic glands in RC(-) mice, in contrast to 65% of prostatic glands in RC(+) mice, developed invasive adenocarcinomas. Compared to castrate RC(+) mice, castrate RC(-) mouse prostate had lower rates of cellular proliferation and higher rates of apoptosis as well as lower levels of MMP7, YBX1, MTA1, and UBE2C proteins. In addition, castrate RC(-) mouse prostate had less angiogenesis, which was associated with decreased levels of COX-2 and VEGF. Moreover, castrate RC(-) mouse prostate had fewer inflammatory cells including lymphocytes, myeloid-derived suppressor cells, and macrophages. CONCLUSIONS: Taken together, our findings suggest that IL-17 promotes development of invasive prostate adenocarcinomas under castrate conditions, potentially through creating an immunotolerant and pro-angiogenic tumor microenvironment.

Detection of human papilloma virus subtypes 16 and P16(ink4a) in invasive squamous cell carcinoma of the fallopian tube and concomitant squamous cell carcinoma in situ of the cervix.

Squamous cell carcinoma (SCC) of the fallopian tube is rare and often diagnosed postoperatively. Cervical cancer is considered as a long-term sequaele, resulting from sexual transmitted infection with certain common high-risk human papilloma virus (HPV) types. The role of human papilloma virus in the development of the tubal SCC is unknown. We report an unusual case of SCC of the fallopian tube, synchronously occurring with cervical SCC in situ in a 49-year-old patient. Histological examination of the entire endometrium revealed no involvement Both tubal and cervical lesions showed the presence of high risk HPV 16 by PCR and increased expression of p16(INK4a) protein. Both SCC of the fallopian tube and cervical SCC in situ were positive for p63, while the non-involved tubal epithelium was positive for WT-1, but negative for p63. In conclusion, the concomitant occurrence of fallopian tube and cervical SCC can be explained by: (i) the 'field effect' of HPV infection resulting in the concomitant development of primary SCC in various sites of the female genital tract; (ii) the primary fallopian tube SSC metastasizing to the uterine cervix; or (iii) primary cervical SCC metastasizing to the fallopian tube. The detection of HPV 16 and p16(INK4a) in both the fallopian tube and cervicalSCCs strengthens the hypothesis of the 'field effect' of HPV infection.

Loss of cell-adhesion molecule complexes in solid pseudopapillary tumor of pancreas.

Solid pseudopapillary tumor of pancreas (SPT) is a rare neoplasm that occurs most often in young females with the two distinct features, the 'solid-cystic' gross appearance, and the 'solid-pseudopapillary' microscopic pattern. It has been reported that almost all SPT tumors contain a mutation in the beta-catenin gene; however, the histogenetic origin of this tumor remains largely a mystery. E-cadherin is a cell adhesion molecule that links to catenins to form cell adhesion junctions, which is associated with the cytoskeleton formation. In this study, we examined the expression of E-cadherin and beta-catenin from SPT in an attempt to determine the molecular basis for the unusual morphology of this tumor. Nine cases of SPT were retrieved from Surgical Pathologic Archives of three institutions, including one male and eight females. H&E slides of each case were reviewed to confirm the diagnosis. The beta-catenin gene was sequenced in one case. E-cadherin and beta-catenin immunostains, were performed on all nine cases. Sequencing analysis on one case showed a point mutation of the beta-catenin gene, confirming previous findings that almost all SPT tumors contain mutation in the beta-catenin gene. Immunostains showed that, in both solid and pseudopapillary areas, all the tumor cells lost expression of E-cadherin, and beta-catenin nuclear expression was observed in all cases. Our findings suggest that loss of cytoplasmic beta-catenin protein in the cell adhesion complex due to beta-catenin gene mutation, results in instability of the complex, loss of E-cadherin in cell membrane, and eventually dissociation of the tumor cells to form the pseudopapillary pattern.

Retroperitoneal mucinous cystadenocarcinoma in a man: case report and review of the literature.

In the English medical literature, 27 cases of primary retroperitoneal mucinous cystadenocarcinoma have been published. We report the second case of a primary retroperitoneal mucinous cystadenocarcinoma in a man. The patient was an 83-year-old man, with a large 26 x 20 x 16-cm retroperitoneal cystic mass causing abdominal discomfort and cachexia, who underwent excision of the mass. Prior reports suggest that this type of tumor has an aggressive clinical course, and surgical excision is the treatment of choice. These rare tumors need to be included in the differential of retroperitoneal cystic tumors.

Cytogenetic and molecular studies of an unusual case of multiple primary alveolar rhabdomyosarcomas: low-level chromosomal instability and reciprocal translocation t(6;11).

Cytogenetic and molecular studies have shown that approximately 80% of cases of alveolar rhabdomyosarcoma (ARMS) have consistent chromosomal translocation of either t(2;13) or t(1;13), resulting in either PAX3-FKHR or PAX7-FKHR gene fusions. However, 20% of the cases diagnosed histologically are negative for these fusion genes. The clinical and pathological properties of the so-called fusion gene negative tumors remain to be defined. We present an unusual case of a 7-year-old boy who developed three separate primary ARMS over a 5-year period, with the first tumor diagnosed at the age of 12 months. The tumors were negative for the characteristic translocations, t(2;13) or t(1;13), but showed evidence of low-level chromosomal instability and a reciprocal chromosomal translocation t(6;11)(q27;q13). PCR amplification of the p53 gene, exons 2-11, followed by DNA sequencing did not detect any germline p53 mutation. These clinical and cytogenetic features have not been reported previously in ARMS. The findings suggest that cytogenetic abnormalities of chromosome 6 may be associated with the development of early onset multiple ARMS in a subgroup of pediatric patients as seen in this case.

Histopathologic and immunohistochemical characterization of a primary papillary thyroid carcinoma in the lateral cervical lymph node.

Lymph nodes in the neck are known to occasionally contain benign epithelial inclusions and can be rare primary site of various tumors usually occurring in other organs. Papillary thyroid carcinoma in the lateral neck lymph node with co-existing ectopic thyroid inclusions has not been reported previously. A 41-year-old male patient, who had normal thyroid function and no history of neck irradiation, was seen with a slowly enlarging mass in the right lateral neck. At surgery the cervical mass was found to be separate from the thyroid proper without any attachments in between. Papillary thyroid carcinoma and co-existing thyroid inclusions were identified within the lateral cervical lymph node. Immunohistochemistry detected strong and diffuse cytoplasmic positivity with antibodies against CK19 and CK903 in papillary thyroid carcinoma. Benign thyroid follicles within the lymph node were only weakly and focally stained. Thorough examination confirmed no malignancy in the total thyroidectomy specimen. Furthermore, small foci of metastatic papillary carcinoma were identified in two ipsilateral lymph nodes from neck dissection specimen. These findings suggest development of primary papillary thyroid carcinoma from malignant transformation of benign intranodal thyroid inclusions.

Isolated recurrence of ductal prostate cancer to anterior urethra.

We report the case of a 74-year-old man with ductal prostate cancer who had originally undergone radiotherapy but developed metastases to the anterior urethral mucosa. This is the fourth such case ever reported in English publications. We suspect the metastases developed from implantation after instrumentation, a common finding in the previously reported cases. Although no specific treatment regimen exists, we believe that local resection followed by androgen deprivation is the treatment of choice in these patients.

Eosinophilic enteritis with systemic lupus erythematosus.

Gastrointestinal manifestations are common in systemic lupus erythematosus (SLE). Eosinophilic enteritis is a rare disorder of uncertain cause that was recently reported for the first time in association with SLE. This report presents a second case of eosinophilic enteritis in a 47-year-old female patient with SLE. The patient presented with recurrent episodes of abdominal pain, nausea, vomiting, and diarrhea. Complete blood counts on occasion showed elevated eosinophil counts. The patient underwent a comprehensive workup over several weeks, culminating in a small bowel biopsy that showed eosinophil infiltration in the muscularis propria, establishing the diagnosis. The patient was treated with a prolonged taper of prednisone with successful resolution of symptoms.

Clinical, imaging, and cytopathological features of solid pseudopapillary tumor of the pancreas: a clinicopathologic study of three cases and review of the literature.

Solid pseudopapillary tumors are rare pancreatic neoplasms of uncertain pathogenesis that rarely metastasize and usually occur in young women. We describe the clinical, imaging, and cytopathological features of solid pseudopapillary tumor of the pancreas. We reviewed the clinical presentation, imaging, morphologic/immunochemical features, and follow-up of three women (age range 26-44). Cases 1, 2, and 3 presented with abdominal wall abscess, multiple endocrine neoplasia, and solid/cystic mass in the pancreatic head, respectively, and computed tomography of abdomen revealed solid/cystic masses with heterogeneous enhancement in body, tail and head of the pancreas, respectively. Case 2 also exhibited a left adrenal mass. Case 3 underwent endoscopic ultrasound of the pancreas, which showed a complex solid/cystic mass with septations. Sampling consisted of fine-needle aspiration (percutaneous or endosonography-guided), and additionally, core biopsy of the pancreatic mass and adrenal lesion in case 2. Aspirates and core biopsy revealed vascular structures with attached monotonous neoplastic cells in papillary-like arrays. Tumor cells had bland nuclear features with grooves, cytoplasmic periodic acid Schiff-positive hyaline globules, and associated myxoid/stromal fragments. Immunochemistry expressed alpha-1-antitrypsin, alpha-1-antichymotrypsin, vimentin, and focal neuron-specific enolase. Cases 1 and 3 underwent pancreatectomy with follow-up consisting of yearly imaging and no recurrences. Case 2 proved metastatic disease to adrenal gland and no follow-up was available. In the setting of typical clinical and imaging findings, an accurate preoperative diagnosis of pancreatic solid pseudopapillary tumor can be established by aspiration cytology and immunochemistry with or without concomitant core biopsy, on the basis of which clinicians decide treatment. This tumor can behave in a malignant fashion.