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PubMed1984

Cutaneous malignant melanoma in West Yorkshire: II. A prospective study of recurrence and prediction of lymph nodal metastasis.

One hundred and fifty patients with cutaneous malignant melanoma, in clinical stage I at diagnosis, were studied prospectively to determine the lymph nodal metastatic pattern of the disease, and to find that combination of clinical and pathological variables best predictive of the probability of its occurrence when combined in a linear logistic regression equation based upon a model by Cox. Details of the general pattern of melanoma recurrence are included to provide a necessary background to the nodal metastatic study. Of 66 patients showing melanoma recurrence in 48 (19 males and 29 females) it took the form of lymph nodal metastasis. Of these 50% showed lymph nodal metastasis within 1.1 years of the primary operation and 90% within 3.8 years. Nineteen clinical and pathological variables were tested for association with lymph nodal metastasis, 15 of which showed a significant association and in 7 of these the association was highly significant (P less than or equal to 0.0001). All 19 variables were included in the logistic regression analysis, 6 being selected as providing the best regression 'goodness of fit' and of these 'maximum tumour thickness (Breslow' and 'sex' emerged as the dominant variables. It is concluded that the analysis described provides surgeons, oncologists, and pathologists with a practical method to assess the likelihood in an individual patient of melanoma recurrence to regional lymph nodes. This should enable surgery or other adjunctive therapeutic regimens to be selected at an early stage.

Adult↗

PubMed1977

Metastatic disease of the parotid gland.

Metastatic lesions of the parotid gland represent the spread of a neoplasm from the primary site to parotid paraglandular, intraglandular, or parenchymal locations. These lesions are frequently difficult to differentiate from primary parotid gland neoplasms. The most common histologic type of neoplasm that metastasizes to the parotid gland is the melanoma. The melanoma is generally found superficial in its metastatic spread. Squamous cell carcinoma is also frequently found, but is usually intraglandular in its metastatic pattern. Although the melanoma and squamous cell carcinoma represent 80 per cent of the metastatic lesions involved in the parotid gland, a variety of other histologic types have been reported. The surgeon must be ready to deal with this complex problem when he enters into an exploratory operation. Even though vigorous treatment is carried out, the histologic types of neoplasms and the anatomic complexities of the area contribute to survival rates between 10 and 15 per cent over a five year period.

Carcinoma, Squamous Cell↗

PubMed1995

Massive metastases from a lobular breast carcinoma from an unknown primary during pregnancy. A case report.

BACKGROUND: Carcinoma of the breast during pregnancy represents 2-5% of all breast cancers. The frequency and histopathologic spectrum of breast cancer are similar in pregnant and nonpregnant women. Infiltrating lobular carcinoma is one of the less understood types of breast cancer, and its metastatic pattern seems to be different from that of infiltrating ductal carcinoma. Breast neoplasms rarely present as cancer from an unknown primary site. CASE: A woman in the third trimester of pregnancy developed carcinoma massively metastatic to the bone marrow and liver from an unknown primary tumor. At 32 weeks' gestation a healthy male was delivered by cesarean section. The patient died 12 hours after delivery. The autopsy revealed an infiltrating lobular carcinoma, 1.5 cm, of the breast. CONCLUSION: Massive metastases from an occult lobular breast carcinoma in a pregnant woman are very rare. Diffuse metastatic spread, which often complicates or delays the diagnosis, is a characteristic pattern of infiltrating lobular carcinoma. Cancer from an unknown primary site during pregnancy is an exceptional finding. If a metastatic adenocarcinoma is diagnosed in a pregnant woman, a breast primary should be strongly suspected.

Adult↗

PubMed1985

High-grade mucoepidermoid carcinoma of the breast.

A case of high-grade mucoepidermoid carcinoma of the breast with a dominantly epidermoid component is presented. The tumour was biochemically oestrogen and progesterone receptor negative. Though the primary tumour was small (1 cm) and without axillary lymph node metastases at mastectomy, the clinical course was rapid. Despite radio-, chemo- and hormonal therapy the patient died 25 months after mastectomy with widespread systemic disease. The metastatic pattern was that of typical breast carcinoma despite the unusual histological appearance of both primary and metastatic tumour tissue.

Antineoplastic Combined Chemotherapy Protocols↗

PubMedDate not supplied

Visualization of the metastatic process by green fluorescent protein expression.

We demonstrate here the visualization of the cancer metastatic process in live tissue in vivo by green fluorescent protein (GFP) expression. The human lung adenocarcinoma cell-line Anip 973 was transfected with the humanized GFP-S65T cDNA and stable high-level GFP-expressing transfectants were established. GFP transfectants were initially inoculated subcutaneously in nude mice. Five weeks after transplantation, when the tumor had reached 1.2 cm in diameter, fragments of subcutaneously tumor were implanted onto the visceral pleura of nude mice by surgical orthtopic implantation (SOI) as a spontenous metastatic model. GFP expressing cells were injected intravenously in nude mice as an experimental hematogenous metastasis model. Mice were sacrificed four and eight weeks after treatment. At eight weeks, SOI-treated mice had lymphogenous (3/4 mice) and direct seeding (3/4) metastasis in the pulmonary hilum, cervical lymph nodes, the mediastinum and contralateral pleural cavity as detected by GFP expression in live tissue. All intravenously injected mice had metastases in the lung (4/4) and some of them had metastases in the brain (2/4) and other organs (1/4) as detected by GFP expression in fresh tissue. Some of the lung metastases produced by intravenous injection remained as dormant small colonies even eight weeks after treatment. These different metastatic patterns after SOI and intravenous injection visualized by GFP expression indicates that initial steps of the metastatic cascade influence the subsequent progression of metastasis.

Animals↗

PubMed1983

Metastatic uveal melanoma. Hepatic cell-surface enzymes, isoenzymes, and serum sialic acid levels in early metastatic disease.

Serum hepatic cell-surface enzymes, isoenzymes, and sialic acid levels may be useful adjuncts in detecting early metastatic disease and in evaluating the tumor burden of patients with uveal melanoma. Hepatic cell-surface enzyme concentrations were elevated in the serum of ten patients with uveal melanoma and liver metastasis and in five patients with other hepatobiliary disorders and in 75 control patients. Five patients in the metastatic group (50%) had serum gamma-glutamyl transpeptidase and 5'-nucleotide phosphodiesterase (5-NPD) bands known to be associated with either primary hepatic carcinoma or carcinoma metastatic to the liver. One patient with uveal melanoma without known metastasis had a positive 5-NPD pattern; metastatic disease was subsequently proved. Higher levels of sialic acid were found in the serum of patients with uveal melanoma and metastatic disease (4 mumole/mL) than in controls (2.4 mumole/mL).

Adult↗

PubMedDate not supplied

Dissemination in athymic nude mice of lacZ transfected small cell lung cancer cells identified by X-gal staining.

The small cell lung cancer cell lines GLC-2 and DMS 456 were genetically labeled with the lacZ gene and examined for invasive and metastatic potential in META/Bom nude mice. The lacZ gene encodes the enzyme beta-D- galactosidase, and cells expressing this enzyme were identified by staining with the chromogenic substrate X-gal. lacZ expressing cells were investigated after subcutaneous (s.c.) inoculation and intravenous (i.v.) injection. The X-gal detection of beta-D-galactosidase activity proved to be a rapid and easy means for specific and highly sensitive identification of metastases. All primary s.c. tumors stained by X-gal. The primary tumors of GLC-2 regularly demonstrated local invasive growth and produced multiple metastases in several organs. In contrast, primary DMS 456 tumors only occasionally demonstrated local invasion and very rarely generated secondary foci. No experimental metastases were found after i.v. injection of the examined tumor lines. The results indicate an intratumoral heterogeneity among individual SCLC tumors in the capacity for invasion and metastatic spread. The different metastatic pattern of GLC-2 after s.c. and i.v. inoculation supports the hypothesis that initial steps of the metastatic cascade occurring in the primary tumor are necessary for the subsequent production of growing metastases.

Animals↗

PubMed1989

Experimental model for metastasis of intraocular melanoma: preventive role of natural killer cells.

A murine melanoma cell line, B16-BL6, was inoculated in various body sites of the mouse, including the anterior chamber of the eye, and an analysis was carried out of the relationship between the anatomical site of tumor inoculation and the tumor growth or the pattern of tumor metastasis. It was found that not only the primary tumor growth but also the metastatic pattern was greatly affected by the site of the primary tumor. Fifteen days after the tumor transplantation, the mean weight of the primary tumors transplanted in the ear or in the abdominal flank became five to ten times larger than those transplanted in the eye or in the footpad. Furthermore, intraocular melanomas rapidly developed lung metastasis, whereas subcutaneous melanoma primarily developed lymph node metastasis. It was also found that natural killer cells had a preventive role in the early phase of hematogenous dissemination from the intraocular melanoma.

Animals↗

PubMed1986

The spectrum of sonographic findings in pancreatic carcinoma.

The ultrasound studies of 59 patients with cancer of the pancreas were reviewed and the findings grouped into two categories: intrapancreatic, which included the appearance of the primary tumor and the pancreatic duct; and extrapancreatic, which included biliary obstruction, hepatic metastases, regional lymph node involvement, ascites, spleen enlargement and invasion, and alteration of the upper abdominal veins. Pancreatic duct dilatation was more evident with smaller tumors of the pancreatic head, while inferior vena cava compression was found not to be a constant finding even with large tumors of the head of the pancreas. Tumor extension to regional lymph nodes was difficult to detect and consequently underestimated. Nonvisualization, occlusion with or without collaterals, and displacement or deformity of the major branches of the portal venous system were detectable sonographically. The liver metastases of pancreatic carcinoma tended to be small and hypoechoic. This is a different pattern from that typically described for other gastrointestinal adenocarcinomas and, in particular, markedly different and distinguishable from the metastatic pattern seen with malignant pancreatic islet cell tumors. The significance of the intra- and extrapancreatic changes seen sonographically in cancer of the pancreas by ultrasound is discussed in relationship to clinical staging and prognosis.

Adenocarcinoma↗

PubMed1993

Signet ring variant of lobular carcinoma of the breast: a clinicopathologic and immunohistochemical study.

Signet ring carcinoma of the breast often metastasizes to gastrointestinal tract and female genital tract. We report clinicopathologic features of 10 breast carcinomas with signet ring features, five of which had unusual metastatic patterns. The primary breast tumor in all these cases was lobular carcinoma. Although signet ring cells were prominent in metastatic sites, the primary tumor lacked signet ring cells in two cases. A linitis plastica-like presentation and presence of signet ring cells in gastric metastases raised a strong possibility of primary gastric carcinoma in three cases. The monoclonal antibody to gross cystic disease fluid protein (GCDFP-15) was positive in signet ring cell-rich areas in the primary breast tumor (8/10) and/or in the metastases in all cases. For comparison we studied GCDFP-15 immunoreactivity in 10 infiltrating lobular and 10 infiltrating ductal breast carcinomas with no obvious signet ring cells, and in 14 signet ring carcinomas from other sites (10 gastric, 2 prostatic, 2 colonic). The gastric, colonic, and one prostatic signet ring carcinoma were nonreactive. One prostatic signet ring carcinoma exhibited focal but unequivocal positivity with GCDFP-15. The cases of this report reinforce the concept that signet ring carcinoma of the breast is usually a variant of lobular carcinoma and not a distinct entity. Signet ring cell predominance in metastases, even in the absence of signet ring cells in the primary tumor, attest to the morpho-functional heterogeneity of lobular carcinoma. GCDFP-15 is a sensitive marker for signet ring breast carcinoma and a very useful adjunct tool in the diagnosis of metastatic signet ring carcinoma of mammary origin.

Adult↗

PubMed1987

Experimental metastasis of mouse embryonal carcinoma cell lines to specific locations.

Embryonal carcinoma cell lines produced tumors in highly specific and unusual sites when injected into mice. The pattern that developed when cells were injected into the left ventricle of the heart involved target organs related either to specific nerve patterns or neuronal outgrowth factors, or to pathways of primordial germ cell migration. Major sites included the ovary, testis, adrenal, iris, whiskers, and male submaxillary gland. Neither local growth responses, determined by direct injection of tumor cells into different organ parenchyma, nor initial attachments, observed upon injection of radiolabeled cells, appeared to sufficiently account for the specificity of tumor metastases occurring after arterial injection. However, tissue from uninjected target sites, but not other tissues, stimulated the in vitro migration of embryonal carcinoma cells. Conditioned medium from only target tissues had a similar effect. These results suggest that the specificity of this tumor pattern may depend on migration responses that are significant in the localization of embryonic germ and neural cells. The specific metastatic pattern observed following i.p. injection of embryonal carcinoma cells, involving only the ovary, appeared to require an additional component of high adhesivity to the target organ.

Animals↗

PubMed2005

Juvenile differentiated thyroid carcinoma and the role of radioiodine in its treatment: a qualitative review.

Well under 15% of differentiated thyroid carcinoma (DTC) is diagnosed at < or =18 years of age. The population is heterogenous and the differences between prepubertal children and pubertals and adolescents are to be considered. Although very little has been reported on children with sporadic DTC under the age of 10 years, juvenile DTC has at least some undeniable differences with adult DTC: (1) larger primary tumor at diagnosis; (2) metastatic pattern and features, namely: (a) greater prevalence of neck lymph node and distant metastases at diagnosis, (b) lungs almost the sole distant metastatic site, (c) pulmonary metastases nearly always functional; (3) closer-to-normal and more frequent sodium-iodide symporter (NIS) expression; and (4) higher recurrence rate but longer overall survival. These differences are especially distinct in prepubertal children. The goals of primary treatment of juvenile DTC are to eradicate disease and extend not only overall, but recurrence-free survival (RFS). Extending RFS is itself a desirable goal in children because it improves quality-of-life, alleviates anxiety during psychologically formative years, reduces medical resource consumption, and may increase overall survival. Primary treatment of DTC generally comprises a combination of surgery, radioiodine ((131)I) ablation, and thyroid hormone therapy applied at varying levels of intensity. Therapeutic decision-making must rely on retrospective adult and/or pediatric outcome studies and on treatment guidelines formulated mostly for adults. Differences between juvenile and adult DTC and physiology dictate distinct treatment strategies for children. We, and many others, advocate a routine intensive approach because of the more advanced disease at diagnosis, propensity for recurrence, and greater radioiodine responsiveness in children, as well as published evidence of significant survival benefits, especially regarding RFS. This intensive approach consists of total thyroidectomy and central lymphadenectomy in all cases, completed by modified lateral lymphadenectomy when necessary and followed by radioiodine administration. However, absence of prospective studies and of universal proof of overall cause-specific survival benefits of this approach have led some to propose more conservative strategies. Most European centers give radioiodine ablation to the vast majority of juvenile DTC patients. Ablation seeks to destroy any residual cancer, including microfoci, as well as healthy thyroid remnant. Large studies have documented the procedure to decrease cause-specific death rates and, in children, to significantly lessen locoregional recurrence rates (by factors of 2-11) independent of the extent of surgery. There is universal agreement on treating inoperable functional metastases with large radioiodine activities. Treatment is especially effective in small tumor foci up to 1 cm in diameter, and should be administered every 6-12 months until complete response, loss of functionality, or attainment of cumulative activities between 18.5-37 GBq (500-1000 mCi). Radioiodine therapy is generally safe. Short-term side effects include nausea and vomiting (more frequent in children than in adults), transient neck pain and edema, sialadenitis (<5% incidence), mild myelosuppression (approximately 25%), transient impairment of gonadal function both in females and males (sperm quality in boys), or nasolacrimal obstruction (approximately 3%), with most cases generally being asymptomatic-moderate, self-limiting, or easily prevented or treated. If pregnancy is ruled out before each (131)I administration, and conception avoided in the year afterward, radioiodine therapy appears not to impair fertility. However, therapeutic (131)I carries a small but definite increase in cancer risk, particularly in the salivary glands, colon, rectum, soft tissue and bone. To better guide primary treatment, different therapeutic combinations should be prospectively compared using RFS as the primary endpoint. Efforts also should be made to identify molecular signatures predicting recurrence, metastasis and mortality.

Adolescent↗

PubMed2026

Circulating Tumor DNA Profiling Defines Risk Classification in Patients With Ewing Sarcoma: A Report From the Children's Oncology Group and the LEOPARD Study.

PURPOSE: Identification of discrete risk groups remains a high priority for patients with Ewing sarcoma (EWS). We sought to prospectively validate circulating tumor DNA (ctDNA) as a prognostic factor and develop clinical-molecular risk groups. METHODS: We conducted a prospective investigator-initiated biology study for patients with localized EWS (LEOPARD) and embedded ctDNA analysis into the North American frontline metastatic study AEWS1221. Eligible patients were younger than 50 years with newly diagnosed EWS. All patients provided a baseline blood sample for analysis, which was subjected to ultralow-pass whole-genome sequencing and hybrid capture panel sequencing for ctDNA quantification, fusion detection, and characterization of STAG2 and TP53 alterations. Serial ctDNA sequencing was conducted on a subset of patients in each study. We tested for associations between ctDNA burden and secondary genomic events, and clinical features and outcomes. RESULTS: One hundred forty patients with localized disease and 255 with metastatic disease provided evaluable pretreatment samples for ctDNA analysis. Elevated baseline ctDNA was associated with stage, tumor size, primary site, indeterminate pulmonary nodules, and metastatic pattern. Elevated pretreatment ctDNA burden was associated with inferior outcomes in patients with localized (n = 140, hazard ratio [HR] = 2.36, P = .032) and metastatic disease (n = 255, HR = 2.15, P = .001). Patients with metastatic disease and TP53 variants and/or persistent on-therapy ctDNA had dismal outcomes. Patients with localized disease, low ctDNA, small tumors, and favorable genomics had no events and constitute a novel low-risk group. Among patients with metastatic disease, those with lung-only disease, low ctDNA, and favorable genomics represent an intermediate-risk group. CONCLUSION: This study prospectively validates pretreatment ctDNA burden as prognostic in EWS. Risk groups that integrate ctDNA burden with clinical-molecular features differentiate patients with low-, intermediate-, and high-risk disease.

Journal Article↗

PubMed2001

Altered expression and localization of the tight junction protein ZO-1 in primary and metastatic pancreatic cancer.

INTRODUCTION: ZO-1 is a tight junction membrane protein that plays a critical role in cell-cell interaction, proliferation, and differ entiation. AIM: To localize and evaluate the expression of ZO-1 in the normal human pancreas, in pancreatic ductal adenocarcinoma (PDAC), and in chronic pancreatitis (CP). METHODOLOGY AND RESULTS: Northern and Western blot analysis revealed ZO-1 expression in all six tested pancreatic cancer cell lines. Expression of ZO-1 mRNA was increased sixfold in PDAC samples in comparison with normal samples (p = 0.04). Confocal microscopy revealed the presence of ZO-1 in the apical and apicolateral areas of ductular cells in the normal pancreas. Similarly, in CP, ZO-1 was localized at apical and apicolateral areas of small proliferating ductular cells and large metaplastic ducts. In PDAC, however, ZO-1 expression was observed irrespective of whether the cancer cells formed duct-like structures or exhibited a diffuse infiltrating pattern. Metastatic pancreatic cancer cells within lymph nodes displayed variable staining patterns, ranging from apical and apicolateral to a diffuse membranous staining. CONCLUSION: These observations suggest that ZO-1 is overexpressed in PDAC and raise the possibility that this overexpression may confer a metastatic advantage to pancreatic cancer cells.

Adult↗

PubMed1988

Clinical aspects of metastases.

In the short term the major hope for reducing cancer mortality is to effect a reduction in the number of patients who develop malignant disease and in the proportion of cancer patients who present with metastases. Hitherto the major emphasis of clinical research on metastases has been directed at detection and elimination rather than prevention or early diagnosis. Extensive data relating histological class and tumour stage to risk of metastasis and metastatic pattern have been compiled from studies of relapse and from invasive and non-invasive staging procedures. However, the biological events involved in the metastatic process and the factors which influence it in relation to the natural history of primary human tumours are poorly understood. Information describing metastatic heterogeneity in individual patients, in terms of therapeutic response or intrinsic sensitivity to cytotoxic agents, is scanty. Similarly, the characteristics of human metastases in relation to the clonal heterogeneity of primary tumours are poorly defined. The clinical application of molecular biological techniques, which has led to the association of gene amplification with tumour behaviour in a range of sites, offers the prospects of improved tumour localization and therapy and, in the longer term, of tumour control by interventions based on a knowledge of the mechanisms that regulate cell growth and differentiation.

Clinical Protocols↗

PubMed2005

Skin homing of Sézary cells involves SDF-1-CXCR4 signaling and down-regulation of CD26/dipeptidylpeptidase IV.

Sézary syndrome (SS) is a rare form of cutaneous T-cell lymphoma (CTCL) characterized by a distinct metastatic pattern mainly involving blood and skin. Chemokines and their receptors play a critical role in cellular recruitment and homing to tissues and in the metastatic process of several tumors including non-Hodgkin T-cell lymphomas (NHLs). Here we report that SS cells express a functionally active CXCR4 and that its ligand SDF-1 is abundantly produced in the skin, which represents the main destination of SS cell spreading. SDF-1 is normally inactivated by proteolytic cleavage by the CD26/dipeptidylpeptidase IV (DPPIV). The lack of CD26 from the cell surface is a hallmark of circulating SS cells. We also show that the CD26(-) phenotype is maintained also in skin-infiltrating neoplastic T lymphocytes and that SS-affected individuals exhibit a reduced activity of plasma soluble CD26. Finally, we observe that the addition of soluble CD26 reduces the migratory response of SS cells to SDF-1 whereas the inhibition of the CD26 peptidase activity in Hut78, a CD26(+) CTCL cell line, enhances the SDF-1-induced migration of these cells. Our findings suggest that the SDF-1-CXCR4 axis could play an important role in skin homing of SS through the regulatory activity of CD26.

Adenosine Deaminase↗

PubMed2005

Gene signatures of progression and metastasis in renal cell cancer.

PURPOSE: To address the progression, metastasis, and clinical heterogeneity of renal cell cancer (RCC). EXPERIMENTAL DESIGN: Transcriptional profiling with oligonucleotide microarrays (22,283 genes) was done on 49 RCC tumors, 20 non-RCC renal tumors, and 23 normal kidney samples. Samples were clustered based on gene expression profiles and specific gene sets for each renal tumor type were identified. Gene expression was correlated to disease progression and a metastasis gene signature was derived. RESULTS: Gene signatures were identified for each tumor type with 100% accuracy. Differentially expressed genes during early tumor formation and tumor progression to metastatic RCC were found. Subsets of these genes code for secreted proteins and membrane receptors and are both potential therapeutic or diagnostic targets. A gene pattern ("metastatic signature") derived from primary tumor was very accurate in classifying tumors with and without metastases at the time of surgery. A previously described "global" metastatic signature derived by another group from various non-RCC tumors was validated in RCC. CONCLUSION: Unlike previous studies, we describe highly accurate and externally validated gene signatures for RCC subtypes and other renal tumors. Interestingly, the gene expression of primary tumors provides us information about the metastatic status in the respective patients and has the potential, if prospectively validated, to enrich the armamentarium of diagnostic tests in RCC. We validated in RCC, for the first time, a previously described metastatic signature and further showed the feasibility of applying a gene signature across different microarray platforms. Transcriptional profiling allows a better appreciation of the molecular and clinical heterogeneity in RCC.

Adult↗

PubMed1984

Target organ patterns of tumors in mice following the arterial dissemination of B16 melanoma cells.

The arrest of B16 melanoma cells and the subsequent development of tumors have been studied following left intraventricular injections (LVI) into mice of radiolabelled and unlabelled cells respectively; the proportions of cardiac output going to different target organs were also determined by LVI of radiolabelled microspheres. B16 cell arrest in the various target organs was as predicted by relative arterial blood supply, except in the lungs and liver where more radioactive counts were detected than could be accounted for in terms of initial arterial dissemination alone; and the numbers of counts remaining in all organs after 24 h were related to the numbers of counts initially obtained. When the incidence of tumor-bearing organs was related to the cell arrest patterns, the organs could be divided into two major distinct groups. Within both of these groups, the patterns of tumor incidence were correlated with cancer cell delivery. These results on a model system suggest that the two major hypotheses used to account for metastatic patterns are not mutually exclusive: the "soil" effect divides the target organs into the two major groups; however, within these groups the incidence of tumors is explicable in terms of the "mechanical" hypothesis.

Animals↗