[Show abstract][Hide abstract] ABSTRACT: Background/Aim: Cellular retinol binding protein-1 regulates retinol bioavailability and contributes to cell differentiation maintenance, but its role in ovarian carcinogenesis remains uncertain. We investigated CRBP-1 expression in ovarian tumors and CRBP-1 signaling-regulated pathways. Materials and Methods: We performed immunohistochemistry, methylation-specific PCR, gene copy number analysis in ovarian tumors and proliferation/apoptosis evaluation, gene array, blot and real-time PCR in CRBP-1-transfected A2780 ovarian cancer cells. Results: CRBP-1 expression was reduced or absent in G2 and G3 ovarian carcinomas. CRBP-1 silencing in 60% of G2 and 66.7% of G3 carcinomas was due to CRBP-1 promoter methylation. A2780 CRBP-1-transfected cells showed increased retinol-induced apoptosis, retinoid-induced reduced clonogenicity and down-regulation of proliferation and transcription genes, including AKT1, AKT3, EGFR, FOS, JUN, STAT1 and STAT5A. Conclusion: CRBP-1 loss in G2/G3 ovarian carcinomas and increased apoptotic susceptibility to retinoids in CRBP-1-transfected-A2780 cells suggest CRBP-1 screening as a target to ensure efficacy of an adjuvant retinoid therapy.
Anticancer research 07/2014; 34(7):3303-12. · 1.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The diagnosis of endometrial hyperplasia or carcinoma in a background of secretory endometrium can be difficult. We attempt to establish the diagnostic criteria to be used in such cases. We examined 80 cases of endometrial hyperplasia, carcinoma, and other conditions with glandular crowding arising in secretory endometrium, analyzed their morphologic features, assessed the volume percentage stroma in each case and performed Ki67 immunostaining on 27 cases. Thirteen cases each of secretory and gestational endometrium served as controls. The mean age of the patients was 45 yr. The non-neoplastic diseases included simple hyperplasia without atypia (56%), endometrial polyps (12.5%), and chronic endometritis with glandular crowding (3%). The proportion of cases with complex hyperplasia without atypia was 10%. Neoplastic diseases included atypical complex hyperplasia (12.5%) and endometrioid carcinoma (6%). The secretory changes were usually less advanced in the hyperplastic glands than in the background endometrium. The morphologic features that best distinguished hyperplasia or carcinoma from secretory endometrium included glandular crowding that stood out from the background; architectural disorder (the long axes of the glands pointing in different directions or parallel to the endometrial surface); dilated, irregularly shaped glands, including budding or branching glands and staghorn-shaped glands; stroma of a polyp; cribriform or confluent glands in cases of carcinoma; nuclear atypia in cases of atypical hyperplasia and carcinoma; and crowded nonsecretory glands. The volume percentage stroma of neoplastic lesions was less than that of non-neoplastic ones (34% vs. 61%, P=0.000001) and that of secretory endometrium (34% vs. 68%, P=0.000038). Non-neoplastic lesions did not have significantly more crowded glands than secretory endometrium (61% vs. 68%, P=0.11). Gestational endometrium had more crowded glands than non-neoplastic lesions (39% vs. 61%, P=0.000004), an approximately equal volume percentage stroma with complex hyperplasia without atypia (39% vs. 43%, P=0.51), and less crowded glands than neoplastic lesions (39% vs. 34%, P=0.03). The Ki67 index of the neoplastic lesions was higher than that of the controls, including secretory and gestational endometria (positive nuclei per 100 epithelial cells, 44.8 vs. 4.6, P=0.0004), of the non-neoplastic lesions (44.8 vs. 5.4, P=0.002) and of complex hyperplasia without atypia (44.8 vs. 9.3, P=0.007). Hyperplasia and carcinoma in secretory endometrium can be diagnosed on the basis of increased glandular crowding, architectural irregularity, nuclear atypia, and increased Ki67 index.
International journal of gynecological pathology: official journal of the International Society of Gynecological Pathologists 01/2014; · 2.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This is a report of a paratubal adult granulosa cell tumor (GCT) located within the right broad ligament in a 62-year-old woman. These are rare tumors with only 8 cases reported so far. Because of an overlap of topographic, morphologic, and immunohistochemical features, it is not always possible to differentiate between the broad ligament GCT and female adnexal tumor of probable Wolffian origin (FATWO). Although nuclear grooving is not an exclusive feature of GCT and can be seen in a variety of other neoplasms, in the context of the differential diagnosis between broad ligament GCT and FATWO, the presence of this feature may be very useful in establishing the diagnosis of broad ligament GCT.
International Journal of Surgical Pathology 12/2011; 19(6):783-6. · 0.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the modulation of cellular retinol-binding protein (CRBP)-1 and the desmosomal plaque proteins plakophilin (PKP)-1 and desmoplakin (DP) in correlation with the Ki67+ proliferation index (PI) during the progression of cervical squamous intraepithelial lesions (SIL) to squamous cell carcinoma (SCC).
Using in situ imaging by brightfield and confocal laser scanning microscopy, the expression of CRBP-1 protein and transcripts, PKP-1, DP and the Ki67 PI were analysed in 38 low-grade (L) SIL, 56 high-grade (H) SIL, 49 SCC, 30 control cervices and 10 human papillomavirus-positive condylomatous lesions.
CRBP-1+ cells increased from 11.4% in the normal cervix to 80.3% in LSILs, 92.3% in HSILs and slightly decreased to 78.3% in invasive SCCs (P = 0.0001) in close association with the Ki67 PI (r =0.41; P < 0.0001). PKP-1+ and DP+ cells were correlated (0.32; P < 0.0001) and decreased from normal (81% versus 92.3%) to LSIL (53.1% versus 85.3%), to HSIL (46.4% versus 67.5%) and SCC (35.1% versus 35.9%). The Ki67+ PI was inversely correlated with DP (-0.20, P = 0.0014) and PKP-1 (-0.19, P = 0.015). Condylomata retained low CRBP-1 and high expression of PKP-1 and DP.
The gain of CRBP-1 and the loss of desmosomal proteins occur early in cervical carcinogenesis.
[Show abstract][Hide abstract] ABSTRACT: Cellular retinol binding protein-1 (CRBP-1) contributes to the maintenance of the differentiative state of endometrial glandular cells through the regulation of bioavailability of retinol and derivatives, but its role in endometrial oncogenetic process remains unclear. Antibodies to CRBP-1, estrogen and progesterone receptors (ER and PR) were applied to paraffin sections of proliferative (n = 10) and secretory endometrium (n = 9), and to endometrial polyps (n = 6), simple (n = 7), complex (n = 3) and atypical endometrial hyperplasias (n = 9) as well as to 47 endometrioid carcinomas of different histological grade (G) (G1, n = 18; G2, n = 19; G3, n = 10). Four serous and two clear cell carcinomas were also examined. In glandular cells, CRBP-1 positivity was mainly cytoplasmic and rarely in the nuclei. CRBP-1 immunodetection was weakly positive in proliferative and low and focal in secretory endometrium and higher in atypical as compared to simple and complex hyperplasias. CRBP-1 expression in G1 endometrioid carcinomas was similar to that in atypical hyperplasias. In the latter, the highest CRBP-1 expression was observed in areas of squamous differentiation. Semiquantitative evaluation revealed a significant decrease of cytoplasmic CRBP-1 immunoreactivity with the increase of tumor grade. Among G3 endometrioid carcinomas, 60% were CRBP-1 negative, whereas the remaining cases showed a very low and focal positivity. Serous carcinomas were also CRBP-1 negative. When areas of different grading were present within the same tumor, less differentiated areas retained a lower CRBP-1 immunoreaction. The progressive decrease of CRBP-1 paralleled that of ER and PR immunodetection. RT-PCR in eight endometrioid carcinomas suggested a decrease of CRBP-1 with the increase of tumor grade also at transcriptional level. Our results indicate that CRBP-1 immunodetection may constitute an additional tool for histological grading of endometrial carcinoma. The CRBP-1 loss during the progression of endometrial cancer suggests a new potential target for pharmacological strategies aimed to counteract its progression by increased intracellular retinol bioavailability.
Modern Pathology 07/2006; 19(6):797-803. · 6.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We report a case of a retiform Sertoli-Leydig cell tumor of intermediate differentiation presenting as a uterine intracavity polypoid mass in a 63-year-old woman. In contrast to sertoliform endometrioid carcinoma and to hitherto reported uterine tumors resembling ovarian sex cord tumors (UTROSCTs), which are primarily characterized by tubular glands and solid tubules, this tumor, which most likely represents a UTROSCT, showed a large spectrum of histologic features typical of a genuine retiform Sertoli-Leydig cell tumor. The diagnosis was confirmed by a battery of immunohistochemical stains, which also served as a tool for differential diagnosis with other neoplasms. The tumor cells were positive for broad spectrum keratin (CK) CK18, vimentin, calretinin, and progesterone receptor. Only a few isolated cells stained for inhibin. The tumor cells were negative for CK7, CK5/6, epithelial membrane antigen (EMA), carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA125), thrombomodulin, 013 (CD99), melan A, alpha-fetoprotein (AFP), placental alkaline phosphatase (PLAP), alpha-1-antitrypsin, estrogen receptor, S100, neurone specific enolase (NSE), chromogranin, synaptophysin, desmin, caldesmon, and CD10. Divergent differentiation of uterine cells seems to be the most likely pathogenetic mechanism. To the best of our knowledge, no UTROSCT showing such a variety of histologic features indicative of a true sex cord tumor has been reported before.
International Journal of Gynecological Pathology 11/2005; 24(4):335-40. · 1.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We report a case of cutaneous bronchogenic cyst, partially lined by gastric mucosa of antral type in a 9-year-old boy. This is, to the best of our knowledge, the first report of gastric mucosa in bronchogenic cutaneous cyst in the literature.
American Journal of Dermatopathology 05/2005; 27(2):145-7. · 1.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Metastases to the uterus are rare, accounting for less than 10% of all cases of metastases to the female genital tract from extragenital cancers. The endometrium is even less frequently affected by metastases. Lobular carcinoma is the most common type of breast cancer that metastasizes to the uterus.
Two cases of infiltrating lobular carcinoma of the breast metastatic to endometrium and myometrium, one of them harboring an endometrioid adenocarcinoma, are reported. Both patients were on tamoxifen therapy and presented with uterine bleeding.
To the best of our knowledge, uterine carcinoma serving as recipient of metastatic carcinoma from the breast has not been previously documented. This possibility should be considered when an unusual bimorphic pattern appears in a tumor until proven otherwise.
[Show abstract][Hide abstract] ABSTRACT: Cellular retinol-binding protein-1 (CRBP-1) contributes to the maintenance of the differentiated state of the endometrium through retinol bioavailability regulation. The aim was to analyse CRBP-1 expression in endometrial stromal cells at eutopic and ectopic sites in different physiopathological conditions.
Antibodies to CRBP-1, CD10 and alpha-smooth muscle actin were applied to proliferative (n = 10), secretory (n = 9) and atrophic (n = 7) endometrium, decidua (n = 4), adenomyosis (n = 5), endometriosis (n = 10), endometrial polyps (n = 9), simple endometrial hyperplasia (n = 6), well-differentiated endometrioid carcinoma (n = 6) and submucosal leiomyomas (n = 5). In some cases, Western blotting and reverse transcription-polymerase chain reaction were also applied. CRBP-1 was expressed by eutopic and ectopic endometrial stromal cells more markedly during the late secretory phase and in decidua of pregnancy. CRBP-1 expression was low in the stroma of atrophic endometrium and absent in myometrium, leiomyomas and cervical stroma. CD10 immunoreactivity was weak in atrophic endometrium and in decidua.
CRBP-1 expression characterizes endometrial stromal cells at eutopic and ectopic sites and appears to be more specific than CD10. The level of CRBP-1 varies in intensity according to hormonal variations, reaching its maximum in predecidua and decidua. Thus, immunodetection of CRBP-1 may help to elucidate the physiopathological changes which occur in endometrial stroma and can also be applied as an adjuvant stromal marker.
[Show abstract][Hide abstract] ABSTRACT: Laminaria are used worldwide for the preparation of the cervix for termination of pregnancy.
The patient presented with recurrent episodes of pelvic inflammatory disease. Her history was significant for treatment with laminaria 4 years before presentation. After 6 months of evaluation, a diagnostic dilation and curettage was performed with removal of laminaria fragments.
Evaluation for complete removal of laminaria is critical. Retention of laminaria should be considered in the workup of patients who have pelvic inflammatory disease or genital infections and have received laminaria in the past.
[Show abstract][Hide abstract] ABSTRACT: Beta-catenin is a cytoskeleton-associated signaling molecule shown to be elevated in various carcinomas but mostly in colon cancer owing to its impaired degradation. In contrast, its close homologue plakoglobin was shown to suppress the tumorigenicity of certain tumor cells. In the present study, we have used a semiquantitative immunohistochemical approach to evaluate the extent of nuclear localization of beta-catenin in human colonic adenocarcinomas and adenomas and compared it to the distribution of plakoglobin in the same tissues. We show that beta-catenin accumulates in the nuclei of the epithelium of primary and metastatic colonic adenocarcinoma as well as in colonic adenomas. In contrast, nuclear plakoglobin levels in these tissues were low, even compared to those found in epithelial cells of normal colon. These results support the view that the increase in beta-catenin levels in colon cancer cells occurs early in the tumorigenic process, leading to its nuclear localization, not only in invasive adenocarcinoma, but also in colonic adenoma with mild dysplasia.
International Journal of Surgical Pathology 11/2001; 9(4):273-9. · 0.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Calcifying fibrous pseudotumor (CFP) is a benign soft tissue lesion composed of thick collagen bundles, scattered fibroblasts, and psammomatous and dystrophic calcifications, located most commonly in the extremities and trunk of children and young adults. The present case in a 36-year-old woman is to the best of our knowledge the first report of a large CFP confined to the mesentery, which, because of torsion, led to acute peritonitis and emergency laparotomy. The typical histologic features were accompanied by a prominent myofibroblastic proliferation along with inflammatory response at the periphery of the lesion. The spindle cells of the lesion were positive for vimentin and focally for CD34 and smooth-muscle actin. Review of the literature and discussion of differential diagnosis in this report focuses on abdominal CFP and other intraabdominal soft tissue lesions, some of which may be precursors of CFP. Int J Surg Pathol 9(3):249-253, 2001
International Journal of Surgical Pathology 08/2001; 9(3):249-53. · 0.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although a desmoplastic stromal reaction in well-differentiated endometrioid adenocarcinoma is considered a major criterion in the differential diagnosis with atypical hyperplasia, this histologic feature has not met with universal approval. Since alpha-smooth muscle (alpha-SM) actin positive myofibroblasts characterize the desmoplastic stromal response in a variety of neoplasms, the present study was undertaken in order to establish whether these cells are also prominent in the stroma of endometrioid carcinoma and if present could be used as a valid criterion in the differential diagnosis between benign and malignant lesions. The present study of 100 endometrial samples showed focal desmoplastic stromal reaction with alpha-SM actin positive myofibroblasts in 30% of small samples and in 50% of hysterectomy specimens with endometrioid carcinoma. In normal endometrium and in benign lesions lacking a desmoplastic reaction, focal stromal alpha-SM actin positivity was a very common finding. Stromal alpha-SM actin-positive cells were also frequently seen in nondesmoplastic stroma of endometrioid carcinoma. Thus the common presence of alpha-SM actin-positive myofibroblasts in normal endometrial stroma and in benign and malignant lesions precludes its usefulness in the diagnosis of well differentiated endometrioid adenocarcinoma, especially in small tissue samples.
International Journal of Gynecological Pathology 08/2001; 20(3):232-8. · 1.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine whether Brenner tumors and transitional cell carcinomas (TCCs) of the ovary are urothelial in type, the immunoprofiles of 14 Brenner tumors, including three malignant examples, and eight ovarian TCCs were compared with those of Walthard nests, urothelium, 12 urinary bladder TCCs and 17 ovarian adenocarcinomas (serous, endometrioid, mucinous, and undifferentiated type). The immunohistochemical stains used included those for cytokeratins CKs 5/6, CK7, CK8, CK13, and CK20, vimentin, CA125, and the specific urothelial differentiation marker uroplakin III. CK7 and CK8 were broadly expressed in most tumors of ovary and bladder examined, while vimentin was focally present in some ovarian TCCs and adenocarcinomas. As in normal and neoplastic bladder urothelium, urothelial markers, including uroplakin III, CK13, and CK20, were detected in the epithelial nests of Brenner tumors. Brenner tumor cells also expressed uroplakins Ia and II. CA125 was observed focally in some Brenner tumors. In contrast, TCCs of the ovary and Walthard nests lacked uroplakins and were essentially negative for CK20 and CK13 but quite strongly expressed CA125. This immunophenotype closely resembled that found in ovarian adenocarcinomas. Thus, it appears that the only true urothelial-type ovarian neoplasm is the Brenner tumor, whereas ovarian TCC most likely represents a poorly differentiated adenocarcinoma with a morphologic transitional cell pattern. These results may explain the controversies as expressed in the recent literature concerning TCC of the ovary and establish its place among the ovarian adenocarcinomas of müllerian type.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 03/2001; 438(2):181-91. · 2.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The cadherins are homotypic adhesion proteins that are important in cell sorting during organogenesis. Classic cadherins include several different types that show tissue specific expression. Specific tissue expression of cadherins often is preserved in neoplastic transformation, and cadherin phenotype can be used to differentiate morphologically similar but histogenetically distinct tumors.
The authors examined by using immunohistochemistry in paraffin sections the expression of E- (epithelial) and P- (placental) cadherin in 39 patients with glandular tumors of the cervix, including invasive adenocarcinoma, villoglandular adenocarcinoma, adenocarcinoma in situ (AIS), and adenoma malignum.
In all cases, E-cadherin was expressed in both normal and malignant glands without appreciable differences. P-cadherin, normally confined to basal epithelial cells and not observed in benign glands, was aberrantly expressed in neoplastic glands in 27 cases, including 96%(23 of 24 cases) of invasive cancers, 40% (2 of 5) of villoglandular carcinomas, 25% (2 of 8) of AIS, and 0% (0 of 2) of adenoma malignum.
The authors' results show that E-cadherin is uniformly expressed in glandular tumors of the cervix with no evidence of decreased expression in these tumors. In addition, P-cadherin is aberrantly expressed in most adenocarcinomas and appears to be preferentially expressed in invasive rather than in situ lesions. Thus, aberrant expression of P-cadherin may be a useful marker of invasive or aggressive clinical behavior in glandular lesions of the cervix.
Cancer 12/2000; 89(10):2053-8. · 4.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate clinical-pathological aspects of mitotically active leiomyomas.
Twenty patients with smooth muscle tumors of the uterus, with 5-9 mitotic figures per 10 high power fields and without atypia or necrosis were studied. The clinical and pathological characteristics of these tumors were reviewed and analyzed.
Patients' ages ranged from 33 to 63 years (mean 42.5 years). The size of the tumors ranged from 1.5 to 9.5 cm (mean 5.4 cm). On gross examination all tumors appeared as typical leiomyomas. Treatment included hysterectomy in 16 patients and myomectomy in four. Follow-up periods ranged from 1.5 to 11 years (mean 6.8 years). None of the patients developed a recurrent tumor.
The benign clinical behavior of such tumors supports their current designation as mitotically active leiomyomas, thus deleting the previous misnomer 'smooth muscle tumors of uncertain malignant potential'. Myomectomy is an appropriate treatment, particularly in young patients interested in reproduction.
[Show abstract][Hide abstract] ABSTRACT: The ICAM-1 molecule plays a role in the interaction of NK cells with a variety of tumor cells, including carcinoma, melanoma and glioblastoma cells. In the present study, we analyzed the effect of IFN-gamma and TNF-alpha on both the expression of HLA-DR and ICAM-1 molecules on HGCN (Germa-2), and on their susceptibility to lysis by LAK cells. Our results show that 1,000 U/ml IFN-gamma induced a substantial increase in the expression of both ICAM-1 molecules and HLA-DR on the cell surface, while the effect of TNF-alpha on the expression of these molecules was substantially less prominent. When Germa-2 cells, previously exposed to 1,000 U/ml IFN-gamma, were employed as target cells in a 4-hour 51Cr release assay, a statistically significant increase in the lysis by LAK cells was noted. These results show that in the presence of IFN-gamma, Germa-2 tumor cells undergo modulation which affects both the expression of ICAM-1 and HLA-DR molecules as well as their susceptibility to lysis by LAK cells.
[Show abstract][Hide abstract] ABSTRACT: The present report of a 25 year old woman with a primary ovarian angiosarcoma is supplemented by histochemical and ultrastructural studies and reviews the literature of this extremely rare neoplasm. Since this ovarian tumor, especially in young women, may constitute a diagnostic pitfall, problems relating to differential diagnosis are emphasized. Although the origin of this neoplasm appears to occur most likely from the rich ovarian vasculature, other less conventional histogenetic theories such as a possible origin in mixed mullerian tumor, in teratoma or in other ovarian germ cell tumors have also been proposed and are considered in this paper.
Pathology - Research and Practice 02/1998; 194(3):183-7. · 1.56 Impact Factor