Detection of Cannabinoid Receptor Expression by Endometriotic Lesions in Women with Endometriosis as an Alternative to Opioid-Based Pain Medication.

Emerging information suggests a potential role of medicinal cannabis in pain medication in addition to enhancing immune functions. Endometriosis is a disease of women of reproductive age associated with infertility and reproductive failure as well as chronic pain of varying degrees depending on the stage of the disease. Currently, opioids are being preferred over nonsteroidal anti-inflammatory drugs (NSAID) due to the latter's side effects. However, as the opioids are becoming a source of addiction, additional pain medication is urgently needed. Cannabis offers an alternative therapy for treating the pain associated with endometriosis. Information on the use and effectiveness of cannabis against endometriotic pain is lacking. Moreover, expression of receptors for endocannabinoids by the ovarian endometriotic lesions is not known. The goal of this study was to examine whether cannabinoid receptors 1 and 2 (CB1 and CB2) are expressed by ovarian endometriotic lesions. Archived normal ovarian tissues, ovaries with endometriotic lesions, and normal endometrial tissues were examined for the presence of endometrial stromal cells using CD10 (a marker of endometrial stromal cells). Expression of CB1 and CB2 were determined by immunohistochemistry, immunoblotting, and gene expression studies. Intense expression for CB1 and CB2 was detected in the epithelial cells in ovarian endometriotic lesions. Compared with stroma in ovaries with endometriotic lesions, the expression of CB1 and CB2 was significantly higher in the epithelial cells in endometriotic lesions in the ovary (P < 0.0001 and P < 0.05, respectively). Immunoblotting and gene expression assays showed similar patterns for CB1 and CB2 protein and CNR1 (gene encoding CB1) and CNR2 (gene encoding CB2) gene expression. These results suggest that ovarian endometriotic lesions express CB1 and CB2 receptors, and these lesions may respond to cannabinoids as pain medication. These results will form a foundation for a clinical study with larger cohorts.

Changes in IL-16 Expression in the Ovary during Aging and Its Potential Consequences to Ovarian Pathology.

Aging in females is not only associated with the changes in hormonal status but is also responsible for dysregulation of immune functions in various organs including ovaries. The goal of this study was to determine whether the expression of interleukin 16 (IL-16), a proinflammatory and chemoattractant cytokine, changes during ovarian aging, to determine factors involved in such changes in IL-16 expression, and to examine if changes in IL-16 expression during aging predisposes the ovary to pathologies. Ovarian tissues from premenopausal women (30-50 years old), women at early menopause (55-59 years old), and late menopause (60-85 years old) were used. In addition, tumor tissues from patients with ovarian high-grade serous carcinoma at early stage (n = 5) were also used as reference tissue for comparing the expression of several selected markers in aging ovaries. The expression of IL-16, frequency of macrophages (a source of IL-16) and expression of microRNA (miR) 125a-5p (a regulator of IL-16 gene) were performed by immunohistochemistry, immunoblotting, and gene expression assays. In addition, we examined changes in nuclear expression of IL-16 expression with regards to exposure to follicle-stimulating hormone (FSH) by in vitro cell culture assays with human ovarian cancer cells. The frequencies of IL-16 expressing cells were significantly higher in ovarian stroma in women at early and late menopause as compared with premenopausal women (P < 0.0001). Similar patterns were also observed for macrophages. Expression of miR-125a-5p decreased significantly (P < 0.001) with the increase in IL-16 expression during aging. Furthermore, expression of nuclear IL-16 increased remarkably upon exposure to FSH. Consequently, ovarian aging is associated with increased expression of IL-16 including its nuclear fraction. Therefore, persistent high levels of FSH in postmenopausal women may be a factor for enhanced expression of IL-16. Effects of increased nuclear fraction of IL-16 need to be examined.

Incidence of malignant transformation in the oviductal fimbria in laying hens, a preclinical model of spontaneous ovarian cancer.

Ovarian high grade serous carcinoma (HGSC) is a lethal form of ovarian cancer (OVCA). In most cases it is detected at late stages as the symptoms are non-specific during early stages. Emerging information suggests that the oviductal fimbria is a site of origin of ovarian HGSC. Currently available tests cannot detect ovarian HGSC at early stage. The lack of a preclinical model with oviductal fimbria that develops spontaneous ovarian HGSC is a significant barrier to developing an early detection test for this disease. The goal of this study was to examine if the oviductal fimbria in hens is a site of origin of HGSC and whether it expresses several putative markers expressed in ovarian HGSC in patients. A total of 135 laying hens (4 years old) were selected from a flock using transvaginal ultrasound (TVUS) imaging, followed by euthanasia and gross examination for the presence of solid masses and ascites. Histological types of carcinomas were determined by hematoxylin and eosin staining. Expression of WT-1, mutant p53, CA-125, PAX2 and Ki67 in normal or malignant fimbriae or ovaries were examined using immunohistochemistry, immunoblotting and gene expression assays. This study detected tumors in oviductal fimbriae in hens and routine staining revealed ovarian HGSC-like microscopic features in these tumors. These tumors showed similarities to ovarian HGSC in patients in expressing several markers. Compared with normal fimbriae, intensities of expression of WT-1, mutant p53, CA-125, and Ki67 were significantly (P<0.05) higher in fimbrial tumors. In contrast, expression of PAX2 decreased gradually as the tumor progressed to late stages. The patterns of expression of these markers were similar to those in ovarian HGSC patients. Thus, tumors of the oviductal fimbria in hens may offer a preclinical model to study different aspects of spontaneous ovarian HGSC in women including its early detection.

Is Regional Lymph Node Metastasis of Head and Neck Paraganglioma a Sign of Aggressive Clinical Behavior: A Clinical/Pathologic Review.

BACKGROUND: Head and neck paraganglioma is a rare neoplasm of the paraganglia. It accounts for <1% of all head and neck tumors. It usually has benign clinical course; however, malignant paraganglioma can only be diagnosed by showing metastatic disease. We undertook a retrospective study to assess the clinical significance of regional lymph nodes metastases in head and neck paragangliomas. DESIGN: From 1993 to 2016, primary head and neck paragangliomas are identified. The patient clinical and histopathologic materials were reviewed. RESULTS: Sixty-five specimens from 62 patients (3 patients with more than 1 specimens) with head and neck paragangliomas were recorded (49 female and 13 males) with mean age of 54 (24-78 years). The locations of the tumors were as follows: carotid body: 30, glomus tympanicum: 11, glomus jugulare: 14, parapharyngeal space: 3, and 1 case each of larynx, skull base, paraglottic area, infratemporal fossa, mastoid, cerebellopontine (CP) angle, and pyriform sinus. On histopathology, we found 5 cases of sclerosing variant. Thirty-two (52%) of the 62 patients had regional lymph node biopsy. Four (12%) of the 32 show metastatic paraganglioma (3 females and 1 male with mean age = 35). Two of the 5 cases of sclerosing variant had positive lymph nodes. No evidence of local recurrence or distant metastasis in the patients with positive lymph nodes with a 6 to 11 years follow-up. One of the 28 patients with negative lymph nodes developed metastatic disease to lumbar spine in 5 years. CONCLUSION: Metastatic paraganglioma to regional lymph nodes may have indolent clinical behavior, with disease-free survival of up to 11 years. The incidence of metastatic disease in lymph nodes was 4 (12%) of 32. Forty percent (2/5) of the cases with sclerosing variant of paraganglioma had lymph node metastases indicating that this tumor may have a more aggressive histological behavior.

Correlation of p16 Expression on Cancer and Stromal Cells With Clinicopathologic and Immunohistochemical Features of Lobular Breast Carcinoma.

BACKGROUND: Cancer-associated fibroblasts, play a central role in the tumor-stroma interaction and promote tumorigenesis. However, it is still unclear how these processes are regulated. The aim of this study is to investigate p16 expression in cancer and stromal cells of invasive lobular carcinoma (ILC). DESIGN: Clinicopathologic parameters and immunohistochemical stains for estrogen receptor (ER), progesterone receptor, E-cadherin, and human epidermal growth factor receptor 2 of 70 ILC cases were retrieved. In addition, immunohistochemical were performed for p53, p16, and cyclin D1. The p16 expression in cancer and stromal cells were correlated with different clinicopathologic parameters. RESULTS: Of the 70 cases, 8 cases were p16- cancer and stromal cells, 14 cases p16- cancer and p16+ stromal cells, 14 cases p16+ cancer and p16- stromal cells, and 34 cases p16+ cancer and stromal cells. Thirty-one of the 59 cases showed axillary lymph node metastases. Nodal involvement, recurrence, and metastasis of ILC with p16+ cancer cells and p16- stromal cells were more frequent compared with other groups. ILC with p16+ cancer and p16- stromal cells were frequently negative for ER, progesterone receptor, and cyclin D1, p53 positive and triple negative compared with other groups. There was no recurrence and metastasis in ILC with p16- cancer and p16+ stromal cells. ILC with p16+ cancer and stromal cells were significantly node negative and were positive for ER and cyclin D1 compared with other groups. CONCLUSIONS: ILC with p16+ cancer and p16- stromal cells were characterized by frequent nodal involvement, recurrence, and metastatic propensity. These results suggest that p16, has novel anticancer properties capable of suppressing cancer cell migration and invasion and pharmacologic restoration of p16 level in stromal fibroblasts may be exploited as therapeutic strategy to prevent nodal or distant metastasis.

Umbilical Lesions: Clinicopathologic Features of 99 Tumors.

BACKGROUND: Umbilical lesions are rare, and can be benign or malignant. This retrospective study was conducted to assess the epidemiological, clinical, and histologic characteristics of umbilical masses. METHODS: Cases of umbilical masses from January 1994 to August 2016 were retrieved from our institution's pathology databases, and their clinicopathological features were reviewed. RESULTS: There were a total of 99 cases of umbilical masses, 78 women (78.8%) and 21 men (21.2%). Of these, 59 were malignant (59.6%) and 40 were benign (40.4%). Among the malignant cases, 48 were women with a mean age of 65 years and 11 were men with a mean age of 66 years. All malignant lesions were secondary tumors. Twenty-five patients (42.3%) had a metastatic tumor to the umbilicus with an average of 7 months from the original diagnosis (12 gynecological, 8 pancreatic/gastrointestinal, 2 lymphomas, and a case each of breast, prostate, and melanoma). Of the patients with a benign diagnosis, 30 were women (75%) with a mean age of 52 years and 10 were men (25%) with a mean age of 43 years. The benign lesions included epidermal inclusion cysts (15/40), endometriosis (11/40), lipomas (3/40), neurofibromas (3/40), fibromas (3/40), abscesses (2/40), and 1 case each of tubular apocrine adenoma, serous cystadenoma, and calcified nodule. CONCLUSION: The most common metastatic tumors to the umbilicus are from the adjacent organs with the gynecologic tract as the most frequent primary followed by the gastrointestinal system. Primary malignant tumors of the umbilical region are rarely identified in clinical practice.

Polycystic Ovarian Condition May Be a Risk Factor for Ovarian Tumor Development in the Laying Hen Model of Spontaneous Ovarian Cancer.

Chronic inflammation and long-standing oxidative stress are potential predisposing factors for developing malignancies, including ovarian cancer (OVCA). Information on the association of ovarian chronic abnormal conditions, including polycystic ovarian syndrome (PCOS), with the development of OVCA is unknown. The goal of this study was to examine if polycystic ovarian conditions are associated with OVCA development. In the exploratory study, 3-4-year-old laying hens were randomly selected and examined for the presence of polycystic ovaries with cancer (PCOC). In the prospective study, hens were monitored by ultrasound scanning to detect the incidence of a polycystic ovaries and subsequent development of OVCA. Tissues from normal ovaries and PCOC were examined for macrophage infiltration, expression of interleukin-16, and superoxide dismutase 2. The exploratory study detected spontaneous PCOC at early and late stages in hens. PCOC in hens were accompanied with influx of macrophages (17.33 ± 2.26 in PCOC at the early stage and 24.24 ± 2.5 in PCOC at the late stage in 20 mm2 areas of tissue as compared with 6.77 ± 1.58 in normal hens). Expression of interleukin-16 was more than 2.5-fold higher and superoxide dismutase 2 was approximately 3-fold higher in PCOC hens than normal hens. The prospective study showed the development of OVCA in some hens with polycystic ovarian condition (PCO). PCOC development in hens was associated with chronic inflammation in the ovary. Laying hens may represent a potential model for the study of spontaneous PCOS and its long-term risk of PCOC development.

Association of Immunosuppression with DR6 Expression during the Development and Progression of Spontaneous Ovarian Cancer in Laying Hen Model.

Ovarian cancer (OVCA) mainly disseminates in the peritoneal cavity. Immune functions are important to prevent OVCA progression and recurrence. The mechanism of immunosuppression, a hallmark of tumor progression, is not well understood. The goal of this study was to determine the immune system's responses and its suppression during OVCA development and progression in hens. Frequencies of CD8+ T cells and IgY-containing cells and expression of immunosuppressors including IRG1 and DR6 in OVCA at early and late stages in hens were examined. Frequencies of stromal but not the intratumoral CD+8 T cells and IgY-containing cells increased significantly (P < 0.01) during OVCA development and progression. Tumor progression was associated with increased expression of IRG1 and DR6 and decreased infiltration of immune cells into the tumor. Frequency of stromal but not intratumoral immune cells increases during OVCA development and progression. Tumor-induced IRG1 and DR6 may prevent immune cells from invading the tumor.

Cytomorphology and Clinicopathologic Correlation of the Recurrent and Metastatic Adult Granulosa Cell Tumor of the Ovary: A Retrospective Review.

Granulosa cell tumors (GCT) of the ovary are low grade tumor with a potential ability of late pelvic recurrences and distant metastases. However, there is sparse literature on the cytopathologic features of metastatic granulosa cell tumors (MGCT). Between 2000 and 2014, eight cases of MGCT were diagnosed by FNA. Clinical, cytologic, and histopathologic features were reviewed. The age ranged from 34 to 84 years. Metastases were found in abdominal wall (4 cases), pelvic mass (1 case), liver (2 cases), and lung (1 case). The time to metastasis ranged from 1 to 14 years. All cases were hypercellular, with both large and small overlapping cell clusters and individual cells. The cytologic features included: naked nuclei (8/8 cases), Call-Exner bodies (2/8 cases), and prominent metachromatic stroma (3/8 cases). Moderate cytoplasm (4/8 cases) to scant delicate cytoplasm (4/8 cases) was seen. Cytoplasmic vacuoles were also noted (6/8 cases). N/C ratios were high although lower than small round cell tumors like lymphoma. Prominent, central nucleoli were also present (6/8 cases) as well as nuclear grooves (2/8 cases). Cell block was available in 3/8 cases and all were positive for inhibin immunostain. Histologic examination of the metastatic tissue confirmed MGCT. The important cytologic features of GCT like uniformity of tumor cells, nuclear grooves and Call-Exner bodies are occasionally present in MGCT. Prominent nucleoli and many naked nuclei were frequent. Therefore, the accurate interpretation of cytologic findings of MGCT requires cytohistologic correlation and inhibin positivity to avoid unnecessary surgical interventions for diagnostic purposes. The possibility of late recurrence of GCT should be kept in mind. Diagn. Cytopathol. 2016;44:1058-1063. © 2016 Wiley Periodicals, Inc.

Cytomorphology, clinicopathologic, and cytogenetics correlation of myelomatous effusion of serous cavities: A retrospective review.

BACKGROUND: Myelomatous effusions (ME) of the serous cavities are rare. Identification of the atypical plasma cells in the body fluids may be critical for prognostic considerations. METHODS: We retrospectively reviewed clinicopathologic findings of 21 serous effusion specimens from 13 cases of ME including 10 pleural, two concurrent pleural and pericardial, and one peritoneal from 1994 to 2014. RESULT: All 13 patients had bone marrow biopsy-proven plasma cell myeloma (PCM), including one plasmablastic-variant, one anaplastic-variant and one plasma cell leukemia. The time between the bone marrow diagnoses to serous cavity involvement ranged from 43 days to 9 years (mean 2.6 years, median 1.8 years). Monoclonal protein types showed predominant IgA subtypes (50%) including IgA-kappa (2), IgA-lambda (3), IgG-kappa (2), IgG-lambda (1) free kappa chain (1) and free lambda chain (1) and three unknown. All 13 patients died of disease (median survival 32 days). Concurrent imaging studies showed evidence of adjacent local disease. Cytology of the serous fluids revealed abundant plasma cells with varying degrees of atypia, including large cells with increased N/Cratios, coarse chromatin, and prominent nucleoli. All were CD138 positive. Of these, Cytology confirmed malignancy in 19/21(90%) cases. Five cases were positive for kappa-light chain and eight cases for lambda-light chain. Cytogenetics of 3/7 cases showed normal karyotype and 4/7 cases showed complex-karyotype. The patients with kappa light-chain had better survival compared to lambda light-chain (p = 0.051, log rank test). CONCLUSION: ME in PCM can present early in the natural history of the disease or very late. The preponderance of IgA-myeloma and complex-cytogenetics abnormalities is a noteworthy finding. Although there are different hypotheses regarding how ME develops in PCM, our finding supports the hypothesis that direct spread of PCM into serous cavities is a likely mechanism. Diagn. Cytopathol. 2016;44:742-747. © 2016 Wiley Periodicals, Inc.

Enhancement of Ovarian Tumor Detection by DR6-Targeted Ultrasound Imaging Agents in Laying Hen Model of Spontaneous Ovarian Cancer.

OBJECTIVE: The lack of an effective early detection test leads to high case to death ratio of women with ovarian cancer (OVCA). To improve early detection, tumor-associated imaging targets need to be established and imaging agents to image these targets need to be developed. Targeted imaging agents offer potential for improvement of signal intensities from their targets. Expression of death receptor 6 (DR6) by ovarian malignant cells and tumor-associated microvessels increases during OVCA development and represents a novel target for ultrasound imaging. The goal of this study was to examine the feasibility of newly developed DR6-targeted ultrasound imaging agents in enhancing early detection of ovarian tumors in laying hen model of spontaneous OVCA. MATERIALS AND METHODS: The study was conducted in an exploratory cross-sectional design using 4-year-old laying hens (n = 130). DR6-targeted imaging agents were developed by conjugating microbubbles with rabbit anti-chicken DR6 antibodies. Changes in signal intensity of ultrasound imaging were determined before and after injection of targeted imaging agents in hens with or without spontaneous OVCA. Following targeted imaging, normal or tumor ovaries were processed for histopathological and immunohistochemical studies. RESULTS: DR6-targeted imaging agents bound with their targets expressed by malignant cells and tumor-associated microvessels in the ovary. Compared with pretargeted imaging, targeted imaging is enhanced by approximately 40% ultrasound echo signal intensity (P < 0.001) from early- and late-stage OVCA. Differences in signal enhancement were not observed among different histological subtypes of OVCA at early or late stages. Higher imaging signal intensities were associated with enhancement in DR6 expression by ovarian malignant cells and increase in the frequency of DR6-expressing microvessels during OVCA development. CONCLUSIONS: The results of this study suggest that DR6-targeted imaging agents enhance the visualization of ovarian tumors and tumor-associated microvessels in hens with early-stage OVCA and will form a foundation for clinical studies.

Characterization of IL-22 and IL-17 Expressing Leukocytes in the Cervix.

PROBLEM: Identification of the types of cells that produce IL-17 and IL-22 in the genital tract can clarify the roles that these cytokines play in responses to pathogens. METHOD OF STUDY: We isolated and stimulated cells from cervical tissue to identify and characterize cytokine-producing cells. RESULTS: Upon stimulation of CD3+ CD4+ endocervical cells, 1.6, 3.4, and 1.5% were induced to produce IL-22, IL-17, and both cytokines, respectively. Stimulation of CD3+ CD4+ ectocervical cells resulted in 3.3% IL-22+, 5.5% IL-17(+) and 2.6% IL-22(+) IL17+ cells. CD45+ CD3- cells had relatively high endogenous levels of cytokine expression that did not increase upon stimulation. Innate lymphoid cells (ILCs) made up 5.7-8% of CD45+ cervical cells and stimulation caused increases in IL-17 and IL-22. CONCLUSION: These studies show that the majority of the CD45+ leukocytes that can be induced to produce IL-22 and IL-17 in cervix are CD3+ CD4+, but ILCs are also present and can make both cytokines.

Prognostic Value of Coexisting Lobular Carcinoma In Situ With Invasive Lobular Carcinoma.

AIMS AND OBJECTIVES: Recent studies show that lobular carcinoma in situ (LCIS) and invasive lobular carcinoma (ILC) share similar genetic molecular biology. There are increasing concerns regarding the biological significance of LCIS. The aim of this study is to investigate whether the presence of coexisting LCIS in ILC affects tumor biology and behavior and to correlate it with other clinicopathologic parameters. MATERIALS AND METHODS: In this study, 254 cases of ILC were included. Clinicopathologic parameters and immunohistochemical stains for estrogen receptor (ER), progesterone receptor (PR), E-cadherin, human epidermal growth factor receptor (HER2), and MIB-1 of 254 ILC cases were retrieved. The patient with ILC and coexisting LCIS were compared with pure ILC cases with respect to different clinicopathologic parameters. RESULTS: Of the 254 cases, 107 cases were pure ILC and 147 cases were ILC with coexisting LCIS. Seventy-six (76/184, 41.32%) cases showed axillary lymph node metastases. Lymph node metastasis was absent in 108 cases, micrometastasis was present in 5 cases, and stage N1, N2, N3 in 51, 5, and 15 cases, respectively. Nodal involvement, locoregional and distant recurrence of ILC with LCIS were less frequent compared with ILC without LCIS with P-value of 0.034 and 0.007, respectively. The presence of coexisting LCIS in ILC predicted higher disease-free survival (DFS) compared with pure ILC (P=0.034, log-rank test). When divided into different strata, ER-positive ILC cases with associated LCIS cases showed better DFS than ER-positive pure ILC cases (P=0.021, log-rank test). Similarly, ILC cases with LCIS in patient less than 50 years showed better DFS than the patient less than 50 years with pure ILC (P=0.045, log-rank test). CONCLUSIONS: In conclusion, ILC coexisting with lobular carcinoma in situ (ILC+LCIS) is characterized by less nodal involvement, lower locoregional, and distant recurrence and better DFS than pure ILC. When divided into different strata, ER-positive and less than 50-year groups with ILC+LCIS show even significant better DFS than pure ILC. These findings suggest that there is biological significance of coexisting LCIS in ILC and that this may have more effect on tumor aggressiveness in certain strata of ILC.

Interleukin 16- (IL-16-) Targeted Ultrasound Imaging Agent Improves Detection of Ovarian Tumors in Laying Hens, a Preclinical Model of Spontaneous Ovarian Cancer.

Limited resolution of transvaginal ultrasound (TVUS) scanning is a significant barrier to early detection of ovarian cancer (OVCA). Contrast agents have been suggested to improve the resolution of TVUS scanning. Emerging evidence suggests that expression of interleukin 16 (IL-16) by the tumor epithelium and microvessels increases in association with OVCA development and offers a potential target for early OVCA detection. The goal of this study was to examine the feasibility of IL-16-targeted contrast agents in enhancing the intensity of ultrasound imaging from ovarian tumors in hens, a model of spontaneous OVCA. Contrast agents were developed by conjugating biotinylated anti-IL-16 antibodies with streptavidin coated microbubbles. Enhancement of ultrasound signal intensity was determined before and after injection of contrast agents. Following scanning, ovarian tissues were processed for the detection of IL-16 expressing cells and microvessels. Compared with precontrast, contrast imaging enhanced ultrasound signal intensity significantly in OVCA hens at early (P < 0.05) and late stages (P < 0.001). Higher intensities of ultrasound signals in OVCA hens were associated with increased frequencies of IL-16 expressing cells and microvessels. These results suggest that IL-16-targeted contrast agents improve the visualization of ovarian tumors. The laying hen may be a suitable model to test new imaging agents and develop targeted anti-OVCA therapeutics.

Mastitis, a Radiographic, Clinical, and Histopathologic Review.

Mastitis is a benign inflammatory process of the breast with heterogeneous histopathological findings, which clinically and radiographically may mimic a mammary carcinoma. We undertook a retrospective study on 37 cases of mastitis in our institution to correlate the radiographic imaging features and the clinical presentation with the histopathological findings. Histologically, there were 21 granulomatous, 7 fibrous, 3 plasma cell, 3 lupus, 2 lymphocytic, and 1 case of acute mastitis. Radiographically, 16/25 (64%) patients with ultrasound studies showed irregular hypoechoic masses suspicious for malignancy. Clinically, 38% of patients had an associated systemic disease.

VEGFR2-Targeted Ultrasound Imaging Agent Enhances the Detection of Ovarian Tumors at Early Stage in Laying Hens, a Preclinical Model of Spontaneous Ovarian Cancer.

Tumor-associated neoangiogenesis (TAN) is an early event in ovarian cancer (OVCA) development. Increased expression of vascular endothelial growth factor receptor 2 (VEGFR2) by TAN vessels presents a potential target for early detection by ultrasound imaging. The goal of this study was to examine the suitability of VEGFR2-targeted ultrasound contrast agents in detecting spontaneous OVCA in laying hens. Effects of VEGFR2-targeted contrast agents in enhancing the intensity of ultrasound imaging from spontaneous ovarian tumors in hens were examined in a cross-sectional study. Enhancement in the intensity of ultrasound imaging was determined before and after injection of VEGFR2-targeted contrast agents. All ultrasound images were digitally stored and analyzed off-line. Following scanning, ovarian tissues were collected and processed for histology and detection of VEGFR2-expressing microvessels. Enhancement in visualization of ovarian morphology was detected by gray-scale imaging following injection of VEGFR2-targeted contrast agents. Compared with pre-contrast, contrast imaging enhanced the intensities of ultrasound imaging significantly (p < 0.0001) irrespective of the pathological status of ovaries. In contrast to normal hens, the intensity of ultrasound imaging was significantly (p < 0.0001) higher in hens with early stage OVCA and increased further in hens with late stage OVCA. Higher intensities of ultrasound imaging in hens with OVCA were positively correlated with increased (p < 0.0001) frequencies of VEGFR2-expressing microvessels. The results of this study suggest that VEGFR2-targeted contrast agents enhance the visualization of spontaneous ovarian tumors in hens at early and late stages of OVCA. The laying hen may be a suitable model to test new imaging agents and develop targeted therapeutics.

Central-type primitive neuroectodermal tumor of the uterus: Case report of remission of stage IV disease using adjuvant cisplatin/etoposide/bevacizumab chemotherapy and review of the literature.

•Bevacizumab was an effective agent in one case of advanced uterine PNET.•VEGF was expressed by the tumor, supporting a mechanism for effectiveness.•Cisplatin/etoposide/bevacizumab should be further studied in clinical trials.•Patient remains disease-free forty-eight months following intervention.

Correlation of clinicopathologic parameters and immunohistochemical features of triple-negative invasive lobular carcinoma.

PURPOSE: Invasive lobular carcinoma (ILC) is a subtype of invasive breast carcinoma. With the advent of gene profiling, breast cancer has been classified into luminal A, luminal B, HER2-overexpressing, and triple-negative carcinoma (TNC). Several studies have described TNC (ER, PR, HER2) as a surrogate for basal-like breast carcinoma. However, there is sparse literature on triple-negative lobular carcinoma (TNLC), as most of them show hormone receptor expression. The aim of this study was to investigate the correlation of clinicopathologic parameters of TNLC that has been demonstrated in invasive ductal carcinoma. MATERIALS AND METHODS: Clinicopathologic parameters and immunohistochemical stains for ER, PR, E-cadherin, HER2, MIB1, and fluorescent in situ hybridization for HER2 of 255 ILC cases were retrieved. In addition, immunohistochemical analysis was performed for p53, c-kit, vimentin, p16, cyclinD1, and BCL2 on 78 cases where 12 were TNC cases and 66 were non-TNC cases. RESULTS: Of the 255 ILC cases, 218 (85.5%) were classic and 37 (14.5%) were pleomorphic. Seventy-seven (30.1%) cases showed axillary lymph node metastasis. There were 14 of the 255 TNC cases (5.49%) that showed higher incidence in the elderly patients. Six of the 37 (16.21%) cases were pleomorphic and 8 of the 218 (3.7%) cases were classic. Positivity for vimentin was seen in 8 of the 12 cases (67.7%), CK 5 in 3 of the 12 (25%) cases, p16 in 11 of the 12 (91.6%) cases, p53 in 8 of the 12 (66.7%) cases, c-kit in 6 of the 12 (50%) cases, and cyclinD1 in 6 of the 12 cases (50%) indicating basal-like phenotype in 3 cases and nonbasal-like phenotype in 9 cases. There was no statistical significance in lymph node metastasis, tumor recurrence, and distant metastasis between TNC and non-TNC. CONCLUSIONS: TNLC showed distinct clinicopathologic features such as more frequently seen in the elderly, pleomorphic, larger tumor size, increased expression of vimentin, CK 5, p16, p53, and c-kit. Not all cases showed basal-like phenotype. TNLC is less frequently seen as compared with TNC in invasive ductal carcinoma.

Intraoperative imprint cytology of ovarian transitional cell (Brenner) tumors: a retrospective study.

Literature on fine-needle aspiration of ovarian transitional cell tumor or Brenner tumors is sparse and mostly confined to isolated case reports of metastatic transitional cell tumors. We undertook a retrospective study of intraoperative imprint cytology of ovarian transitional cell tumors to better define the cytologic features of this uncommon ovarian tumor. Between 2005 and 2012, a total of 19 ovarian transitional cell tumors were recorded in our surgical pathology files, 10 of which had concomitant imprint cytologic material available for review. The 10 patients included in this study ranged in age between 43 and 73 years (mean age: 54 years). Nine neoplasms were histologically benign and one was borderline. Nine cases had satisfactory cytologic material for review. The cytologic features can be summarized as follows: the eight benign tumors showed abundant naked nuclei in the background, small and large clusters of tumor cells, abundant cytoplasm, smooth nuclear membranes, and lack of nuclear pleomorphism and mitoses. Single plasmacytoid cells with dense blue abundant cytoplasm, perinuclear vacuoles, nucleoli, microfollicle formation, nuclear grooves, binucleation/multinucleation, and extracellular eosinophilic material were some of the other features that were appreciated. The cytologic features of the one case of borderline transitional cell tumor were similar to those of the benign tumors except for the presence of rare mitoses, easily identifiable nuclear pleomorphism and irregular nuclear membranes. This study highlights some characteristic cytologic features of benign/borderline transitional cell tumors of the ovary which can be of help in recognizing this uncommon neoplasm.

Interleukin 16 expression changes in association with ovarian malignant transformation.

OBJECTIVE: Long-term unresolved inflammation has been suggested as a risk factor for the development of various malignancies. The goal of this study was to examine whether the expression of interleukin (IL)-16, a proinflammatory cytokine, changes in association with ovarian cancer (OVCA) development. STUDY DESIGN: In an exploratory study, changes in IL-16 expression in association with OVCA development and progression were determined using ovarian tissues and serum samples from healthy subjects (n = 10) and patients with benign (n = 10) and malignant ovarian tumors at early (n = 8) and late (n = 20) stages. In the prospective study, laying hens, a preclinical model of spontaneous OVCA, were monitored (n = 200) for 45 weeks with serum samples collected at 15-week interval. Changes in serum levels of IL-16 relative to OVCA development were examined. RESULTS: The frequency of IL-16-expressing cells increased significantly in patients with OVCA (P < .001) compared to healthy subjects and patients with benign ovarian tumors. The concentration of serum IL-16 was higher in patients with benign tumors (P < .05) than in healthy subjects and increased further in patients with early-stage (P < .05) and late-stage (P < .03) OVCA. Increase in tissue expression and serum levels of IL-16 in patients with early and late stages of OVCA were positively correlated with the increase in ovarian tumor-associated microvessels. Prospective monitoring showed that serum levels of IL-16 increase significantly (P < .002) even before ovarian tumors become grossly detectable in hens. CONCLUSION: This study showed that tissue expression and serum levels of IL-16 increase in association with malignant ovarian tumor development and progression.