Expression of the membrane mucins MUC4 and MUC15, potential markers of malignancy and prognosis, in papillary thyroid carcinoma.

BACKGROUND: Papillary thyroid carcinoma (PTC) is the most frequent carcinoma of the thyroid gland and has a relatively good prognosis. However, it is important to identify PTC characteristics that indicate high risk for recurrence and metastasis. To date, overexpression of the membrane mucin, MUC1, has been investigated as a key molecular event in the pathogenesis of aggressive PTC. However, other membrane-associated mucins, matrix metalloproteinase-13 (MMP-13) and tissue inhibitor of metalloproteinase-13 (TIMP-3), have not been studied yet. The aim of this study was to evaluate the expression levels of MUC4, MUC15, MMP-13, and TIMP-3 and their prognostic significance in PTC. METHODS: We analyzed MUC4, MUC15, MMP-13, and TIMP-3 expression in 10 PTC and 10 normal thyroid tissue samples using real-time reverse transcription-polymerase chain reaction. Tissue array blocks were obtained from 98 PTC cases. Tumor regions and nontumor regions were analyzed in tissue array blocks and immunohistochemistry studies were conducted using sectioned slides. Semiquantitative scores were correlated with clinicopathological factors of 98 PTC patients. RESULTS: MUC4- and MUC15-specific mRNA was increased by 78-fold and 4.75-fold, respectively, in PTC samples compared with normal thyroid tissues. MMP-13 and TIMP-3 gene expression levels were decreased by approximately 0.39-fold and 0.53-fold, respectively. By immunohistochemistry, MUC4 and MUC15 expression levels were increased in PTC samples compared with normal thyroid tissues (p < 0.001). MMP-13 and TIMP-3 expression levels were decreased in PTC samples compared with normal thyroid tissues (p < 0.001). High MUC4 scores were significantly correlated with small tumor size and papillary thyroid microcarcinoma subtype. High MUC15 scores were significantly correlated with age (≥45 years), distant metastasis, and multifocality. CONCLUSIONS: MUC4 and MUC15 were overexpressed in PTC, and high MUC15 expression was associated with high malignant potential. MUC15 may serve as a prognostic marker and potential novel therapeutic target in PTC.

Effect of {beta}4 integrin knockdown by RNA interference in anaplastic thyroid carcinoma.

BACKGROUND: Integrin α6ß4 is a known tumor antigen; however, its function in different subtypes of thyroid cancer is not known. This study reports that α6ß4 expression is selectively up-regulated in anaplastic thyroid cancer (ATC) cells, the most malignant subtype of human thyroid cancer. MATERIALS AND METHODS: To assess the contribution of α6ß4 in ATC progression, cell proliferation, motility and soft agar assay were performed in vitro and a xenograft tumor growth assay was performed in vivo. RESULTS: Knockdown of ß4 integrin subunit expression by shRNA in ATC cells reduced the proliferation, migration, and anchorage-independent growth of ATC cells in vitro and xenograft tumor growth in vivo. CONCLUSION: These data suggest that integrin α6ß4 contributes to the development of aggressive forms of thyroid cancer with poor prognostic potential, such as ATC, and thus may be a novel therapeutic target for the treatment for this subtype of thyroid cancer.

Visually discernible [18F]fluorodeoxyglucose uptake in papillary thyroid microcarcinoma: a potential new risk factor.

CONTEXT: A significant number of papillary thyroid microcarcinomas (PTMCs), despite excellent prognosis, show aggressive features such as extrathyroidal extension (EE) and lymph node metastasis (LNM) that may not always be detected preoperatively or intraoperatively. The relapse rate appears also substantial. OBJECTIVE: To assess the value of [(18)F]fluorodeoxyglucose (FDG) uptake in PTMC as a potential risk factor for preoperative risk stratification. METHODS: This retrospective study included 87 patients (17 males and 70 females; mean age = 51.2 yr, range 29-74 yr) with a unifocal PTMC who underwent preoperative FDG-positron emission tomography (PET)/computed tomography (CT)and total thyroidectomy and central lymph node dissection. Statistical analyses were performed to compare the gender, age, tumor size, and FDG uptake in PTMC with the presence of histopathologically proven EE and central LNM (cLNM). RESULTS: Of the 87 patients, 44 (51%) had EE, and 27 (31%) had cLNM. PET/CT showed visually discernible FDG uptake in 46 PTMCs (53%). FDG positivity of PTMCs was the only significant variable correlated with both EE and cLNM; there was a significant difference in the prevalence of both EE (70 vs. 29%) and cLNM (41 vs. 19.5%) between the FDG-positive and FDG-negative groups. In contrast, other already known risk factors, i.e. gender, age, and size, showed a correlation with only one or neither of EE and cLNM. CONCLUSION: The results indicate that visual FDG positivity in PTMCs is a potential risk factor that can be useful for preoperative risk stratification. Prospective studies would be warranted to assess the long-term benefit and cost effectiveness of preoperative FDG-PET/CT.

Absence of activating mutations of CXCR4 in pituitary tumours.

OBJECTIVE: Mutations of the gsp oncogene are responsible for 30-40% of GH-producing pituitary adenomas and 10% of nonfunctioning pituitary adenomas (NFPAs). However, the pathogenetic mechanism of the remaining pituitary tumours still remains to be identified. Recently, the interaction between the chemokine stromal cell-derived factor 1 and its receptor CXCR4 was found to play an important role in GH production and cell proliferation in various pituitary adenoma cell lines. As CXCR4 is a Gi-coupled chemokine receptor, its constitutive activating mutations may be involved in pituitary tumour formation by cyclic adenosine monophosphate (cAMP)-independent, ERK-related pathways. PATIENTS AND METHODS: We investigated whether somatic activating-mutations of CXCR4 might be a possible tumourigenic mechanism for gsp-negative GH-secreting pituitary adenomas and NFPAs. Direct sequencing of polymerase chain reaction-amplified products for coding exons of CXCR4 were performed using genomic deoxyribonucleic acid samples from 37 GH-producing pituitary tumour tissues that were negative for the gsp mutation and 14 CXCR4 expressing NFPAs. RESULTS: Immunohistochemical analyses and double immunofluorescent staining of sectioned paraffin-embedded pituitary tissues revealed that CXCR4 is highly expressed in GH-producing pituitary adenomas and NFPAs. Direct sequencing showed that two synonymous mutations in exon 2 (87 C > T and 414 C > T) were detected in 4 out of 51 pituitary tumours. CONCLUSION: Our results indicate that an activating mutation of the CXCR4 may not be a common pathogenetic mechanism in GH-producing pituitary tumours and NFPAs.

Predicting recurrence of nonfunctioning pituitary adenomas.

CONTEXT: Nonfunctioning pituitary adenomas are commonly diagnosed as large tumors. Most are detected incidentally during imaging studies or as a result of neurological manifestations. Depending on severity, most patients with large tumors require surgery and adjunctive therapies because of the high rate of tumor recurrence. The ability to predict the recurrence of a tumor at the time of the initial surgery would be helpful in deciding whether adjunctive therapy is necessary and decreasing morbidity. We investigated the use of several cellular markers for predicting the recurrence of nonfunctioning pituitary adenomas. OBJECTIVE: A tissue array block was made using tissue from 35 cases of nonfunctioning pituitary adenomas (16 cases with early recurrence 4 yr after surgery, and nine cases without recurrence). Levels of tumor tissue cellular markers associated with cell proliferation or apoptosis were analyzed, and immunohistochemical study of cellular markers was conducted using sectioned slides from the tissue array block. RESULTS: High Ki-67 and TUNEL labeling indexes were associated with recurrent nonfunctioning pituitary adenomas. Tumors with a high level of expression of phospho-Akt, phospho-p44/42 MAPK, and PTTG1 were associated with early recurrence. However, high levels of expression of phospho-CREB and ZAC1 were inversely associated with recurrence. CONCLUSIONS: Tumors with high levels of expression of phospho-Akt and phospho-p44/42 MAPK and low levels of expression of phospho-CREB and ZAC1 should be followed closely and may require adjunctive therapy to prevent tumor recurrence.

Diagnostic efficacy and characteristic feature of MRI in pulmonary hamartoma: comparison with CT, specimen MRI, and pathology.

OBJECTIVES: To determine the diagnostic efficacy of magnetic resonance imaging (MRI) in pulmonary hamartoma and observe the significant MRI features, other than fat or characteristic calcification revealed by computed tomography (CT). METHODS: Six hamartomas were included and surgically resected, and we prospectively studied MRI in cases showing suggestive findings of hamartoma or indeterminate nodule on CT. We analyzed the tumor on CT and MRI (available enhancement study in 4) focusing on cleftlike structure in comparison with specimen MRI (n = 3) and histopathologic findings: presence, shape, and distribution of the cleftlike structure and signal intensity and enhancement of the cleftlike structure and main portion. RESULTS: Computed tomography revealed suggestive findings of pulmonary hamartoma (fat or popcorn calcification) in only 3. All MRI revealed cleftlike structures particularly evident on T2-weighted images with same detectability as its specimen MRI: peripheral linear or curvilinear inclusions with sometimes intratumoral cleftlike space (n = 3), variable signal intensity, and frequent enhancement (3 in 4) pathologically correlated with the variable mesenchymal tissue components and amount arrayed along respiratory epithelial cells lining the cleft and richer vascularity than main portion of pulmonary hamartoma. CONCLUSIONS: Magnetic resonance imaging study is a useful diagnostic tool, when a discrete pulmonary nodule demonstrates neither fat nor calcification on CT, for detecting the quite typical cleftlike structure in a pulmonary hamartoma and could provide diagnostic confidence.

Nodular gastritis and pathologic findings in children and young adults with Helicobacter pylori infection.

PURPOSE: The aim of this study was to investigate the pathologic characteristics of nodular gastritis in children and young adults infected with Helicobacter pylori (H. pylori). MATERIALS AND METHODS: A total of 328 patients were enrolled in this study, and the diagnosis of H. pylori infection was done with gastroduodenal endoscopy concomitant with a CLO(TM) test and pathologic analysis of the biopsy specimens. Diagnoses of normal, superficial gastritis, nodular gastritis, and peptic ulcer disease were made from the gastroduodenal endoscopic findings. The density of H. pylori organisms in the gastric mucosa was rated as normal, mild, moderate, or marked. The pathologic findings of nodular gastritis were based on the histopathologic findings of inflammation, immune activity, glandular atrophy and intestinal metaplasia. Each of these findings was scored as either normal (0), mild (1), moderate (2), or marked (3) according to the updated Sydney system and using visual analog scales. The gastritis score was the sum of the four histopathologic scores. RESULTS: In this study, nodular gastritis (50.6%) was most common, and mild density (51.5%) H. pylori infection was also common upon microscopic examination. Intestinal metaplasia occurred in 9 patients (2.7%). CONCLUSION: Logistic regression revealed a significant increase in the incidence of nodular gastritis with gastritis score (p=0.008), but not an association with sex, age, or H. pylori density. Gastritis score was the only significant factor influencing the occurrence of nodular gastritis. Intestinal metaplasia, which was originally thought to be a pre-malignant lesion, occurred in 2.7% of the patients with H. pylori infection.

Sclerosing lobular hyperplasia: sonographic pathologic correlation.

The objective was to evaluate the sonographic findings of sclerosing lobular hyperplasia (SLH) of the breast and to correlate the sonographic findings and the pathologic features. This study consisted of 9 patients with pathologically proven sclerosing lobular hyperplasia who had undergone a preoperative imaging study. We retrospectively reviewed 9 ultrasonograms and 6 mammograms. In each patient mammographic findings including, shape and margin, and ultrasonographic findings including the size, length-to-anteroposterior ratio, shape, margin, internal echo pattern, and the presence and location of internal echogenic septum, were evaluated. Histopathologic correlations focused on characteristic imaging findings. Of the 6 mammograms, 4 cases showed a lobular (3 of 6) or an oval shaped mass (1 of 6) with a partly obscured margin (4 of 6). The remaining 2 cases showed heterogeneously dense breast without visible mass. Ultrasonograms showed a lobular (5 of 9) or an oval (4 of 9) shaped mass with a circumscribed margin (9 of 9). The mean length/anteroposterior ratio was 1.98. Intratumoral echogenic septum was present in 8 cases. Six cases had a peripherally arising septum. Histopathologic review revealed that this septum was correlated to interlobular sclerosis. A peripherally arising intratumoral echogenic septum on ultrasonography seen in SLH might be explained by the interlobular sclerosis.

Steatocystoma multiplex: mammographic and sonographic manifestations.

OBJECTIVE: This study was performed to identify the typical imaging features of steatocystoma multiplex on mammography and sonography. CONCLUSION: Steatocystoma multiplex is manifest by multiple clinically palpable skin-colored or yellow nodules scattered on the axillae and the anterior chest wall. Steatocystoma multiplex is included in the differential diagnoses of lipoma, fat necrosis, galactocele, epidermal cyst, and so on, so radiologists need to be aware of its distinguishing features. The findings of a well-circumscribed round fat-density nodule on mammography or an intradermal hypoechoic nodule on sonography, combined with a family history of steatocystoma multiplex (40%) and an extensive bilateral spatial distribution of nodules, confirm the diagnosis of steatocystoma multiplex.

Mucinous versus nonmucinous gastric carcinoma: differentiation with helical CT.

PURPOSE: To assess the capability of helical computed tomography (CT) to assist in the differentiation between mucinous and nonmucinous gastric carcinomas, with a focus on the thickened stomach wall itself. MATERIALS AND METHODS: In 62 patients with pathologically proved mucinous (n = 21) or nonmucinous (n = 41) gastric carcinomas, contrast material-enhanced helical CT images were obtained. The gross appearance, contrast enhancement pattern, predominant thickened layer, and degree of enhancement were retrospectively evaluated. Statistical analyses were performed with Fisher exact, chi(2), and Student t tests. A P value of less than.05 was considered to indicate a statistically significant difference. RESULTS: The most common type of gross appearance in both carcinomas was fungating: It occurred in 71% of patients with mucinous carcinomas and in 59% of patients with nonmucinous carcinomas. The next most common gross appearance type was ulcerative (24% of patients) in nonmucinous carcinomas and diffusely infiltrative (29% of patients) in mucinous carcinomas (P =.009). The most common contrast enhancement pattern was homogeneous (61% of patients) in nonmucinous carcinomas and layered (62% of patients) in mucinous carcinomas (P =.001). These findings were significantly different. The predominantly affected thickened layer was the high-attenuating inner layer or the entire layer (88% of patients) in nonmucinous carcinomas and the low-attenuating middle or outer layer (57% of patients) in mucinous carcinomas. Only two mucinous tumors showed miliary punctate calcifications in infiltrative lesions. CONCLUSION: Helical CT may assist in distinguishing mucinous from nonmucinous gastric carcinoma, primarily on the basis of enhancement pattern, predominant layer of the thickened wall, gross appearance, and presence of calcifications.

Clinicopathologic review of pulmonary silicone embolism with special emphasis on the resultant histologic diversity in the lung--a review of five cases.

It is known that the subcutaneous injection of silicone can lead to severe pulmonary complications, followed in some patients by respiratory failure. Currently, silicone is being increasingly applied in the field of plastic surgery and, unfortunately, the illicit injection of silicone fluid by uncertified practitioners is not uncommon in Korea. We offer a critical pathologic review of 5 cases of pulmonary silicone embolism following illegal injection to the vaginal wall, four of which were fatal and came to legal autopsy. Our findings again confirm that subcutaneously injected silicone can gain access to the pulmonary vascular tree and cause pulmonary embolism. The histologic changes observed in the lung are variable and include four patterns i.e., the mere presence of silicone emboli, congestion and hemorrhage, acute pneumonitis, and diffuse alveolar damage despite the severe critical course in all cases. We were unable to find any histologic pattern that correlates well with the clinical course. Apart from producing emboli in the pulmonary vessels, subcutaneous injection of silicone can obviously cause serious pulmonary disease due to its ability to induce acute to induce acute pneumonitis and even possibly acute respiratory distress syndrome.