Biomedical subjects

Takaaki Sano

Publications and source records attributed to Takaaki Sano.

At least 19 recordsLinked to original sources

PubMed2007

Clear cell carcinoid tumor of the distal common bile duct.

BACKGROUND: Carcinoid tumors rarely arise in the extrahepatic bile duct and can be difficult to distinguish from carcinoma. There are no reports of clear cell carcinoid (CCC) tumors in the distal bile duct (DBD) to the best of our knowledge. Herein, we report a CCC tumor in the DBD and review the literature concerning extrahepatic bile duct carcinoid tumors. CASE PRESENTATION: A 73-old man presented with fever and occult obstructive jaundice. Ultrasonography, computed tomography (CT) and magnetic resonance cholangiopancreaticography (MRCP) demonstrated a nodular tumor projection in the DBD without regional lymph node swelling. Under suspicion of carcinoma, we resected the head of the pancreas along with 2nd portion duodenectomy and a lymph node dissection. The surgical specimen showed a golden yellow polypoid tumor in the DBD (0.8 x 0.6 x 0.5 cm in size). The lesion was composed of clear polygonal cells arranged in nests and a trabecular pattern. The tumor invaded through the wall into the fibromuscular layer. Immunohistochemical stains showed that neoplastic cells were positive for neuron-specific enolase (NSE), chromogranin A, synaptophysin, and pancreatic polypeptide and negative for inhibin, keratin, CD56, serotonin, gastrin and somatostatin. The postoperative course was uneventful and he is living well without relapse 12 months after surgery. CONCLUSION: Given the preoperative difficulty in differentiating carcinoid from carcinoma, the pancreaticoduodenectomy is an appropriate treatment choice for carcinoid tumors located within the intra-pancreatic bile duct.

Adenocarcinoma, Clear Cell↗

PubMed2006

Prognostic model of stage II non-small cell lung cancer by a discriminant analysis of the immunohistochemical protein expression.

PURPOSE: We aimed to identify the key proteins that influence the prognosis of non-small cell lung cancer (NSCLC) using protein expression profiles of previously known prognostic markers. METHODS: Thirty-one cases of Stage II NSCLC with 5-year follow-up data were selected. Tissue microarrays (TMA) and immunohistochemistry were used to make protein expression profiles of 18 previously reported immunohistochemical prognostic markers and their value in NSCLC was statistically re-evaluated by a discriminant analysis. RESULTS: For the discriminant analysis using marker protein expression profiles, we selected three significant markers, TTF-1, RCAS1 and c-MET, to evaluate each patient's 5-year survival. The requested discriminant function was V = -1.08754 x (RCAS1 score) - 0.83174 x (TTF1 score) + 0.55204 x (cMET score) + 5.46972, and V = 0 served as a cut-off point. The correctness for evaluating a patient's 5-year survival by a discriminant analysis was 87.1%. CONCLUSIONS: A discriminant analysis is thus considered to be a useful statistical method for analyzing the protein expression profiles obtained by combined TMA and immunohistochemical techniques using archival NSCLC tissues. However, the sample size and selection of the marker protein depending on the histology greatly influence the results of a NSCLC study.

Antigens, Neoplasm↗

PubMed2006

Unique case of pulmonary bronchial gland type tumor with broad spectrum of cell differentiation from the terminal duct-acinar unit to excretory duct.

In the lung, acinic cell carcinoma (ACC) is a rare form of tumor. Reported herein is a unique bronchial gland-type tumor diagnosed as well-differentiated ACC that developed in the B9 bronchus of the left lung. Various immunohistochemical and histochemical staining partly satisfied the diagnosis of ACC. Moreover, this tumor contained various sizes of mucous cysts lined by columnar mucous cells, which produced abundant mucin positive for Alcian blue, which is usually present in mucoepidermoid carcinoma. Therefore, the present case is a unique tumor having a broad spectrum of cell differentiation from the terminal duct--acinar unit to the striated duct and excretory duct. This is the first case of unique bronchial gland-type tumor with mixed histological features of ACC and mucoepidermoid carcinoma.

Carcinoma, Acinar Cell↗

PubMed2006

Predictive and prognostic role of activated mammalian target of rapamycin in cervical cancer treated with cisplatin-based neoadjuvant chemotherapy.

The present study was designed to clarify the expression and prognostic significance of activated Akt and mTOR in cervical cancer and their correlation with response to neoadjuvant chemotherapy (NAC). Immunohistochemical analysis for p-Akt and p-mTOR expression was performed on paraffin-embedded biopsy specimens from 25 patients with advanced cervical cancer (stage Ib2-IIb). We correlated this finding with various clinicopathological variables and prognosis by uni- and multivariate analyses. All patients received cisplatin-based NAC, and primary tumor response was evaluated by RECIST criteria and then classified as a positive or negative response. Activation of Akt was detected in the cytoplasm and nucleus of the cancer cells in 12 patients (48%), whereas p-mTOR was detected in the cytoplasm and membrane of the cancer cells in 13 patients (52%). Post NAC evaluation of the primary tumor revealed 68% (17/25) responsive tumors. The expression of p-mTOR and distant metastasis significantly correlated with the response to NAC (p = 0.0101 and p = 0.0107); however, there was no significant correlation between p-Akt and p-mTOR expression and any of the clinicopathological characteristics of the patients. In the univariate analysis, activated Akt and mTOR were found to be significant prognostic indicators (p < 0.05). In multivariate analysis, p-mTOR expression retained its significance as an independent poor prognostic marker (p = 0.0178). In summary, our present study showed that cervical cancer expressed Akt and mTOR activation. Moreover, the expression of phosphorylated mTOR may have a role as a marker to predict response to chemotherapy and survival of cervical cancer patients who are treated with cisplatin-based neoadjuvant chemotherapy. Our results suggest that the mTOR cascade may be a promising target for therapeutic intervention in cervical cancer.

Adult↗

PubMed2005

Pulmonary pleomorphic liposarcoma.

Pulmonary liposarcoma is extremely rare with 6 cases previously reported in the English literature. The following is a report of a 36-year-old man with pulmonary liposarcoma. The patient had chest pain and a mass shadow in the right lower lung field was revealed on a chest X-ray film. A computed tomography and magnetic resonance imaging showed a heterogeneous tumor, compressing the right lower lobe of the lung. Because of the fatty tissue component in the tumor on the chest computed tomography, and the appearance as an extrapulmonary mass, preoperative diagnosis was posterior mediastinal liposarcoma. But thoracotomy revealed that the tumor originated from the lung. Right lower lobectomy and lymph node dissection was carried out with no additional therapy. The pathological diagnosis was pleomorphic liposarcoma originated from the lung. Two months after the operation, the patient died of respiratory failure due to local recurrence.

Adult↗

PubMed2005

Large cell neuroendocrine carcinoma of the lung: a comparison with large cell carcinoma with neuroendocrine morphology and small cell carcinoma.

Large cell neuroendocrine carcinoma (LCNEC) of the lung is a malignant neuroendocrine tumor clinicopathologically similar to and falling in-between atypical carcinoid tumor and small cell lung carcinoma (SCLC). The diagnosis of LCNEC is based mainly on a characteristic neuroendocrine morphology and biological neuroendocrine differentiation. In order to know the discrepancy between morphological and biological neuroendocrine differentiation, LCNEC was immunohistochemically and molecular biologically compared with large cell carcinoma with neuroendocrine morphology (LCCNM), which lacked only biological neuroendocrine differentiation among the criteria of LCNEC. Immunohistochemically, disruption of the RB pathway, namely a lack of RB expression and simultaneous overexpression of p16 protein, was characteristic of LCNEC, but not LCCNM. In G2/M cell cycle regulation, 14-3-3 sigma expression was markedly reduced in LCNEC. Moreover, the antibody 34 beta E12 recognizing a set of large-sized keratin gave a different staining pattern between LCNEC and LCCNM. The immunohistochemical data suggested that LCNEC has a similar biological marker profile to SCLC and different from LCCNM. However, a loss of heterozygosity (LOH) analysis using microsatellite markers showed a high frequency of LOH at 3p in both LCNEC and LCCNM as well as in SCLC. Morphological neuroendocrine differentiation might not be identical to biological neuroendocrine differentiation in large cell carcinoma of the lung.

Aged↗

PubMed2005

PKC theta, a novel immunohistochemical marker for gastrointestinal stromal tumors (GIST), especially useful for identifying KIT-negative tumors.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor in the digestive tract and the majority of GIST has characteristic gain-of-function mutations of the c-kit gene, which encodes the KIT receptor for stem cell factor. The present study aimed to establish the usefulness of protein kinase C theta (PKC theta) as an immunohistochemical marker for GIST in comparison with KIT immunohistochemistry. PKC theta immunohistochemistry was carried out not only on 48 cases of GIST and another 40 cases of gastrointestinal mesenchymal tumors, but also on 24 cases of various tumors known to be immunohistochemically positive for KIT. Immunohistochemically, 41 out of 48 cases (85%) of GIST were positive for PKC theta, and its expression was confirmed by Western blot analysis using six cases of surgically resected GIST. In the present study there were six GIST immunohistochemically negative for KIT, which histologically revealed a myxoid epithelioid appearance characteristic to that of GIST with platelet-derived growth factor receptor alpha mutation. All six GIST were immunohistochemically positive for PKC theta. No PKC theta immunoreactivity was observed in other gastrointestinal mesenchymal tumors and various KIT-positive tumors except for three cases (14%) of gastrointestinal schwannomas. The present study revealed that PKC theta is an immunohistochemically novel and useful marker for GIST, especially for GIST negative for KIT.

Biomarkers, Tumor↗

PubMed2005

Papillary adenocarcinoma of the lung is a more advanced adenocarcinoma than bronchioloalveolar carcinoma that is composed of two distinct histological subtypes.

To clarify the clinicopathological nature of papillary adenocarcinoma (PA) of the lung, 20 cases of PA were collected consecutively from resected adenocarcinoma of the lung, studied immunohistochemically and, using molecular techniques, compared with bronchioloalveolar carcinoma (BAC). Clinicopathologically, PA occurred in 7.4% and dominantly in female patients. Morphologically, PA was divided into two subtypes according to the presence of residual alveolar structures, detected by elastica van Gieson stain. One of these subtypes was closely related to the morphology of BAC and might be diagnosed as adenocarcinoma with mixed subtypes. The other PA subtype was composed of tall columnar cells and grew compressively, which was similar to type F adenocarcinoma previously reported by Noguchi et al. Immunohistochemical studies using lung tissue-specific antigens, progression markers and tumor suppressor products found that PA seemed a more advanced adenocarcinoma than BAC, but no differences were observed among PA subtypes. Molecular biological analysis using three microsatellite markers at chromosome 3p revealed more frequent loss of heterozygosity in PA than BAC, with no differences among PA subtypes. These findings suggest that PA is a more advanced adenocarcinoma subtype than BAC. Further investigations are needed to clarify true PA as clinicopathologically and biologically independent from other histological subtypes of adenocarcinoma of the lung.

Adenocarcinoma, Bronchiolo-Alveolar↗

PubMed2005

Increasing 14-3-3 sigma expression with declining estrogen receptor alpha and estrogen-responsive finger protein expression defines malignant progression of endometrial carcinoma.

14-3-3 sigma (sigma) is a negative regulator of the cell cycle and contributes to G2 arrest. Lack of its expression due to hypermethylation of CpG islands has been reported in some carcinomas. A recent study showed that 14-3-3 sigma was down-regulated through proteolysis by estrogen-responsive finger protein (Efp). Here, we investigated the expression of 14-3-3 sigma, hormone receptors, Efp and p53 in 86 cases of endometrial adenocarcinoma and 46 cases of normal or non-neoplastic endometria by means of immunohistochemistry and methylation-specific polymerase chain reaction. In normal endometrium, 14-3-3 sigma was overexpressed in the mid- to late-secretory phase due to hypomethylation. In endometrial adenocarcinoma, 14-3-3 sigma expression was low in low grade endometrioid adenocarcinoma due to hypermethylation, and increased significantly with increasing histological grade due to hypomethylation. 14-3-3 sigma expression inversely correlated with estrogen receptor alpha, progesterone receptor and Efp, and positively correlated with myometrial invasion and lymph node metastasis. These results suggest that 14-3-3 sigma was one of the menstrual cycle-related proteins regulated by epigenetic methylation, and its expression was influenced by epigenetic methylation or hormone receptors in progression of endometrial adenocarcinoma, and therefore was more than just a cell-cycle regulator.

14-3-3 Proteins↗

PubMed2005

A comparison of interobserver reproducibility of Gleason grading of prostatic carcinoma in Japan and the United States.

CONTEXT: Gleason grading is now the sole prostatic carcinoma grading system recommended by the World Health Organization. It is imperative that there be good interobserver reproducibility within this system worldwide. To our knowledge, there are no studies, using the same specimens, that compare the interobserver reproducibility of Gleason grading in Japan and the United States. OBJECTIVE: To compare the interobserver reproducibility of Gleason grading of prostatic carcinoma in Japan and the United States using, in Japan, images from the identical biopsy glass slides that were originally graded in the United States. DESIGN: Microsopic images from 37 needle biopsies of prostatic carcinoma were placed on CD-ROM and distributed to 14 Japanese pathologists for grading. These 14 physicians included 8 general pathologists and 6 pathologists with a special interest in urologic pathology. The needle biopsies had been previously reviewed so that a consensus diagnosis could be formed by a panel of urologic pathologists in the United States and Canada. Interobserver agreement with the consensus diagnoses was calculated by determining the overall kappa coefficient for the Japanese pathologists and then compared to the interobserver agreement among American general pathologists who had previously graded identical needle biopsies from which the CD-ROM images had been taken. RESULTS: The interobserver agreement with the consensus diagnoses for the 4 Gleason grading groups (Gleason grades 2-4, 5-6, 7, and 8-10) among the Japanese urologic pathologists in this series of cases was substantial (overall kappa = 0.68), and for the Japanese general pathologists, it was moderate (overall kappa = 0.49), similar to that reported in the earlier study of American general pathologists (overall kappa = 0.44). The major interobserver reproducibility problem for both Japanese and American general pathologists is undergrading. The major areas of undergrading are the underdiagnosis of Gleason scores 5-6 as Gleason scores 2-4, and the underdiagnosis of cribriform sheets and fragments of cribriform Gleason pattern 4 carcinoma as Gleason pattern 3. CONCLUSIONS: The interobserver reproducibility of the Gleason grading for this collection of specimens was similar among Japanese and American general pathologists. The overall kappa values for these generalists of 0.44 and 0.49 are only in the moderate (0.41-0.60) range of interobserver agreement when compared to 0.68, substantial (0.61-0.80) agreement, for Japanese urologic pathologists. Educational efforts to improve Gleason grading have been shown to be effective and are clearly warranted.

Adenocarcinoma↗

PubMed2004

Usefulness of liquid-based cytology specimens for the immunocytochemical study of p16 expression and human papillomavirus testing: a comparative study using simultaneously sampled histology materials.

BACKGROUND: In cervical lesions, the overexpression of p16 is reported to be closely associated with high-risk human papillomavirus (HPV) infection. The objective of the current study was to confirm the usefulness of liquid-based cervical specimens for p16 staining as well as tissue sections. METHODS: A total of 98 patients with cervical lesions were entered into the current study. After the cytologic examination using liquid-based cervical smears, the same slides were immunostained for p16 and were compared with slides of simultaneously obtained, immunohistologically stained tissue sections. Moreover, the status of the HPV infection was examined by polymerase chain reaction using residual cytologic samples. RESULTS: Using liquid-based Pap smears, 98 cases were diagnosed as atypical squamous cells of undetermined significance (38 cases), low-grade squamous intraepithelial lesion (12 cases), high-grade squamous intraepithelial lesion (HSIL) (33 cases), and invasive carcinoma (15 cases). The concordance rate between the cytologic and histologic diagnoses was found to be higher in high-grade lesions compared with low-grade lesions. Immunohistochemistry revealed that all HSIL and invasive carcinoma cases contained p16-positive cells in the liquid-based Pap smears and diffuse p16 staining was observed in all high-grade lesions with greater than CIN Grade 3 cervical intraepithelial neoplasia except for two adenocarcinoma cases. Of the 98 cases, 60 were found to be positive for high-risk HPV and 55 of these 60 HPV-positive cases were found to be p16 positive on cytologic examination. There were 16 cases that demonstrated marked discrepancies between the cytologic and histologic diagnoses. CONCLUSIONS: The results of the current study confirmed that the immunohistochemical detection of p16 was more sensitive and specific than HPV status in cervical lesions using a liquid-based method as well as tissue samples, suggesting that p16 should be used as a satisfactory biomarker for the primary screening of cervical cytology.

Adenocarcinoma↗

PubMed2004

Immunohistochemical analysis of 14-3-3 sigma and related proteins in hyperplastic and neoplastic breast lesions, with particular reference to early carcinogenesis.

In order to confirm the role of 14-3-3 sigma (sigma) as a tumor suppressor in breast carcinogenesis, we have studied the expression of 14-3-3sigma immunohistochemically in usual ductal hyperplasia (UDH), ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) breast lesions. Immunostaining for estrogen receptor alpha (ERalpha), p53 and estrogen-responsive RING finger protein (Efp) was also carried out. Immunohistochemically, expression of 14-3-3sigma was seen in 92% UDH lesions and gradually decreased from 65% in DCIS to 23% in IDC. The expression of ERalpha decreased gradually from UDH to DCIS to IDC, while p53 showed an inverse staining pattern to that of ERalpha. The expression of Efp showed no significant difference among the three breast lesions. Hence, the present immunohistochemical study confirmed 14-3-3sigma as a tumor suppressor in breast carcinogenesis. A similar immunohistochemical analysis was then carried out on columnar cell hyperplasia with atypia (CCHA), in which the expression pattern of tumor suppressor 14-3-3sigma, ERalpha and p53 suggested that it might be possible that CCHA is a precancerous lesion.

14-3-3 Proteins↗

PubMed2004

Immunohistochemical expression of 14-3-3 sigma protein in various histological subtypes of uterine cervical cancers.

14-3-3 sigma (sigma) has been a major G2/M checkpoint control gene and has demonstrated that its inactivation in various cancers occurs mostly by epigenetic hypermethylation, not by genetic change. In order to confirm 14-3-3sigma protein expression together with p16 and p53 in cervical cancers, immunohistochemistry was performed using various histological subtypes of cervical cancers and dysplasia. Strong and diffuse immunoreactivity for 14-3-3sigma was uniformly observed in all the cervical dysplasia (17/17) and squamous cell carcinomas (29/29) including human papillomavirus (HPV)-negative cases. Even in adenosquamous carcinomas and adenocarcinomas of the cervix, immunohistochemical expression of 14-3-3sigma was shown with relatively high frequency (13/15, 87% and 22/27, 81%). In the in situ hybridization study, mRNA of 14-3-3sigma was expressed in six of eight immunohistochemical-negative cases. Therefore, the undetectable expression of 14-3-3sigma protein in cervical cancers might, at least in part, be due to a proteolysis not epigenetic hypermethylation. It is of interest that cancers without 14-3-3sigma expression were predominantly those lacking HPV DNA, and that there were no cases with concomitant inactivation of 14-3-3sigma and p16 in the present study. These observations are consistent with the hypothesis that inactivation of either 14-3-3sigma or p16 has an effect equivalent to the expression of E6 and E7 oncoproteins of HPV.

14-3-3 Proteins↗

PubMed2003

Immunohistochemical demonstration of 14-3-3 sigma protein in normal human tissues and lung cancers, and the preponderance of its strong expression in epithelial cells of squamous cell lineage.

In order to confirm 14-3-3 sigma (sigma) protein distribution in human tissues, immunohistochemistry was performed using various paraffin-embedded human tissues. In normal human tissues, the strongest immunoreactivity for 14-3-3sigma protein was observed in squamous epithelia at various sites, followed by basal cells of the trachea, bronchus and basal or myoepithelial cells of various glands. Moderate to weak 14-3-3sigma immunoreactivity was seen in the epithelial cells of the alimentary tract, gall bladder, urinary tract and endometrium. In the lung, 14-3-3sigma immunoreactivity was also observed in hyperplastic type II alveolar cells and metaplastic squamous cells. Immunohistochemical study using non-small-cell lung cancers revealed that 14-3-3sigma immunoreactivity was stronger in squamous cell carcinomas than in adenocarcinomas. The present study revealed that 14-3-3sigma expression was exclusively present in various epithelial cells and had a tendency to be stronger in cells destined for squamous epithelium or differentiating toward squamous cells in human normal and neoplastic cells.

14-3-3 Proteins↗

PubMed2003

Synergistic decline in expressions of p73 and p21 with invasion in esophageal cancers.

The significance of the p73 gene, a homologue of the p53 gene, in esophageal cancers is not fully understood. In order to clarify the role of p73 expression in esophageal cancers, p73 expression was immunohistochemically investigated in 106 surgically resected esophageal cancers and the results were compared with various clinicopathological factors. In normal esophageal epithelium, the expression of p73 was observed only in the nuclei of basal cells. In esophageal cancers, p73 immunoreactivity was observed in all intraepithelial lesions except one cancer, and was reduced with cancer invasion, to 78% and 64% at superficial invasion and deep invasion sites, respectively. However, p73 expression was not correlated with any other clinicopathological factor. The expressions of p53 and p21 were also investigated in esophageal cancer. To evaluate the status of the p53 gene mutation immunohistochemically, two monoclonal antibodies (DO7 and PAb240) were used. There seemed to be an inverse correlation between p73 expression and p53 mutation. Moreover, the expression of p21 was highly correlated with p73 expression irrespective of the p53 mutation status. In human esophageal cancers, p73 expression decreased with increasing degree of tumor invasion, and its decreased expression in local advanced tumor caused down-regulation of p21 expression, which might reflect tumor progression.

DNA-Binding Proteins↗

PubMed2002

Ileal perforation caused by cytomegalovirus infection in a patient with recurrent gastric cancer: report of a case.

We report a case of ileal perforation caused by cytomegalovirus (CMV) infection in a patient with peritoneal recurrence of gastric cancer. Emergency laparotomy revealed a pinhole-sized perforation in a reddish segment of the small bowel, 100 cm proximal to the terminal ileum, and peritoneal carcinosis of recurrent gastric cancer invading the transverse colon and the gastrojejunal anastomosis of a Billroth-II procedure. The affected ileum was resected, a primary anastomosis was performed, and a colostomy was made in the ascending colon. The histology of the ileum revealed acute inflammation with vasculitis and CMV inclusions in the macrophages and endothelial cells and evidence of CMV on immunostaining. There was no evidence of cancer cell invasion or any other pathogens. Although the prognosis associated with bowel perforation due to CMV infection is poor, emergency surgery saved our patient's life.

Cytomegalovirus Infections↗

PubMed2002

Aberrant expression of pRb, p16, p14ARF, MDM2, p21 and p53 in stage I adenocarcinomas of the lung.

Cancers are always associated with cell cycle abnormalities. To clarify the cell cycle abnormalities present in lung adenocarcinomas, various cell cycle regulatory proteins of both the pRb and p53 pathways were studied immunohistochemically in 50 cases of stage I adenocarcinoma of the lung. In regard to the pRb pathway, most adenocarcinomas showed frequent expression of both p16 and pRb proteins, and aberrant expression in the pRb pathway was observed in about one-quarter of stage I adenocarcinomas. In regard to the p53 pathway, the frequency of immunohistochemical positivity was 8% for p14ARF, 64% for MDM2, 20% for p53 and 24% for p21. In this pathway, the immunohistochemical profile of p14ARF-negative/MDM2-positive/p53-negative is characteristic of stage I adenocarcinoma of the lung. An inverse relationship was found between MDM2 and p53 protein and was associated with the differentiation status of stage I adenocarcinoma of the lung. Our results suggest that the disruption of the pRb and p53 pathways is frequently observed in the early stages of lung adenocarcinoma and might play an important role in the growth and differentiation of adenocarcinoma of the lung.

Adenocarcinoma↗

PubMed2001

Microcalcifications of breast cancer and atypical cystic lobules associated with infiltration of foam cells expressing osteopontin.

We studied the pattern of calcification and the expression of osteopontin protein and mRNA by the histiocytes and noninvasive carcinoma cells of 20 breast cancers and the histiocytes and atypical ductal cells of sixteen cases of atypical cystic lobules. Ten breast cancers showed low-grade cribriform carcinoma in situ containing secretory material; the remaining ten cancers displayed high-grade carcinoma in situ with central necrosis characteristic of comedo type carcinoma. Hematoxylin-eosin and Kossa staining revealed calcium hydroxyapatite calcifications in 80% of cribriform type carcinomas, 50% of comedo type carcinomas, and 56% of atypical cystic lobules. Immunohistochemical staining demonstrated osteopontin protein in intraluminal secretory material, necrotic debris, or stroma, and in histiocytes in all the Kossa-positive carcinomas and atypical cystic lobules. In situ hybridization revealed osteopontin mRNA mainly in the histiocytes and especially in those near the calcifications. In two cases, rare carcinoma cells contained osteopontin protein and mRNA. The close relation between hydroxyapatite crystals and osteopontin-producing histiocytes suggests that osteopontin plays a role in the biomineralization that occurs in certain noninvasive breast cancers and atypical cystic lobules. The differences in the morphology of the calcifications and the intraductal contents suggest that the mechanism leading to the osteopontin production might vary depending on the underlying lesion.

Biomarkers, Tumor↗