Shuichi Kurihara

Endometrial stromal sarcomas and related high-grade sarcomas : immunohistochemical and molecular genetic study of 31 cases

Classification and terminology of non–low-grade endometrial sarcomas, which show significant nuclear atypia, have been controversial. Currently, these tumors seem to be classified all together into “undifferentiated endometrial sarcoma (UES).” However, it remains unclear whether these non–low-grade sarcomas are universally “undifferentiated.” We divided these sarcomas morphologically into undifferentiated endometrial sarcoma with nuclear uniformity (UES-U) and undifferentiated endometrial sarcoma with nuclear pleomorphism (UES-P), and compared their molecular genetic and immunohistochemical profiles. Eighteen low-grade endometrial stromal sarcomas (ESS-LG), 7 UES-U, and 6 UES-P were examined. All the patients with ESS-LG were still alive, either with or without disease, whereas 4 of the 5 patients with advanced stage UES-U and all 3 of the patients with advanced stage UES-P had died of the disease. JAZF1-JJAZ1 fusion transcript was detected in 6 (50%) out of 12 ESS-LG and in 1 (33%) of 3 UES-U, whereas it was not detected in any of the cases of UES-P. ESS-LG and UES-U frequently showed positive immunoreaction for estrogen receptor (ESS-LG: 94%, UES-U: 57%) and progesterone receptor (ESS-LG: 94%, UES-U: 57%), whereas all the UES-P were negative for these receptors. Nuclear β-catenin expression was more frequently recognized in ESS-LG (47%) and UES-U (85%), compared with UES-P (33%). Moreover, nuclear accumulation of p53 and TP53 gene missense mutations were limited to 3 UES-P cases. Our data suggest that UES-U shares some molecular genetic and immunohistochemical characteristics with ESS-LG, but UES-P considerably differs from ESS-LG.

Coincident expression of β -catenin and cyclin D1 in endometrial stromal tumors and related high-grade sarcomas

Aberrant activation of the Wnt signaling pathway has been implicated in tumorigenesis of a wide range of tumors, including colorectal cancer. Regarding endometrial stromal tumors and related high-grade sarcomas, there have been some reports regarding nuclear accumulation of β-catenin. To clarify the function of the aberrant Wnt signaling pathway in these tumors, we searched for mutations of the CTNNB1 (β-catenin) gene and APC gene by PCR direct sequencing and analyzed the methylation status of SFRP genes. We also examined overexpression of cyclin D1 and MMP-7, which are direct target genes of β-catenin. Eight endometrial stromal nodules, 16 low-grade endometrial stromal sarcomas, and 13 undifferentiated endometrial sarcomas were examined. PCR and direct sequencing revealed no mutation of the β-catenin gene or the APC gene. Concerning the promoter methylation status of SFRP genes, methylation-specific PCR revealed no significant difference between the group with nuclear β-catenin expression and that without nuclear β-catenin expression. Immunohistochemistry revealed overexpression of cyclin D1 in 2 out of 8 endometrial stromal nodules, 1 out of 17 low-grade endometrial stromal sarcomas, and 6 out of 13 undifferentiated endometrial sarcomas, and these 6 undifferentiated endometrial sarcomas simultaneously expressed nuclear β-catenin. Interestingly, all six undifferentiated endometrial sarcoma cases with cyclin D1 overexpression histologically featured rather uniform nuclei. In contrast, the six cases of undifferentiated endometrial sarcoma with highly pleomorphic nuclei were all negative for cyclin D1. In conclusion, among endometrial stromal tumors and related sarcomas, undifferentiated endometrial sarcomas featuring uniform nuclei were characterized by frequent coincident expression of β-catenin and cyclin D1. This finding raises the possibility that cyclin D1 is upregulated by β-catenin in these high-grade sarcomas previously called high-grade endometrial stromal sarcoma.

Immunohistochemical characterization of mullerian mucinous borderline tumors: possible histogenetic link with serous borderline tumors and low-grade endometrioid tumors

Mullerian mucinous borderline tumor and gastrointestinal mucinous borderline tumor are considered mucinous tumor subtypes. However, it has been reported that mullerian mucinous borderline tumor shares many clinicopathologic features with serous borderline tumor. Furthermore, some investigators have explained the histogenesis of mullerian mucinous borderline tumor by metaplastic and hyperplastic transformation of endometriosis (Fukunaga M, Ushigome S. Epithelial metaplastic changes in ovarian endometriosis. Mod Pathol. 1998;11:784-788). The purpose of this study is to substantiate the concept that mullerian mucinous borderline tumor is histogenetically closer to serous borderline tumor or low-grade endometrioid tumor than to gastrointestinal mucinous borderline tumor by directly comparing their immunophenotype. A total of 80 cases of low-grade ovarian tumors composed of 20 mullerian mucinous borderline tumors, 20 gastrointestinal mucinous borderline tumors, 20 serous borderline tumors, and 20 low-grade endometrioid tumors were immunohistochemically evaluated for the expression of estrogen receptor, progesterone receptor, vimentin, WT-1, beta-catenin, and PTEN. Almost all cases of mullerian mucinous borderline tumor, serous borderline tumor, and low-grade endometrioid tumor showed diffuse and strong nuclear expression of estrogen receptor and progesterone receptor. In addition, about half of the mullerian mucinous borderline tumor, serous borderline tumor, and low-grade endometrioid tumor cases showed focal but strong vimentin cytoplasmic expression. In contrast, gastrointestinal mucinous borderline tumor showed no expression of estrogen receptor, progesterone receptor, or vimentin, except for 1 case in which estrogen receptor expression was very focally and weakly observed. WT-1 nuclear expression was observed in most serous borderline tumors and only 15% of low-grade endometrioid tumor, but mullerian and gastrointestinal mucinous borderline tumor cases were completely negative. beta-Catenin nuclear expression was significantly more frequent in low-grade endometrioid tumor than in mullerian mucinous borderline tumor, gastrointestinal mucinous borderline tumor, or serous borderline tumor. PTEN expression was significantly lower in low-grade endometrioid tumor than in mullerian mucinous borderline tumor, gastrointestinal mucinous borderline tumor, and serous borderline tumor. Multiple comparisons of quantitative immunoreactivities of estrogen receptor, progesterone receptor, and vimentin revealed that the gastrointestinal mucinous borderline tumor expression profiles were significantly different from those of mullerian mucinous borderline tumors, serous borderline tumors, and low-grade endometrioid tumors. The immunohistochemical expression profiles of estrogen receptor, progesterone receptor, and vimentin substantiate the concept that the histogenesis of mullerian mucinous borderline tumor is closer to those of serous borderline tumor and low-grade endometrioid tumor than to that of gastrointestinal mucinous borderline tumor. However, aberrant beta-catenin and PTEN protein expression, both of which are known to contribute to the tumorigenesis of low-grade endometrioid tumor, appeared to be less important for the tumorigenesis of mullerian mucinous borderline tumor.

Squamous cell carcinoma arising in mature cystic teratoma of the ovary: an immunohistochemical analysis of its tumorigenesis.

Aims:  Squamous cell carcinoma (SCC) is the most common form of malignant transformation in mature cystic teratoma (MCT) of the ovary. Some investigators have suggested the possibility of origin from columnar epithelium. The aim of this study was to analyse such tumours immunohistochemically to elucidate their histogenesis.

Nuclear localization of E-cadherin but not beta-catenin in human ovarian granulosa cell tumours and normal ovarian follicles and ovarian stroma

Ohishi Y, Oda Y, Kurihara S, Kaku T, Kobayashi H, Wake N & Tsuneyoshi M
(2011) Histopathology58, 423–432
Nuclear localization of E‐cadherin but not beta‐catenin in human ovarian granulosa cell tumours and normal ovarian follicles and ovarian stroma

Inhibin‐producing ovarian granulosa cell tumor as a cause of secondary amenorrhea: Case report and review of the literature

We report the case of 31‐year‐old patient with an inhibin B‐secreting granulosa cell tumor of the left ovary who presented with secondary amenorrhea. Preoperative serum hormonal levels were as follows: follicle‐stimulating hormone (FSH) 0.3 mIU/mL, luteinizing hormone (LH) 9.81 mIU/mL, estradiol 142.0 pg/mL and inhibin B 2429 pg/mL. Gonadotropin‐releasing hormone (GnRH) test revealed no FSH response and a normal LH response. After removal of the tumor, the levels of FSH and inhibin B returned to within the normal range, and regular menses resumed 27 days postoperatively. In premenopausal women, secondary amenorrhea may be the initial manifestation of granulosa cell tumor. A low FSH level coupled with normal levels of E2 and LH, the inhibition of the FSH response to GnRH and an elevated inhibin level suggest the presence of an inhibin‐secreting ovarian tumor and also rule out the possibility of isolated FSH deficiency.

Malignant transformation of mature cystic teratoma to squamous cell carcinoma involves altered expression of p53- and p16/Rb-dependent cell cycle regulator proteins

Ovarian mature cystic teratomas (MCT) uncommonly undergo malignant transformation to squamous cell carcinoma (SCC). While alterations in the p53 tumor suppressor gene and protein have been shown, few studies have analyzed other molecular changes leading to this malignant conversion. The purpose of the present study was to investigate 21 samples of SCC arising in MCT for altered expression in known p53‐ and p16/Rb‐dependent cell cycle regulatory proteins, and the association between their expression and cellular proliferation and histological features. Overexpression of the p53 protein was observed in 14 SCC (67%), while four (19%) had point mutations in the p53 gene. Reduced expression of the p16 protein was observed in 18 SCC (86%), while p16 gene alterations (hypermethylation (29%) and point mutation (33%)) were found in 11 (52%). Furthermore, a statistically significant correlation was observed between p53 and Rb overexpression (P = 0.0010), and the overexpression of both p53 and Rb was respectively significantly correlated with increased cellular proliferation. The results indicate that alterations in both the p53 and p16‐Rb pathways are associated with SCC arising in MCT.

E-cadherin nuclear staining is useful for the diagnosis of ovarian adult granulosa cell tumor

We recently have demonstrated nuclear localization of E-cadherin in ovarian adult granulosa cell tumors (Histopathology 2011;58:423). The purpose of the present study is to investigate the diagnostic utility of E-cadherin nuclear staining for the differential diagnosis between ovarian adult granulosa cell tumor and its morphological mimics. Tissue samples taken from 81 ovarian tumors and 20 extraovarian tumors were immunohistochemically stained using monoclonal anti-E-cadherin antibody recognizing cytoplasmic domain (clone 36 supplied by BD Biosciences, San Jose, CA). The ovarian tumors consisted of 30 adult granulosa cell tumors, 3 Sertoli-stromal cell tumors, 14 fibrothecomas, 5 carcinoid tumors, 1 large cell neuroendocrine carcinoma, 18 endometrioid adenocarcinomas, and 10 poorly differentiated serous adenocarcinomas. Extraovarian tumors consisted of 16 uterine endometrial stromal neoplasms and 4 pulmonary small cell carcinomas. Only tumor cells with nuclear staining were considered positive in this study. Ninety percent of adult granulosa cell tumors, 67% of Sertoli-stromal cell tumors, 64% of fibrothecomas, 75% of endometrial stromal neoplasms, 75% of small cell carcinomas, and the one large cell neuroendocrine carcinoma showed E-cadherin nuclear expression, whereas all the ovarian carcinoid tumors, endometrioid adenocarcinomas, and poorly differentiated serous adenocarcinomas were negative. E-cadherin nuclear staining is useful in distinguishing between adult granulosa cell tumors and ovarian adenocarcinomas or carcinoid tumors. However, it is of limited use for distinguishing between adult granulosa cell tumors and endometrial stromal neoplasms or small cell carcinomas. E-cadherin should be included in the immunohistochemical panel for an accurate diagnosis of ovarian adult granulosa cell tumors.

Low-grade dedifferentiated liposarcoma of the neck: magnetic resonance imaging and pathological correlation

Dedifferentiated liposarcoma is defi ned as a malignant adipocytic neoplasm showing a transition from welldifferentiated liposarcoma to nonlipogenic sarcoma. In most cases the nonlipogenic component presents with high-grade morphology, although the concept of lowgrade dedifferentiation has increasingly been recognized in recent years. Radiologically, especially with magnetic resonance imaging (MRI), a typical presentation of dedifferentiated liposarcoma is the coexistence of fatty and nonfatty components, so a radiological diagnosis of ordinary (high-grade) dedifferentiated liposarcoma is not diffi cult in most cases. On the other hand, the radiological fi ndings of low-grade dedifferentiated cases have not been investigated at all. Dedifferentiated component of (high-grade) dedifferentiated liposarcoma usually presents low intensity on T1weighted images and heterogeneous high intensity on T2-weighted images. However, we experienced a case where the dedifferentiated component showed low to intermediate intensity on both T1and T2-weighted MR images. In this report, we present a case of lowgrade dedifferentiated liposarcoma of the neck with emphasis on the correlation between MRI and pathological fi ndings. We also discuss the importance of recognizing the radiological fi ndings of such a case.

Unusual sonographic appearance of synovial sarcoma of the anterior abdominal wall

We report a case of synovial sarcoma in a 58‐year‐old woman arising from the anterior abdominal wall. Sonography demonstrated a large mass with an unusual complex “honeycomb” echotexture. Doppler imaging displayed increased vascularity in the solid parts of the tumor.