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The clinical significance of "adenoid" formations of neoplastic astrocytes, imitating metastatic carcinoma, in gliosarcomas. A review of five cases.

Five cases of supratentorial gliosarcomas occurring in middle-aged and elderly patients are reported. In the gliomatous portions of the tumors there were areas with clusters and ribbons of cuboidal cells forming a cribriform pattern and structures resembling ducts and glands of a metastatic adenocarcinoma. Where the adenoid structures were embedded in a mucoid matrix, an imitation of mucus-producing ("colloid") carcinoma was created. In one patient who had a large pelvic mass (later identified as a benign leiomyoma) the histology of the brain tumor suggested a metastatic müllerian carcinosarcoma. The pseudoglandular elements in each case could be identified as being composed of primitive astrocytes, partly by finding transitions to more mature and typical astrocytes and partly by positive staining with the immunoperoxidase method for glial fibrillary acidic protein (GFAP). The recognition of this morphologic variant of malignant glial tumors is important, particularly in patients of the age group in which primary carcinomas elsewhere in the body occur with increasing frequency. In such patients the correct diagnosis of their brain tumor can avoid the added post-craniotomy discomfort and expense of a "workup for a primary tumor."

Adenocarcinoma↗

Identification of differentially expressed genes in hepatocellular carcinoma and metastatic liver tumors by oligonucleotide expression profiling.

BACKGROUND: The characterization of differentially expressed genes between cancerous and normal tissues is an important step in the understanding of tumorigenesis. Global gene expression profiling with microarrays has now offered a powerful tool to measure the changes of thousands of genes in any carcinoma tissues in an effort to identify these key disease-related genes. To compare the gene expression of a primary liver carcinoma, metastatic carcinoma to the liver, and normal liver, the authors analyzed tissue from six primary hepatocellular carcinomas (HCCs), five colorectal adenocarcinoma metastases to the liver, and eight normal livers. METHODS: Samples were processed from total RNA to fragmented cRNA and hybridized onto Affymetrix GeneChip(R) expression arrays. Analyses were performed to determine the consensus pattern of gene expression for primary liver carcinoma, metastatic liver carcinoma, and normal liver tissue and their changes in expression level. RESULTS: In hepatocellular carcinoma, 842 genes were overexpressed, and 393 genes were underexpressed in comparison with genes of normal liver tissue. Of note, 7 of the 20 most increased identified known genes previously have been associated with liver carcinoma or other types of cancers. The 13 additional identified genes until now have not previously shown strong association with cancers. Furthermore, the authors identified 42 genes and 24 expressed sequence tags that are expressed at a significant level in both HCC and metastastic tumors, presenting a list of marker genes indicative of cancerous liver tissue. CONCLUSIONS: In this study, genes that can be involved in the production of and maintenance of hepatic carcinomas were identified. These data offer new insight into genes that are potentially important in the pathogenesis of liver carcinoma, as well as additional targets for new strategies for cancer therapy and treatment.

Adult↗

Vasculogenic mimicry and tumor angiogenesis.

Tumors require a blood supply for growth and hematogenous dissemination. Much attention has been focused on the role of angiogenesis-the recruitment of new vessels into a tumor from pre-existing vessels. However, angiogenesis may not be the only mechanism by which tumors acquire a microcirculation. Highly aggressive and metastatic melanoma cells are capable of forming highly patterned vascular channels in vitro that are composed of a basement membrane that stains positive with the periodic acid-Schiff (PAS) reagent in the absence of endothelial cells and fibroblasts. These channels formed in vitro are identical morphologically to PAS-positive channels in histological preparations from highly aggressive primary uveal melanomas, in the vertical growth phase of cutaneous melanomas, and in metastatic uveal and cutaneous melanoma. The generation of microvascular channels by genetically deregulated, aggressive tumor cells was termed "vasculogenic mimicry" to emphasize their de novo generation without participation by endothelial cells and independent of angiogenesis. Techniques designed to identify the tumor microcirculation by the staining of endothelial cells may not be applicable to tumors that express vasculogenic mimicry. Although it is not known if therapeutic strategies targeting endothelial cells will be effective in tumors whose blood supply is formed by tumor cells in the absence of angiogenesis, the biomechanical and molecular events that regulate vasculogenic mimicry provide opportunities for the development of novel forms of tumor-targeted treatments. The unique patterning characteristic of vasculogenic mimicry provides an opportunity to design noninvasive imaging techniques to detect highly aggressive neoplasms and their metastases.

Animals↗

Is there no influence of local control on the rate of metastases in high-grade soft tissue sarcoma?

Primary host and tumor-related prognostic factors, the occurrence of local recurrence, and the time interval between diagnosis of the primary tumor and metastatic disease were analysed in 39 patients with metastatic Grade 4 soft tissue sarcoma. The pattern of prognostic factors and the timing of metastases were the same in patients with and without local recurrence. Thus, primary prognostic factors alone may determine the risk of metastases in high-grade soft tissue sarcoma; local recurrence per se may not influence the prognosis in these cases.

Female↗

Survival after first recurrence of breast cancer. The Miami experience.

BACKGROUND: Four hundred thirty-three patients with recurrent breast cancer were treated by the authors at a large medical breast oncology facility from 1976-1982. The median survival time from first relapse (MSFR) for the 193 patients whose survival experience was not confounded by lead-time bias was 26 months. This MSFR is similar to that of most series published in the 1970s and 1980s and is approximately double that of series published in the 1960s. METHODS: In this series, regression analysis identified disease-free interval (DFI), estrogen receptor (ER) status, and dominant disease site as significant prognostic variables, similar to other published series. RESULTS: In 113 patients with known ER values, DFI, and dominant metastatic sites, a prognostic spectrum of MSFR patterns was identified among combinations of these three variables. The MSFR ranged from 15 months for poor risk patients with negative ER values, visceral dominant sites, and DFI of less than 24 months, to more than 90 months for good risk patients with positive ER values, soft tissue dominant sites, and DFI of more than 24 months. Although menopausal status alone was not a significant prognostic variable in regression analysis, 66% of premenopausal patients had a constellation of "poor" prognostic variables. CONCLUSIONS: This type of prognostic factor analysis at first relapse could help identify subsets of patients who might be considered for aggressive investigational therapies such as high-dose chemotherapy with autologous bone marrow reconstitution.

Breast Neoplasms↗

Loss of heterozygosity and genomic instability in synchronous endometrioid tumors of the ovary and endometrium.

BACKGROUND: The unknown etiology of endometrioid carcinomas of the ovary and the relatively high frequency of a concomitant carcinoma of the endometrium in these patients warrants study of such tumors. The aim of this study was to identify the genetic alterations involved in endometrioid ovarian cancer development, and to determine whether primary tumors of the endometrium and synchronous primary endometrioid tumors of the ovary could be distinguished based on differing patterns of genetic alterations. The distinction of metastatic carcinoma of the ovary from other synchronous primary tumors is often difficult but has important therapeutic and prognostic implications. METHODS: This study examined the genetic alterations at 28 polymorphic DNA markers in the DNA of tumors of 17 patients with endometrioid carcinoma of the ovary, including 5 nonmetastatic ovarian tumors, 5 ovarian tumors metastatic to the uterus, and 7 endometrioid ovarian tumors with a synchronous primary endometrial tumor. RESULTS: Chromosomes 17 and 22 were found to be the most common sites of loss of heterozygosity (LOH) in the 17 patients studied. Loss of heterozygosity on chromosome 17 was associated with advanced stage ovarian tumors. In 96% of LOH events in the metastatic tumors, LOH was observed in the primary tumor and in the metastatic site. Conversely, in four of seven synchronous tumors in which LOH was observed, LOH was confined to the ovarian tumor. Genomic instability was identified in two of seven patients with synchronously occurring tumors that did not demonstrate LOH. A positive family history was noted for these two patients. CONCLUSIONS: A lack of shared genetic alterations and in synchronously occurring endometrial and endometrioid ovarian tumors indicates independent developmental pathways for these tumors. Loss of heterozygosity on chromosome 17 in endometrioid ovarian carcinoma may indicate transition to a more aggressive tumor.

Carcinoma↗

Phenotypic persistence after reoxygenation of hypoxic neuroblastoma cells.

Fast-growing solid tumors are usually insufficiently vascularized, leading to areas with necrosis and/or poorly oxygenated cells. Tumor cells adapt to acute hypoxic stress. Central to this adaptation are the hypoxia-inducible transcription factors (HIFs), which are degraded at normoxic but become stabilized at hypoxic conditions. Hypoxic (1% O2) neuroblastoma cells downregulate sympathetic nervous system marker genes, whereas neural crest cell markers are upregulated, suggesting that hypoxic tumor cells adopt a less mature phenotype, which in the clinical setting would translate to more aggressive tumors with increased metastatic potential. Here, we compared gene expression patterns in neuroblastoma cells grown at 1%, 5% (a physiologic oxygen level) and 21% O2. At 5% O2, cells developed a weak hypoxic phenotype and HIF-2 alpha, but not HIF-1 alpha, was acutely stabilized. At 1% O2, HIF-2 alpha protein remained present in long-term cultures, while HIF-1 alpha was present only transiently. The stability of the hypoxia-induced dedifferentiated phenotype in cells acutely reoxygenated at either 21% or 5% O2 persisted for at least 24 hr. Genes associated with a differentiated state, like NPY, ChrA and ChrB, were still downregulated and hypoxia-induced genes, like TH and Id2, remained upregulated. Thus, if these culture conditions are viewed as models for acute reoxygenation of metastasizing hypoxic tumor cells, our data suggest that an aggressive hypoxic phenotype persists for 24 hr or more, which might be long enough for the cells to be able to home to secondary sites, in part as a consequence of their immature hypoxic characteristics.

Adaptation, Physiological↗

Cervical metastases from small bowel carcinoid tumors.

Small bowel carcinoid tumors usually metastasize to regional lymph nodes and the liver but metastases to the neck are extremely rare. Over a ten-year period 48 cases of small bowel carcinoid were diagnosed at our institution and of these, three cases (6%) were associated with neck metastases--one to the thyroid gland and two to cervical lymph nodes. The former patient and one of the latter patients had symptoms of the carcinoid syndrome. The other patient was asymptomatic and presented with a solitary neck mass. Urine levels of 5-hydroxyindolacetic acid (5-HIAA) were elevated in the two symptomatic patients but were undetectable in the asymptomatic patient. Extirpation of the involved cervical nodes and the primary small bowel lesion was performed in two patients. In addition, both patients have received chemotherapy with 5-fluorouracil. One patient remains asymptomatic four years after diagnosis but the other patient continues to have five to six bowel movements per day nine months after operation. Small bowel resection was performed in the patient with a metastasis to the thyroid. This patient died of sepsis after a second operation for an intraabdominal abscess. The histological patterns of the primary tumor and the metastatic lesions were similar and the cells of the metastases contained argentaffin-positive granules. We conclude that 1) an intraabdominal carcinoid tumor should be considered as the location of the primary tumor in patients who present with a neck mass containing metastatic carcinoid and 2) the prognosis for patients with extraabdominal metastases is similar to that for patients with intraabdominal disease only.

Adult↗

Secreting peritoneal mesothelioma. Report of a case with cytological, ultrastructural, morphometric and histological studies.

A 29 year old woman, living in an area with a high level of asbestos exposure, developed the clinical features of peritoneal mesothelioma. The quantitative cytological features differed from those of other mesotheliomas described in the literature in that the tumor cells had a large amount of vacuolated cytoplasm and an extremely low N/C ratio, resulting in a "benign" appearance. The ultrastructural study provided evidence for the production and accumulation of secretory products (mucolipids) by the tumor cells. Treatment with chemotherapy and radiation resulted in temporary remission, lasting for 20 months. However the patient then developed pulmonary involvement of the carcinomatosa a form and pleural tumors. The cytological pattern and the morphometric features of the metastatic floating malignant mesothelial cells in the pleural fluid closely resembled those of the primary peritoneal tumor. This case appears to be an example of secretory peritoneal mesothelioma with a bad prognosis, not withstanding the well-differentiated appearance of the tumor cells.

Adult↗

Primary leiomyosarcoma of the lung in a girl.

Leiomyosarcoma of the lung is a type of tumour rarely found in childhood. It arises from smooth muscle either of bronchial or arterial walls, has a variable pattern of local growth, blood-borne metastatic spread with lymph nodes sparing and a clinical course characterized by fever, cough and worsening dyspnea. We report a case which occurred in a 14-year-old girl, reviewing all the other cases found in the literature.

Adolescent↗

Flow cytometric analysis of the DNA content in cultured human brain tumor cells.

Analysis of DNA content in cultured cells derived from 5 benign and 8 malignant human brain tumors was performed by flow cytometry, using propidium iodide as fluorochrome. Normal, non-stimulated human lymphocytes were used as controls. Cells harvested from the first confluent subculture had DNA distribution histograms similar to those of a replicating, non-synchronous population of diploid cells. This observation was made on all cultures, regardless of the DNA distribution patterns in the original tumors, including two metastatic tumors which originally had a predominantly triploid DNA content. After 3 to 5 transfers an increase in the proportion of cells with a wide range of DNA content was observed in some cultures. These changes were usually associated with a loss of cell viability. These observations suggest that in the experimental setting described, in vitro proliferation of human tumor cells may be selectively associated with cells with diploid amounts of DNA.

Adenoma↗

Polymorphous low-grade adenocarcinoma of the nasopharynx. Case report and review of the literature.

BACKGROUND: The polymorphous low-grade adenocarcinoma of the nasopharynx is a rare disease. Polymorphous low-grade adenocarcinoma is a minor salivary gland neoplasm which occurs frequently in the mucosa of the soft and hard palates, in the buccal mucosa and in the upper lip. To date this entity has been identified within the oral cavity and only one case within the nasopharynx and some cases in the parotid gland. It has a slow infiltrating growing pattern with frequent perineural invasion and low metastatic potential. CASE REPORT: We report on a patient with non-papillary polymorphous low-grade adenocarcinoma in the nasopharynx which extended intracranially. The patient underwent primary radiotherapy. The CT showed partial response to radiotherapy and the patient is alive 51 months after the diagnosis his state being unchanged. CONCLUSION: The treatment for minor salivary gland tumor is primarily surgical. It is reported that the polymorphous low-grade adenocarcinoma has been known to have poor response to radiotherapy. However, we believe that in addition to its favorable biological behavior, the radiotherapy in this localization may result in longer survival.

Adenocarcinoma↗

Liver metastasis from thyroid carcinoma 32 years after resection of the primary tumor: report of a case.

Follicular thyroid carcinoma is a differentiated cancer originating from the follicular cells in the thyroid gland. A 73-year-old woman, who had undergone curative resection of thyroid carcinoma 32 years earlier, was referred to our hospital after ultrasonography showed a solid mass in the liver. Laboratory data revealed positive hepatitis B core antibody, but all other values were normal. Computed tomography showed a round tumor, about 1.5 cm in diameter, which was enhanced early and washed out later, in segment 5 of the liver. She underwent laparotomy and partial resection of the liver. Microscopic examination showed follicular cells with minimal atypia growing in a thyroid follicular pattern with colloids, whereby a diagnosis of metastatic liver cancer from thyroid follicular carcinoma was made. This is a rare case of solitary liver metastasis appearing 32 years after eradication of primary follicular carcinoma. Although the reason for the delayed presentation of the metastatic lesion remains unclear, this case shows that patients with differentiated thyroid cancer should be followed up for their entire life.

Adenocarcinoma, Follicular↗

Intrahepatic metastasis of hepatocellular carcinoma: a histopathologic study.

Developmental processes of intrahepatic metastasis were examined in 75 selected cases of hepatocellular carcinoma (HCC) arising in cirrhotic livers. According to their prevalent sites of formation, metastatic nodules were divided into the portal type (59 of 75, 78.7%) and the acinar type (16 of 75, 21.3%). In general the tumor histology was similar to that of primary lesions. The acinar type usually developed via coalescence of scattered tumor cell clusters formed within pseudolobules. In seven cases classified as acinar type, the nodules were composed of well-differentiated tumor cells which were arranged in trabeculae of almost normal thickness (normotrabecular subtype). In four out of these seven cases, the lesions could be clearly defined as metastatic. The subtype could not be determined when only a few discrete nodules were present, as in the remaining three cases. The nodules of the normotrabecular subtype tended to contain a central core of less-differentiated HCC in association with tumor growth, giving rise to a feature of nodule-in-nodule lesions. It is concluded that there do occur metastatic nodules showing well-differentiated, normotrabecular pattern and that these nodules are available for studying developmental steps of early HCCs.

Carcinoma, Hepatocellular↗

The correlation between the spread of metastases by level in the axillary nodes and disease-free survival in breast cancer. A multifactorial analysis.

Axillary lymph nodes were separated from 492 radical or modified radical mastectomies for primary breast cancer and examined according to their anatomical level corresponding to their position along the theoretical pathway of lymph drainage from the breast. The patterns of metastasis and the relationship between metastatized levels and disease-free survival were investigated to see whether complete axillary dissection is necessary for the staging and the planning of adjuvant therapy in breast cancer. Progressive involvement from level I (proximal) to level III (distal) was found in 206 specimens (80.8% of tumors with axillary metastases), while discontinuous or "skip" metastases were present in 49 (19.2%), including 38 (14.9%) with positive nodes at level II or III but not at level I. "Skip" metastasis was more frequent when fewer than four nodes were positive, and not related to either the size of the primary tumor or its location. The effect of age, menopausal status, tumor size, node status, number of positive nodes, anatomic level of axillary node involvement, estrogen and progesterone receptors, and adjuvant therapies on disease-free survival was evaluated using a multivariate proportional hazard model and life table analysis. This showed that disease-free survival was strongly related to the number of positive nodes (P less than 0.001), tumor size (P = 0.001) and level of node involvement (P = 0.01) as independent prognostic factors. Moreover, the subset of patients with four or more positive nodes and involvements of level III had a higher risk of recurrence (25% recurrence-free patients 5 years after mastectomy). The high frequency of "skip" metastases and the prognostic value of both the level of involvement and the number of metastatic nodes suggest that a complete axillary dissection is needed in the surgical management of breast cancer to obtain all the data useful in the planning of adjuvant therapy.

Axilla↗

A genetic basis for metastasis.

The progression of a normal cell to one that is malignant is characterized by at least four progressive but potentially separable behavioural patterns identifying the immortal, tumorigenic, invasive and metastatic phenotypes. A multitude of steps appear to be involved in both transformation from normality and progression to malignancy as characterized by the acquisition of metastatic behaviour. Consequently, it seems unlikely that a single gene can directly manifest expression of the metastatic phenotype in normal cells unless it can induced pleiotropic effects. Indeed, a single trait uniquely characterizing the metastatic phenotype has never been identified. The possibility of a single gene suppressing the metastatic phenotype seems much greater. One possible candidate for such a gene is nm23, the expression of which correlates with reduced metastatic potential in several tumours including breast cancer in humans. Although the numbers involved are still small, the correlation of nm23 expression with breast cancer outcome offers potential in using this system as a prognostic aid in clinical diagnosis of this disease. Its possible role as an indicator of metastatic potential in other human tumours remains to be evaluated, although current evidence suggests that it is unlikely to be of use in colon cancer. Further significant progress requires molecular dissection of the mode of action of its product.

Humans↗

Differences in survival for patients with resectable versus unresectable metastases from pancreatic islet cell cancer.

Well-differentiated islet cell tumors can be associated with aggressive biology, resulting in early metastases to the liver. This study was carried out to determine whether survival for patients with malignant islet cell tumors and synchronous liver metastases is affected by complete surgical resection. Thirty-one patients with synchronous liver metastases from islet cell cancer underwent surgical exploration with the intent for complete tumor resection, and all patients underwent resection of the pancreatic primary. The patients were divided into two groups, those with resectable versus unresectable liver metastases. Twenty-six of 31 (84%) patients underwent complete resection of both the primary tumor and all liver metastases, and 5 (16%) patients underwent only complete resection of the pancreatic primary without liver resection. To extirpate the primary tumor, a pancreaticoduodenectomy was performed in 11 of the 26 (42%) completely resected patients and in 4 of the 5 (80%) incompletely resected patients, P = NS. The remainder of the patients underwent distal pancreatectomy. There were no statistical differences in primary tumor size, lymph node metastases, or adjuvant treatments between patients with resected and unresected liver metastases. The median overall survival for the completely resected group was 78 months, longer than the 17 months for the group with unresectable liver metastases (P = 0.06). Complete tumor resection (or the tumor biology that allows such complete resection) affords a survival advantage to patients with metastatic islet cell tumors of the pancreas. Patterns of liver metastases from islet cell tumors, specifically multiple bilobar metastases that are not amenable to resection and/or ablation, predict a poor outcome despite resection of the primary pancreatic tumor.

Adult↗

Dual mode regulation of migration by lysophosphatidic acid in human gastric cancer cells.

Lysophosphatidic acid (LPA), which interacts with at least three G protein-coupled receptors (GPCRs), LPA1/Edg-2, LPA2/Edg-4, and LPA3/Edg-7, is a lipid mediator with diverse effects on various cells. Here, we investigated the expression profiles of LPA receptors and patterns of LPA-induced migration in gastric cancer cells. Northern blot analysis revealed that various gastric cancer cells expressed variable levels of LPA1, LPA2, and LPA3 without a consistent pattern. Using a Boyden chamber assay, LPA markedly increased cell migration of LPA1-expressing cells, the effects of which were almost totally abrogated by Ki16425, an LPA antagonist against LPA1 and LPA3. In contrast, LPA by itself did not significantly induce migration in MKN28 and MKN74 cells, which exclusively expressed LPA2. However, when hepatocyte growth factor (HGF) was placed with LPA in the lower chamber, LPA induced migration of these cells in a dose-dependent manner. Immunoprecipitation analysis revealed that LPA induced transient tyrosine phosphorylation of c-Met in LPA2-expressing cells, which suggests that the transactivation of c-Met by LPA causes a cooperative migratory response with HGF to these cells. Our results indicate that LPA regulates the migration of gastric cancer cells in a receptor-specific manner and suggest that the expression pattern of LPA receptors may affect the metastatic behavior of gastric cancer.

Chemotaxis↗