Toshiro Yokoyama

Tumor Growth Suppression in Pancreatic Cancer by a Putative Metastasis Suppressor Gene Cap43/NDRG1/Drg-1 through Modulation of Angiogenesis

Cap43 has been identified as a nickel- and calcium-induced gene, and is also known as N-myc downstream-regulated gene 1 (NDRG1), Drg-1 and rit42. It is also reported that overexpression of Cap43 suppresses metastasis of some malignancies, but its precise role remains unclear. In this study, we asked how Cap43 could modulate the tumor growth of pancreatic cancer. Stable Cap43 cDNA transfectants of pancreatic cancer cells with Cap43 overexpression showed similar growth rates in culture as their control counterparts with low Cap43 protein level. By contrast, Cap43 overexpression showed a marked decrease in tumor growth rates in vivo. Moreover, a marked reduction in tumor-induced angiogenesis was observed. Gelatinolytic activity by matrix metalloproteinase-9 and invasive ability in Matrigel invasion activity were markedly decreased in pancreatic cancer cell lines with high Cap43 expression. Cellular expression of matrix metalloproteinase-9 and two major angiogenic factors, vascular endothelial growth factor and interleukin-8, were also significantly decreased in cell lines with Cap43 overexpression as compared with their parental counterparts. Immunohistochemical analysis of specimens from 65 patients with pancreatic ductal adenocarcinoma showed a significant association between Cap43 expression and tumor microvascular density (P = 0.0001) as well as depth of invasion (P = 0.0003), histopathologic grading (P = 0.0244), and overall survival rates for patients with pancreatic cancer (P = 0.0062). Thus, Cap43 could play a key role in the angiogenic on- or off-switch of tumor stroma in pancreatic ductal adenocarcinoma.

Characteristic Morphology of Invasive Micropapillary Carcinoma of the Breast: An Immunohistochemical Analysis

OBJECTIVE Invasive micropapillary carcinoma of the breast is a distinct variant of breast cancer. In the present study, we analyzed potential immunophenotypic changes in invasive micropapillary carcinoma. METHODS Specimens from 15 patients with invasive micropapillary carcinoma were analyzed using clinicopathological and immunohistochemical methods. We also examined the relationship between clinicopathological factors using the Ki-67 labeling index. RESULTS Immunohistochemical staining for cytoplasmic p63 expression was seen in four (27%) tumors, and p63 nuclear expression was also observed in four (27%) tumors. Involucrin and 34betaE12 were expressed in the invasive micropapillary carcinoma component of nine (60%) and four (27%) tumors, respectively. Cytokeratin 5/6 was expressed in three (20%) tumors and cytokeratin 14 staining was negative in all tumors. In one tumor (case 3), vimentin, epithelial membrane antigen and cytokeratin 8/18 were co-expressed. Four tumors (27%) were negative for the estrogen receptor/progesterone receptor/HER2. However, 11 out of 15 (73%) tumors were positive for the estrogen receptor. The Ki-67 labeling index was significantly higher in cases with p63 tumor expression than in those without (P < 0.0001), and also higher in cases with lymph node metastasis than in cases without (P = 0.0029). CONCLUSIONS Nuclear expression of p63, involucrin and 34betaE12 were detected indicating squamous differentiation. Cytoplasmic p63 expression was also identified. The fact that the Ki-67 labeling index was significantly higher in such cases may have been associated with the aggressive behavior of these tumors. Our findings suggest that the characteristic morphology of invasive micropapillary carcinomas may be due to immunophenotypical and oncogenic changes.

Management of breast papillary lesions diagnosed in ultrasound-guided vacuum-assisted and core needle biopsies

To assess the outcome of breast papillary lesions diagnosed by ultrasound‐guided core needle biopsy (CB) or vacuum‐assisted ‘mammotome’ biopsy (MT), the accuracy of these diagnoses, and whether it is justified not to undertake surgical excision of non‐malignant papillary lesions so diagnosed.

Cytologic features of the endometrial adenocarcinoma: Comparison of ThinPrep and BD surepath preparations

We compared the cytoarchitectural features used for the cytologic diagnosis of endometrial adenocarcinoma (EC) using ThinPrep® (TPS = ThinPrep Sample) and BD SurePath™ (SPS = SurePath Sample) preparations. In 20 patients, a direct endometrial sample using the Uterobrush was obtained. Nineteen cases of EA and one case of carcinosarcoma were studied. TPS and SPS were performed according to the manufacturers recommendations. Moreover, after the TPS preparation, the residual material was also used to prepare an SPS sample (TP–SPS = ThinPrep–Surepath sample). The following points were investigated in both preparations: (1) number of cell clumps; SPS had a significantly higher (20.9) than TPS (1.7) and TP–SPS (10.3); (2) long axis of clumps; SPS had a significantly higher (215.4) than TPS (146.0); (3) rate of cell clumps with longer axes than 200 μm; SPS had a significantly higher (36.7) than TPS (15.2) and TP–SPS (24.2). TP–SPS showed higher values than TPS; (4) nuclear area; TPS had a significant higher (61.2) than SPS (40.8) and TP–SPS (38.6); (5) degree of overlapping nuclei; SPS (3.4) had a significantly higher number of overlapping nuclei than TPS (0.7) and TP–SPS (2.1); (6) nuclear chromatin pattern; no significant differences for the nuclear chromatin pattern were found in the three different methods. The poor performance of TPS versus SPS and TP–SPS was explained with the heavy blood contamination of the samples, and the absence of adhesive coating in the slides is used for TPS. Further investigation of technical differences in liquid‐based cytology methodologies is needed. Diagn. Cytopathol. 2013;41:673–681.

p63 Expression of Clear Myoepithelial Cells in Epithelial-Myoepithelial Carcinoma of the Salivary Gland A Useful Marker for Naked Myoepithelial Cells in Cytology

The typical form of epithelial‐myoepithelial carcinoma (EMC) is a double‐layered ductal structure, but occasionally EMC presents as a predominant solid growth of clear myoepithelial cells. In the current study, the authors analyzed the distribution and visual patterns of p63‐positive clear myoepithelial cells in EMC.

Transient reduction and activation of circulating dendritic cells in patients with acute myocardial infarction.

BACKGROUND Dendritic cells (DCs) are highly potent professional antigen-presenting cells that play a central role in initiating the primary immune response. Accumulating evidence suggests that immune-mediated inflammation plays an important role in the pathophysiology of AMI, but the mechanism that triggers such immune responses is unknown. METHODS Using multi-color flow-cytometry, we determined the numbers of circulating myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in patients with AMI (n = 26) or stable angina pectoris (SAP) (n = 19), and in age-matched control subjects (n = 19). The DC activation markers CD40 and CD83 were also measured. RESULTS On admission, circulating mDC and pDC counts were significantly lower in AMI patients compared to control subjects and SAP patients (mDC, P < 0.01; pDC, P < 0.05). The activation markers of mDCs in AMI patients were significantly higher and returned to the levels of control subjects or SAP patients 3 days after AMI (mDC, P < 0.05; pDC, P < 0.05). Reductions of circulating mDC and pDC numbers were restored 7 days after the onset of AMI. Furthermore, we found that the recovery of the circulating DC numbers 14 days after AMI was correlated with the alterations of creatine kinase-MB (CK-MB) (mDC, r = 0.48, P < 0.05; pDC, r=0.52, P < 0.01) and brain natriuretic peptide (BNP) (mDC, r = 0.53, P < 0.01; pDC, r = 0.51, P < 0.01). CONCLUSION Our findings suggest that the transient reduction and activation of circulating DCs may play important roles in the pathophysiology of myocardial injury after AMI.

Myxomatous fibroadenoma of the breast: correlation with clinicopathologic and radiologic features

Fibroadenoma is a frequently encountered benign tumor that must be differentiated from carcinoma. Fibroadenomas often exhibit myxedematous changes (myxomatous fibroadenoma). We focused on myxomatous fibroadenomas and evaluated their diagnostic imaging and clinicopathologic findings. We examined the (1) clinicopathologic findings of myxomatous fibroadenomas out of 113 fibroadenomas among 592 needle biopsy cases and (2) clinical findings of 27 patients with fibroadenoma who underwent surgical resection. One hundred thirteen (19%) of 592 cases were fibroadenoma, of which 45 cases (40%) were myxomatous fibroadenoma. Based on ultrasonography findings, the depth to width ratio was significantly higher in the myxomatous fibroadenoma group (0.79 ± 0.26) compared with the non-myxomatous fibroadenoma group (0.64 ± 0.26) (P < .01). Forty-two patients were subjected to needle biopsy to differentiate fibroadenoma from carcinomas based on ultrasonography and clinical findings, of which 13 cases (31%) were myxomatous fibroadenoma. These lesions showed a relatively round shape and increased posterior echo enhancement with internal hyperechogenicity on ultrasonography. Among 17 resected cases suspected of malignancy that showed rapid growth and/or size greater than 3 cm, 16 cases were myxomatous fibroadenoma. Tumors showing rapid growth and a relatively large size, a high depth to width ratio, a relatively round shape, and posterior echo enhancement with internal hyperechogenicity on ultrasonography require differentiation from (mucinous) carcinoma but are histologically more likely to be myxomatous fibroadenoma. Understanding the histologic features and combining the ultrasonography findings of myxomatous fibroadenomas may permit reduction in the number of unnecessary needle biopsies for tumor-forming lesions.

Characterization of the epithelial components in pleomorphic adenoma of the salivary gland

OBJECTIVE To clarify the cytomorphologic characteristics of luminal epithelial cells (LEC) and neoplastic myoepithelial cells (NMC) in pleomorphic adenoma (PA). STUDY DESIGN Imprint cytologic smears stained with Papanicolaou stain were examined in 20 patients with PA (including recurrent cases). Immunocytochemistry was performed using the antibodies of epithelial membrane antigen (EMA) and carcinoembryonic antigen (CEA); cells positive for both CEA and EMA were interpreted as LEC and those negative as NMC. RESULTS LEC were found in 9 of 20 cases as cell clusters in various shapes or as isolated cells with ample cytoplasm. NMC were classified into four types according to their visual patterns and cytoplasmic features: type A, isolated cells with ample cytoplasm; type B, isolated naked cells; type C, cluster of cells with ample cytoplasm; and type D, cluster of cells with scant cytoplasm. NMC were found in all 20 cases, with an absolute incidence of 100%, 90%, 65% and 50%, respectively. CONCLUSION The different features of NMC (Types A-D) are essential to a specific differential diagnosis. This classification was useful to discriminate PA from other salivary gland tumors with NMC.

Cytomorphologic features of a polymorphous low grade adenocarcinoma of the palate. A report of 2 cases with immunocytochemistry.

BACKGROUND Polymorphous low grade adenocarcinoma (PLGA) is a histologically low grade tumor of minor salivary gland origin. It is important to differentiate PLGA from other salivary gland tumors with myoepithelial differentiation, such as pleomorphic adenoma, adenoid cystic carcinoma and epithelial myoepithelial carcinoma. Here we report 2 cases of PLGA originating in the palate and describe the cytomorphologic and immunocytochemical features. CASES The patients were a 55-year-old woman and a 63-year-old man. Both presented with a mass in the palate. Clinically the mass appeared malignant, and resection was performed. Cytologically the tumor cells were composed of sheet clusters, pseudopapillary epithelial clusters, naked cells and stromal components. Immunocytochemically the tumor cells showed strong expression of carcinoembryonic antigen (CEA) and vimentin. CONCLUSION PLGA may be difficult to distinguish from other salivary gland tumors with myoepithelial differentiation. However, the cytopathologist should be aware of the distinctive cytomorphologic features of PLGA, demonstrating immunopositivity to CEA and vimentin.

Evaluation of inadequate, indeterminate, false-negative and false-positive cases in cytological examination for breast cancer according to histological type

BackgroundWe previously investigated the current status of breast cytology cancer screening at seven institutes in our area of southern Fukuoka Prefecture, and found some differences in diagnostic accuracy among the institutions. In the present study, we evaluated the cases involved and noted possible reasons for their original cytological classification as inadequate, indeterminate, false-negative and false-positive according to histological type.MethodsWe evaluated the histological findings in 5693 individuals who underwent cytological examination for breast cancer (including inadequate, indeterminate, false-negative and false-positive cases), to determine the most common histological types and/or features in these settings and the usefulness/limitations of cytological examination for the diagnosis of breast cancer.ResultsAmong 1152 cytologically inadequate cases, histology revealed that 75/173 (43.6%) cases were benign, including mastopathy (fibrocystic disease) in 38.6%, fibroadenoma in 24.0% and papilloma in 5.3%. Ninety-five of 173 (54.9%) cases were histologically malignant, with scirrhous growing type, invasive ductal carcinoma (SIDC) being significantly more frequent (49.5%) than papillotubular growing type (Papi-tub) (P < 0.0001), solid-tubular growing type (P = 0.0001) and ductal carcinoma in situ (DCIS) (P = 0.0001). Among 458 indeterminate cases, 54/139 (38.8%) were histologically benign (mastopathy, 30.0%; fibroadenoma, 27.8%; papilloma, 26.0%) and 73/139 (52.5%) were malignant, with SIDC being the most frequent malignant tumor (37.0%). Among 52 false-negative cases, SIDC was significantly more frequent (42.3%) than DCIS (P = 0.0049) and Papi-tub (P = 0.001). There were three false-positive cases, with one each of fibroadenoma, epidermal cyst and papilloma.ConclusionsThe inadequate, indeterminate, false-negative and false-positive cases showed similar histological types, notably SIDC for malignant tumors, and mastopathy, fibroadenoma and papilloma for benign cases. We need to pay particular attention to the collection and assessment of aspirates for these histological types of breast disease. In particular, several inadequate, indeterminate and false-negative cases with samples collected by aspiration were diagnosed as SIDC. These findings should encourage the use of needle biopsy rather than aspiration when this histological type is identified on imaging. Namely, good communication between clinicians and pathological staff, and triple assessment (i.e., clinical, pathological and radiological assessment), are important for accurate diagnosis of aspiration samples.Virtual slidesThe virtual slide(s) for this article can be found here:http://www.diagnosticpathology.diagnomx.eu/vs/7349809170055423