Identification of signal peptide domain SOST mutations in autosomal dominant craniodiaphyseal dysplasia.

Sclerosteosis and Van Buchem disease are related recessive sclerosing bone dysplasias caused by alterations in the SOST gene. We tested the hypothesis that craniodiaphyseal dysplasia (CDD) (MIM 122860), an extremely rare sclerosing bone dysplasia resulting facial distortion referred to as "leontiasis ossea", could also be caused by SOST mutations. We discovered mutations c.61G>A (Val21Met) and c.61G>T (Val21Leu) two children with CDD. As these mutations are located in the secretion signal of the SOST gene, we tested their effect on secretion by transfecting the mutant constructs into 293E cells. Intriguingly, these mutations greatly reduced the secretion of SOST. We conclude that CDD, the most severe form of sclerotic bone disease, is part of a spectrum of disease caused by mutations in SOST. Unlike the other SOST-related conditions, sclerosteosis and Van Buchem disease that are inherited as recessive traits seem to be caused by a dominant negative mechanism.

Liposarcoma: exploration of clinical prognostic factors for risk based stratification of therapy.

BACKGROUND: Prognosis and optimal treatment strategies of liposarcoma have not been fully defined. The purpose of this study is to define the distinctive clinical features of liposarcomas by assessing prognostic factors. METHODS: Between January 1995 and May 2008, 94 liposarcoma patients who underwent surgical resection with curative intent were reviewed. RESULTS: Fifty patients (53.2%) presented with well differentiated, 22 (23.4%) myxoid, 15 (16.0%) dedifferentiated, 5 (5.3%) round cell, and 2 (2.1%) pleomorphic histology. With the median 14 cm sized of tumor burden, about half of the cases were located in the retroperitoneum (46.8%). Seventy two (76.6%) patients remained alive with 78.1%, and 67.5% of the 5- and 10-year overall survival (OS) rates, respectively. Low grade liposarcoma (well differentiated and myxoid) had a significantly prolonged OS and disease free survival (DFS) with adjuvant radiotherapy when compared with those without adjuvant radiotherapy (5-year OS, 100% vs 66.3%, P = 0.03; 1-year DFS, 92.9% vs 50.0%, respectively, P = 0.04). Independent prognostic factors for OS were histologic variant (P = 0.001; HR, 5.1; 95% CI, 2.0 - 12.9), and margin status (P = 0.005; HR, 4.1; 95% CI, 1.6-10.5). We identified three different risk groups: group 1 (n = 66), no adverse factors; group 2, one or two adverse factors (n = 28). The 5-year OS rate for group 1, and 2 were 91.9%, 45.5%, respectively. CONCLUSION: The histologic subtype, and margin status were independently associated with OS, and adjuvant radiotherapy seems to confer survival benefit in low grade tumors. Our prognostic model for primary liposarcoma demonstrated distinct three groups of patients with good prognostic discrimination.

Conization using electrosurgical conization and cold coagulation for international federation of gynecology and obstetrics stage IA1 squamous cell carcinomas of the uterine cervix.

OBJECTIVE: This study was performed to evaluate the efficacy and feasibility of electrosurgical conization and cold coagulation as definitive treatments for patients with International Federation of Gynecology and Obstetrics stage IA1 squamous cell carcinoma of the cervix and a resection margin free from (micro)invasive carcinoma after conization. METHODS: Patients with stage IA1 cervical squamous cell carcinoma without lymphovascular space invasion who had been treated by electrosurgical conization and cold coagulation and who wanted to preserve fertility (or only undertake conservative treatment) were followed up without further surgical intervention. Patients with invasive or microinvasive carcinoma at resection margins or positive endocervical resection margins were excluded from the study. Cervicovaginal smears and colposcopic examination were performed at regular intervals. Disease recurrence was defined as a histologic diagnosis of cervical intraepithelial neoplasia 2 or higher-grade lesions. RESULTS: A total of 85 patients enrolled were deemed eligible to be involved in the study. The median follow-up period was 81.0 months (range, 13-127 months). Nineteen of the 85 patients had exocervical resection margins. There was one case of recurrence, which was node-positive invasive cancer recurrence (1.2%, 1/85), in patients with negative resection margins. CONCLUSIONS: These results suggest that electrosurgical conization with cold coagulation is a feasible treatment and could be used as a definitive therapy for patients with stage IA1 cervical squamous cell carcinoma without lymphovascular space invasion. In addition, patients having cervical intraepithelial neoplasias 2 and 3 at exocervical resection margins could be followed up carefully without further treatment after conization and cold coagulation.

Chondrolipoma in the pelvic cavity: a case report.

A chondrolipoma is an extremely rare form of a benign mesenchymal tumor containing mature cartilage and fatty tissue. Chondrolipomas may be found in almost any part of the body, particularly in the connective tissue of the breast, head and neck area, as well as in the skeletal muscle. However, to the best of our knowledge, chondrolipomas located in the pelvic cavity have not been reported. In this case report, we describe a case of a chondrolipoma in the pelvis, and show that it has its own characteristic imaging findings, which included the composition of fatty tissue and calcification in most parts, as well as some focal areas of chondroid tissue based on the CT and MR findings.

Biliary parasitic diseases including clonorchiasis, opisthorchiasis and fascioliasis.

Parasitic infection of the biliary tree is caused by liver flukes, namely Clonorchis sinensis and Opisthorchis viverrini. These flukes reside in the peripheral small bile ducts of the liver and produce chronic inflammation of the bile duct, bile duct dilatation, mechanical obstruction, and bile duct wall thickening. On imaging, peripheral small intrahepatic bile ducts are dilated, but the large bile ducts and extrahepatic bile ducts are not dilated or slightly dilated. There is no visible caused of obstruction. Sometimes, in heavy infection, adult flukes are demonstrated on sonography, CT or MR cholangiography as small intraluminal lesions. The flukes in the gallbladder may appear as floating, small objects on sonography. Chronic infection may result in cholangiocarcinoma of the liver parenchyma or along the bile ducts. Human infection of Fasciola hepatica, a cattle flukes, may occur inadvertently, and the flukes migrate in the liver (hepatic phase) and reside the bile ducts (biliary phase). Image findings in the hepatic phase present with multiple, small, clustered, necrotic cavities or abscesses in the peripheral parts of the liver, showing "tunnels and caves" sign, reflecting parasite migration in the liver parenchyma. In the biliary phase, the flukes are demonstrated in the intra- and extrahepatic bile ducts and the gallbladder as small intraluminal flat objects, sometimes moving spontaneously. Bile ducts are dilated.

Papillary serous carcinoma in ovaries of normal size: a clinicopathologic study of 20 cases and comparison with extraovarian peritoneal papillary serous carcinoma.

OBJECTIVE: The aim of this study was to compare the clinicopathological features of papillary serous carcinoma in ovaries of normal size and primary peritoneal carcinoma (PPC). METHODS: Among 167 patients diagnosed with advanced primary serous ovarian carcinoma over a 9-year period, 20 patients with a normal ovarian size (not larger than 4 cm in the longest diameter) were selected for this study after a review of the pathologic materials. The clinicopathological characteristics of the patients were compared with those of seven patients with PPC, diagnosed using the GOG criteria during the same period. RESULTS: All the patients with ovarian carcinoma and five of seven PPC patients had small ovarian tumors. There were few significantly different features between the two groups. The patients with ovarian carcinoma were younger than those with PPC (median age of 52 vs. 64 years, P=0.007) and tended to have a lower baseline CA125 level (median value of 937 vs. 2870 U/mL, P=0.097), less severe omental involvement (P=0.057), and a more complete response to adjuvant chemotherapy (89% vs. 57%, P=0.064). CONCLUSIONS: Although the sample size was small, there was no meaningful difference between patients with papillary serous carcinoma in ovaries of normal size and PPC. Therefore, further studies will be needed to determine the relevance of the GOG rules in distinguishing between the two groups.

Immunohistochemical study of the expression of adhesion molecules in ovarian serous neoplasms.

To clarify possible roles of adhesion molecules including E-cadherin, beta- and gamma-catenin, CD44s, CD44v6, CD56, and CD99 in ovarian serous neoplasms, an immunohistochemical study was undertaken for 23 benign, 40 borderline, and 95 malignant ovarian serous neoplasms using tissue microarray (TMA). Significantly reduced expression of E-cadherin, and overexpression of CD44s, CD56, and CD99 were more frequently observed in adenocarcinomas than in benign and borderline tumors. Expression of CD44v6 and nuclear beta- and gamma-catenin were detected only in borderline tumors and adenocarcinomas. Reduced expression of E-cadherin was also correlated with high tumor grade (P=0.03), presence of peritoneal seeding (P=0.03), and low overall survival rate (P=0.02). Overexpression of CD44s was significantly associated with high tumor grade (P=0.04), advanced stage (P=0.03), and low overall survival rate (P=0.02). CD56 was increasingly expressed in the case of advanced stage (P=0.005) and peritoneal seeding (P=0.001). Nuclear staining for gamma-catenin was correlated with tumor progression (P=0.004) and advanced International Federation of Gynecology and Obstetrics (FIGO) stage (P=0.02). Only CD44s expression and stage were correlated with overall survival in multivariate study. These results suggest that although E-cadherin, CD44s, CD56, and nuclear gamma-catenin immuno-expression seem to be useful prognostic markers for serous neoplasm of the ovary, CD44s expression and FIGO stage are independent prognostic factors.

Differentiation of the various lesions causing an abnormality of the endometrial cavity using MR imaging: emphasis on enhancement patterns on dynamic studies and late contrast-enhanced T1-weighted images.

The objectives of this study were to determine the usefulness of magnetic resonance (MR) imaging in the differentiation of various lesions causing an abnormality of the endometrial cavity by evaluating the imaging features on dynamic contrast-enhanced study and late contrast-enhanced T1-weighted images (T1WI). Contrast-enhanced MR imaging of 59 pathologically proven lesions that showed an abnormality of the endometrial cavity, including 32 endometrial cancers, five sarcomas, nine hyperplastic polyps, nine submucosal myomas, three hyperplasia, and one adenomyoma, were retrospectively reviewed. The enhancement degree and patterns on dynamic contrast-enhanced study and late contrast-enhanced T1WI were compared among different pathologies. On dynamic contrast-enhanced study, 72% (23/32) of endometrial cancers showed early peak enhancement to be reached within 1 min following intravenous administration of contrast material. On late-contrast-enhanced T1WI, lesions showed weak enhancement with gradual washout. Ninety-five percent (21/22) of benign lesions and 100% (5/5) of sarcomas showed late peak enhancement to be reached in 2-3 min following intravenous administration of contrast material. On late contrast-enhanced T1WI, both of these lesions showed persistent strong enhancement. Different enhancement patterns on dynamic contrast-enhanced MR imaging and late contrast-enhanced T1WI can provide a useful clue in the differentiation of various lesions causing an abnormality of the endometrial cavity.

Calretinin, CD34, and alpha-smooth muscle actin in the identification of peritoneal invasive implants of serous borderline tumors of the ovary.

The correct identification of invasive implants in the peritoneum in serous borderline tumors (SBTs) of the ovary is an important determinant of diagnosis, treatment, and prognosis. Although the histologic criteria to distinguish noninvasive from invasive implants have been defined, the distinction can still be difficult. We examined the presence and distribution of mesothelial cells, stromal fibrocytes, and myofibroblasts in invasive and noninvasive peritoneal implants in 100 noninvasive, 100 invasive, and 100 metastatic nests/foci from 20 cases of SBTs with peritoneal implants, 10 serous carcinomas with peritoneal metastasis, and 10 cases of endosalpingiosis by immunostaining for calretinin, CD34, and alpha-SMA. All 100 invasive nests from seven SBTs and all 100 metastatic nests from the cases of serous carcinoma showed loss of calretinin+ mesothelial cells and stromal CD34+ fibrocytes around the nests. In contrast, 72/100 noninvasive nests displayed the presence of mesothelial cells around the nests and 68 displayed preservation of surrounding stromal fibrocytes. Alpha-smooth muscle actin positive myofibroblasts were present as a stromal response in 100/100 metastatic nests, 100/100 invasive nests and 54/100 noninvasive nests. The loss of mesothelial cells and stromal fibrocytes surrounding invasive nests together with a proliferation of myofibroblasts as demonstrated by immunostaining proved to be a sensitive and specific tool to separate invasive from noninvasive implants and represents an important adjunct to morphologic diagnosis. Combined sensitivity and specificity of the three antibodies was 100 and 81%, respectively. These methods, however, may not be helpful for small biopsies of noninvasive desmoplastic implants. The distribution of these cells provides some insights into the histogenesis of invasive and noninvasive implants in SBTs.

Cyclin E, p27 and mutant p53 do not predict the prognosis in AJCC stage II colorectal carcinomas.

BACKGROUND/AIMS: Carcinogenesis is characterized by the abnormal regulation of cell cycle. The abnormal expression of the regulators of cell cycle may be related to the prognosis. Since the clinical significance of the expression of the three proteins in colorectal carcinomas is still controversial, we evaluated the prognostic value of the expression of cyclin E, p27 and mutant p53 in stage II colorectal cancer. METHODS: The expression levels of cyclin E, p27 and mutant p53 proteins in 41 patients with stage II colorectal carcinomas were analyzed by immunohistochemistry. RESULTS: In the univariate analysis, the level of CEA at diagnosis was associated with disease relapse. In the multivariate analysis, the clinicopathological variables such as age, gender, site of primary tumor, tumor size, state of tumor differentiation and preoperative plasma CEA level were not associated with disease relapse. When Kaplan-Meier survival curves were constructed to determine the prognosis, cyclin E, p27 and mutant p53 expressions did not predict poor prognosis. CONCLUSIONS: Our results suggested that the expression of cyclin E, p27 and mutant p53 proteins did not predict the clinical outcome in the stage II colorectal carcinomas.

Extensive and divergent chromosomal losses in squamous and spindle-cell components of esophageal sarcomatoid carcinoma.

Sarcomatoid carcinoma of the esophagus is an unusual type of squamous cell carcinoma (SCC) with a variable component of sarcomatoid spindle cells (SA). The loss of heterozygosity (LOH) involving multiple cancer-associated chromosomal arms has been reported to have a concerted, rather than an individual, effect on tumor progression. In order to delineate the role of LOH in the evolution of a biphasic tumor, the carcinoma in situ (CIS), invasive squamous cell carcinoma (ISCC), and SA components from a sarcomatoid carcinoma of the esophagus were compared for their clonality and extent of LOH. Forty microsatellite markers on the cancer-associated chromosomes, 3p, 4p, 5q, 8p, 9p, 13q, 17p, and 18q, were used for the polymerase chain reaction-based LOH analysis. All eight sarcomatoid carcinomas tested revealed extensive LOHs, involving an average of seven chromosomal arms. All CIS, ISCC, and SA components carried not only a high-level primary LOH (mean chromosomal involvement, 5.3) in common but also a low-level secondary LOH (mean chromosomal involvement, 1.8) in disparity. Interestingly, more secondary LOHs were always burdened in the CIS (four cases) rather than the matched ISCC. SA had a greater (four cases), equal (one case), or fewer (one case) number of secondary LOHs than ISCC. Given that excessive chromosomal losses may confer a disadvantage for tumor growth or a benefit for a metaplastic transformation, these results suggest that the multidirectional differentiation of a SCC precursor is stimulated by extensive and divergent LOHs acquired at the initial or early stages, and a precursor burdened with excessive LOH either remains in CIS or expands as a SA component.

Schwannomas of the gastrointestinal tract: clinicopathological features of 12 cases including a case of esophageal tumor compared with those of gastrointestinal stromal tumors and leiomyomas of the gastrointestinal tract.

We analyzed the clinicopathological features of 12 gastrointestinal (GI) schwannomas and compared them with those of 37 GI stromal tumors (GISTs) and 15 leiomyomas. Grossly, the schwannomas showed rubbery to firm, yellow-white to tan, glistening, and often trabeculated cut surfaces, resembling soft tissue schwannomas. The GISTs were firm to soft or fish-flesh tan, gray-pink, or variegated tumors with a degenerative change, and the leimyomas resembled typical uterine leiomyomas. Histologically, GI schwannomas were moderately cellular tumors with focal significant nuclear pleomorphism and rare mitotic figures. A characteristic peripheral lymphoid cuff was observed in all cases, but was indistinct in two cases. The GISTs were highly cellular spindle cell, epithelioid or, occasionally, pleomorphic tumors with basophilic appearance. Leiomyomas were paucicellular tumors with eosinophilic appearance. Immunohistochemically, schwannomas were S-100 protein- and glial fibrillary acidic protein (GFAP)-positive, but were negative for c-kit, CD34, and smooth muscle actin (SMA). GISTs were all c-kit- and/or CD34-positive, but GFAP-negative. Leiomyomas were SMA-positive and were negative for c-kit, CD34, S-100 protein, and GFAP. The mean Ki-67 index of schwannoma was 0.7, and those of GIST and leiomyoma were 5.9 and 0.3, respectively. The patients with schwannomas and leiomyomas had a favorable outcome, whereas 12 patients with GISTs showed progression and died of disease. The separation of GISTs from schwannomas is clinically important because the former group has a high risk of malignant behavior. GI schwannomas differed from the conventional soft tissue schwannomas in that they had peripheral lymphoid cuffs, lacked fibrous capsule and vascular hyalinization, and rarely showed degenerative changes. GI schwannomas, however, resembled soft tissue schwannomas in many aspects, and the clinical, gross, histological, and immunohistochemical features were different from those of GISTs and leiomyomas.

Fine needle aspiration cytology (FNAC) of gastrointestinal stromal tumor: an emphasis on diagnostic role of FNAC, cell block, and immunohistochemistry.

Recently the origin of gastrointestinal stromal tumors (GISTs) is thought be the interstitial cells of Cajal or primitive stem cells. This study was performed to evaluate the roles of fine needle aspiration cytology (FNAC), cell block preparation, and immunohistochemistry in the diagnosis of GISTs. Nine cases of GIST in which FNAC was performed were included in this study. Cytologically, the tumor cells characteristically occurred in closely packed cohesive tissue fragments with high cellular density often in bloody background. The tumor cells often formed fascicles with parallel, side-by-side arrangements of the nuclei. Histologically, GISTs were highly cellular spindle or epithelioid tumor with basophilic appearance. Immunohistochemically, GISTs were c-kit positive in all of nine cases, CD34 positive in seven, focally SMA positive in two, and S-100 and GFAP negative in all. Both histologic and cell block sections showed the same histologic and immunohistochemical features. Cytomorphologically GISTs show a broad morphologic spectrum but rarely a significant nuclear pleomorphism and the assessment of malignant potential is difficult based on cytology alone. However, in the appropriate clinical and radiologic setting, a confident diagnosis of primary or metastatic GIST can be established by FNAC, cell block, and immunohistochemistry.