Expression of adhesion molecules and Ki-67 in female adnexal tumor of probable Wolffian origin (FATWO): report of two cases and review of the literature.

Female adnexal tumor of probable Wolffian origin (FATWO) is a rare entity which is believed to originate from mesonephric (Wolffian) remnants on the basis of its location where the remnants are abundant. Its behavior is usually indolent, although some cases can recur or metastasize. The authors present the clinicopathological features of two cases of FATWO arising in the broad ligament, and focus on the expression of adhesion molecules and proliferative marker. Mesonephric duct remnants are also examined in an attempt to elucidate the histogenesis of FATWOs. The two FATWOs were well-circumscribed solid masses arising in the leaves of the broad ligament and histological examination revealed a mixture of cysts and tubules imparting a sieve-like pattern and mucin-negative eosinophilic secretion within these tubules. Immunohistochemically, the tumors showed the expression of cytokeratin 7 and 20, high-molecular-weight cytokeratin, and calretinin, which closely resembled that of the mesonephric duct remnants. Regarding CK 20, CD 10, EMA, S-100 protein, and vimentin their expression was in part not identical with previous studies. E-cadherin, alpha and beta-catenin were strongly expressed along the cell membrane of the tumor cells. The Ki-67 labeling index of FATWO was 0% and 3.2% in each case. The preservation of the E-cadherin-catenin complex and low Ki-67 labeling index could explain the indolent behavior and low malignant potential of this tumor.

Cytoplasmic expression of fibroblast growth factor receptor-4 in human pituitary adenomas: relation to tumor type, size, proliferation, and invasiveness.

The pathogenesis of pituitary adenomas remains unknown. A pituitary tumor-derived (ptd) isoform of fibroblast growth factor receptor-4 (ptd-FGFR4) has been implicated in the neoplastic process. To further understand the expression of FGFR4 in sporadic human pituitary adenomas, we studied 137 pituitary adenomas of various types (102 adenomas from Japanese patients and 35 adenomas from Canadian patients) and 10 nontumorous pituitaries using a polyclonal antiserum that recognizes the C terminus of FGFR4 and analyzed possible relationships among expression of FGFR4, patient nationality, tumor type, size, invasion, and the labeling index of the proliferation marker Ki-67 using the MIB-1 antibody. Cytoplasmic expression of FGFR4 protein was observed in 57.8% of Japanese cases and 62.8% of Canadian cases. FGFR4 reactivity was absent in all 10 normal adenohypophysial tissues examined. FGFR4 expression in pituitary adenomas was restricted mainly to the cytoplasm, a pattern similar to that seen in rat pituitary cells transfected with human ptd-FGFR4 but different from that of cells transfected with wild-type FGFR4, which displayed membrane localization of staining. Protein from primary human adenomas migrated as a 65-kDa species consistent with the predicted size of ptd-FGFR4. FGFR4 protein expression was frequently found in adenomas containing GH, ACTH, or FSH/LH and was also found in null cell adenomas, but reactivity was relatively rare in prolactin-containing adenomas in both Japanese and Canadian groups. The expression of FGFR4 protein was stronger in macroadenomas than in microadenomas (P = 0.02) and high levels of FGFR4 expression (moderate or greater density staining) were more frequently observed in macroadenomas than in microadenomas (P < 0.05). High levels of FGFR4 expression also correlated significantly with the proliferation marker Ki-67 (P = 0.002) and tended (but not significantly) to be found in invasive tumors. These data are consistent with a role for ptd-FGFR4 in pituitary tumorigenesis in a majority of human pituitary adenomas. Moreover, detection of FGFR4 cytoplasmic staining may provide an ancillary diagnostic tool in the diagnosis of pituitary adenoma, particularly in equivocal cases.

Role of E-cadherin, alpha-, beta-, and gamma-catenins, and p120 (cell adhesion molecules) in prolactinoma behavior.

E-cadherin/catenin complex regulates cellular adhesion and motility and is believed to function as an invasion suppressor system. In a number of cancers, abnormal and reduced expression of E-cadherin/catenin complex is associated with tumor invasion and metastasis. Prolactinomas show frequent invasion on the surrounding structures, despite their histologically benign nature. Furthermore, gender-based differences in endocrine and surgical findings are found in patients with prolactinoma. To understand biological factors governing prolactinoma behavior, this study analyzed the expression of E-cadherin; alpha-, beta-, and gamma-catenins; p120; and cell proliferation marker MIB-1 labeling index in 13 invasive tumors (9 in men, 4 in women), 26 noninvasive tumors (4 in men, 22 in women), and 8 normal anterior pituitaries by immunohistochemistry. Immunostaining of E-cadherin; alpha-, beta-, and gamma-catenins; and p120 showed a membranous pattern of reactivity and generally stronger in normal pituitaries than in prolactinomas. Expression of E-cadherin and beta-catenin was significantly lower in invasive than in noninvasive prolactinomas (P <.002 and P <.005, respectively), and reduced expression of E-cadherin and beta-catenin was more frequent in invasive than in noninvasive prolactinomas (P <.001 and P <.05, respectively); in contrast, gamma-catenin expression showed higher in invasive than in noninvasive prolactinomas (P <.05). Expression of E-cadherin was significantly lower in macroprolactinomas than in microprolactinomas (P <.01), and decreased expression of E-cadherin and beta-catenin predicted high MIB-1 expression (P <.05). Moreover, the expression of E-cadherin and beta-catenin was significantly lower in macroprolactinomas in men than in those in women (P <.01 and P <.02, respectively). No statistical correlations were observed between expression of alpha-catenin, p120, and clinicopathologic features. In conclusion, the reduction of E-cadherin and beta-catenin expression was related to invasiveness and proliferative status of prolactinomas and correlated with the more aggressive behavior of prolactinomas in men compared with in women.

Expression of E-cadherin, b-catenin, and Ki-67 in goblet cell carcinoids of the appendix: an immunohistochemical study with clinical correlation.

Goblet cell carcinoid (GCC) of the appendix is a rare entity, of which both the histogenesis and biologic behavior remain controversial, and prognostic tools and therapeutic strategies for this unusual tumor have yet to be defined. The aim of this study was to analyze expression of E-cadherin and b-catenin in GCCs of the appendix with long-term follow-up data as related to the expression of Ki-67 proliferation marker to provide a rationale for treatment guidelines. We analyzed the expression of E-cadherin, b-catenin, and Ki-67 in 11 GCCs of the appendix and control groups of typical carcinoids of the large intestine (n = 29), well to moderately differentiated adenocarcinomas of the colon (n = 10), poorly differentiated adenocarcinomas of the colon (n = 12), and normal appendiceal tissues (n = 10). There was no significant difference between the GCCs and normal appendiceal tissues regarding the expression of E-cadherin or b-catenin (p = 0.297 and 0.103, respectively). The percentage of positive GCC cells ranged between 0.52 and 10.35% (4.27 +/- 0.80), and only one case had a score >10%. Metastatic tumor spread and death were found in high MIB-1 labeling index (LI) cases of GCC (>3%). Our findings suggest that the behavior of the majority of GCCs might be indolent and different from adenocarcinomas because of the preserved expression of E-cadherin and b-catenin and relatively low MIB-1 LI. However, some of these tumors act aggressively and MIB-1 LI might be a good parameter to determine the therapeutic procedure.

Alterations of E-cadherin, alpha-catenin and beta-catenin expression in neuroendocrine tumors of the gastrointestinal tract.

Neuroendocrine tumors (NETs) of the gastrointestinal tract comprise a heterogeneous group of neoplasms arising from the diffuse neuroendocrine system. These tumors strongly differ from each other on the basis of different pathogenetic, clinical, functional, histological, and prognostic patterns. Previous studies have shown that abnormal and reduced expression of the E-cadherin/catenin complex in several human cancers is associated with tumor dedifferentiation, advanced clinical stages, and poor survival rate. We assessed correlations between the expression of E-cadherin and catenins, Ki-67, and the following clinicopathological factors: age, embryological site of origin, size, histological growth pattern, the depth of penetration into the intestinal wall, and the presence of metastasis. In this study, reduction of membranous E-cadherin expression to a variable degree was detected in more than two-thirds (42 of 51) of gastrointestinal NETs (19 foregut, 8 midgut, and 24 hindgut) belonging to the complete neuroendocrine neoplastic spectrum [18 well-differentiated NETs, 22 well-differentiated neuroendocrine carcinomas (NECs), and 11 poorly differentiated NECs]. The reduction of E-cadherin expression was concomitant with the reduction of alpha-catenin (44 of 51) and beta-catenin (35 of 51) expression. Our immunohistochemical analysis demonstrated significant differences of percentage of membranous positive cells of E-cadherin, alpha-catenin, or beta-catenin between normal tissues and well-differentiated NETs (P=0.0038, P=0.004, and P=0.0329, respectively), well-differentiated NECs (P<0.001, P<0.001, and P<0.001, respectively) and poorly differentiated NECs (P=0.0002, P<0.0002, and P=0.0002, respectively). Among the gastrointestinal NETs, there were significantly more positive cells of E-cadherin, alpha-catenin, or beta-catenin in well-differentiated NETs than well-differentiated NECs (P=0.0006, P=0.0065, and P=0.0001, respectively) or poorly differentiated NECs (P=0.0053, P=0.0041, and P<0.001, respectively). MIB-1 labeling index generally showed a low proliferative activity in well-differentiated NETs (0.49+/-0.37) and well-differentiated NECs (0.662+/-0.66). A high proliferation rate was observed in poorly differentiated NECs (41.518+/-16.59). MIB-1 labeling index was significantly higher in poorly differentiated NECs than well-differentiated NETs and well-differentiated NECs (P<0.0001 and P<0.0001, respectively). E-cadherin, alpha-catenin, and beta-catenin expression were correlated significantly with transmural tumor invasion (P<0.0001, P=0.0001, and P<0.0001, respectively) and with size (P=0.0013, P=0.0001, and P<0.0001, respectively). These results indicate that the alteration in the E-cadherin/catenin expression may be involved in the growth and progression of gastrointestinal NETs.

Morules with optically clear nuclei in ovarian borderline endometrioid tumor.

Optically clear nuclei (OCN) have been observed in morules of some neoplasms and in some conditions unrelated to the development of the morules. We first report a case of ovarian borderline endometrioid tumor (BET) showing the morules associated with OCN. The patient was a 47-year-old premenopausal woman with a left ovarian cystic tumor, atypical endometrial hyperplasia, and elevated serum levels of FSH, LH, estradiol, and CA 125. The resected ovarian tumor measured 6 cm in diameter, and showed a papillary growth. Histologically, the ovarian tumor was consistent with BET, and the morules with OCN were scattered. Immunohistochemically, OCN were proven to be rich in biotin. An aberrant nuclear expression of beta-catenin was observed in both the tumor cells and the morular cells. Our case may suggest the possibility that the appearance of OCN with or without morules in ovarian tumors is related to endometrioid differentiation of the tumor cells, and should be recognized as a diagnostic clue of ovarian endometrioid tumors. Although female sex hormones have been reported to play a role in the occurrence of OCN, the participation of beta-catenin mutation has also been suggested.