Expression of platelet-derived growth factors and their receptors in ovarian clear-cell carcinoma and its putative precursors.

Recent studies have shown that platelet-derived growth factors and their receptors are frequently co-expressed in ovarian cancers. Herein, we investigated the role of the platelet-derived growth factor pathway in the development of ovarian clear-cell adenocarcinoma, a highly chemoresistant form of ovarian cancer. Immunohistochemical expression of platelet-derived growth factor receptor-alpha and receptor-beta, platelet-derived growth factor A-chain and B-chain was examined in 31 cases of clear-cell adenocarcinoma and 56 coexisting putative precursor lesions: 17 non-atypical and 19 atypical endometrioses, and 10 non-atypical and 10 atypical clear-cell adenofibroma components. Twenty-one solitary endometrioses were also examined. Vascular endothelial cells were always positive for all the markers examined, and were used as positive controls. The frequencies of positivity for platelet-derived growth factor receptor-alpha and receptor-beta, and platelet-derived growth factor A-chain increased in accordance with higher cytologic atypia in the putative precursors: 71, 47, and 59% in the 17 non-atypical endometrioses, 84, 73, and 84% in the 19 atypical endometrioses, 0% each in the 10 non-atypical clear-cell adenofibromas, 100, 90, and 90% in the 10 atypical clear-cell adenofibromas, and 97, 97, and 100% in the 31 clear-cell adenocarcinomas, respectively. Positivity for platelet-derived growth factor B-chain increased in accordance with increased atypia in clear-cell adenofibroma: 0% in non-atypical clear-cell adenofibromas, 30% in atypical clear-cell adenofibromas, and 60% in coexisting carcinomas. However, in contrast, positivity for platelet-derived growth factor B-chain decreased in accordance with increased atypia in endometriosis coexisting with clear-cell adenocarcinomas: 35% in non-atypical endometrioses, 11% in atypical endometrioses, and 5% in coexisting carcinomas. Platelet-derived growth factor receptor-alpha and receptor-beta, and their ligands A-chain and B-chain were positive in 14, 29, 19, and 62% of the solitary endometrioses, respectively. These results indicate activation of the platelet-derived growth factor pathway in ovarian clear-cell adenocarcinomas and suggest biological differences between carcinomas that arise in association with clear-cell adenofibroma vs endometriosis.     

Intraductal carcinoma of mammary-type apocrine epithelium arising within a papillary hydradenoma of the vulva. Report of a case and review of the literature.

We report and immunohistochemically document the first (to the best of our knowledge) case of malignancy in which an intraductal carcinoma resembling apocrine breast cancer arose within a papillary hidradenoma of the vulva. Papillary hidradenoma is generally thought to originate from apocrine sweat glands, but a derivation from milk line remnants of the vulva should also be considered. Immunoreactivities for low- and high-molecular-weight cytokeratins, alpha-smooth-muscle-specific actin, carcinoembryonic antigen, S100 protein, and gross cytic disease fluid protein 15, an antigen of apocrine differentiation, show features that resemble those of an intraductal apocrine breast cancer. Positivity for gross cystic disease fluid protein 15 as well as the presence of estrogen and progesterone receptors suggest that tumor cells are controlled by ovarian steroid hormones. To our knowledge, no cases of malignancy arising from a papillary hidradenoma have been proved to date. Therefore, we also discuss previously reported cases of putative cancers that have developed in papillary hidradenomas. In the case presented herein, a local excision with a narrow rim of surrounding tissue was performed, and the patient was alive and well, without signs of recurrence, after 2 years of follow-up.     

Serous papillary adenocarcinoma of the female genital organs and invasive micropapillary carcinoma of the breast. Are WT1, CA125, and GCDFP-15 useful in differential diagnosis?

Serous papillary adenocarcinoma of the female genital organs and invasive micropapillary carcinoma of the breast have close histologic similarities. Thus, when these cancers occur synchronously or metachronously in the same patient, it is difficult to determine the primary site. We examined 23 serous papillary adenocarcinomas (16 ovarian, 5 endometrial, and 2 peritoneal) and 37 invasive micropapillary carcinomas of the breast (12 pure and 25 mixed types) on immunohistochemical expression of Wilm's tumor antigen-1 (WT1), CA125, and gross cystic disease fluid protein-15 (GCDFP-15), which have been reported to be useful in the differential diagnosis of primary ovarian carcinomas versus metastatic breast cancer to the ovary. The positive rates of WT1, CA125, and GCDFP-15 in serous papillary adenocarcinomas were 78%, 78%, and 0%, respectively, and the corresponding rates in invasive micropapillary carcinomas were 3%, 40%, and 38%. The CA125-positive rate of invasive micropapillary carcinoma was higher than the rate reported for other types of breast carcinomas. We consider CA125 to be not always useful in the differential diagnosis of serous papillary adenocarcinoma and invasive micropapillary carcinoma. Although the positive rate of WT1 was significantly higher in serous papillary adenocarcinoma than in invasive micropapillary carcinoma, WT1 expression in endometrial serous papillary adenocarcinoma was infrequent (20%). WT1 and GCDFP-15 could be useful markers for the differential diagnosis of ovarian and peritoneal serous papillary adenocarcinoma versus breast invasive micropapillary adenocarcinoma. However, the availability of GCDFP-15 is limited because of the low positive rate of GCDFP-15 in invasive micropapillary carcinomas.     

Pathogenesis and diagnostic significance of nuclear grooves in thyroid and other sites

Nuclear grooves are longitudinal invaginations of the nuclear envelope bilayer, which constitute a characteristic feature of papillary thyroid carcinoma. Their pathogenesis is not yet clear, but there is evidence for the involvement of a signaling pathway downstream of the protooncogene RET. The presence of nuclear grooves is not specific for papillary thyroid carcinoma because it has been documented in other types of thyroid neoplasms, in nonneoplastic thyroid lesions, in ovarian neoplasms (Brenner, adult granulosa cell, and transitional cell tumors), in breast carcinomas, in cervicovaginal and endometrial smears, in papillary neoplasms of several organs (such as papillary transitional cell carcinoma of the bladder, papillary renal cell carcinoma, papillary endometrioid carcinoma of the prostate), in thymic carcinomas, and in nonepithelial tumors.     

Sonographic detection of thyroid cancer in breast cancer patients

The purpose of our study was to analyze the incidence of incidental thyroid cancers which were detected by simultaneous sonographic examination of breast and thyroid glands. Between January 2001 and March 2004, 518 patients were diagnosed with breast cancer after modified radical mastectomy (n=369) or breast conserving surgery (n=149). We screened thyroid glands when we examined breast for diagnosis and follow-up after surgery. If we found the sonographic finding of suspicious for malignancy in thyroid, we immediately performed ultrasound-guided fine needle aspiration biopsy (FNAB). Forty-two cases showed suspicious sonographic findings and of those, 18 cases (42.9%) were determined to have suspicious malignant cytology by ultrasound guided FNAB. Among 518 breast cancers, total 13 cases (2.5%) were diagnosed with papillary carcinoma after thyroidectomy. The mean longest diameter of the thyroid masses was 9.9 mm (range 1-30 mm). Six cases (6/13, 46.2%) were diagnosed as simultaneous breast and thyroid cancers, and the rest of the thyroid cancers were detected after 6 to 33 months (mean 16.5 months) after surgery. In conclusion, the patients with breast cancer had a high incidence (2.5%) of thyroid cancer. Sonographic screening is useful for the early detection of thyroid cancer.     

Fine-needle aspiration cytology of metastatic ovarian carcinoma to the breast

Metastatic ovarian carcinoma to the breast is rare. It represents a diagnostic challenge to the cytologist. It usually signifies a progressive widespread metastatic ovarian tumor with a poor prognosis. This report evaluates the breast fine-needle aspiration (FNA) cytomorphologic features of six cases of metastatic ovarian carcinoma and compares them to those reported in the literature. The cytologic features included hypercellularity, abundant papillary fragments, and necrotic background. The tumor cells showed high nuclear/cytoplasmic ratio, anisonucleosis, prominent nucleoli, and psammoma bodies in cases of serous papillary carcinoma. In addition, the clear-cell carcinoma had prominent finely vacuolated and clear cytoplasm, multinucleated giant cells, and papillary fragments with hobnail nuclei. Recognition of these unusual patterns in a breast FNA cytology should raise the suspicion of a metastatic ovarian tumor. Direct comparison between the breast FNA cytology and the original primary ovarian tumor should confirm the diagnosis. The proper diagnosis of metastatic ovarian cancer to the breast will prevent unnecessary surgical treatment and ensure the appropriate therapy. Diagn Cytopathol 1996;15:1–6. © 1996 Wiley-Liss, Inc.     

Solid and cystic ultimobranchial body remnants in the thyroid

In this study we determined the incidence rate (89%) and characterized the morphology of ultimobranchial body (UBB) remnants found in 18 serially sectioned neonatal thyroid glands. Although UBB remnants are often referred to as solid cell nests, we found cystic features in 55%. Ciliated columnar cells were seen in 23%. One contained a large pseudo-papilla. The UBB cells had nuclei with features reminiscent of papillary carcinoma nuclei in that they were enlarged, oval, and contained finely dispersed chromatin when compared with follicular cell nuclei. Both papillary carcinomas and UBB remnants are common, occur as tiny, solid, or cystic thyroid entities in patients of all ages, may contain papillary structures, and share some common nuclear features. Therefore, it is important to include UBB remnants in the differential diagnosis of minute thyroid entities and to recognize their morphologic features.     

CA125 and thyroglobulin staining in papillary carcinomas of thyroid and ovarian origin is not completely specific for site of origin

AIMS: A 70-year-old woman presented with metastatic psammoma body-rich papillary carcinoma in a supraclavicular lymph node. No primary site was evident. The tumour showed strong staining for CA125 and weak staining for thyroglobulin. Prompted by this case we aimed to assess the reliability of immunostaining for CA125 and thyroglobulin in making the distinction between thyroid and ovarian papillary carcinoma. METHODS AND RESULTS: Nine papillary carcinomas of the thyroid and 17 serous papillary carcinomas of the ovary were stained for CA125 and thyroglobulin, as well as CAM 5.2, LP 34, carcinoembryonic antigen (CEA), S100 and diastase/periodic acid-Schiff. Nine of nine thyroid carcinomas stained for thyroglobulin; in addition CA125 was positive in four of nine. Normal surrounding thyroid also showed some reaction. Seventeen of 17 ovarian serous carcinomas were positive for CA125; in addition one case showed moderately strong staining for thyroglobulin. Mucin stains were positive in 14/17 ovarian serous carcinomas, but negative in all thyroid carcinomas. The other antibodies assessed showed no useful differences in staining frequency. Conclusion: Many cases of papillary carcinoma of the thyroid show CA125 staining, and this feature therefore has little positive predictive value for an ovarian origin. Occasional cases of ovarian papillary carcinoma may show staining for thyroglobulin, and this result should therefore be interpreted cautiously.     

Hereditary ovarian cancer. Pedigree studies, Part II

Hereditary ovarian carcinoma is heterogenous. There are at least three genetic variants, namely, hereditary site-specific ovarian carcinoma, hereditary breast/ovarian carcinoma syndrome, and Lynch syndrome II. Early age of onset characterizes these disorders. A crucial hallmark of these disorders is the integral association of extraovarian cancers, such as carcinoma of the endometrium and colon in Lynch syndrome II. We have described 24 pedigrees of ovarian cancer-prone families in order to depict the several differing heterogenous variants. Interest in hereditary ovarian cancer has increased remarkably, due in part to the fact that its surveillance has been wholly unsatisfactory, as have therapeutic measures. Prevention through prophylactic oophorectomy offers hope. However, there is a risk for extraovarian peritoneal serous papillary carcinoma, consonant with primary cancer of the ovary. This must be discussed with these at-risk patients. Until a biomarker of acceptable sensitivity and specificity is identified, the family history must remain the key to hereditary ovarian cancer diagnosis.     

血清TSH和甲状腺激素水平与乳腺癌关系的探讨

目的:探讨乳腺癌患者TSH和甲状腺激素水平的变化及其意义。方法:采用放射免疫分析和微粒子化学发光免疫分析检测了80例乳腺癌患者和100例健康对照者的血清T3、T4、TSH及rT3的含量。结果:乳腺癌患者血清T3水平和T3/rT3比值显著低于健康对照组,且随病情的加重逐渐下降,各组间经统计学比较均有显著性差异(P<0.01)。与此相反,血清rT3水平则显著地高于健康对照组,与病损程度呈正相关(P<0.01)。各组间血清T4、TSH水平与健康对照组比较无明显差异(P>0.05)。结论:测定血清T3、rT3浓度有助于乳腺癌患者病情严重程度和预后的判断。     

The Prevalence of Autoimmune Disorders Among Patients With Primary Ovarian Failure*

ABSTRACT: Eighty-one patients who had a diagnosis of primary ovarian failure were studied to determine its possible association with autoimmune disorders. All 81 patients displayed 46, XX chromosome complements. On ovarian biopsy, either few or no follicles were demonstrated in 79 patients, and, in two patients, primordial follicles were more abundant. The two patients with a large number of primordial follicles had normal function of other endocrine organs; however, 15 of the 79 patients demonstrating few or no ovarian follicles had associated failure of other endocrine glands, and one patient had myasthenia gravis. Thirteen of these 15 patients sought treatment because of secondary amenorrhea, the age at onset ranging from 11 to 34 years. Of the 81 patients, 11 had primary amenorrhea and 70 had secondary amenorrhea. Among the 79 patients with few or no ovarian follicles, endocrine glandular failure, in addition to ovarian failure, was found in two patients with primary amenorrhea and in 13 patients with secondary amenorrhea. The association of polyglandular failure syndrome and primary ovarian failure, along with demonstration of a lymphocytic infiltrate in ovaries and circulating antibodies in sera of women with premature ovarian failure, suggests that an autoimmune mechanism may be a cause of primary ovarian failure in some cases.     

Mutation analysis of the BRCA1 gene in 23 families with cases of cancer of the breast, ovary, and multiple other sites.

Germline mutations in the BRCA1 tumour suppressor gene on chromosome 17q21 are responsible for approximately half of the cases of hereditary breast cancer, including the majority of familial breast/ovarian cancers. To increase our knowledge of the spectrum of BRCA1 mutations, we have extended our analysis to include patients with varied family histories of cancer of the breast, ovary, and at multiple other sites. We have analysed 23 unrelated familial cases using direct sequencing or a combination of dideoxy fingerprinting and sequencing procedures. Twenty one of these families contained three or more cases of breast or ovarian cancer and two families had one case of breast cancer diagnosed before the age of 40 and one case of ovarian cancer. The common frameshift mutation 5382insC was detected in two patients, and the 185delAG mutation was found in a family of Ashkenazi Jewish descent. The novel frameshift mutation 3450del4 (CAAG) was detected in a patient who developed breast cancer at the age of 28 and ovarian cancer at the age of 34. Three other women in this family were diagnosed with breast cancer at the ages of 26, 29, and 40. The novel framshift mutation 2953del3+C was found in a French Canadian woman who had developed two primary cancers of the breast at the age of 37 and 38 and renal cancer at the age of 38.     

A PARK2 polymorphism associated with delayed neuropsychological sequelae after carbon monoxide poisoning

Background

The PALB2 c.2323C>T [p.Q775X] mutation has been reported in at least three breast cancer families and breast cancer cases of French Canadian descent and this has been attributed to common ancestors. The number of mutation-positive cases reported varied based on criteria of ascertainment of index cases tested. Although inherited PALB2 mutations are associated with increased risks of developing breast cancer, risk to ovarian cancer has not been fully explored in this demographically unique population.

Methods

We screened the PALB2 p.Q775X variant in 71 families with at least three cases of breast cancer (n=48) or breast and ovarian cancers (n=23) that have previously been found negative for at least the most common BRCA1 and BRCA2 mutations reported in the French Canadian population and in 491 women of French Canadian descent who had invasive ovarian cancer and/or low malignant potential tumors of the major histopathological subtypes.

Results

We identified a PALB2 p.Q775X carrier in a breast cancer family, who had invasive ductal breast carcinomas at 39 and 42 years of age. We also identified a PALB2 p.Q775X carrier who had papillary serous ovarian cystadenocarcinoma at age 58 among the 238 serous subtype ovarian cancer cases investigated, who also had breast cancer at age 52.

Conclusion

Our findings, taken together with previous reports, support adding PALB2 c.2323C>T p.Q775X to the list of cancer susceptibility genes for which founder mutations have been identified in the French Canadian population.     

Correlation between BRAF mutation and the clinicopathological parameters in papillary thyroid carcinoma with particular reference to follicular variant

Mutation of the BRAF gene is common in thyroid cancer. Follicular variant of papillary thyroid carcinoma is a variant of papillary thyroid carcinoma that has created continuous diagnostic controversies among pathologists. The aims of this study are to (1) investigate whether follicular variant of papillary thyroid carcinoma has a different pattern of BRAF mutation than conventional papillary thyroid carcinoma in a large cohort of patients with typical features of follicular variant of papillary thyroid carcinoma and (2) to study the relationship of clinicopathological features of papillary thyroid carcinomas with BRAF mutation. Tissue blocks from 76 patients with diagnostic features of papillary thyroid carcinomas (40 with conventional type and 36 with follicular variant) were included in the study. From these, DNA was extracted and BRAF V600E mutations were detected by polymerase chain reaction followed by restriction enzyme digestion and sequencing of exon 15. Analysis of the data indicated that BRAF V600E mutation is significantly more common in conventional papillary thyroid carcinoma (58% versus 31%, P = .022). Furthermore, the mutation was often noted in female patients (P = .017), in high-stage cancers (P = .034), and in tumors with mild lymphocytic thyroiditis (P = .006). We concluded that follicular variant of papillary thyroid carcinoma differs from conventional papillary thyroid carcinoma in the rate of BRAF mutation. The results of this study add further information indicating that mutations in BRAF play a role in thyroid cancer development and progression.     

Thyroid disease in relation to breast cancer

Summary A controversy exists in regard to thyroid function and breast cancer. Hypothyroidism has been suggested as being either protective from breast cancer or predisposing to the disease. It has been hypothesized that a deficiency in circulating thyroid hormones may hypersensitize the mammary glandular epithelium toward prolactin and estrogens, thus aiding in the development of breast neoplasia. On the other hand, thyroid hormone replacement therapy has been connected with an increased risk of breast cancer, but this has been contested. At this time the American Thyroid Association recommends that, if indicated, hypothyroid patients should take their thyroid hormone medication.Hyperthyroidism has been associated with a decreased risk of breast cancer. Also, in hyperthyroid patients with inoperable breast cancer, the malignant growth is thought to be slowed. However, this, too has been disputed. Moreover, hyperthyroidism has been connected with the development of breast cancer in premenopausal women.At present no role of thyroid hormone in the pathobiology of breast cancer can be defined. It seems that the thyroid-breast cancer controversy can only be resolved by a prospective study preferably on postmenopausal women correlating thyroid (T₃, T₄, PBI), pituitary (TSH, TRH, Prolactin), and adrenocortical (androgens) function tests with the clinical examination of thyroid, breast, and genital apparatus and determination of the estrogen status (vaginal smear, plasma estrogens) as well.     

High frequency and allele‐specific differences of BRCA1 founder mutations in breast cancer and ovarian cancer patients from Belarus

Bogdanova NV, Antonenkova NN, Rogov YI, Karstens JH, Hillemanns P, Dörk T. High frequency and allele‐specific differences of BRCA1 founder mutations in breast cancer and ovarian cancer patients from Belarus. Breast cancer and ovarian cancer are common malignancies in Belarus accounting for about 3500 and 800 new cases per year, respectively. For breast cancer, the rates and age of onset appear to vary significantly in regions differentially affected by the Chernobyl accident. We assessed the frequency and distribution of three BRCA1 founder mutations 5382insC, 4153delA and Cys61Gly in two hospital‐based series of 1945 unselected breast cancer patients and of 201 unselected ovarian cancer patients from Belarus as well as in 1019 healthy control females from the same population. Any of these mutations were identified in 4.4% of the breast cancer patients, 26.4% of the ovarian cancer patients and 0.5% of the controls. In the breast cancer patients, BRCA1 mutations were strongly associated with earlier age at diagnosis, with oestrogen receptor (ER) negative tumours and with a first‐degree family history of breast cancer, although only 35% of the identified BRCA1 mutation carriers had such a family history. There were no marked differences in the regional distribution of BRCA1 mutations, so that the significant differences in age at diagnosis and family history of breast cancer patients from areas afflicted by the Chernobyl accident could not be explained by BRCA1. We next observed a higher impact and a shifted mutational spectrum of BRCA1 in the series of Byelorussian ovarian cancer patients where the three founder mutations accounted for 26.4% (53/201). While the Cys61Gly mutation appeared underrepresented in ovarian cancer as compared with breast cancer cases from the same population (p = 0.01), the 4153delA mutation made a higher contribution to ovarian cancer than to breast cancer (p < 0.01). BRCA1 mutations were significantly enriched among ovarian cancer cases with a first‐degree family history of breast or ovarian cancer, whereas the median age at ovarian cancer diagnosis was not different between mutation carriers and non‐carriers. Taken together, these results identify three BRCA1 founder mutations as key components of inherited breast and ovarian cancer susceptibility in Belarus and might have implications for cancer prevention, treatment and genetic counselling in this population.     

Pancreatic, hepatic, splenic, and mesenteric mucinous cystic neoplasms (MCN) are lumped together as extra ovarian MCN

Mucinous cystic neoplasms (MCN) of the pancreas are mucin-producing cystic tumors with an ovarian-like stroma (OLS). In the present study MCN were obtained from 27 patients. These MCN were derived from 22 pancreas, three livers, spleen, and mesentery. MCN in various organs have common clinicopathological profiles, being unilocular or multilocular cystic tumors, with a fibrous capsule and lined by mucin-secreting epithelium associated with an underlying subepithelial OLS. The OLS showed strong positivity for alpha-smooth muscle actin (alpha-SMA) and vimentin and weak, focal positivity for desmin. Both estrogen receptors and progesterone receptors were expressed in the nuclei of OLS cells. In addition, 20 ovarian MCN and 13 normal ovaries were studied with particular attention to the stroma. The stroma of ovarian MCN was strongly immunopositive for alpha-SMA and vimentin and focally positive for desmin, whereas normal ovarian stroma was immunonegative for both alpha-SMA and desmin. The OLS of MCN mentioned here was similar to the septa of ovarian MCN but not to ovarian stroma. In conclusion, MCN in various organs should be lumped together as 'extra ovarian' MCN. The OLS was identified on the basis of myofibroblastic proliferation both in response to neoplastic development and dependent on hormones.     

Calcifications in ovary and endometrium and their neoplasms.

In this study, we investigated the role of hormones in the pathogenesis of calcifications in ovary and in endometrium and their neoplasms of the gynecologic tract and assessed the anatomic location and incidence of these calcifications. The study consists of three parts designed to investigate the pathogenesis, the location, and the incidence of calcifications in ovary and endometrium and their neoplasms. In the first part, 79 female guinea pigs were divided into 10 groups, and different hormones, given weekly for 12 months, were administered to the guinea pigs by group. A control group of 7 guinea pigs received sterile water. Calcifications developed in 5 of 7 guinea pigs treated with prolactin, 10 of 20 treated with human chorionic gonadotropin, 5 of 11 treated with estradiol, 3 of 7 treated with estrone, 1 of 6 treated with growth hormone, and 1 of 10 treated with testosterone; in 20 of the guinea pigs, the calcifications developed in the stroma of the endometrium, and in 5 guinea pigs, they developed in the ovary. The second part of the study consisted of an evaluation of the specific location of calcifications in 43 consecutive human surgical ovaries and endometria. Calcifications were seen only in the stroma in 100% of the ovarian serous adenofibroma specimens; in ovarian serous borderline neoplasms, the stroma contained 70 to 100% of the calcifications, and the epithelium had 0 to 30% of the calcifications. In ovarian serous carcinoma specimens, the calcifications were seen in the stroma in 50 to 60% of the cases, in the epithelium in 40% of the cases, and in areas of necrosis in 10% of the cases. The third part of the study was directed to determine the frequency of calcifications in ovarian lesions. We found that all cases of endosalpingiosis and ovarian low-grade serous carcinoma had calcifications, whereas 80% of the cases of serous borderline tumor had calcifications, and only 50% of the cases of ovarian high-grade serous carcinoma contained calcifications. The results of this study indicate that the majority of the calcifications in the ovary and the endometrium and their neoplasms are present in the stroma. This is most probably secondary to metabolic changes, which could be related to hormones and not caused by degenerative changes in epithelial cells.     

Biotin-rich, optically clear nuclei express estrogen receptor-beta: tumors with morules may develop under the influence of estrogen and aberrant beta-catenin expression

Recent studies have indicated that aberrant beta-catenin expression may be a common denominator for the morular formation of tumors from various anatomic sites. The evidence for the influence of female sex hormones in the formation of morules has been circumstantial, most previous studies having failed to demonstrate female sex hormone receptors in the morular cells. We investigated a possible role of estrogen receptor (ER)-beta in the occurrence of tumors that form morules with biotin-rich optically clear nuclei (BROCN)(BROCN-family tumors) and its possible relationship with aberrant nuclear/cytoplasmic (N/C) beta-catenin expression. We immunostained 14 BROCN-family tumors, including 6 low-grade adenocarcinomas of the fetal lung type, 3 papillary thyroid carcinomas of cribriform-morular variant (CMV), 2 ovarian endometrioid tumors, 2 colonic adenocarcinomas, and 1 gallbladder adenoma, as well as 4 cases of endometrial tissue with BROCN during gestation, for ERbeta, ERalpha, progesterone receptor (PgR), beta-catenin, and, on a subset of cases, c-Fos and MIB-1 as well. BROCN in all 18 cases expressed ERbeta but not ERalpha or PgR. In the BROCN-family tumors, the morular cells and budding glandular cells expressed ERbeta in the cytoplasm and BROCN, which overlapped with the N/C expression pattern of beta-catenin. Beta-catenin showed only membranous expression in the endometrial glands during gestation. In CMV and ovarian endometrioid tumors, nuclear expression of ERalpha and PgR were observed in association with N/C beta-catenin expression only in the glandular component. C-Fos was also constantly and strongly expressed in BROCN in all cases examined. The MIB-1 labeling index was low in the morular area, ranging from 1% to 3%. The present study indicates that N/C co-localization of ERbeta and beta-catenin is a feature common to the morules with BROCN that appear in the BROCN-family tumors from various anatomic sites. Whether the estrogen-signaling pathway and the Wnt-signaling pathway have crosstalk, cooperating in the development of the BROCN-family tumors, awaits further study.