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PubMed1999

Integrin alpha6beta1 role in metastatic behavior of human pancreatic carcinoma cells.

The factors that determine the metastatic behavior of pancreatic tumor cells are incompletely understood. In this study, we first demonstrate differences in adhesion properties, integrin expression and in vivo integrin function in the metastatic tumor cell line PaTu 8988s compared with the non-metastatic cell line PaTu 8988t. Both cell lines were derived from the same original tumor and exhibit identical genetic fingerprints. Using in vitro adhesion assays performed on purified extracellular matrix components, adhesion of PaTu 8988s cells was significantly increased on the basal membrane component laminin and decreased on the interstitial matrix protein fibronectin compared to PaTu 8988t cells. By immunocytochemistry and flow cytometry, and in correspondence with their adhesive properties, the metastatic PaTu 8988s cells did express a distinct pattern of integrin subunits. Laminin-binding integrins alpha6 and beta4 were overexpressed in PaTu 8988s cells. Fibronectin-binding alpha5 integrins were present at higher levels in the non-metastatic PaTu 8988t cells, whereas the beta1 subunit expression did not differ. Adhesion to laminin or fibronectin was specific and was mediated via integrins alpha6beta1 and alpha5beta1, respectively. In addition, metastasis formation in vivo after injection of cells into the tail vein of nude mice was inhibited by preincubation of PaTu 8988s cells with antibodies directed against the integrin alpha6 or beta1. We conclude that alpha6beta1 integrins are overexpressed and functionally active in metastatic human pancreatic carcinoma cells, and participate in metastasis formation probably through binding to the basal membrane component laminin.

Animals↗
PubMed1983

Patterned distribution of metastases from malignant melanoma in humans.

Malignant melanoma has an unpredictable clinical course in terms of metastatic behavior, and further understanding might lead to improved therapeutic intervention with immune agents or antagonists. To determine whether metastases show patterns or are randomly distributed, we analyzed the distributions of metastases in the 56 patients with metastatic malignant melanoma, subjected to complete autopsy at The Johns Hopkins Hospital, using parametric statistics and cluster analysis. Variables examined included age, race, sex, location of primary tumor, length of survival, mode of therapy, histology of tumor, location of metastases, and extent of tumor infiltration at each metastatic site. The results indicate that the distributions of metastases from malignant melanoma are patterned such that significant positive correlations (p less than 0.05 or better) were observed among various tissues and organs. We identified several aggregations with respect to the distributions of metastases: (a) central nervous system; (b) mesodermal; (c) endocrine; (d) reticuloendothelial; and (e) foregut. Organs and tissues comprising each aggregation were interrelated by their similar developmental origins or functions. A very highly significant negative correlation between central nervous system and hepatic metastases (p less than 0.001) was also demonstrated by cluster analysis. We concluded that the distributions of metastases from malignant melanoma are not random; the patterns of metastases may be related to the embryological derivation of tissues involved.

Adult↗
PubMed2001

Detection of occult metastatic lymph nodes in the neck with gray-scale and power Doppler US.

PURPOSE: To determine the most accurate criterion for predicting malignancy of small cervical lymph nodes with gray-scale ultrasound (GSUS) and power Doppler ultrasound (PDUS). MATERIAL AND METHODS: Findings of 69 pathologically verified cervical nodes (38 benign, 31 malignant) in 57 patients without wide echogenic hilum on GSUS that measured less than 10 mm in minimal axial diameter were prospectively studied. Minimal and maximal axial diameters, ratios of minimal to maximal axial diameters, and presence or absence of calcification or necrosis of the nodes were assessed. On PDUS, vascularity in the node was classified into 4 pattern groups. A logistic model was used to evaluate the significant factors for predicting malignancy. RESULTS: The logistic model revealed that the minimal axial diameter and vascularity patterns were the only significant factors for malignancy. Using the minimal axial diameter, a node larger than 8 mm showed the highest accuracy (73%) with 45% sensitivity and 93% specificity. Of the vascularity patterns, spotted or peripheral pattern had the highest accuracy (80%) with 61% sensitivity and 93% specificity. A combined criterion of the minimal axial diameter larger than 8 mm and spotted or peripheral pattern increased the accuracy to 82% and sensitivity to 77% but specificity decreased to 86%. CONCLUSION: A combined criterion of minimal axial diameter and vascular patterns was most accurate for diagnosing occult metastatic lymph nodes in the neck.

Adult↗
PubMed2006

Late relapse of metastatic testicular nonseminomatous germ cell cancer: surgery is needed for cure.

OBJECTIVE: To identify patients with late relapse of metastatic, nonseminomatous germ cell tumour (NSGCT) and to evaluate the patterns of relapse, treatment and outcome, as such relapse at >2 years after complete remission to treatment for metastatic disease (late relapse) is uncommon, but with prolonged follow-up is becoming increasingly recognized. PATIENTS AND METHODS: Between 1980 and 2004, 1405 patients with testicular GCTs were identified who presented to Southampton University Hospital; 742 had NSGCTs or combined testicular GCTs, of whom 405 received primary chemotherapy for metastatic disease. In all, 329 (81%) patients achieved a complete response (CR) to initial treatment, with 101 of them (31%) requiring surgical resection of residual masses after chemotherapy. Any patient relapsing at >2 years after a CR to initial treatment (late relapse) was assessed in detail. RESULTS: In all, 20 patients had a late relapse, 17 of whom received initial treatment locally and three of whom were initially treated elsewhere. Most (65%) late relapses were asymptomatic and detected by routine cross-sectional imaging or rising levels of tumour markers. Late relapse occurred at a median (range) of 108 (26-217) months (approximately 9 years) after CR. Fifteen (75%) patients underwent only surgery for late relapse, including five who had invasive malignant germ cell cancer within the resected specimens. Fourteen of 15 surgically treated patients remained alive at a median of 44 (9-184) months from initial treatment for late relapse; one had died with progressive recurrent germ cell/epithelial malignancy. Five (25%) patients were initially treated with chemotherapy for late relapse; three of them died from progressive germ cell cancer and the two survivors both had surgical excision of residual abnormalities after salvage chemotherapy. Overall, 15 of 20 (75%) men remain alive with no evidence of disease; one further patient is currently undergoing salvage treatment for his third relapse. CONCLUSION: Late relapse is uncommon after modern therapy for metastatic GCTs. Surgical treatment for localized disease, where possible, is associated with prolonged disease-free and overall survival. By contrast, chemotherapy is associated with a low response rate and a poor outcome.

Adolescent↗
PubMed1994

CT of the liver in patients with metastatic breast carcinoma treated by chemotherapy: findings simulating cirrhosis.

OBJECTIVE: Although the hepatotoxic effects of systemic chemotherapy are well known, CT findings in the liver after systemic chemotherapy have received little attention in the literature. In some patients with breast carcinoma metastatic to the liver who have received chemotherapy, a morphologic pattern develops similar to that associated with cirrhosis. This pattern is characterized by a lobular hepatic contour, segmental volume loss, and enlargement of the caudate lobe. The purpose of this study was to describe the CT appearance of this pseudocirrhosis and to correlate it with pathologic findings. MATERIALS AND METHODS: We reviewed 65 CT examinations of 22 patients with stage IV breast carcinoma with hepatic metastases, who were receiving systemic chemotherapy and for whom abdominal CT scans showed pseudocirrhosis. Nineteen of 22 patients had follow-up CT scans at intervals ranging from 1 to 15 months. Criteria for the diagnosis of pseudocirrhosis included a lobular hepatic contour, segmental volume loss, and enlargement of the caudate lobe. CT findings were correlated with pathologic findings in seven patients. RESULTS: In all patients, CT scans showed retraction of the capsular surface of the liver (15 diffuse, seven focal) with a lobular margin, a finding also seen in advanced cirrhosis. The retraction occurred at the site of subjacent metastases. Findings evolved over 1-3 months. Six of seven patients had pathologic findings suggestive of nodular regenerative hyperplasia. No patients had pathologic evidence of cirrhosis. CONCLUSION: In patients undergoing systemic chemotherapy for breast cancer metastatic to the liver, a pattern may develop that mimics the CT appearance of hepatic cirrhosis. Pathologic findings suggest nodular regenerative hyperplasia as a possible cause.

Adult↗
PubMed2002

An overview of neck node sonography.

RATIONALE AND OBJECTIVES: Gray scale and power Doppler sonography are commonly used to evaluate cervical lymph nodes. This study was undertaken to identify which of the features used in ultrasound of cervical lymph nodes is readily applicable in routine clinical practice. METHODS: Two hundred and eight-six patients diagnosed with cervical lymphadenopathy were included in the study. The largest node in each patient was included in the study and the nature of the node was assessed by fine-needle aspiration cytology. Lymph nodes were assessed for their gray scale and Doppler sonographic features. RESULTS: Metastatic, lymphomatous, and tuberculous nodes were round (63-94%) and without echogenic hilus (57-91%). Sharp borders were found in metastatic and lymphomatous nodes (56-100%), but uncommon in tuberculosis (49%). Capsular or mixed vascularity is common in metastatic, lymphomatous, and tuberculous nodes but not found in reactive nodes. Except metastatic nodes from papillary carcinoma of the thyroid that showed low resistance, metastatic nodes had a higher vascular resistance than reactive nodes. Micronodular echo pattern is common in lymphomatous nodes. Hyperechogenicity and punctate calcification are typical features for metastatic nodes from papillary carcinoma of the thyroid. Intranodal cystic necrosis, adjacent soft tissue edema, matting and displaced hilar vascularity are common features in tuberculosis. CONCLUSIONS: Using gray scale and power Doppler sonography, metastatic, lymphomatous, and tuberculous nodes can be differentiated from reactive nodes. Metastatic nodes from papillary carcinoma, lymphoma, and tuberculosis can be identified. However, it is difficult to differentiate metastatic nodes from squamous cell carcinomas, nasopharyngeal carcinoma, and infraclavicular carcinomas, and differentiate metastatic nodes (nonthyroid primary) from tuberculous lymphadenitis.

Humans↗
PubMedDate not supplied

Activity and inhibition by cytotoxic and antimetastatic drugs of cathepsin B-like cysteine proteinase in transplantable leukemias in mice.

The cellular levels of cathepsin B-like cysteine proteinases have been determined in a panel of transplantable mouse leukemias possessing a different potential to metastatize to the liver after i.p. implantation. The higher enzymatic activity observed in L1210 leukemic cells matches their higher capacity for hepatic infiltration. No significant difference is observed for TLX5 lymphoma and P388 leukemia, in spite of their different liver invasiveness, and their enzymatic levels do not significantly differ from that of the non-invasive Ehrlich ascitic carcinoma. The in vivo administration of the antimetastatic drugs ICRF159 and DM-COOK, or of the cytotoxic drugs cyclophosphamide, cisplatin, CCNU and GANU, does not cause a pattern of enzyme inhibition matching the tumor metastatic potential and the increase in life-span of the treated tumor bearing mice, indicating that the inhibition of cathepsin B-like cysteine proteinase is not involved in either their cytotoxic or their antimetastatic action.

Animals↗
PubMed2000

Lipiodol enhanced CT scanning of malignant hepatic tumors.

From August 1984 to March 1991, 41 patients with malignant liver tumors, 30 males and 11 females, aged 30-75 years were treated at Ramathibodi Hospital with injection of mitomycin-C lipiodol emulsion into the tumor via the feeding artery followed by embolization of the feeding artery with gelfoam particles. The patients comprised 30 cases of hepatocellular carcinoma, 4 cases of cholangiocarcinoma and 7 cases of metastatic tumors of which one was from CA stomach, three were from CA breast, and three from CA colon. The vascularity of the tumor was assessed in angiogram obtained prior to treatment and retention pattern of lipiodol in the tumor was evaluated in lipiodol-enhanced CT scan images taken 2-4 weeks following therapy. The results showed that lipiodol CT scan images exhibited four patterns of lipiodol retention in the tumor appearing as opacity as follows (1) homogenous (2) heterogeneous (3) ring-like and (4) none. Lipiodol retention pattern appeared to be somewhat related to vascularity of the tumor. Most of the hypervascular tumors such as hepatocellular carcinoma had homogeneous lipiodol accumulation pattern if the tumor size was less than 5 cm. Metastatic tumors and cholangiocarcinoma showed heterogeneous or ring-like pattern of lipiodol accumulation because they were relatively hypovascular. Hypervascular hepatocellular carcinoma may exhibit heterogeneous or ring-like pattern if they are larger than 5 cms, and have multiple feeding arteries, necrosis or AV shunting. Hepatocellular carcinoma with AV shunting may not show any lipiodol accumulation at all.

Adult↗
PubMed2000

Common and epithelioid variants of hepatic angiomyolipoma exhibit clonal growth and share a distinctive immunophenotype.

Angiomyolipoma represents a rare liver tumor of uncertain histogenesis that is commonly considered a hamartoma. A series of 12 hepatic angiomyolipomas, including 3 samples of the epithelioid subtype, was analyzed for clonality using the human androgen receptor gene locus (HUMARA). Four of 6 informative cases revealed monoclonality. The polyclonal pattern in the 2 remaining cases was most probably caused by excessive infiltration of inflammatory cells. Monoclonality with an identical X-chromosomal inactivation pattern in all nodules was found in a multifocal recurrent tumor indicating a metastatic process. Despite the morphologic heterogeneity, all tumors displayed an identical immunohistochemical labeling pattern. It is concluded that different subtypes of hepatic angiomyolipoma exhibit a monoclonal and hence probably neoplastic growth and share an identical immunophenotype suitable for their identification even in small biopsy specimens. The epithelioid subtype may give rise to intrahepatic metastasis.

Adult↗
PubMed2007

The gene expression profile represents the molecular nature of liver metastasis in colorectal cancer.

The major cause of death in colorectal cancer is related to liver metastasis. Although the metastatic process has been well studied, many aspects of the molecular genetic basis of metastasis remain unclear. Elucidation of the molecular nature of liver metastasis is urgent to improve the outcome of colorectal cancer. We analyzed the chronological gene expression profiles of 104 colorectal samples corresponding to oncogenic development including normal mucosa, localized and metastasized primary tumors, and liver metastatic lesions as fundamental samples using a custom cDNA microarray. The gene expression patterns in 104 samples were classified into four groups closely associated with their metastatic status, and the genes of each group appropriately reflected the metastatic process. To investigate the existence of metastatic potential in primary tumors using metastasis-related genes detected by chronological analysis, we performed a hierarchical cluster and supervised classification analysis of 28 independent primary tumors. Hierarchical cluster analysis segregated the tumors according to their final metastatic status, rather than their clinical stages, and the profile of metastasized primary tumors resembled one of a metastatic lesion apart from a primary lesion rather than one of a non-metastasized primary tumor. Using the supervised classification approach, the expression profile of these genes allowed the classification of tumors diagnosed as localized cancer into two classes, the localized and the metastasized class, according to their final metastatic status. The disease-free survival and overall survival were significantly longer in the localized class than the metastasized class. Chronological analysis of the gene expression profile provides a better understanding of the metastatic process. Our results suggest that the metastatic potential is already encoded in the primary tumor and is detectable by a gene expression profile, which allows the prediction of liver metastasis in patients diagnosed with localized tumors and also the design of new strategies for the treatment and diagnosis of colorectal cancer.

Aged↗
PubMed1997

Isolation of a novel gene showing reduced expression in metastatic colorectal carcinoma cell lines and carcinomas.

To investigate genes involved in metastatic stages of cancer, we analyzed expression of mRNAs in three cell lines derived from murine colon adenocarcinoma 26 by means of a differential display method. Each of these lines exhibits distinct metastatic characteristics. Among many bands representing different expression patterns in the display, we confirmed by northern analysis that a gene corresponding to one amplified fragment, termed grm2 (gene related to metastasis 2), was expressed more abundantly in NL4, the derivative with the lowest metastatic potential, than in cell lines NL17, an experimentally metastatic derivative, and in NL22, a spontaneously metastatic derivative. Using the grm2 fragment as a probe, we isolated murine cDNA clones and subsequently human cDNA clones corresponding to the GRM2 gene. The human and mouse homologues both encode proteins of 600 amino-acid residues, which show weak homologies to proteins belonging to the myosin family. When we examined the expression levels of this novel gene in human colon cancers and in corresponding metastatic foci, we found that in more than half of these tissues, expression was significantly reduced in association with malignant potential. Our results imply that in humans the GRM2 gene product may regulate the metastatic phenotype of some colorectal cancers.

Adenocarcinoma↗
PubMed1988

Distinction between hepatocellular carcinoma, cholangiocarcinoma, and metastatic carcinoma based on immunohistochemical staining for carcinoembryonic antigen and for cytokeratin 19 on paraffin sections.

An antiserum to carcinoembryonic antigen (CEA) and a monoclonal antibody to cytokeratin 19 (CK 19) were studied for their suitability as diagnostic reagents for the differential diagnosis of primary and secondary malignant epithelial tumours of the liver, on paraffin sections. With the antiserum to CEA, positive bile canalicular structures were found in 60 per cent of the hepatocellular carcinomas. All the cholangiocarcinomas and 66.6 per cent of the metastatic carcinomas were positive for CEA, without displaying a canalicular staining pattern. All the hepatocellular carcinomas were negative for CK 19. All the cholangiocellular carcinomas and the metastatic carcinomas were positive for CK 19. This staining profile may prove helpful in difficult diagnostic cases.

Adenocarcinoma↗
PubMed1990

Differential reactivities of carcinoembryonic antigen (CEA) and CEA-related monoclonal and polyclonal antibodies in common epithelial malignancies.

To evaluate the role of carcinoembryonic antigen (CEA) in solving problems of tumor histogenesis in surgical pathology, monoclonal antibodies to four distinct epitopes of CEA (E-Z-EM) were applied to paraffin sections of 303 epithelial neoplasms from multiple sites. Two epitopes were CEA specific (D14 and B7.1), one was shared with nonspecific cross-reacting antigen (NCA) (B7.8), and the fourth (B18) was common to CEA, NCA, and biliary glycoprotein antigen (BGP). A sample of the tumors (n = 110) was also stained with a polyclonal anti-CEA (DAKO). Gastrointestinal adenocarcinomas, including esophageal and gastric (n = 19), small intestinal (n = 8), colorectal (n = 56), biliary tract (n = 8), and pancreatic adenocarcinomas (n = 14), were consistently positive with all five antibodies. Other predominantly gland-forming carcinomas tested, comprising lung (n = 22), ovary (n = 18), and endometrium (n = 12), were either invariably negative with all five antibodies (endometrial adenocarcinoma, non-mucinous ovarian adenocarcinoma) or demonstrated selective and variable positivity (lung: D14, 50%; ovarian mucinous: D14, 50%). Among large polygonal cell carcinomas (hepatocellular carcinoma, renal cell carcinoma, melanoma, and adrenal carcinoma), only hepatomas stained positively, showing a distinctive canalicular staining pattern with the B18 (BGP epitope) (55%) and polyclonal antibody (50%). In the small polygonal cell carcinoma category, true CEA positivity was rare in breast (D14, 10% and B7.1, 14%) and never seen in prostatic carcinomas and carcinoid tumors. A subset of these breast (8 of 42), prostate (4 of 22), and carcinoids (4 of 7) showed exclusive positivity for the B18 antibody (NCA/BGP epitope). Ovarian serous papillary carcinomas (n = 14), papillary carcinomas of thyroid (n = 12), transitional cell carcinomas of the bladder (n = 11), and mesotheliomas (n = 3) were negative with all monoclonal antibodies. Metastatic carcinomas (n = 74) showed a similar pattern of reactivity to primary tumors. The authors conclude that CEA immunostaining may assist in identifying the histogenesis of epithelial tumors in several morphologic categories; that differential reactivities of the CEA monoclonal antibody panel exceed those of the polyclonal antibody; and that the discriminating power of the monoclonal panel is related to whether (1) CEA is or is not produced or (2) NCA or BGP is produced without concomitant CEA production. There is little evidence to support a concept of site-specific CEA species.

Antibodies, Monoclonal↗
PubMed1996

Spiculated axillary adenopathy.

PURPOSE: To describe the mammographic and sonographic appearance of a pattern of spiculation of the contour of axillary lymph nodes. MATERIALS AND METHODS: Eleven cases of axillary nodes with spiculated contour were prospectively identified on routine mammograms. All cases were in women with breast cancer. Sonograms of axillary nodes were available in three cases. Medical records were reviewed, and histologic and nodal histopathologic findings and patient outcome were correlated. RESULTS: All women had primary, invasive breast carcinoma. Although disease was evident mammographically, four of nine women for whom the results of the physical examination were known did not have palpable adenopathy. Nodes were iso-to hyperdense (compared with breast parenchyma) on mammograms and were hypoechoic with irregular margins on sonograms. The spiculated pattern of the nodes correlated with extension of metastatic tumor in axillary nodes into perinodal fat. At a mean follow-up of 17 months, one patient was dead of disease, eight were alive with disease, and two were alive without disease. CONCLUSION: A pattern of spiculated axillary adenopathy in a patient with breast cancer appears to be consistent with extranodal extension of tumor into perinodal fat. This finding suggests a biologically aggressive tumor with a poor prognosis.

Adult↗
PubMedDate not supplied

Immunohistochemical staining of metastatic ductal carcinomas of the breast by monoclonal antibodies used in imaging and therapy: A comparative study.

Five monoclonal antibodies (MoAbs)(L6, 170H.82, 155, BrE-3 and BR96), most of which have been previously shown to target breast cancer and not normal tissues by immunoscintigraphic imaging, were evaluated for their frequency and pattern and immunohistochemical staining in 67 to 116 metastatic lesions from patients with ductal carcinoma of the breast. Immunoperoxidase staining in 75% or more of the cells occurred in 56/116 (48%) for L6, 44/89 (49%) for Br, -96, 58/102 (57%) for 155, 62/99 (84%) for 170H.82, and 65.67 (97%) for BrE-3. With the first three MoAbs, an additional 6-10% of the tumors showed staining in 50-75% of tumor cells. These results illustrate that most patients with metastatic ductal carcinoma have cancer tissue in which a high percent of cells will react to several of these selected MoAbs that target different epitopes. The high expression of the MoAb targets throughout the tumor tissue makes these antibodies potential candidates to carry immunologically directed radioimmunotherapy and is an aid in selecting patients for treatment.

Animals↗
PubMed2001

Microphthalmia transcription factor in the immunohistochemical diagnosis of metastatic melanoma: comparison with four other melanoma markers.

The diagnosis of metastatic malignant melanoma (MMM) may be difficult in surgical pathology, often complicated by the unpredictable spread of this tumor and its great variability on histologic evaluation. Traditionally used immunohistochemical markers on melanomas are insufficient because of either a relative lack of specificity (S100 protein) or variably reported sensitivity (HMB45). Information about some newer markers, such as tyrosinase (TYR) and Melan A, is more limited. Recently, based on the study of a small number of tumors, it was suggested that microphthalmia transcription factor (MITF) is 100% sensitive in the identification of metastatic melanoma. In the current study, we compared the diagnostic usefulness of MITF with that of four other markers in 266 cases of conventional metastatic melanomas from different sites, 33 cases of desmoplastic melanomas, and 1 case of melanoma with rhabdoid features. The specificity of MITF was evaluated by using a representative sample of control tumors. Microphthalmia transcription factor with nuclear positivity was seen in 235 of 266 cases of conventional MMM (88%), usually in more than 30% of tumor cells. However, some melanomas had only foci of MITF- and TYR-positive cells, whereas the majority of cells were generally S100 protein-positive. Only 1 of 30 desmoplastic melanomas (3%) had MITF-positive cells, representing epithelioid foci resembling conventional melanoma. Two cases had TYR in a similar pattern; all were HMB45-negative. One metastatic melanoma with rhabdoid features was negative for MITF and other markers except the S100 protein. Half of the S100 protein negative conventional melanomas (6 of 12) were MITF-positive, whereas 4 of 20 (20%) TYR-negative tumors had reactivity for MITF. The percentages of positive cases of MMM (10% or more tumor cells positive) diagnosed with the four other markers in descending order were 90% (S100 protein and TYR), 78% (melan-A), and 66% (HMB45). Microphthalmia transcription factor appeared to be specific, because significant reactivity was not found in 112 carcinomas, 20 lymphomas, 20 angiosarcomas, 20 fibrous histiocytomas, and 20 malignant peripheral nerve sheath tumors. However, positive nuclei were found focally among reactive histiocytes, especially in osteoclasts, epithelioid histiocytes, and sporadic other histiocytes. Microphthalmia transcription factor may be a valuable addition to the marker panel used in diagnosing melanoma, in combination with S100, TYR, and the other markers, but it is not present in cases of desmoplastic melanomas.

Angiomyolipoma↗