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Expression of inhibin-alpha by granular cell tumors of the gallbladder and extrahepatic bile ducts.

This is the first report of inhibin-alpha expression in granular cell tumors. A Medline search of the literature revealed no case reports of granular cell tumors in any location of the body being tested for inhibin-alpha immunohistochemically, by enzyme-linked immunosorbent assay, by radioimmunoassay, or by immunoprecipitation. Seventeen cases of previously diagnosed granular cell tumors of the gallbladder and extrahepatic bile ducts with hematoxylin and eosin-stained sections, and S-100 protein immunostain were retrieved from the archives of the Armed Forces Institute of Pathology. All cases were reviewed for diagnostic accuracy and then immunostained for inhibin-alpha (with endogenous biotin blocking). All 17 (100%) cases were diffusely positive for inhibin-alpha immunostain. Previous studies of inhibin-alpha-positive lesions reported in the literature include sex cord stromal tumors (granulosa cell tumors, luteinized thecomas, Leydig cell tumors), placental and gestational trophoblastic lesions, and adrenal cortical tumors. This study adds the granular cell tumor to the list of inhibin-positive lesions and should prove helpful in differential diagnosis of these lesions.

Adolescent↗

Polypoid endometriosis: a clinicopathologic analysis of 24 cases and a review of the literature.

We describe 24 cases of polypoid endometriosis, most of which were referred because of problems in differential diagnosis, particularly distinction from a low-grade müllerian neoplasm. The patients were 23 to 78 years (mean 52.5 years) of age. Seven patients were on unopposed estrogen, four on combined estrogen-progestin therapy, and one patient had a synchronous ovarian thecoma. The most common clinical presentations were a pelvic mass, vaginal polypoid masses, and large bowel obstruction. In some cases, the intraoperative findings suggested a neoplasm. Sites of involvement in order of frequency included colon, ovary, uterine serosa, cervical and/or vaginal mucosa, ureter, fallopian tube, omentum, bladder, paraurethral and paravaginal soft tissue, and retroperitoneum. Multiple sites were involved in seven cases. Five cases occurred within ovarian or extraovarian endometriotic cysts. The lesions ranged up to 14 cm in size and formed polypoid, pink, gray or tan, masses. On microscopic examination, the polypoid masses were composed of an admixture of endometriotic glands and stroma. A variety of glandular architectural patterns were observed, sometimes in combination, most commonly cystic and noncystic simple hyperplasia, but also simple or complex hyperplasia with atypia, disordered proliferative, and cystic atrophy. Various types of epithelial metaplasia (tubal, mucinous, squamous, papillary syncytial metaplasia) were common. Hemorrhage, fibrosis, prominent thick-walled blood vessels, hemosiderin-laden histiocytes, and decidual change were also present in some cases. Eighteen cases were associated with usual (nonpolypoid) endometriosis. In one case, polypoid endometriosis merged with a mucinous borderline tumor of endocervical-type. In all but two cases, polypoid endometriosis lacked periglandular stromal hypercellularity, stromal atypia, and intraglandular stromal papillae, helping distinguish it from adenosarcoma. Focal intraglandular stromal papillae were noted in two cases with focal mild periglandular stromal hypercellularity in one of them, but no stromal atypia was present in either case. Follow-up data in 17 patients indicated that 15 patients were alive without evidence of residual disease, 1 was alive with residual endometriosis, and 1 died of other causes. In conclusion, polypoid endometriosis is a rare manifestation of endometriosis that may be mistaken for a neoplasm on clinical, intraoperative, or pathologic assessment. Some cases may be attributable to exogenous hormones or hyperestrinism and, like conventional endometriosis, some may evolve into a premalignant or, rarely, a neoplastic lesion. The main lesion in the differential is a müllerian (mesodermal) adenosarcoma.

Adenosarcoma↗

Leiomyomas of the ovary.

Two cases of ovarian leiomyoma as casual findings in oophorectomy specimens are reported. Both were small (1.5 and 1.0 cm), one had leiomyoblastomatous and symplastic features, and the other was associated with an adjoining multilocular mucinous cystadenoma and atypical hyperplasia in the endometrium. Both coexisted with uterine leiomyomas, which they resemble morphologically. Distinction from thecoma-fibroma was made by the immunohistochemical demonstration of desmin and characteristic electronmicroscopic features of smooth muscle.

Adult↗

Ovarian sex cord-stromal tumors: an immunohistochemical study including a comparison of calretinin and inhibin.

Because ovarian sex cord-stromal tumors (SCST) are morphologically heterogeneous neoplasms that are relatively infrequently encountered, their diagnosis can be difficult. Immunohistochemical staining may be useful for establishing the diagnosis in problematic cases. We studied 53 ovarian SCSTs to characterize their immunohistochemical staining pattern: 17 adult granulosa cell tumors (AGCTs), 4 juvenile granulosa cell tumors (JGCTs), 3 sex cord tumors with annular tubules (SCTATs), 9 Sertoli-Leydig cell tumors (SLCTs), 10 fibromas, 5 fibrothecomas (FTs), and 5 thecomas. In 8 of the 53 cases, the tissue studied was from a metastatic site. The immunopanel included calretinin, inhibin, WT1, cytokeratin cocktail, epithelial membrane antigen (EMA), and cytokeratin 5/6 (CK5/6). The fibromas and FTs were also tested with CD10. The extent of staining was assessed in a semiquantitative fashion and ranked on a scale of 0 through 4+. All of the tumors, except for 1 metastatic SLCT, were positive for calretinin. Forty-five of the cases (85%) stained for inhibin; 1 metastatic AGCT, 3 fibromas, and 4 FTs were negative. WT1 was present in 39 tumors (74%), with expression most prominent in the SLCTs. The cytokeratin cocktail stained 23 of the 53 tumors (43%), whereas just 1 tumor was positive for EMA (1+ in a JGCT). All tumors were negative for CK5/6, and the 15 fibromas and FTs were negative for CD10. We conclude that because cytokeratin is frequently expressed by SCSTs, in particular by granulosa cell tumors, SLCTs, and SCTATs, the inclusion of EMA in a panel may help to exclude epithelial neoplasms. In addition, WT1, present in normal granulosa cells, is expressed by a majority of SCSTs. Finally, these results demonstrate that calretinin is at least as sensitive as inhibin for ovarian SCSTs overall and that it is more sensitive than inhibin for fibromas and FTs.

Biomarkers, Tumor↗

OCT4: a novel biomarker for dysgerminoma of the ovary.

The prognosis and therapy for dysgerminomas are different from those of other ovarian tumor types, making accurate diagnosis imperative for patient care. OCT4 (POU5F1) is a transcription factor involved in the regulation of pluripotency during embryonic development. It can be detected in both pluripotent cells and other early germ cells. This study examines the expression of OCT4 in both dysgerminoma and nondysgerminomatous neoplasms involving the ovary. Formalin-fixed, paraffin-embedded cell blocks of 33 cases of dysgerminoma including 2 cases of gonadoblastoma associated with dysgerminoma and 3 cases of metastatic dysgerminoma, and 111 cases of nondysgerminomatous neoplasms involving the ovary were stained using the antibody against OCT4. All cases of dysgerminomas and gonadoblastomas were positive for OCT4 with strong nuclear staining. More than 90% of dysgerminoma cells in each case showed diffuse strong nuclear staining. In addition, 3 metastatic dysgerminomas also showed uniform strong nuclear staining. All nondysgerminomatous tumors (mature teratoma, 14; yolk sac tumor, 4; Sertoli-Leydig cell tumor, 15; granulosa cell tumor, 22; Brenner tumor, 3; carcinoid tumor, 4; struma ovarii, 2; fibroma, 5; thecoma, 1; serous adenocarcinoma, 5; endometrioid adenocarcinoma, 4; small cell carcinoma, 6; stromal sarcoma, 1; malignant lymphoma, 6; metastatic malignant melanoma, 1; metastatic carcinoid, 2; metastatic small cell carcinoma, 1; and metastatic lobular carcinoma of the breast, 1) were negative for OCT4, except for some cases of clear cell adenocarcinoma of the ovary. Four of 14 clear cell adenocarcinomas showed focal positive nuclear immunoreactivity for OCT4. OCT4 is a sensitive and relatively specific biomarker for the detection of dysgerminoma. It may also be useful in the diagnosis of gonadoblastoma, which contains similar cells and may be associated with dysgerminoma. OCT4 may aid in the detection of small foci of metastatic dygerminoma in extraovarian sites and may also help distinguish dysgerminoma from other primary and metastatic tumors of the ovary.

Adenocarcinoma, Clear Cell↗

Sclerosing stromal tumours of the ovary.

Sclerosing stromal tumours of the ovary have recently been described as a histologically and clinically distinct subgroup within the thecoma-fibroma spectrum of benign ovarian sex cord stromal tumours. Reported cases occurred predominantly in young women and only occasional tumours showed evidence of hormonal activity. The present series of five cases expands the spectra of both histological patterns and clinical presentations and suggests that the entity of sclerosing stromal tumours may not be as clearly circumscribed as has been previously reported.

Adolescent↗

Giant paraovarian myxoma.

We present an extremely rare case of a successfully operated giant (6700 g) paraovarian myxoma and uterus myomatosus in a 49-year-old woman. Preoperative examination (biochemical investigations, ultrasound and computed tomography scan) and perioperative findings did not identify a malignant tumor so that total abdominal hysterectomy/bilateral salpingo-oophorectomy and tumorectomy was chosen to treat the patient. Histologically, the tumor was clearly differentiated from the surrounding tissue. In solid regions there were spindle-shaped cells arranged in sheaves and within the profuse, well-vascularized myxomatous stroma there were star-shaped cells. Immunohistochemical analysis showed that tumor cells were positive to vimentin and smooth muscle actin. Electron microscopic analysis showed that tumor cells had ultrastructural characteristics that corresponded to cells in fibroma and thecoma in a profuse intercellular matrix, which confirmed the result of light microscopy.

Fallopian Tubes↗

Sclerosing stromal tumor of ovary.

A case of an extremely rare, benign ovarian lesion occurring in young women is presented and its pathology discussed. Radiographically it simulated a large calcified fibroid. The diagnosis should be considered in a young woman with menstrual irregularity and pelvic mass where fibroma and thecoma are unlikely.

Adolescent↗

Functioning ovarian tumors: direct and indirect findings at MR imaging.

There are many kinds of ovarian tumors and tumorlike conditions that produce estrogen or androgen. Magnetic resonance imaging can demonstrate not only ovarian tumors but also an enlarged uterus with a thick endometrium, even in cases of a clinically latent excess of estrogen. These clinical and indirect imaging findings can aid in the differential diagnosis of ovarian tumors. Granulosa cell tumor and thecoma are well-known estrogen-producing tumors. In pediatric or postmenopausal patients, they manifest as precocious pseudopuberty or postmenopausal bleeding, respectively. Conversely, Sertoli-Leydig cell tumor is representative of hormone-producing tumors that cause virilization. However, there are other functioning ovarian tumors besides the sex cord-stromal tumors. It is well known that metastatic ovarian tumors often have androgen-producing stroma and that mucinous cystadenoma sometimes produces estrogens. Most other ovarian tumors can produce sexual hormones in their stroma. In addition, some endocrinologic abnormalities (eg, polycystic ovary syndrome) also cause virilization.

Adolescent↗

Expression of betaglycan, an inhibin coreceptor, in normal human ovaries and ovarian sex cord-stromal tumors and its regulation in cultured human granulosa-luteal cells.

Activins and inhibins are often antagonistic in the regulation of ovarian function. TGFbeta type III receptor, betaglycan, has been identified as a coreceptor to enhance the binding of inhibins to activin type II receptor and thus to prevent the binding of activins to their receptor. In this study we characterized the expression and regulation pattern of betaglycan gene in normal ovaries and sex cord-stromal tumors and in cultured human granulosa-luteal cells from women undergoing in vitro fertilization. Expression of betaglycan mRNA was detected by RT-PCR or Northern blotting in normal ovarian granulosa, thecal, and stroma cells as well as in granulosa-luteal cells. Immunohistochemical analysis revealed positive staining for betaglycan in antral and preovulatory follicular granulosa and thecal cells and in corpora lutea of normal ovaries. Furthermore, betaglycan expression was detected in the vast majority of granulosa cell tumors, thecomas, and fibromas, with weaker staining in granulosa cell tumors compared with fibrothecomas. In cultured granulosa-luteal cells, FSH and LH treatment increased dose-dependently the accumulation of betaglycan mRNA, as did the protein kinase A activator dibutyryl cAMP and the protein kinase C inhibitor staurosporine. In contrast, the protein kinase C activator 12-O-tetradecanoyl phorbol 13-acetate had no significant effect on betaglycan mRNA levels. Treatment with prostaglandin E(2) and with its receptor EP2 subtype agonist butaprost increased betaglycan mRNA accumulation and progesterone secretion dose- and time-dependently. In summary, betaglycan gene is expressed in normal human ovarian steroidogenic cells and sex cord-stromal ovarian tumors. The accumulation of its mRNA in cultured granulosa-luteal cells is up-regulated by gonadotropins and prostaglandin E(2), probably via the protein kinase A pathway. The specific expression and regulation pattern of betaglycan gene may be related to the functional antagonism of inhibins to activin signal transduction in human ovaries.

Activins↗

Parathyroid hormone-like peptide in normal and neoplastic human endocrine tissues.

PTH-like peptide (PLP) is produced by tumors commonly associated with hypercalcemia as well as nonneoplastic tissues and several endocrine glands and tumors. To characterize the distribution of PLP in human endocrine tissues and tumors, we localized PLP in formalin-fixed paraffin-embedded material using the avidin-biotin-peroxidase technique with polyclonal antisera. Among peptide hormone-producing tissues, PLP was identified in nontumorous adenohypophysis and pituitary adenomas; medullary thyroid carcinomas; normal, hyperplastic, and adenomatous parathyroids; adrenal medulla and pheochromocytomas; normal pancreatic islets; and endocrine tumors of pancreas, gut, and lung, including small cell carcinomas. In other endocrine tissues PLP was identified in nontumorous thyroid follicular epithelium, colloid nodules, and follicular neoplasms; normal adrenal cortex, adrenocortical adenomas, and carcinomas; nontumorous testicular Leydig cells; normal ovarian granulosa and thecal cells; an ovarian thecoma and a granulosa cell tumor; placental trophoblast; and decidua. These results demonstrate that PLP is localized in many normal and neoplastic endocrine cells, including those not known to influence extracellular calcium homeostasis. The presence of PLP in a variety of endocrine tissues suggests that it may play a local physiological role in the growth or function of endocrine cells.

Adrenal Cortex Neoplasms↗

Activating mutation of the stimulatory G protein (gsp) as a putative cause of ovarian and testicular human stromal Leydig cell tumors.

Activating mutations of the G protein genes have been associated with the development of several endocrine neoplasms. Such activating mutations, gip2, affecting the alpha-subunit of the G alpha i2 protein were previously described by a single group in 30% of ovarian sex cord stromal tumors. Other activating mutations of the alpha-subunit of the Gs (gsp) have been identified in GH-secreting and nonfunctioning pituitary tumors, autonomous thyroid adenomas, and all affected McCune-Albright tissues, but not in sex cord stromal tumors. In the present study, we investigated the presence of gip2 and gsp mutations in 14 human sex cord stromal tumors. Six Leydig cell tumors (4 ovaries and 2 testes), 2 thecomas, 2 granulosa cell tumors, 3 androblastomas, and 1 gonadoblastoma (sex cord and germ cell) were included in this study. Genomic DNA was obtained from either fresh-frozen tumor tissues or paraffin-embedded sections and in some cases from blood samples. Using PCR, denaturing gradient gel electrophoresis, and direct sequencing, we detected 4 tumors (66.6%) with the gsp mutation (R201C) in our series of ovarian and testicular Leydig cell tumors. In contrast, no gip2 mutations were found in any of the sex cord stromal tumors studied. In conclusion, our findings suggest that the putative oncogene gsp may play a significant role in the molecular mechanism of these tumors.

Adolescent↗

Krukenberg's tumor of the ovary: MR imaging features.

OBJECTIVE: Krukenberg's tumors are metastatic tumors of the ovary. Some of these tumors had hypointense solid components on T2-weighted MR images. The purpose of this study was to evaluate the MR features of Krukenberg's tumors and to compare them with those of other solid ovarian tumors to determine whether hypointense solid components on MR images were characteristic of Krukenberg's tumors. MATERIALS AND METHODS: Twelve patients with 21 surgically proven Krukenberg's tumors of the ovary were included in the study; the tumors were bilateral in nine and unilateral in three. The MR images were studied to determine the morphologic characteristics and signal intensity patterns of the tumors (especially the presence or absence of hypointense solid components on T2-weighted images and isointense components on T1-weighted images). MR findings were correlated with histopathologic results. The MR features of 26 additional benign or malignant solid primary ovarian tumors were reviewed for comparison. RESULTS: Of the 21 Krukenberg's tumors, 14 were mostly solid and seven were entirely cystic or mostly cystic on MR images. All had sharp margins, and the oval configuration was preserved in 16. Twelve (57%) of the 21 tumors showed various amounts of hypointense solid components in random distribution or predominantly in the periphery on MR images; pathologically, these components corresponded to areas of dense collagenous stroma. MR imaging also showed that the cystic components within the masses had either well-defined or ill-defined borders. Multiseptation was noted in two masses. Of the 26 additional primary ovarian tumors, only three showed hypointense solid components on MR images. These included thecoma, fibrothecoma, and poorly differentiated adenocarcinoma. CONCLUSION: Our findings suggest that identification of hypointense solid components within an ovarian mass on T2-weighted MR images is a characteristic, although not specific, finding for Krukenberg's tumors, especially when the tumors are bilateral, have sharp margins, and have an oval configuration.

Adult↗

Sonographic features of Brenner tumor of the ovary.

The sonographic findings in four patients with benign Brenner tumors of the ovary are described. Computed tomography (CT) was also obtained in one case. The neoplasms were solid, hypoechoic masses, usually exhibiting good through transmission of sound. Two neoplasms contained peripheral calcifications; one was inseparable from the uterus and was misdiagnosed as a leiomyoma; the other was well-demonstrated by CT but only in retrospect was the peripherally located calcification identified. Sonographically, Brenner tumors are similar to other solid ovarian neoplasms, particularly fibromas-thecomas, and can also be confused with pedunculated leiomyomas.

Adult↗

Assessment of ovarian tumor vascularity with transvaginal color Doppler sonography.

This report describes the results of transvaginal color Doppler sonography (TV-CDS) of 43 surgically proved ovarian masses. Waveform analyses of the signals arising from specific vessels (i.e., peripheral, central, septal) adjacent to and within these masses were correlated to those seen on macroscopic pathologic evaluation. The mean and standard deviation of the pulsatility indices (PI) of 32 benign lesions (1.8 +/- 0.8) were higher than 11 malignant ones (0.8 +/- 0.6) (P = 0.03). However, the range of benign (4.0 to 0.7) and malignant (1.5 to 0.4) lesions did overlap. Low PIs (less than 1.0) were found in five relatively benign lesions (one case each of dermoid cyst, cystadenoma containing a dermoid cyst, endometrioma, benign sclerosing stromal tumor, and thecoma), but also in all 11 malignant or borderline malignant lesions (nine cystadenocarcinomas, two germ cell tumors), causing an overlap between the PIs of some benign and malignant masses. With a 100% negative predictive value, our preliminary data suggest that TV-CDS can effectively exclude malignancy. However, with a positive predictive value of 73%, one in four malignant lesions diagnosed by TV-CDS will be benign.

Adolescent↗

[Preoperative assessment of asymptomatic adnexal tumors by positron emission tomography and F 18 fluorodeoxyglucose].

AIM: To evaluate use of F-18-FDG-PET in assessment of dignity of asymptomatic adnexal masses. METHODS: 85 asymptomatic patients with suspicious, asymptomatic adnexal masses were evaluated. Static FDG-PET (Exact HR+ or ECAT 931) imaging of the abdomen was performed following application of 222-555 MBq F-18-FDG. Iterative reconstruction was applied. PET data were analysed visually, at first without and second together with MRT images. Final diagnosis was made by histopathology. RESULTS: FDG-PET allowed correct identification of 4 of 8 malignant adnexal tumors. False negative results were obtained in 2 adenocarcinomas stage pT1a and 2 borderline-tumors. In 60 out of 77 benign adnexal masses malignancy could be excluded. False positive FDG-uptake, partly because of misinterpretation of gastrointestinal activity, was found in 3 inflammatory processes, 1 teratoma, 1 benign schwannoma, 1 dermoid cyst, 1 benign thecoma, 1 serous cyst, 1 serous cystadenoma, 2 mucinous cystadenomas, 2 corpus luteum cysts, 3 endometriosic cysts and 1 sactosalpinx. The overall sensitivity and specificity of FDG-PET alone were 50% and 78%. Evaluation together with MRT images showed a sensitivity of 50% and a specificity of 86%. CONCLUSION: Sensitivity of FDG-PET in detection of borderline-tumors and early stage ovarian cancer seems to be limited. Low incidence of malignant ovarian tumors requires for assessment of dignity a procedure of high specificity, that is not reached by FDG-PET neither without nor together with MRT images for topographic orientation. Therefore use of FDG-PET for assessment of dignity in suspicious, asymptomatic ovarian tumors is limited.

Adolescent↗

Sclerosing stromal tumour of the ovary--a case report.

Sclerosing stromal tumour (SST) of the ovary is a rare, benign tumour of the ovary, distinct from thecoma-fibroma group of tumours because of predominant occurrence below 30 years of age, lack of hormonal manifestations and histologic heterogenity. A case of 17-year-old female patient is described in the present article. The differential diagnosis is also discussed.

Adolescent↗

Ovarian tumors in young females. A laparoscopic approach.

Ovarian tumors are one of the major preoccupations in the everyday practice of gynecology. During the period January 1997 through December 2000, 54 cases of ovarian tumors in young females aged 14-20 years were diagnosed and managed laparoscopically in our institution. Twenty-two cases of mature cystic teratoma, 12 cases of endometriosis, eight cases of serous cystadenoma, five cases of mucinous cystadenoma, three cases of fibroma-thecoma, two cases of serous low-malignant tumors and one case of mucinous low-malignant tumor were found. The management of ovarian tumors during this age by laparoscopic techniques represents an efficient and safe procedure.

Adolescent↗