Malignant Brenner tumor of the ovary with transformation to trabecular carcinoid: an immunocytochemical and electron microscopic study.

Ovarian Brenner tumors are typically of surface epithelial-stromal origin; however, cases associated with mature cystic teratoma and/or struma ovarii possibly have a teratomatous derivation. Although argyrophil cells have been described in ovarian Brenner tumors and in urinary bladder epithelium, we are not aware of any previous reports of carcinoid arising from a malignant Brenner tumor of the ovary. In this study, we describe an 85-year-old woman who had a low-grade malignant Brenner tumor with progressive proliferation of neuroendocrine cells and transformation to trabecular carcinoid as demonstrated by immunocytochemistry and electron microscopy.

On the site of origin of epithelial tumors of the ovary.

Ovaries removed at 1,050 autopsies (accidental deaths) and from 300 patients with various benign gynaecological diseases were studied in search of the incipient benign epithelial tumors. One percent of the ovaries contained incipient mucinous tumors, 1.1%--Brenner tumors, 0.5%--endometrioid tumors. The exact percentage of the serous tumors was difficult to establish because of the absence of morphological criteria that distinguish these tumors from tumor-like conditions (inclusion cysts). The mucinous and Brenner tumors, as well as some serous tumors were located deep in the medullary or hilar regions of the ovary and were not connected to the covering of the ovary. The theory of incessant ovulation that links ovulatory damage of the ovarian surface with the initiation of neoplastic growth does not explain the genesis of all epithelial tumors. It is more likely that the latter two types arise in other parts of the female gonad. The process of morphogenesis of epithelial benign tumors is closely related to stromal alterations, specific for each histogenetic entity.

Brenner tumor of the ovary: a comparative immunohistochemical and ultrastructural study with transitional cell carcinoma of the bladder.

Because of a fancied light microscopic resemblance to transitional epithelium (urothelium), Brenner tumor (BT) of the ovary is commonly described as a transitional cell neoplasm. An inability to detect a great deal of similarity between the two at the ultrastructural level prompted this electron microscopic study comparing 3 benign Brenner tumors with normal urothelium and 6 transitional cell carcinomas (TCC) of varying histologic grade from the urinary bladder. To complement the ultrastructural observations, the immunophenotype of 8 benign BTs was evaluated together with that of 12 TCCs of the bladder using antibodies to thrombomodulin (TM), cytokeratin 20, cytokeratin 7, and carcinoembryonic antigen (CEA), all of which have been shown to react with TCCs of urothelial origin. At the ultrastructural level, there was only limited evidence of a morphologic likeness between the epithelial cells of BTs and those of the benign or neoplastic urothelium. The immunophenotype of the two tumors also differed significantly in that there was no reactivity for TM or cytokeratin 20 in the BTs, while these markers were expressed in the TCCs. Both BTs and TCCs were positive for cytokeratin 7 and may express CEA.

Fine needle aspiration cytology of a subcutaneous metastasis of a malignant Brenner tumor of the ovary. A case report.

The fine needle aspiration cytologic findings of a subcutaneous metastasis from a malignant Brenner tumor of the ovary are described. Polygonal cells in clusters and single cells with fine cytoplasmic elongations, moderately pleomorphic nuclei having granular chromatin and multinucleate cells, occasional but prominent grooving of nuclei and many mitotic figures were the salient cytologic features. The cytohistologic correlation was good. The rare metastatic site of this unusual ovarian neoplasm makes this an interesting case and the first of its kind to the best of our knowledge.

Case report of a malignant Brenner tumor with hyperestrogenism.

A rare malignant Brenner tumor of the ovary presenting with hyperestrogenism in a 79 year old woman was examined immunohistochemically and by light and electron microscopy. High pre-operative serum and urinary estrogen concentrations, low serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, and histologically confirmed atypical endometrial hyperplasia suggested the presence of hyperestrogenism. The reduction in serum and urinary estrogen and the increase in serum LH and FSH concentrations after tumor removal confirmed that the tumor was synthesizing estrogen. Histologically, the malignant element was predominantly a squamous cell carcinoma. Transitional cell carcinoma was partially found on the cyst wall. There was a spectrum of morphologic changes between benign and malignant elements with an intermediate area with a proliferating Brenner tumor. Immunohistochemically, only the carcinoembryonic antigen was positive exclusively on the malignant element as well as in the microcyst in the benign epithelial cord, whereas all of the markers for germ cell tumors were negative. The ultrastructural features of the stromal cells were of two types: fibroblasts and steroid-producing cells. The latter type of cells might correspond morphologically to estrogen-producing cells. The present case is the fourth report showing a malignant Brenner tumor combined with apparent hyperestrogenism.

Ovarian Brenner tumors and transitional cell carcinoma: recent developments.

Brenner tumor variants--such as metaplastic, proliferating, and low-malignant-potential (three categories recently designated as intermediate Brenner tumors)--and malignant Brenner tumors are unusual tumors presenting problems in classification. DNA ploidy and S-phase reflect the intermediate status of metaplastic, proliferating, and low-malignant-potential Brenner tumors. The category of "transitional cell carcinoma of the ovary" has been proposed for those primary ovarian carcinomas in which definite urothelial features are present, but no benign, metaplastic, and/or proliferating Brenner tumor is identified. Two subtypes have been described, the papillary and the malignant Brenner-like types. These tumors are more aggressive than malignant Brenner tumors, but they appear to respond better to chemotherapy than other types of ovarian epithelial cancer.

[Ultrastructure of malignant Brenner tumor].

Electron microscopic study of five malignant Brenner tumors showed that the histologic features resembled nonkeratinized squamous carcinoma of uterine cervix. Intracytoplasmic glands and cysts, abundant glycogen, numerous desmosome, cilia and desmosome-tonofilament complex were the ultrastructural features of malignant Brenner tumor. Among them, cilium is characteristic for ovarian surface epithelium and Mullerian epithelium, rather than for uro-epithelium. The desmosome-tonofilament complex is the specific structure for squamous cell, also not for uro-epithelium. So the appearance of cilium in malignant Brenner tumor indicates that the tumor is derived from Mullerian epithelium, and the presence of desmosome-tonofilament complex evidences that the tumor cells possess the characteristics of squamous cells. This study further proves that malignant Brenner tumor arises from Mullerian epithelium.

Ultrastructure of malignant Brenner tumor of the ovary.

Six malignant Brenner tumors of the ovary were studied electronmicroscopically. The histologic features of the tumors resemble to those of nonkeratinized squamous cell carcinoma of the uterine cervix. The ultrastructural features of malignant Brenner tumor included intracytoplasmic glands and cysts, presence of cilia, abundant glycogen, numerous desmosome-tonofilament complex, of which the cilium is most characteristic in the ovarian surface epithelium or Mullerian epithelium, but not in uroepithelium. Desmosome-tonofilament complex, the ultrastructure specific for the squamous epithelium, was not seen in the uroepithelium. We conclude that the appearance of cilium in malignant Brenner tumor indicates that the tumor is derived from the Mullerian epithelium, and that the presence of desmosome-tonofilament complex evidences that the tumor cells have differentiated into squamous epithelium. Our findings have proved that the malignant Brenner tumor arises from the Mullerian epithelium and recapitulates the vaginocervical epithelium.

Brenner tumor of the ovary: a correlative histologic, histochemical, immunohistochemical, and ultrastructural investigation.

The histologic, histochemical, immunohistochemical, and ultrastructural features of Brenner tumor (BT) were studied. BT was compared with transitional bladder cells, and close similarities between the two tissues were identified. Abundant glycogen in all cellular layers, an alcianophilic/sialomucinic surface mucous coat, and argyrophilic cells characterized both BT and bladder epithelium. Immunohistochemically, chromogranin and neuron-specific enolase reactivity was observed in all cases examined. An additional relevant finding was the presence of serotonin-storing cells in both BT and urothelium. Moreover, carcinoembryonic antigen, epithelial membrane antigen, and keratin reaction were found in BT and urothelium, indicating an additional antigenic similarity. Additionally, malignant Brenner tumor was ultrastructurally found to share many common features with the bladder tissue. The distinct histochemical, ultrastructural, and antigenic pattern of BT, primarily of the transitional type, is emphasized.

The cytokeratin profiles of ovarian common "epithelial" tumors.

An improved immunohistochemical determination of the cytokeratin profiles of epithelia and their neoplasms is possible using monoclonal antibodies that will either identify all 19 cytokeratins (AE1/3) or delineate specific subsets (35 beta H11, 34 beta E12, 34 beta B4 and Cam 5.2). Ovarian common "epithelial" tumors (CET) contain cytokeratin filaments. To determine the nature and differences in the cytokeratin profiles of ovarian CET, eight benign Brenner tumors, four serous cystadenofibromas, 28 mucinous tumors, 27 serous tumors and six endometrioid, five clear cell and five undifferentiated carcinomas, as well as nine normal ovaries were immunostained with the above five antibodies. AE1/3 staining was predominant, while Cam 5.2 and 35 beta H11 displayed the most frequent staining thereafter. Statistically significant staining differences were found between a number of tumor groups using the antibodies 35 beta H11, 34 beta E12 and Cam 5.2. In this study, all ovarian CET, except the benign Brenner tumors, displayed a predominantly low molecular weight cytokeratin profile. The same profile in the normal surface epithelium lends credence to the belief that these tumors are derived from this epithelium. A significant staining difference between some of the tumor types using some of the antibodies suggests a possible ancillary, diagnostic role of cytokeratin profiling in situations where exact tumor typing is difficult.

Malignant Brenner tumor with peritoneal metastasis.

A case of malignant Brenner tumor with peritoneal metastasis in a 67-year-old woman was reported. The multilocular cystic tumor of right ovary was 420 g in weight, and their cystic walls were covered with multilayered tumor cells showing papillary pattern very frequently. The tumor was histologically transitional cell carcinoma with occasional glandular structures but no squamous differentiation corresponding to grade 2 or 3 urinary bladder carcinoma. The pattern of benign Brenner tumor was not identified, but there was some area of proliferating Brenner tumor. Immunohistochemically, carcinoembryonic antigen was detected in several tumor cells, especially in the intercellular spaces among them, and cytokeratin was detected only in some tumor cells. Ultrastructurally, the malignant Brenner tumor shared many common features with the benign one and also bladder tumor. Intercellular spaces with microvilli were frequently found and thought to be important for diagnosis. The morphologic criteria of this rare tumor are discussed.

The ultrastructure of selected gynecologic neoplasms.

Several articles have been published recently that discuss the role of electron microscopy in the diagnosis and study of gynecologic neoplasms. It becomes apparent from those works and the review just presented that, although an ultrastructural study is not necessary for reaching a diagnosis of many of these tumors, it may be necessary or supportive in identifying the more poorly differentiated ones. Furthermore, electron microscopy is valuable in providing evidence for the histogenesis of some of these neoplasms. Unfortunately for the pathologist, a certain level of morphologic differentiation (and an absence of metaplasia) in a cell is usually necessary for these goals to be achieved. For example, an adenomatoid tumor (see the article by Dr. Srigley, Mr. Toth, and Mr. Edwards in this issue) of the fallopian tube can readily be accepted as being composed of mesothelial cells, because both the neoplastic cells and normal mesothelial cells have the same highly differentiated features of long, slender microvilli, prominent intercellular junctions, and many microfilaments. On the other hand, there is very little resemblance between the granulosa cells of a granulosa-cell tumor and mature mesothelial cells. Thus, if one of the theories of histogenesis of granulosa cells were correct--namely, that they are derived ultimately from mesothelial lining--the ultrastructural evidence would rest on recognizing a similarity between the two types of cells at an earlier stage of differentiation. The neoplastic granulosa cell has differentiated along a separate, specialized line in which the ultrastructural resemblance to the parent cell is partly, if not completely, lost. Another example of the type of information that electron microscopy can provide is in relation to the common epithelial tumors. There is good evidence that the serous tumors in this group arise from mesothelium, although ultrastructurally their differentiation has veered from a mesothelial direction to one in which the cells have a complement of organelles related to secretory activity. Paradoxically, the mucinous cystic tumors, which have been classified traditionally as tumors of surface epithelial origin, are now thought to be of germ-cell origin in some cases, as examples of monophyletic teratomas. The ultrastructural evidence for this conclusion rests on the presence of anchoring filaments in the microvilli of the neoplastic cells, similar to those of normal intestinal epithelium, and on an admixture of various types of gastrointestinal cells, including those that contain dense-core granules (argentaffin cells).(ABSTRACT TRUNCATED AT 400 WORDS)

Endocrine cells in the prostate gland, urothelium and Brenner tumors. Immunohistological and ultrastructural studies.

Endocrine cells are a normal constituent of the prostate gland, prostatic urethra and urinary bladder mucosa. Positive results using immunohistochemical technics were obtained only with antiserotonin antibodies. In normal tissues, there was a close similarity between the distribution of argyrophilic cells (Grimelius) and serotonin-storing cells. Some striking features were the patchy distribution of endocrine cells, the presence of slender cytoplasmic processes occasionally reaching the luminal surface and the paucity of specialized cells in bladder mucosa. It is unlikely that endocrine cells participate in conventional neoplasms of prostate and bladder. Exceptions are lobular hyperplasia, certain adeno-carcinomas of prostate and inverted papilloma of bladder. An ultrastructural study permitted the distinction of two types of endocrine cells characterized by a different morphology of their granules. Another relevant finding was the presence of serotonin-storing cells in Brenner tumors. The latter observation emphasizes the close similarity between this neoplastic epithelium and urothelium. This implies that endocrine cells may be of mesodermal derivation.

The Brenner tumor: a report of multiple tumors.

A case of multiple Brenner tumors was studied with light and electron microscopy. Among the epithelial elements, argyrophil cells were found in addition to the typical "transitional" and mucus-secreting cells. In some areas, it was not possible to distinguish epithelial from tumor stromal cells. By electron microscopy, dense-core secretory granules were identified, as well as previously undescribed cytoplasmic tubular bodies. Some epithelial cells were intimately associated with reticulin and collagen. Some stromal cells had desmosomes, dense bodies, incomplete basal lamina, and, occasionally, multivesicular bodies, which suggests epithelial differentiation. Previous authors have documented morphologic similarities and continuity between Brenner-tumor epithelium and ovarian cells of almost every type. The inference is that there are multiple possible sources for the Brenner tumor. Classification must therefore be based on realize differentiation rather than presumed cell of origin.

Bilateral malignant Brenner tumor: report of a case with ultrastructural study.

An unusual case of bilateral malignant Brenner tumor with liver and omental metastases is reported. The tumor was histologically a transitional cell carcinoma comparable to a grade III bladder carcinoma. A benign component was not identified, but there were a few nests of malignant epithelial cells distributed in a dense stroma, a pattern identical to that seen in a benign Brenner tumor. Whether this represents malignant change in a previously benign focus or a well differentiated part of a de novo carcinoma is unclear. Nevertheless it is suggested that the current histologic criteria for malignant Brenner tumor be modified to exclude the requirement of an intimately associated benign Brenner tumor. Ultrastructurally the malignant Brenner tumor has many features of the benign Brenner tumor. Some features, notably the basal lamina, micropinocytotic vesicles, nd intracytoplasmic microfibrils, are herein described for the first time in a malignant Brenner tumor.

Histogenesis of Brenner tumors, I: histology and ultrastructure.

The histology of 36 benign and four proliferative Brenner tumors is reviewed, and the ultrastructural features of benign Brenner tumors are described. Evidence is presented for the origin of these tumors from celomic inclusion cysts through transitional metaplasia of the cyst lining and progressive growth of branching cords of transitional epithelium. Ovarian lesions associated with the Brenner tumor are described, particularly those containing mucinous epithelia, and their significance is discussed.

Lysosomes in Brenner's tumor simulating secretory argentaffin granules.

Argentaffin cells were searched for in the epithelial nests of 30 Brenner's tumors, with the Fontana-Masson stain for the screening. Although these cells were found in five tumors, ultrastructural examination of one case, in which the argentaffin cells were multiple, identified the cytoplasmic granules as lysosomes and not as amine precursor uptake and decarboxylation (APUD)-type granules. We conclude that the epithelial component of Brenner's tumors consists of urothelium only and does not include the cells containing argentaffin APUD-type granules.

Mixed Brenner and adenomatoid tumor of the testis: an ultrastructural study and histogenetic considerations.

A previously unreported association of Brenner and adenomatoid tumor found in the tunica vaginalis testis is presented. Many ultrastructural features found in mesothelial cells such as intercellular spaces, deeply indented nuclei, tonofilaments and tight desmosomes, were also shared by cells present in both neoplastic patterns. The previous histogenetic origins ascribed to testicular Brenner tumors are discussed and the evidence for their origin in the mesothelium considered.