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Some skin adnexal tumors display both epithelial and myoepithelial cell populations and can be broadly categorized as biphasic tumors. These include apocrine hidrocystoma, mixed tumor, adenomyoepithelioma (AME), and adenoid cystic carcinoma (ACC). Myoepithelioma is the myoepithelial cell-predominant type in this category. Cutaneous AME is exceedingly rare and usually has a benign prognosis, but it is considered to have the potential for local recurrence and metastasis. We report the case of a 57-year-old man with a 1-year history of an ulcerated nodule on his scalp. Microscopically, it was a defined cutaneous nodule with a focal lobulated architecture, composed of epithelial cells forming ducts and myoepithelial cells distributed around the ducts. In addition to these findings of typical AME, the present case focally revealed atypical features, such as increased mitotic activity (7/10 high power fields), invasive growth, and necrosis. However, cytological atypia was not significant. We conclusively diagnosed cutaneous AME with atypical features, suggesting malignant potential. Moreover, areas showing appearances similar to apocrine hidrocystoma, mixed tumor, myoepithelioma, and ACC were focally observed. We present a unique case of cutaneous AME exhibiting histopathological heterogeneity. The recognition of morphological variation could be helpful in appropriately diagnosing and treating AME of the skin.

Twin-twin transfusion syndrome (TTTS) complicates approximately 10% of monochorionic twin pregnancies and is associated with almost 90% mortality if left untreated. Fetoscopic laser photocoagulation (FLP) is the first-line therapy for TTTS, and an overall twin survival rate of 75% and at least one survival rate of 90% have been established. We report a case of TTTS complicated with bleeding from the uterine wall by inserting the procedure after FLP. The patient consequently underwent emergency caesarean section. The bleeding was uncontrollable due to atonic bleeding and emergency hysterectomy was performed. To detect the possibility of amniotic fluid embolism (AFE), biochemical blood samples demonstrated that there was no inflow of fetal ingredients in blood vessels of uterine tissue. There was no evidence of damage to any specific vessels by histopathological staining. These findings indicated that the cause of massive bleeding was unlikely to have been AFE. It was concluded that atonic bleeding was likely caused by uncontrollable hemorrhage from an injury lesion where an endoscope had been inserted.

We report an unique case of a patient who showed coexistence of three nevus lipomatosus cutaneus superficialis (NLCS) with typical, cutaneous adenolipoma (AL)-like, and dermal spindle cell lipoma (SCL)-like histopathological features. A 53-year-old woman presented with a 20-year history of skin-colored and slightly elevated nodules. These lesions were separately located on the lateral side (lesion 1) and medial side (lesion 2) of her left buttock and on her right thigh (lesion 3). Microscopically, all were ill-defined dermal lesions with some subcutaneous involvement and were mostly composed of mature adipocytes. The adipocytes formed small aggregates around blood vessels in the upper dermis. Lesions 1, 2, and 3 were diagnosed as NLCS, and additional features were recognized in lesions 2 and 3. Lesion 2 revealed eccrine glands and ducts amongst the lipomatous component, as seen in cutaneous AL. Lesion 3 had scattered CD34-positive spindle cells, which is representative of dermal SCL. These appearances were considered to be on the morphological spectrum of NLCS. In all three lesions, CD34-positive cells proliferated between the upper dermal blood vessels and their peripheral mature adipocytes. This pathological finding could be principal in NLCS and might be associated with its pathogenesis.

Aims: The nuclear proliferation marker Ki67 assayed by immunohistochemistry has multiple potential uses in breast cancer, but an unacceptable level of interlaboratory variability has hampered its clinical utility. The International Ki67 in Breast Cancer Working Group has undertaken a systematic programme to determine whether Ki67 measurement can be analytically validated and standardised among laboratories. This study addresses whether acceptable scoring reproducibility can be achieved on excision whole sections. Methods and results: Adjacent sections from 30 primary ER+ breast cancers were centrally stained for Ki67 and sections were circulated among 23 pathologists in 12 countries. All pathologists scored Ki67 by two methods: (i) global: four fields of 100 tumour cells each were selected to reflect observed heterogeneity in nuclear staining; (ii) hot-spot: the field with highest apparent Ki67 index was selected and up to 500 cells scored. The intraclass correlation coefficient (ICC) for the global method [confidence interval (CI) = 0.87; 95% CI = 0.799–0.93] marginally met the prespecified success criterion (lower 95% CI ≥ 0.8), while the ICC for the hot-spot method (0.83; 95% CI = 0.74–0.90) did not. Visually, interobserver concordance in location of selected hot-spots varies between cases. The median times for scoring were 9 and 6 min for global and hot-spot methods, respectively. Conclusions: The global scoring method demonstrates adequate reproducibility to warrant next steps towards evaluation for technical and clinical validity in appropriate cohorts of cases. The time taken for scoring by either method is practical using counting software we are making publicly available. Establishment of external quality assessment schemes is likely to improve the reproducibility between laboratories further.

Lanthanum (La) deposition has been observed in gastrointestinal mucosa of dialysis patients treated with La carbonate to treat hyperphosphatemia in the 6 years since its authorization in Japan. We investigated gastrointestinal biopsies from 112 dialysis patients, and found 15 cases of histiocytic aggregation with crystalloids and one case of duodenitis with histiocyte aggregation without crystalloids in the 30 patients treated with La carbonate. No histiocytic lesions were observed in the 82 patients without La carbonate administration. So far in total 70 cases of La deposition in the alimentary tract have been reported, including our 16 cases. Neither clinical nor histological findings other than histiocytic aggregation were specific in the patients with La deposition. We also compared the groups with and without La deposition, revealing that the daily and total doses of La carbonate showed statistically significant correlations with La deposition. However the causality with their histologic features, e.g. intestinal metaplasia and degree of inflammation, were inconclusive between the two groups. Although no critical symptoms have been reported, it is necessary to accumulate more cases to clarify the mechanism of La deposition, because dialysis patients must take phosphate buffers for a long period.

Estradiol (E2) increases not only the cell growth but also the cancer stem cell (CSC) proportion in estrogen receptor (ER)-positive breast cancer cells. It has been suggested that the non-canonical hedgehog (Hh) pathway activated by E2 plays an important role in the regulation of CSC proportion in ER-positive breast cancer cells. We studied anti-CSC activity of a non-canonical Hh inhibitor GANT61 in ER-positive breast cancer cells. Effects of GANT61 on the cell growth, cell cycle progression, apoptosis and CSC proportion were investigated in four ER-positive breast cancer cell lines. CSC proportion was measured using either the mammosphere assay or CD44/CD24 assay. Expression levels of pivotal molecules in the Hh pathway were measured. Combined effects of GANT61 with antiestrogens on the anti-cell growth and anti-CSC activities were investigated. E2 significantly increased the cell growth and CSC proportion in all ER-positive cell lines. E2 increased the expression levels of glioma-associated oncogene (GLI) 1 and/or GLI2. GANT61 decreased the cell growth in association with a G1-S cell cycle retardation and increased apoptosis. GANT61 decreased the E2-induced CSC proportion measured by the mammosphere assay in all cell lines. Antiestrogens also decreased the E2-induced cell growth and CSC proportion. Combined treatments of GANT61 with antiestrogens additively enhanced anti-cell growth and/or anti-CSC activities in some ER-positive cell lines. In conclusion, the non-canonical Hh inhibitor GANT61 inhibited not only the cell growth but also the CSC proportion increased by E2 in ER-positive breast cancer cells. GANT61 enhanced anti-cell growth and/or anti-CSC activities of antiestrogens in ER-positive cell lines.

Objective The Breast Marker Cocktail from Biocare Medical comprises five antibodies recognising p63, and cytokeratins (CKs) 7, 18, 5 and 14. Immunohistochemistry using this cocktail is useful for diagnosing proliferative intraductal breast lesions. However, cytology using the cocktail has not been reported. Methods We report 139 cases of mammary samples collected by fine needle aspiration (FNA) for which histological diagnoses were available. After cell transfer, immunocytochemistry was performed using the cocktail, and clusters of cells were classified. A cluster with no or limited CK5/14 expression (

A 69-year-old postmenopausal woman was referred because she had been taking tamoxifen for four years. Tissues obtained by endometrial curettage were immunopositive for p53, but there was no definite malignancy. At age 73, cytology again showed abnormalities, so we repeated complete endometrial curettage. Again, there was no malignancy, but p53 immunostaining was widely positive. At age 75, hysterectomy was performed because cytological examination showed increasingly abnormal findings and the patient opted for surgery. In the resected uterus, endometrial glands were replaced by malignant cells resembling papillary serous carcinoma cells with high-grade nuclei, but there was no stromal or myometrial invasion. The pathological diagnosis was intraepithelial serous endometrial carcinoma. This is a rare case because we could follow the patient for 6 years by endometrial cytology or endometrial curettage and we observed gradual transformation into endometrial intraepithelial carcinoma.

AIMS Mammary metaplastic carcinoma is a rare breast carcinoma, and may present diagnostic difficulty. Alpha-B-crystallin has been recently reported to be expressed in basal-like and metaplastic carcinomas. METHODS AND RESULTS Thirty-three metaplastic carcinomas, 44 conventional high-grade carcinomas and 28 mesenchymal spindle cell neoplasms as controls were assessed for their expression of αB-crystallin and conventional basal-like phenotypic markers CK5/6, CK14, p63, c-kit and epidermal growth factor receptor (EGFR) by immunohistochemistry. Alpha-B-crystallin staining was positive in 68% of the metaplastic carcinomas with cytoplasmic staining in all tumour cell components. CK5/6, CK14, p63, c-kit and EGFR stained 43%, 68%, 45%, 21% and 25% of the metaplastic carcinomas, respectively. Combining these markers, 84% of the metaplastic carcinomas expressed either αB-crystallin or CK14. In comparison, only 14% (six cases) of conventional high-grade carcinoma and 7% (two cases) of mesenchymal spindle cell neoplasm expressed αB-crystallin; all but one of these carcinomas were ER/PR/HER2 triple-negative. CONCLUSIONS Using αB-crystallin for diagnosis of metaplastic carcinoma gives a 68% sensitivity, 88% specificity, 74% positive predictive value, 85% negative predictive value and 78% accuracy. The sensitivity is enhanced to 84% with combinations of αB-crystallin/CK14. Alpha-B-crystallin may be used as an adjunct marker in the diagnosis of metaplastic carcinoma.

Retinoids regulate cell proliferation and differentiation in normal and neoplastic tissue. These effects are mainly mediated by two types of nuclear retinoid receptors, retinoic acid receptors (RAR) and retinoid X receptors (RXR). RXR have been demonstrated to play important roles in esophageal carcinoma, but the expression of RXRβ and RXRγ has not been examined in esophagus. Therefore, we examined the immunoreactivity of all subtypes of RAR and RXR in 53 non-neoplastic esophageal epithelium and 74 esophageal squamous cell carcinoma tissues. In non-neoplastic epithelium RARβ immunoreactivity was marked in the basal layer and weak in the suprabasal layer, but immunoreactivity of other retinoid receptors was detected in both of layers. In addition, the status of RARβ and RXRβ immunoreactivity inversely correlated with that of lymph node metastasis (P= 0.0477 and P= 0.0034, respectively); decreased RXRβ immunoreactivity of carcinoma cells was positively associated with adverse clinical outcome of the patients (P= 0.0187). These findings all indicate the important roles of retinoid receptors, especially, RXR in the esophageal squamous cell carcinoma.

The aim of the present study is to clarify the critical roles of vasohibin in cervical carcinomas. We investigated the expression ratios of vasohibin and vascular endothelial growth factor (VEGF) receptor-2 on endothelium and microvessel density, lymphatic vessel density (LVD) by immunohistochemistry. Sixty-one squamous cell carcinoma (SCC), 18 mucinous adenocarcinoma (Adenocarcinoma), 38 carcinoma in situ (CIS), and 35 normal cervical epithelium were collected. We investigated the expression of vasohibin and compared it with the expression of VEGF receptor-2 (VEGFR-2, KDR/flk-1), and CD34 in the stromal endothelium. Expression of VEGF was counted using the histological score (H score). D2-40 was used as a marker for lymphatic endothelial cells to investigate LVD. The microvessel density of the normal cervical epithelium was significantly lower than that of CIS, SCC, and Adenocarcinoma (P < 0.05). The expression ratio of vasohibin in the normal cervical epithelium was significantly lower than that of SCC and Adenocarcinoma (P < 0.05). The expression ratio of VEGFR-2 of the normal cervical epithelium was significantly lower than that of SCC and Adenocarcinoma (P < 0.05). The LVD of the normal cervical epithelium was significantly lower than that of CIS, SCC, and Adenocarcinoma (P < 0.05). For normal cervical epithelium, CIS, and SCC, there was a moderate correlation between the expression percentage of vasohibin and the expression percentage of VEGFR-2 (P < 0.05, r(2) = 0.3018). This is the first study to elucidate the correlation between the expression of vasohibin in the stromal endothelial cells and the expression of VEGFR-2 in human cervical carcinomas.

S. Hata, N. Kanomata, Y. Kozuka, M. Fukuya, E. Ohno and T. Moriya Significance of collagenous and mucinous spherulosis in breast cytology specimens Objective: Spherulosis of the breast is a rare but distinct benign morphological entity. As there are few cytological reports of breast spherulosis, the significance of spherulosis among cytological specimens is unclear. The objective was to document cytological aspects of spherulosis. Methods: A total of 3491 consecutive breast fine needle aspiration cytology (FNAC) samples and 69 nipple discharge cytology samples were reviewed. Papanicolaou-stained slides with or without Romanowsky staining were analysed. The corresponding 1926 histological specimens were also reviewed. Results: We detected 17 cases of collagenous spherulosis (CS) and/or mucinous spherulosis (MS) among 3560 breast cytology specimens (0.48%). All samples were from women, who varied in age from 22 to 69 years. CS and/or MS were present in 15 of 3491 FNAC specimens (0.43%) and in two of 69 nipple discharge cytology specimens (2.9%). Corresponding histological specimens were available for 14 of the 17 specimens. Of the 14 specimens, 12 consisted of intraductal papilloma, one of fibroadenoma, and one of fibrocystic change. There was no spherulosis among the 1251 cytological specimens of malignant diseases. Conclusions: Cytological evidence of spherulosis is a good indicator of intraductal papilloma.

We have previously reported on vasohibin as a novel endothelium-derived vascular endothelial growth factor (VEGF)-inducible inhibitor of angiogenesis. The aim of our present study was to define the role of vasohibin in endometrioid endometrial adenocarcinoma. We collected 78 sections of endometrial carcinoma for assessment using immunohistochemistry. Twenty-seven were well differentiated (G1), 25 were moderately differentiated (G2), and 26 were poorly differentiated endometrioid adenocarcinomas (G3). We also included 12 sections of normal cyclic endometria, six of which were in the proliferative phase and six were in the secretory phase. We investigated the expression of vasohibin, and compared it to VEGF receptor-2 (VEGFR-2: KDR/flk-1), CD34, Ki-67, VEGF-A, and D2-40 (as a lymphatic vessel marker). We assessed the ratio of vasohibin- and VEGFR-2-positive vessels in the stroma of endometrial carcinoma. Immunohistochemical assessment was classified as negative or positive based on staining intensity. Vasohibin was selectively expressed on vascular endothelial cells in both cyclic endometria and endometrial carcinomas. Vasohibin was highly expressed in the normal functional endmetrium of the secretory phase, especially in the spiral artery, and was highly expressed in all grades of endometrioid adenocarcinomas. The stromal endothelial cells in G3 expressed vasohibin and VEGFR-2 more frequently than these in G1. In endometrioid adenocarcinomas, there was a significant correlation between the expression percentage of vasohibin and that of VEGFR-2 (P < 0.0001, r(2) = 0.591). This is the first study to elucidate the correlation between expression of vasohibin in the stromal endothelial cells and that of VEGFR-2 in human carcinomas.

TP53 mutations are a poor prognostic factor in breast cancers. The present study sets out to identify the gene set that determines the expression signature of the TP53 status (TP53 signature) and to correlate it with clinical outcome. Using comprehensive expression analysis and DNA sequencing of the TP53 gene in 38 Japanese breast cancer patients, a gene set from differentially expressed genes was isolated, depending on the TP53 status. As independent external datasets, two published datasets were introduced for validation of TP53 status predictions (251 Swedish samples) and survival analysis (both the Swedish and 295 Dutch samples). Thirty-three gene sets were identified from microarray analysis. Predictive accuracy of the TP53 status by gene expression profiling was 83.3% in the test set (n = 12). TP53 signature has the ability to predict recurrence-free survival (RFS) of 29 stage I and stage II Japanese breast cancers (log rank, P = 0.032), and RFS, overall survival of two independently published datasets (log rank, both P < 0.0001). Multivariate analysis has shown that the TP53 signature an independent and significant prognostic factor with a hazard ratio (HR) for recurrence and survival in two external datasets (P < 0.0001). The TP53 signature is also a strong prognostic factor in the subgroups: estrogen-receptor positive, lymph node positive and negative, intermediate/high risk in St. Gallen criteria, and high risk in National Cancer Institute (NCI) criteria (log rank, P < 0.0001). TP53 signature is a reliable and independent predictor of the outcome of disease in operated breast cancer.

Malignant ovarian neoplasms derived from ovarian epithelium that produce estrogen are rare among postmenopausal women. Presented herein is a case of stage Ic(a) endometrioid adenocarcinoma in the right ovary of an 81-year-old woman, who complained of mammary tenderness, pain and atypical genital bleeding. Her serum estradiol (E2) concentration was 83 pg/mL before treatment, and the endometrial thickness measured by transvaginal ultrasonography was 5 cm, much thicker than that expected for a woman in her 80s. After surgery, her complaints disappeared and her serum E2 level decreased to normal postmenopausal levels. Immunohistochemical studies demonstrated that the enzymes required to produce estrogen were present in the tumor. Immunohistological data indicated that this epithelial ovarian cancer could produce estradiol by itself, through potential interactions between cancer cells and stromal cells, and that the high level of estradiol in the patient's serum was caused by intratumoral production. This case indicates that in addition to stromal tumors, such as granulosa cell tumors, theca cell tumors, adenofibroma and so on, malignant epithelial tumors with a functioning stroma should also be considered when evaluating ovarian tumors with estrogen production in the elderly.

We report on a 49-year-old woman with osteosarcoma arising in the breast. She had undergone two consecutive excision biopsies for right breast tumors at ages 40 and 42 years. The tumors were diagnosed as a fibroadenoma and a benign phyllodes tumor, respectively. At age 46 years, she noticed a gradually enlarging mass in the same breast. After 3 years, at age 49 years, total mastectomy was performed. The tumor occupied the entire breast and measured 12×9×8.5 cm. The tumor cells were spindle-shaped and pleomorphic, with large, irregular nuclei and distinct nucleoli. Many tumor cells had characteristics of osteoblastic and chondroblastic elements producing osteoid, osseous, and cartilaginous intracellular substances. Pathologic mitoses and apoptotic cells were frequent. Neoplastic cells had infiltrated the skin. Blood and lymph vessel invasion was present. Tumor cells expressed vimentin, osteopontin, vascular endothelial growth factor, CD10, and alkaline phosphatase, but did not express keratin. Chemotherapy was not effective. The patient died of multiple pulmonary metastases 9 months after mastectomy.

BACKGROUND Estrogen sulfotransferase (EST) and steroid sulfatase (STS) are known to be involved in in situ estrogen production in estrogen dependent human cancer such as breast cancer, but unknown in prostate cancer. MATERIALS AND METHODS We first examined whether these enzymes above were expressed and actually involved in estrogen production and metabolism in prostate cancer cell lines (LNCaP, DU-145, and PC-3). We than examined the expression of EST and STS in human prostate cancer tissues obtained from surgery (n = 52) using immunohistochemistry. RESULTS mRNAs of both enzymes were detected in all prostate cancer cell lines examined, and the synthesis of estrone (E1) and estradiol (E2) was also confirmed in these cell lines. In addition, STS immunoreactivity was detected in 44 cases (85%) and EST in 39 cases (75%), respectively. CONCLUSIONS STS and EST are expressed and may be involved in local production and metabolism of estrogens in human prostate cancers. Prostate 66: 1005–1012, 2006. © 2006 Wiley-Liss, Inc.

BACKGROUND Because cellular atypia is often limited in endometrial hyperplasia and well-differentiated endometrial adenocarcinoma (WHO Grade 1 adenocarcinoma), diagnostic criteria for endometrial cytology have not been fully established. New diagnostic criteria based on the composition and architecture of tissue fragments (cytoarchitecture) in the smears were used in the present study. Cytologic features are of less importance because the distinction between endometrial hyperplasia and Grade 1 adenocarcinoma relies more on architectural features than cellular changes. Cell clumps of various size are usually collected abundantly with cytologic material using a disposable scraping device and it was noticed that those cell clumps reflected the histologic architecture. The purpose of the current study was to determine the form of the cytoarchitecture that reflects the histologic structure and to examine the cellular features in endometrial hyperplasia and Grade 1 adenocarcinoma. METHODS The frequency of each type of cell clump (tube or sheet-shaped pattern, dilated or branched pattern, irregular protrusion, and papillotubular pattern) were obtained from 49 cases of normal proliferative endometrium (NPE) (patient age range, 28–51 yrs; average age, 39.9 yrs), 63 cases of endometrial hyperplasia without atypia (EH) (patient age range, 35–65 yrs; average age, 47.7 yrs), 13 cases of endometrial hyperplasia with atypia (AEH) (patient age range 47–65 yrs; average age, 53.8 yrs), and 49 cases of Grade 1 adenocarcinoma (patient age range, 42–73 yrs; average age, 58.9 yrs). RESULTS Certain characteristics of the cytoarchitecture were observed. In the NPE, cell clumps with a tube or sheet-shaped pattern were found in 97.5% of cases. In the EH, cell clumps with a dilated or branched pattern were found in 34.9% of cases. In the Grade 1 adenocarcinoma, cell clumps with irregular protrusions were found in 61.8% cases, whereas a papillotubular pattern was present in 29.7% of cases. CONCLUSIONS The results of the current study revealed that cytoarchitectural criteria appear to be more useful for the cytologic assessment of endometrial lesions, especially for the diagnosis of endometrial hyperplasia and Grade 1 adenocarcinoma. Cancer (Cancer Cytopathol) 2006. © 2006 American Cancer Society.

Careful cytomorphologic evaluation of abnormal endometrial lesions has made accurate and reproducible microscopic assessment possible. Histopathology of patients with dysfunctional uterine bleeding due to an anovulatory cycle usually contain endometrial glandular and stromal breakdown (EGBD) and papillary metaplasia on the endometrial surface epithelium, if an appropriate sample has been collected. We often recognized abnormal cell clumps in the cytological smears with EGBD cases. They were composed of metaplastic cells, and some irregular small projection figures were observed from the margins of the cell clumps. We describe the quantitation of metaplastic clumps with irregular protrusions (MCIP) in endometrial endocyte samples. The current study presents the cytomorphological characteristics of the metaplastic changes recognized in EGBD cases. During a 7-yr period, 144 cases for which histopathological diagnoses were obtained following endometrial curettage, after collecting a direct endometrial sample using the endocyte. The material comprised 49 cases of normal proliferative endometrium (NPE) (patients aged 28-51, average 39.9), 32 cases of EGBD (patients aged 30-67, average 49.6), and 63 cases of endometrial hyperplasia without atypia (EH) (patients aged 35-65, average 47.7). The following points were investigated: (1) the occurrence of metaplastic cells; (2) the occurrence and the frequency of MCIP; and (3) the occurrence of MCIP that contains condensed stromal clusters. Metaplastic cells were seen in 93.8% of the EGBD cases. Cytomorphologic pattern identified with MCIP was 90.6%, and its frequency showed 16.1%. The occurrence of MCIP that contain condensed stromal clusters (93.1%) showed a strong association in comparison with other lesions, such as NPE and EH. Our data appear to indicate that the appearance of MCIP with condensed stromal clusters originated from the papillary metaplasia, which occurred on the endometrial surface epithelium. The cytologic observation of those cells may be a useful indicator for providing the nature of EGBD endometrium.

Endometrial carcinoma is the most common invasive neoplasm of the female reproductive tract. Early detection and accurate diagnosis of these lesions and its precursor by endometrial cytology is now accepted in Japan and regarded as an effective primary method of evaluating endometrial pathology (atypical hyperplasia or carcinoma). Careful cytomorphologic evaluation of the abnormal endometrial lesions has made possible an accurate and reproducible microscopic assessment. The current study was conducted to determine the significance of endometrial cytology on disordered endometrium associated with anovulation when compared with endometrial hyperplasia. From January 1998 through April 2004, 144 cases on which histopathological diagnoses were obtained by endometrial curettage after taken direct endometrial sample by Endocyte. The materials comprise 49 cases of normal proliferative endometrium, and 63 cases of endometrial hyperplasia without atypia were prepared as control cases. The cytomorphology was examined involving so-called endometrial glandular and stromal breakdown (EGBD). EGBD cases evidenced significant numbers of stromal cells condensed and formed compact nests with hyperchromatic nuclei and little or no cytoplasm. They were often associated with fragmented clusters of endometrial glands with condensed cluster of stromal cells. Both the fragmented cluster of endometrial glands and condensed cluster of stromal cells are a characteristic cytologic feature of EGBD endometrium on the cyto-architectural diagnosis. The combination of these cellular patterns is highly specific to this abnormal pathological condition in EGBD endometrium. To improve the accuracy of the cytodiagnosis, it is important that the cytology of the EGBD endometrium should be diagnosed negative; as a result, we can achieve successful endometrial cytology with cyto-architectural criteria for the endometrial pathology.

Steroidogenic acute regulatory protein (StAR), P450 side-chain cleavage enzyme (P450scc) and 3 beta-hydroxysteroid dehydrogenase enzyme (3beta-HSD) are all involved in the transport of cholesterol and production of progesterone. In situ production of sex steroids including progesterone have been considered to play important roles in pathogenesis and/or development of common epithelial ovarian carcinomas. In this study, StAR, P450scc, and 3beta-HSD were immunolocalized in 100 cases of ovarian carcinoma and results were then correlated with clinicopathological and prognostic parameters of individual patients including status of progesterone receptor (PR) in tumor cells. Results of immunohistochemistry were further characterized by real-time PCR analysis in 20 cases of epithelial ovarian carcinomas in which frozen tissues were available for examination. StAR, P450scc, and 3beta-HSD immunoreactivity was detected predominately in the cytoplasm of carcinoma cells. Results of real-time PCR analysis were correlated with those of immunohistochemical studies. StAR, P450scc, and 3beta-HSD H scores demonstrated significant inversed statistical correlation with FIGO stage, residual size of the tumor, and Ki67 LI. A positive statistically significant correlation was detected between StAR H score and PR-B LI. Multivariate statistical analysis demonstrated that the status of intratumoral StAR, FIGO stage, and residual tumor size all turned out to be independent prognostic factors for the clinical outcome of the patient. The presence of StAR, a cholesterol transporter for steroidogenesis in human epithelial ovarian carcinoma, may reflect the ability of these tumors to produce progesterone in situ that could influence biological behavior of these tumors, especially through progesterone dependent inhibition of tumor cell proliferation.

Invasive micropapillary carcinoma (IMPCa) of the breast refers to a unique variant of invasive ductal carcinoma, but its biological behavior has not been elucidated well. We analyzed 16 IMPCa cases (10 pure type, six mixed type). The incidence of IMPCa was 1.0% of all primary breast carcinoma. High nuclear grade (75.0%), as well as poorly differentiated histological grade (81.3%), was frequently seen. Lymph node metastases were evident in 92.9% of the examined cases, and about half of them showed more than 10 positive nodes. Comparison between serially experienced invasive ductal carcinoma, not otherwise specified (IDC-NOS), revealed that both high nuclear grade and poor histological grade were significantly more frequent (P < 0001), there was a lower frequency of positive estrogen receptor/progesterone receptor (P < 0.05, P < 0.01), a higher frequency of HER-2 overexpression (P < 0.025), and more frequent lymph node metastases (P < 0.05) in IMPCa. The comparison between lymph node positive IDC-NOS did not show any statistically significant differences in frequency for positive p53, matrix metalloproteinase protein-2 (MMP-2), vascular endothelial growth factor (VEGF) or E-cadherin. However, IMPCa showed a significantly increased number of blood vessels counted by CD34 immunostains (P < 0.05). These results suggest that IMPCa is, at least, the same or more aggressive than lymph node positive cases of IDC-NOS. Hence, not only the high incidence of lymph node metastases but also distant, blood-borne metastases may be important.

A rare case of hepatoid adenocarcinoma (HAC) of the gallbladder occurred in a 72-year-old man who presented with abdominal pain and was admitted to hospital. Ultrasonography and computed tomography revealed a mass in the gallbladder, multiple nodules in the liver and enlargement of the lymph nodes. He was diagnosed as having a gallbladder carcinoma with multiple liver and lymph node metastases. Cholecystectomy and partial hepatectomy was performed. Histologically, most of the mass in the gallbladder was composed of cells with eosinophilic cyto-plasm arranged in a trabecular pattern, which resembled hepatocellular carcinoma, but there was a component of well-differentiated adenocarcinoma in the mucosa. Immunohistochemically these hepatoid tumor cells were positive for Hepatocyte (Hepatocyte Paraffin 1: Hep Par1), which is considered highly sensitive and highly specific for hepatocyte differentiation. Based on these findings, this case was diagnosed as hepatoid adenocarcinoma of the gallbladder, which is generally a vary rare neoplasm in the literature, but should be included in the differential diagnosis of a mass in the gallbladder.

DAX-1 is a member of the nuclear receptor superfamily and is thought to be involved in the regulation of steroidogenesis. Its expression has been detected primarily in endocrine neoplasms such as adrenocortical as well as pituitary tumors in human, but its biological roles have not been examined well in sex steroid-dependent neoplasms. The aim of this study is to detect the expression of DAX-1 in common epithelial ovarian carcinomas in order to evaluate its possible biological significance. DAX-1 immunoreactivity was examined using immunohistochemistry. The correlation between the status of DAX-1 immunoreactivity and clinicopathological parameters and disease-free survival of the patients in a series of 60 cases of common epithelial ovarian carcinoma was examined. The status of DAX-1 immunoreactivity was evaluated using H score. DAX-1 immunoreactivity was widely detected in the nuclei of common epithelial ovarian carcinoma cells. There was a significant positive correlation between DAX-1 immunoreactivity and clinical staging (P = 0.0241), tumor grade (P = 0.0115), the residual size of the tumor (P = 0.0014) and Ki-67 labeling index (P =0.0001). In univariate survival analysis, a significant association was detected between DAX-1 immunoreactivity and shortened patient survival (P = 0.0157). Other significant prognostic parameters were clinical stage, residual size of tumor and Ki-67. In multivariate analysis, DAX-1 immunoreactivity, clinical stage, residual size of tumor and Ki-67 all turned out to be independent prognostic factors for shortened survival. In conclusion, DAX-1 immunoreactivity is considered to be a new independent marker of poor prognosis or adverse clinical outcome in patients with epithelial ovarian carcinoma, possibly through altering in situ steroids production.

Microinvasive ductal carcinoma of the breast, namely ductal carcinoma in situ with microinvasion (T1mic) as defined by the American Joint Committee on Cancer (AJCC) Staging Manual, is a rare disease, although it is increasing because of widespread use of mammography. The aim of the present study was to describe the clinicopathological and immunohistochemical features of this entity. Twenty-eight patients who were diagnosed as T1mic from January 1997 to August 2002 were studied by using 3-5 mm-thick serial sections with hematoxylin-eosin staining. Immunohistochemical staining for the estrogen receptor (ER), progesterone receptor (PR), p53, Ki-67, and HER-2 were performed. All 28 patients were female, with a mean age of 48.8 years. Twenty-six patients (93%) revealed mammographic abnormalities on routine examination. All foci of the invasions were measured using an ocular micrometer. Invasive foci consisted of isolated cells or cell clusters, or appeared as a tongue-like projection of tumor through the basement membrane of the duct of ductal carcinoma in situ (DCIS). The mean number of invasive foci was 3, and the mean size was 0.6 mm. We found that high nuclear grade and predominant comedo subtype of DCIS components were 57.1% and 46.4%, respectively. Twenty-four cases (86%) demonstrated necrosis of DCIS components. Microinvasion was often associated with periductal stromal reaction (71.5%) and/or a lymphocytic infiltration (78.6%). All patients, excluding two, received axillary resection (the mean number of lymph nodes examined per case was 12), and none had lymph node metastasis. The positive expression of ER and PR strongly related to low grade nuclei and non-comedo subtype; however, the positive expression of HER-2 and P53 related to high grade nuclei and comedo subtype (P

OBJECTIVE In situ metabolism and synthesis of oestrogens are considered to play important roles in the pathogenesis and development of human endometrial endometrioid adenocarcinoma. Approximately 3-5% of patients with these neoplasms are under age 40, some of whom have been treated with progestogen alone as a primary therapy for both atypical endometrial hyperplasia and adenocarcinoma in order to preserve their fertility. Medroxyprogesterone acetate (MPA) has been used extensively in the treatment of both breast and endometrial disorders as an endocrine therapy. However, details of the alterations of in situ oestrogen metabolism following progestogen treatment have yet to be fully elucidated. DESIGN, PATIENTS AND MEASUREMENTS In this study we examined the immunolocalization of 17beta-hydroxysteroid dehydrogenase (17beta-HSD) types 1 and 2, oestrogen receptor (ER), progesterone receptor (PR)A + PRB, PRB, and Ki67 in progestogen-treated endometrial endometrioid adenocarcinoma (16 cases). We compared our findings both prior to and following treatment. These findings were then correlated with the treatment outcome of individual patients in order to elucidate factors associated with the response to treatment. RESULTS 17beta-HSD type 2 immunoreactivity was detected in 8/16 cases examined, whereas 17beta-HSD type 1 immunoreactivity was undetected in all cases examined. 17beta-HSD type 2 positive immunostaining, PRA + PRB labelling index (LI), and PRB/PRA + PRB ratio were all significantly higher in cases responding to the treatment than in those not responding. There were no significant correlations between responsive and nonresponsive cases for positive 17beta-HSD type 1 immunostaining, Ki67 LI, ER LI and age. There were no significant differences in the positive immunostaining for 17beta-HSD types 1 and 2, Ki67 LI, ER LI, PRA + PRB LI, age and PRB/PRA + PRB ratio between specimens taken prior to and following progestogen treatment. CONCLUSION These results suggest that in situ abundance of 17beta-HSD type 2 and PR, especially PRB, can predict the possible response of patients with endometrial carcinoma to progestogen treatment.

Helicobacter pylori infection is currently considered to be a major cause of acute and chronic gastritis, and of gastric and duodenal ulcers. Superoxide dismutase (SOD) is well known for scavenging superoxide radicals such as reactive oxygen species (ROS), subsequently protecting cells from oxidative injury, and for maintaining tissue homeostasis. In this study, we therefore evaluated the level of SOD activity and protein expression, as well as various factors associated with oxidative injury, in H. pylori-positive (n = 46) and -negative (n = 28) gastric mucosa obtained from endoscopy, in order to elucidate the possible biological significance of SOD in these mucosa. Overall SOD activity was significantly higher in H. pylori-positive mucosa (15.5 +/- 7.0 U/mg protein) than in negative mucosa (9.2 +/- 10.6 U/mg protein), and decreased markedly following H. pylori eradication (8.2 +/- 4.2 U/mg protein). Enzyme-linked immunosorbent assay (ELISA) analysis of SOD revealed that the manganese SOD (Mn-SOD) level in H. pylori-positive mucosa (1166.7 +/- 435.2 ng/mg protein) was significantly higher than in control tissues (446.3 +/- 435.3 ng/mg protein) and in mucosa obtained following eradication therapy (431.9 +/- 189.9 ng/mg protein). The level of Mn-SOD protein showed a significant correlation with degree of inflammation in the gastric mucosa. Moreover, Mn-SOD immunolocalization patterns were well correlated with the activity and protein levels evaluated by ELISA. Factors presumably associated with oxidative injury in human gastric mucosa, including terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling, Ki-67, 8-hydroxydeoxyguanosine and single-stranded DNA, were all significantly higher in H. pylori-positive gastric mucosa than in control tissue and in tissue following eradication. These results all suggest that Mn-SOD, but not cytoplasmic copper-zinc SOD, plays an important role as an anti-oxidant against ROS generated in H. pylori-infected gastric mucosa and, subsequently, in the maintenance of cell turnover in gastric mucosa.

We report a case of an extraordinarily large tumorous form of ALHE developing on the occiput of a 57-year-old Japanese male. Histologically, it was characterized by increased numbers of small blood vessels, fibrosis, and lymph follicle formations with massive eosinopilia in the dermis in addition to an occluded artery in the deep dermis.

Androgen metabolism and possible actions are considered to play some roles in human epithelial ovarian neoplasms, but the details have not been well studied. We have examined the expression of 5alpha-reductase type 1 and type 2, which catalyze the conversion of testosterone to more active androgen, 5alpha-dehydrotestosterone, and androgen receptor (AR), using immunohistochemistry (104 cases) and reverse transcription-polymerase chain reaction (RT-PCR) (16 cases) as a first step toward understanding the metabolism and possible actions of androgens in human common epithelial ovarian carcinoma. 5alpha-Reductase type 1 was immunopositive in 75 / 104 cases (72.0%), and 5alpha-reductase type 2 in 52 / 104 cases (50.0%) (P < 0.001). There was no significant correlation between patterns of immunolocalization and clinicopathological parameters examined. Median labeling index (LI) for AR was 17.8% (range 0 - 84.4%) which was significantly higher in serous carcinoma than other histological types (P < 0.001). There was a significant positive correlation between 5alpha-reductase type 1 immunoreactivity and AR LI (P = 0.0027), but no significant correlation was detected in 5alpha-reductase type 2. Results of RT-PCR analysis were also consistent with those of immunohistochemistry. The relatively wide distribution of 5alpha-reductase type 1, and its correlation to AR status in human epithelial ovarian malignancies suggest that this isozyme plays important roles in androgen metabolism and actions in these tumors.

We report a case of isolated unilateral absence of a pulmonary artery. The first clinical symptom that was manifested in the patient was recurrent hemoptysis, and subsequent angiography revealed that the main pulmonary artery was absent in the right lung, which was being fed only from the systemic circulation. Right pneumonectomy was performed, and neither the main pulmonary artery nor its remnant was detected in the resected right lung. Histologically, there were many muscular vessels in the resected lung, with intimal proliferation, or with plexiform-like lesions. The alveolar septum was moderately thickened and alveolar capillary vessels were dilated. We examined the alveolar capillary endothelial cells of the resected lung for immunoreactivity to thrombomodulin (TM) and von Willebrand factor (vWF). The endothelial cells were negative for TM and positive for vWF, while in the normal lung control group, these cells were positive for TM and negative for vWF. We considered that the hemodynamics of the systemic circulation in the resected lung caused the alteration of immunohistochemical characteristics in alveolar capillary endothelial cells.

Evaluation of HER-2/neu status is important in the management of patients with breast carcinoma, especially in determining the possible application of trastuzumab, a humanized anti-HER-2/neu monoclonal antibody. Chromogenic in situ hybridization (CISH) detection of the HER-2/neu oncogene is a newly developed in situ hybridization method that utilizes a robust and unique-sequence DNA probe labeled with digoxygenin, and sequential incubations with antidigoxygenin fluorescein, antifluorescein peroxidase, and diaminobenzidine. In this study, we examined 20 archival specimens of human breast carcinoma using CISH, and we correlated findings with immunohistochemical findings for HER-2/neu. HER-2/neu immunohistochemistry was carried out with HercepTestTM, a standardized immunohistochemical examination system for HER-2/neu overexpression in surgical pathology specimens. CISH analysis could be done in 18 out of 20 cases examined. Gene copy signals for HER-2/neu were recognized as intranuclear brown dots in both neoplastic and non-neoplastic cells. Seven carcinomas showed an increased number or size of signals and were interpreted as being positive for HER-2/neu amplification. Eight cases were positive with the HercepTestTM. Seven out of eight carcinoma cases found to overexpress immunoreactive HER-2/neu also demonstrated HER-2/neu gene amplification following CISH analysis. There was a significant correlation between immunohistochemical and CISH analyses (P< 0.001). We found that CISH was a specific, sensitive and easily applicable method for the detection of HER-2/neu gene amplification, which may be used together with immunohistochemical examination for the evaluation of patients with breast carcinoma.

Malignant mixed mesodermal tumor is a rare tumor of the ovary and its histogenesis is controversial. We report the case of an ovarian tumor that seemed to be a pure carcinoma and recurred as a carcinosarcoma, and suggest a possible histogenesis for this kind of tumor. The patient was a 62-year-old Japanese woman. The primary tumor was confined to the right ovary and was a histologically poorly differentiated endometrioid adenocarcinoma with focal squamous differentiation. The tumor recurred as peritoneal dissemination 9 months later showing a histological appearance of carcinosarcoma of heterologous type. The recurrent tumor also contained intermingled foci of similar histology as the primary tumor. The carcinomatous component of the recurrent tumor showed more obvious differentiation to adenocarcinoma with increased expression of epithelial markers compared to the primary tumor. Epithelial membrane antigen was positive also in a few cells of the sarcomatous component, which implies that this tumor had features of metaplastic carcinoma. The DNA ploidy pattern of the primary ovarian tumor was diploid, while an additional aneuploid subpopulation appeared in the recurrent tumor. These findings suggest the possible histogenesis of carcinosarcoma of the ovary as progression and clonal evolution of endometrioid adenocarcinoma.

Retinoic acid (RAR) and retinoid X receptors (RXR) are essential in the transcriptional actions of retinoids. To date, RAR and RXR have not been examined in precancerous lesions and / or ductal carcinoma in situ (DCIS) in human breast. Therefore, we examined RAR and RXR subtypes in DCIS (58 cases), atypical ductal hyperplasia (ADH) (32 cases), and proliferative disease without atypia (PDWA) (32 cases) to study the status of these RARs and RXRs. Immunoreactivities for RAR alpha, RXR alpha, RXR beta, and RXR gamma were all detected in the nuclei of normal ductal epithelia. Immunoreactivity for RAR beta was detected exclusively in the nuclei of myoepithelial cells, but not in normal ductal epithelia. Immunoreactivity for RAR gamma was not detected in any of the breast tissues examined except for a few cases of PDWA and ADH, and 11 cases of DCIS. The RXR alpha labeling index (LI) was significantly higher in both DCIS (mean 77.9) and ADH (mean 77.7) than in PDWA (mean 62.8) (P < 0.001). RXR beta LI was significantly lower in DCIS (mean 81.5) than in both ADH (mean 91.1) and PDWA (mean 91.9) (P = 0.0001). Immunoreactivity for RAR alpha, RXR alpha, RXR beta and RXR gamma was widely distributed compared to that of RAR beta and RAR gamma in DCIS, ADH and PDWA. RAR alpha LI was significantly correlated with Ki67 LI in DCIS (P = 0.0040), especially in estrogen receptor (ER)-positive DCIS. Our results suggest that RXRs are much more widely distributed than RARs in intraductal proliferative lesions of tne human breast, but ER-positive DCIS cases with high cell proliferative activity are associated with RAR alpha, suggesting the possible involvement of retinoids through RAR alpha in tumor cell proliferation in DCIS.

Ovarian hyperstimulation syndrome (OHSS) is the most serious complication of ovulation induction with exogenous gonadotropins, such as human menopausal gonadotropin and follicle-stimulating hormone. These hormones are considered to increase capillary permeability and cause third space fluid shift. We report an autopsy case of severe OHSS in a 28-year-old Japanese female. The patient developed bilateral chest pain and progressive dyspnea during the course of administration of human gonadotropins. Pleural effusion and hypouresis clinically disappeared 4 days after the onset of the symptoms, but the patient died suddenly of rapid respiratory insufficiency. Autopsy examination revealed massive pulmonary edema, intra-alveolar hemorrhage and pleural effusion without any evidence of pulmonary thromboembolism. Histopathological examination of the ovary demonstrated multiple well-developed follicle formations, consistent with OHSS. It is very important to recognize that massive pulmonary edema can occur in a patient with OHSS. To the best of our knowledge, this is the first autopsy report of a patient with severe OHSS.

Background. Several studies have suggested that ductal carcinoma in situ (DCIS) of the comedo type (variably defined) is biologically more aggressive than other patterns of DCIS and more likely to progress rapidly to invasive carcinoma. Methods. Eighty-five pure DCISs were compared histopathologically with 64 carcinomas containing both intraductal and infiltrating ductal components (mixed DCIS/IDC). Results. Solid DCIS with and without necrosis was seen more frequently seen in the mixed DCIS/IDC series, especially in cases with less than 50% DCIS. Periductal stromal inflammation and multifocality also were seen more frequently in mixed DCIS/IDC than in pure DCIS. High nuclear grade and high mitotic activity were also more common in the DCIS component of the mixed cases and were well correlated with the intraductal and infiltrating components of the same tumors in most of the cases. The frequency of axillary lymph node metastases was correlated with the proportions of stromal invasion but not with the DCIS subtypes. When the criteria (solid growth pattern, high nuclear grade, and central necrosis) for the diagnosis of intraductal comedocarcinoma were analyzed separately, the first of these correlated most strongly with mixed DCIS/IDC compared with pure DCIS, the second less strongly, and the third not at all, although central necrosis has been considered the main or only diagnostic criterion for comedocarcinoma in several previous reports. Conclusions. Solid growth pattern and high nuclear grade are the most important histopathologic features of DCIS used to predict progression to invasive carcinoma. No major changes between the intraductal and invasive elements of the same tumors were noted, but other studies have suggested that markers of aggressiveness either increase or decrease in the progression to invasion. These conflicting data require further investigation.

The objective of this study was to introduce the clinical and cytological aspects of myospherulosis. A total of 5,174 consecutive breast fine needle aspiration (FNA) cytology cases were reviewed, among which 23 cases of myospherulosis of the breast were found, all in female patients. The main findings of myospherulosis, best seen with the Papanicolaou stain, consisted in the observation of spherules that were homogeneously smooth or contained one or more internal dense bodies. Routine Papanicolaou-stained slides with or without Romanowsky staining were analyzed. Immunocytochemistry was conducted for carbonic anhydrase 1 (CA1), glycophorin C, KP1, and PGM1. The patients' ages ranged from 41 to 79 years (mean age: 56 years). Of the 23 patients, 21 had a previous history of breast surgery. Cytologically malignant or suspicious diagnoses were made in four of the 23 cases. The size of parent bodies varied from 18.2 to 151 μm (mean, 52 μm). The size of spherules ranged from 2.1 to 16.4 μm (mean, 6.6 μm). Immunocytochemistry showed that the myospherules reacted with anti-CA1 and anti-glycophorin C antibodies. Most breast myospheruloses occur in patients with a history of breast surgery. Immunocytochemistry for CA1 and glycophorin C can enhance the diagnosis of myospherulosis.

A case of non-traumatic systemic clostridial sepsis associated with severe hemolytic anemia is reported. The patient's illness progressed rapidly and she died despite intensive care. Post-mortem examination revealed emphysematous cholecystitis, a liver abscesses and sponge-like systemic organs with many Gram-positive bacilli. A culture from bile demonstrated Clostridium perfringens. We suspected that the focus of the infection was emphysematous cholecystitis. Such cases are very rare, but clinicians should be alert to the possibility of their ocurrence, since early diagnosis and therapy may cure the patient.

Liposarcoma arising from the renal sinus is rare and there have been no reports of intravenous extended liposarcoma of the renal sinus thus far. We report a case of liposarcoma of the renal sinus that extended into the renal venous lumen. A 58-year-old woman was referred to our hospital for an intravascular fatty tumor of the right renal vein incidentally discovered by an abdominal screening ultrasonogram. Computer tomography revealed a fatty tumor extending from the right kidney to the right renal vein with no evidence of metastatic lesions. Total right nephrectomy and extirpation of the intravascular tumor of the right renal vein were carried out. Pathological findings showed well-differentiated liposarcoma of the renal sinus. The tumor invaded to the right renal vein and the renal parenchyma.

A case of minimal change renal disease associated with thymoma and pancreatic carcinoma is reported. A clinical manifestation of nephrotic syndrome developed about 5 weeks before the patient's demise and two different primary tumors were revealed only at the time of autopsy. Circumstantial evidences support that minimal change disease was a paraneoplastic process related to thymona rather than either the one related to pancreatic carcinoma or a mere coincidence. Review of the literature disclosed five cases of thymona with associated nephrotic syndrome. Herein, we report another case of such an unusual association and compare the present case with the previously reported.