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PubMed2000

The spectrum of neuroendocrine differentiation among gastrointestinal carcinoids: importance of histologic grading, MIB-1, p53, and bcl-2 immunoreactivity.

CONTEXT: The advent of panneuroendocrine markers has helped to better depict the heterogeneity of gastrointestinal carcinoids. Consequently, it has been proposed that these tumors constitute a histologic spectrum that includes well-, moderately, and poorly differentiated carcinoids. However, the reproducibility of this grading system and its prognostic importance have sometimes been called into question. OBJECTIVE: To investigate the potential utility of cell proliferation and oncoprotein markers in augmenting the histologic classification. DESIGN AND SETTING: Retrospective study; tertiary care teaching hospital. METHODS: Fifty-eight patients with 41 well-differentiated, 12 moderately differentiated and 5 poorly differentiated carcinoids from various topographic sites of the gastrointestinal tract were selected and immunostained for panneuroendocrine markers, MIB-1, p53, and bcl-2. MAIN OUTCOME MEASURES: Degree of association between histologic grading, MIB-1, p53, and bcl-2 immunoreactivity and carcinoid metastatic behavior. RESULTS: The group comprised 30 males and 28 females whose mean age was 52.7 years (range, 14-81). Mean follow-up time was 85.8 months. All 58 patients tested positive for chromogranin A and/or synaptophysin. The group was divided into nonmetastatic (42/58, or 72.4%) and metastatic (16/58, or 27.6%) cases. Histologic grading tended to be associated with metastatic spread, but this occurrence of metastases did not attain statistical significance (P =.08). Positivity for MIB-1 (P =.004) and p53 (P =.04) was significantly associated with metastatic behavior, whereas bcl-2 was not (P = 0. 63). CONCLUSIONS: Although an organoid pattern and neuroendocrine immunophenotype help to define the spectrum of gastrotestinal carcinoids, this study suggests that the histologic grading of these tumors has some limitations with respect to predicting metastatic behavior. However, MIB-1 and p53 can compliment histologic grading as prognostic indicators in this regard while bcl-2 appears to be less useful.

Adolescent↗

PubMed2002

(Neonatal) retinoblastoma in the first month of life.

OBJECTIVES: To identify patients with retinoblastoma whose conditions were diagnosed at the age of 1 month or younger and to describe their clinical features (including ocular and patient survival) and the development of second nonocular tumors. MATERIALS AND METHODS: A retrospective study of 1831 patients. The cumulative incidence of second cancer development was analyzed using the Kaplan-Meier method. RESULTS: Forty-six patients were identified as having a diagnosis of retinoblastoma at the age of 1 month or younger (mean age, 18.5 days). Family history (31 patients [67%]) exceeded leukocoria (6 patients [13%]) as the most common reason for detection. Twenty-six (56%) of the 46 patients were seen with unilateral retinoblastoma, with 22 ultimately developing cancer in the fellow eye. At the initial diagnosis, 81 (85%) of the 95 tumors were detected in zones 1 and 2. Eighty-two (93%) of the 88 subsequent tumors were located in zones 2 and 3. In the 26 patients who had unilateral retinoblastoma, 16 of the initially affected eyes and 21 of the fellow eyes were salvaged. In the 19 (44%) of 20 patients who were seen initially with bilateral retinoblastomas, 31 (82%) of the 38 eyes were salvaged. The mean follow-up was 10.9 years. The incidence of second nonocular cancers reached 54% by 23.7 years for the patients who received radiation therapy, while the incidence was 0% for the patients who did not. Four (8.7%) of the 46 patients developed metastatic disease and died; 3 of these patients had documented metastases in the first month of life (one at birth). CONCLUSIONS: The most common manifesting sign of children diagnosed as having retinoblastoma in the first month of life is family history. Eyes with Reese-Ellsworth group I retinoblastomas were the most common. In patients with bilateral and unilateral retinoblastoma, new (subsequent) ocular tumors developed in a centrifugal pattern. Despite an early diagnosis, patients' eyes came to enucleation, and metastatic disease and death occurred from ocular metastases. In patients who received radiation therapy, the probability of developing second nonocular cancer is 54% by 23.7 years; no second cancers developed in patients who did not receive radiation therapy.

Cohort Studies↗

PubMed1997

'Revertant' DCIS in human axillary breast carcinoma metastases.

Recent experimental evidence obtained in Scid mice has suggested that the metastatic process is in large part epigenetically regulated and undergoes partial reversion once the metastatic process is completed: the metastatic colonies become more engaged in the process of growing in situ than actively metastasizing. Based on this experimental evidence, examples were sought of metastatic human cancers where similar reversion to an in situ growth state was occurring. Review of 200 cases of metastatic human breast cancer revealed a 21 per cent incidence of reversion to a ductal carcinoma in situ (DCIS) growth pattern within axillary nodal metastases. The revertant DCIS areas were characterized by an intact and circumferential basement membrane, as demonstrated by extracellular laminin and type IV collagen immunoreactivity. These revertant DCIS areas could be distinguished from primary DCIS, however, by the absence of surrounding myoepithelial cells in the former, identified in the latter by their positive maspin, S-100, and smooth muscle actin immunoreactivity. The pattern of revertant DCIS, poorly differentiated (comedo) (13 per cent), intermediate (non-comedo) (6 per cent), or well-differentiated (non-comedo) (2%), exhibited complete 100 per cent concordance with the primary DCIS pattern. The concordance of histological patterns held true for even the subtypes of DCIS determined by architectural pattern, such as the micropapillary or cribriform subtypes. Nuclear size by digital image analysis and Her-2/neu, p53, and Ki-67 status in the revertant DCIS also exhibited complete concordance with the primary DCIS counterparts. Cases exhibiting a revertant DCIS pattern tended to be ER-negative/EGFR-positive and exhibited significant nodal involvement (mean number, 9; mean area, 90 per cent) compared with cases lacking a revertant pattern (mean number, 4; mean area, 15 per cent) (P < 0.01) These findings suggest that reversion of the metastatic phenotype may also be occurring within autochthonous human metastasis.

Axilla↗

PubMed1998

Comparative analysis of the in vivo expression of tyrosinase, MART-1/Melan-A, and gp100 in metastatic melanoma lesions: implications for immunotherapy.

A variety of human melanoma-associated antigens (MAA) have been identified that can be recognized by T lymphocytes in a major histocompatibility complex-restricted fashion. Among them, tyrosinase, MART-1/Melan- A, and gp100 are derived from nonmutated melanocyte lineage-specific antigens (Ag). These Ag can be recognized by CD8+ and, in the case of tyrosinase, CD4+ T cells. The in situ expression of these MAA may be a significant cofactor in determining the recognition of melanoma targets by Ag-specific T cells. In this study, we examined the patterns of expression of these MAA using immunohistochemical methods on 30 metastatic tumor deposits derived from 25 patients. MAA expression was heterogeneous among the 30 specimens and also within individual lesions. Of note, 23% of the samples examined failed to express the gp100 protein, and 17% of samples had no detectable expression of MART-1. In contrast, all lesions demonstrated some degree of tyrosinase expression even in cases where both gp100 and MART-1 were not detectable. In addition, 60% of samples (18 of 30) showed strong positivity for tyrosinase (> 75% of cells staining) compared with 40% for gp100 and 36% for MART-1. Currently, a number of experimental immunotherapies for melanoma are directed against the MAA tyrosinase, MART-1, and gp100. Although threshold levels of Ag required for T-cell recognition have not yet been defined, tumor-associated Ag expressed in high density, such as tyrosinase, may be better targets for future immunotherapy trials.

Antigens, Neoplasm↗

PubMedDate not supplied

Changes in the tumorigenic and metastatic properties of murine melanoma cells treated with a triazene derivative.

Treatment of B16/BL6 murine melanoma cells in vitro with the 'xenogenizing' agent potassium p-(3-methyl-1-triazeno)benzoate (MM-COOK) had a profound impact on the tumorigenic and metastatic properties of the tumor, an effect that was only detectable in immunologically intact hosts. The treated tumor cells gave rise to a considerably smaller number of experimental and spontaneous pulmonary metastases and displayed an impaired growth rate in vivo, but were highly tumorigenic and metastatic in irradiated recipients. Moreover, the drug-treated cells retained the in vitro growth pattern and plating efficiency of the parent line, and were able actively to immunize intact hosts. Studies aimed at clarifying the mechanisms responsible for the decreased metastatic potential of the cells treated with MM-COOK indicated the involvement of host immune responses largely mediated by cells in the T-dependent compartment with no major contribution of natural immunity effector mechanisms.

5-Methylcytosine↗

PubMed1988

Differentiation of hepatic metastases from hepatic hemangiomas and cysts by using MR imaging.

T1-weighted and T2-weighted pulse sequences were employed for MR imaging of hepatic metastatic tumors (98 patients), hemangiomas (24 patients), and cysts (seven patients); a 0.6-T superconducting magnet was used. In a retrospective study, signal intensity and morphology were used to establish criteria for differentiating metastases from hemangiomas and cysts. The signal intensity of the lesion alone failed to be an etiologic discriminator because over 96% of all masses had a signal intensity less than that of liver on T1-weighted sequences, and at least 90% had a signal intensity greater than that of liver on T2-weighted sequences. Morphologic features depicted on T2-weighted images were more specific than those depicted on T1-weighted images in differential diagnosis. Amorphous, target, and halo signs and a change in morphology were present only in metastatic disease, with a frequency of 45%, 27%, 13%, and 12%, respectively. Two other morphologic patterns--doughnut and lightbulb signs--were found to have overlapping causes. Overall, at least one of the specific signs was observed in 92% of patients with metastatic disease. These data suggest that T2-weighted pulse sequences are essential for discriminating between hepatic metastases and hepatic hemangiomas and cysts. MR imaging is a promising technique for distinguishing these lesions.

Cysts↗

PubMed2003

Identification of differentially expressed genes in isogenic highly metastatic and poorly metastatic cell lines of R3230AC rat mammary adenocarcinoma.

Tumour metastasis occurs as a result of a cascade of events including alterations in the expression of various genes. The identification of such genes is essential to understanding formation of metastasis. In a previous study, highly metastatic (LN4.D6) and poorly metastatic (CAb.D5) cell lines were obtained from the rat mammary adenocarcinoma cell line R3230AC. Subtractive hybridization was used to identify differentially expressed genes between these two cell lines. We identified eight cDNA clones in CAb.D5 and six cDNA clones in LN4.D6 that were differentially expressed. One of the cDNA clones in each cell line had no homology with known sequences. Expression patterns of these differentially expressed genes were examined in a pair of rat mammary and prostate adenocarcinoma cell lines. Compared with cell lines examined, cDNA FF-10 was only expressed in CAb.D5; however, cDNA RB-8, RE-1, RF-5 were only expressed in the highly metastatic LN4.D6. No correlation was observed between expression patterns of the differentially expressed genes and metastatic potential of these cells. However, differential expression of genes, especially cytokeratins (CK8 and CK5) and collagens (III and IV) between highly metastatic and low metastatic rat mammary adenocarcinoma cell lines might initiate further investigation of these genes in metastatic process.

Adenocarcinoma↗

PubMed2000

Dietary 4-HPR suppresses the development of bone metastasis in vivo in a mouse model of prostate cancer progression.

The effects of the synthetic retinoid N-(4-hydroxyphenyl) retinamide (4-HPR) on prostate cancer metastasis in vivo were evaluated in the mouse prostate reconstitution (MPR) model. MPRs were produced by infection of either heterozygous (+/-) or nullizygous (-/-) p53-mutant fetal prostatic epithelial cells with the recombinant retrovirus Zipras/myc 9. Previous studies have documented that loss of p53 function potentiates metastasis in this model system. MPRs were grafted into homozygous (+/+) p53 male mice, fed a 4-HPR containing diet or a control diet and maintained until the status of tumor progression dictated sacrifice. Under these experimental conditions, treatment with 4-HPR did not have a significant effect on primary tumor wet weight for either p53 +/- or p53 -/- MPRs. For, p53 +/- MPRs the animals fed the 4-HPR diet had a slight improvement in survival and a significant reduction in the number of mesenteric metastases (P = 0.0477, t-test). Notably, in p53 +/- MPRs the incidence of metastasis to lumbar spine and sternum was 92% in the control animals compared to 54% in the 4-HPR treated animals (P = 0.035, chi2-test). In p53 -/- MPRs there was a trend toward a reduction in the number of soft tissue metastases to lung and liver in the 4-HPR group relative to the control diet group and a statistically significant reduction in the incidence of metastasis to bone was demonstrated in that 50% of control animals versus 30% of 4-HPR treated p53 -/- animals harbored bone metastases (P = 0 < 0.05, chi2-test). Cell lines were established from portions of the primary tumor and from selected metastatic deposits in each experimental group. Clonal analysis, by retroviral integration pattern, indicated increased clonal diversity in both the primary tumors and metastasis-derived cell lines from 4-HPR treated animals relative to the control animals. In vitro treatment with 4-HPR did not reveal discriminating differences between cell lines derived from primary tumors and bone metastases or control and treatment groups in regard to growth arrest or apoptotic responses. Overall these studies indicate limited anti-tumor and anti-metastatic activity in this highly aggressive in vivo mouse model of prostate cancer, yet 4-HPR treatment significantly suppressed the development of bone metastases in p53 +/- and p53 -/- MPRs revealing a novel and potentially clinically useful activity of this retinoid.

Animals↗

PubMed2005

A phase II study of epirubicin, cisplatin and capecitabine combination chemotherapy in patients with metastatic or advanced gastric cancer.

OBJECTIVES: The purpose of this study was to evaluate the antitumor activity and safety of an epirubicin, cisplatin, and capecitabine (ECX) combination in patients with metastatic or advanced gastric cancer. PATIENTS AND METHODS: Patients with metastatic or advanced measurable gastric adenocarcinoma received ECX combination chemotherapy. Epirubicin 50 mg/m2 and cisplatin 60 mg/m2 were administered on day 1 by intravenous injection. Capecitabine 1,000 mg/m2 twice daily was administered orally on day 1-14. The cycle was repeated every 3 weeks. RESULTS: Fifty-four patients were enrolled in this study. Fifty patients were assessable for responses and 53 for toxicity. A total of 250 cycles were administered. The overall best response rate by intent-to-treat analysis was 59% including 52% partial responses and 7% complete responses. Median response duration and time to progression was 5.8 and 6 months, respectively. Median survival for all patients was 9.6 months (95% CI, 8.7-10.5 months). The most common grade 3/4 hematological adverse event was neutropenia in 31% (76 cycles) including febrile neutropenia in 4.8% (11 cycles). Non-hematological toxicity was generally mild and reversible. Grade 3/4 nausea, vomiting and stomatitis occurred in 8, 9, and 8% of the patients, respectively. Hand-foot skin reactions developed in 51% of patients, but most were self-limited. Grade 3 occurred in only 4%. One patient died of neutropenic sepsis. CONCLUSIONS: ECX combination regimen showed high anti-tumor activity with a tolerable toxicity pattern as a front-line chemotherapy for patients with metastatic or advanced gastric cancer.

Adenocarcinoma↗

PubMed1995

The role of CD44 splice variants in human metastatic cancer.

The large family of CD44 splice variants are likely to serve multiple functions in the embryo and in the adult organism. This is reflected in their complex patterns of expression. In molecular terms these functions are largely unknown. Certain splice variants (CD44v) can promote the metastatic behaviour of cancer cells. In human colon and breast cancer the presence of epitopes encoded by exon v6 on primary resected tumour material indicates poor prognosis. Metastasis-promoting splice variants differ from those that seem not to have a role in the induction of metastasis by the formation of homomultimeric complexes in the plasma membrane of cells. This may increase their affinity to ligands such as hyaluronate. The affinity can be further regulated over a range from low to very high by cell-specific modification. The fact that CD44v epitopes are found on normal epithelial cells such as skin, cervical epithelium and bladder enforces cautious evaluation of the significance of CD44v expression in human cancer. Nevertheless, certain epitopes can serve as tools in early diagnosis of certain cancers and will facilitate the development of specific targeted therapy.

Biomarkers, Tumor↗

PubMed2005

Gastrointestinal stromal tumor: new nodule-within-a-mass pattern of recurrence after partial response to imatinib mesylate.

PURPOSE: To investigate a new pattern of tumor recurrence observed at imaging in patients with metastatic gastrointestinal stromal tumor (GIST) after initial partial response to imatinib mesylate. MATERIALS AND METHODS: Ninety-two patients with metastatic GIST who underwent treatment in a clinical trial with oral imatinib mesylate were followed up for 29 months. An institutional review board-approved protocol was used. The study complied with the Health Insurance Portability and Accountability Act, and written informed consent was obtained from all patients. Images of the chest, abdomen, and pelvis, acquired with computed tomography (CT), positron emission tomography (PET), and, in some cases, magnetic resonance imaging, were evaluated for treatment response and disease recurrence. Thirty-nine patients (29 men, 10 women; age range, 18-84 years; mean, 49.2 years) had recurrent disease after an initial variable period of response (range, 2-24 months; median, 14.4 months). Initial response was determined with findings of decreased uptake of fluorine 18 fluorodeoxyglucose at PET, shrinkage of tumor, and decreased attenuation at CT. Images were evaluated for disease recurrence by two experienced radiologists who were blinded to each other's interpretation but not to clinical details. Final reading was performed by consensus. RESULTS: A nodule within a mass was seen in 21 of 39 patients (in intrahepatic tumor [n = 8], extrahepatic tumor [n = 10], or both intra- and extrahepatic tumors [n = 3]) and was the first sign of disease progression in 17 of 21 patients. Other patterns of recurrence included new site of disease (n = 7), regrowth of preexistent lesion (n = 20), and mixed (more than one) pattern (n = 9). Disease progression was verified at needle biopsy (n = 16), follow-up imaging (n = 14), and/or surgical resection (n = 9). CONCLUSION: A nodule within a mass is an important sign of recurrent GIST, but measurements of overall tumor size may not enable detection of such nodules.

Adolescent↗

PubMed1993

Biosynthesis and regulation of Le(x) and SA-Le(x) glycolipids in metastatic human colon carcinoma cells.

This report concerns the stepwise biosynthesis in vitro of Sialyl Lewis X, (SA-Le(x)), a carcinoembryonic antigen, in human colon carcinoma KM12 cells exhibiting different metastatic behaviors. The significance of SA-Le(x) has become even more apparent since the detection of its terminal epitope NeuAc(alpha 2-3)Gal beta 1-4(Fuc alpha 1-3)GlcNAc-, as the binding ligand of the selectin family member ELAM-1. The activity level of galactosyltransferase GalT-4 which catalyzes the formation of core nLcOse4Cer (Gal beta 1-4GlcNAc beta 1-3Gal beta 1-4Glc-Cer) is very high in all the metastatic lines tested with highly metastatic lines (KM12-SM) exhibiting the highest activity. The same activity pattern for galactosyltransferase is also observed when tested with iLcOse5Cer (GlcNAc beta 1-3nLcOse4Cer), the precursor for polylactosamine glycolipid. Sialyltransferase SAT-3 which catalyzes the formation of LM1 (NeuAc alpha 2-3nLcOse4Cer), the precursor for SA-Le(x), is also present in all the metastatic cell lines although the activity levels are much lower compared to galactosyltransferase. The fucosyltransferase FucT-3, which catalyzes the formation of R'-Gal-Fuc(alpha 1-3)GlcNAc-R linkage, is active with both nonsialylated substrate, nLcOse4Cer, and sialylated substrate, LM1 (NeuAc alpha 2-3nLcOse4Cer) with the formation of either Le(x) (Gal beta 1-4(Fuc alpha 1-3)GlcNAc beta 1-3Gal beta 1-4Glc-Cer) or SA-Le(x) (NeuAc alpha 2-3nLcOse4Cer). However, the sialylated substrate LM1 is preferred to enzymatic activity since it exhibited lower Km (46 microM) than that of nLcOse4Cer (67 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Carbohydrate Conformation↗

PubMed2004

Immunoreactivity of hepatocyte paraffin 1 monoclonal antibody in cutaneous metastatic tumors.

Hepatocyte paraffin 1 (Hep Par 1), a monoclonal antibody recognizing an antigen thought to be specific for hepatocyte mitochondria, is considered the most specific and sensitive marker of normal and neoplastic hepatocytes and has been used in diagnosing hepatocellular carcinomas. Recent data suggest that the specificity of Hep Par 1 for hepatic neoplasms is not absolute; nonhepatic neoplasms might express this marker. We assessed the value of Hep Par 1 in the diagnosis of cutaneous metastases of visceral tumors by immunostaining 65 biopsy or excision specimens with Hep Par 1. Hepatocarcinomas (primary and metastatic to the skin) showed specific (coarse granular intracytoplasmic) immunoreactivity. A similar reactivity pattern was found in 5 of 10 metastases of bronchial adenocarcinoma. Nonspecific (weak, nongranular) cytoplasmic immunoreactivity was observed in 5 cases of nonhepatic skin metastases. Hep Par 1 seems to be a sensitive marker of hepatocellular carcinomas metastatic to the skin, but its specificity is not absolute because it might be expressed in metastases of nonhepatic tumors, namely bronchial adenocarcinomas. Hep Par 1 should be used with caution in the investigation of cutaneous metastases from an unknown primary site, preferably in conjunction with other markers of neoplastic hepatocytes.

Adenocarcinoma↗

PubMedDate not supplied

[A prospective study on nephrotoxicity induced by continuous infusion of high-dose ifosfamide (15/m2)].

BACKGROUND: A good response rate to high-dose ifosfamide (HDIFO) has been reported in metastatic osteosarcoma and soft tissue tumors. As standard dose of IFO (< 12 g/m2) can give several renal complications and patients previously treated with nephrotoxic drugs are at high risk of nephrotoxicity, a prospective study to evaluate the pattern of nephrotoxicity induced by HDIFO was carried out. METHODS: Twelve patients (11 metastatic osteosarcoma, 1 synovial sarcoma; mean age 17, R 14-34) were treated with 4 courses of HDIFO/ MESNA (15 g/m2, IV 5 day continuous infusion with bicarbonate and K supplements). All but two were previously treated with cisplatin and methotrexate. Several parameters of renal function were measured before treatment, after each HDIFO course and two months after chemotherapy completion. RESULTS: Significant changes in the urinary excretion of beta 1-microglobulin, beta 2-microglobulin, Alanine Aminopeptidase, N-Acetil-beta, D-glucosaminidase and a significant reduction in phosphate tubular absorbtion according to the cumulative dose of IFO infused, were observed. Phosphaturia and hypophosphatemia occurred in all the patients studied. In 5 patients, CrCl fell below 70 ml/min with normal serum creatinine level after 45 g/m2 IFO. Plasma bicarbonate concentration less than 20 mmol/l was observed in 5 of 48 HDIFO courses. Glycosuria was detected in 4 patients. Two months after chemotherapy completion, mild glycosuria and slightly reduced CrCl persisted in two patients, whereas the other parameters of renal function studied were similar to the baseline values. An acute, usually reversible subclinical nephrotoxicity involving glomerule and renal tubule was demonstrated in all the patients treated with HDIFO. A persisting subclinical renal impairment was shown with mild glycosuria (2/12 patients) and slightly reduced CrCl (2/12 patients).

Adolescent↗

PubMed2000

Expression of carbohydrate antigens in advanced-stage ovarian carcinomas and their metastases-A clinicopathologic study.

OBJECTIVE: Up-regulated expression or loss of expression of various carbohydrate antigens on the surface of cancer cells has been associated with a metastatic phenotype and poor survival in epithelial malignancies of different origins. The object of this study was to investigate the expression of carbohydrate antigens in two groups of patients diagnosed with advanced-stage ovarian carcinoma-one with an extremely favorable outcome and the other with a uniformly poor survival. METHODS: Sections from 76 paraffin-embedded blocks (primary ovarian carcinomas and metastatic lesions) from 45 patients diagnosed with advanced-stage ovarian carcinomas (FIGO stages III-IV) were immunohistochemically stained using five monoclonal antibodies for Lewis(y) (Le(y))(two antibodies), Sialyl Lewis(x) (Slex), Tn, and Sialyl Tn (STn) antigens. Patients were divided in two groups based on outcome. Long-term survivors (21 patients) and short-term survivors (24 patients) were defined using a double cut-off of 36 months for disease-free survival (DFS) and 60 months for overall survival (OS). Staining results for primary tumors and metastases were analyzed separately. RESULTS: Mean follow-up period was 70 months. The mean values for DFS and OS were 109 and 125 months for long-term survivors and 3 and 25 months for short-term survivors. Staining for all four antigens was seen in the majority of cases (range = 72-96%) and tended to be comparable in primary tumors and their metastases. However, absence of immunoreactivity for STn was seen in 9/38 (24%) metastatic lesions and only 1/38 (3%) primary tumors. This finding did not reach statistical significance (P > 0.05). A combined pattern of membranous and cytoplasmic staining was predominant in the majority of cases. Enhanced staining for Le(y) and STn was detected in the invasive front of some tumors, while Slex and Tn immunoreactivity did not relate to cell location. Primary tumors and metastatic lesions of long-term survivors displayed immunoreactivity patterns that were comparable to those of short-term survivors. In the evaluation of survival curves, more diffuse staining for Slex showed marginal correlation with poor survival (P = 0.05), while a trend toward poorer survival was seen in tumors that were more extensively stained for Le(y) and Tn (P > 0.05). CONCLUSIONS: Le(y), Slex, STn, and Tn antigens are widely expressed in primary ovarian carcinomas and their metastases. Altered expression of Sialyl Tn is observed with tumor progression in a fraction of ovarian carcinomas. Expression of membrane carbohydrate residues is prevalent in tumors of both long-term and short-term survivors and does not appear to be a strong predictor of disease outcome. However, larger studies are needed to further elucidate the role of these molecules in ovarian carcinogenesis.

Adult↗

PubMed1999

[An approach to the cytologic diagnostic criteria of hepatocellular carcinoma by fine needle aspiration biopsy].

OBJECTIVE: To identify useful cytologic features for diagnosis of hepatocellular carcinoma (HCC). METHODS: Fine needle aspiration(FNA) smears from 61 patients with proven HCC, 19 patients with metastatic tumors in the liver and 16 patients with non-neoplastic lesion of the liver were reviewed in order to detect the relevant cytologic changes associated with HCC. Step-wise logistic regression analysis was done to select useful cytologic features in discriminating HCC from metastatic tumors and non-neoplastic lesions of liver. RESULTS: Nine cytologic features observed were significantly associated with HCC: abundant tissue fragments(91.8%); trabecular pattern(91.8%); sinusoidal endothelial cells (47.5%); polygonal cells with centrally placed nuclei(82.0%); increased nuclear to cytoplasmic ratio(95.1%); large nucleoli(55.7%); bile granules(31.1%); cytoplasmic vacuoles(27.9%) and atypical naked hepatocyte nuclei(88.5%). In distinquishing HCC from metastatic tumors, polygonal cells with centrally placed nuclei, bile granules and trabecular pattern were useful cytologic features. Of the 61 patients with HCC, the logistic model correctly predicted 60(98.4%) as having HCC, while of the 19 patients with metastatic tumors, 18(94.7%) were correctly predicted. In distinquishing HCC from non-neoplastic liver disease, abundant tissue fragments, trebecular pattern, increased nuclear to cytoplasmic ratio and atypical naked hepatocyte nuclei were selected. When the four criteria were used, the sensitivity of diagnosing HCC was 100% and the specificity was 93.8%. CONCLUSION: Abundant tissue fragments, polygonal cells with centrally placed nuclei, increased nuclear to cytoplasmic ratio, trebecular pattern, atypical naked hepatocyte nuclei and bile granules are useful features for identifying HCC by FNA biopsy.

Biopsy, Needle↗

PubMed1983

Distribution of anionic surface sites on human melanocytes and human melanoma cells in culture.

With cationized ferritin (CF) as an ultrastructural marker for anionic cell surface sites, cultured guinea pig melanocytes display a uniquely homogeneous labelling pattern and a striking absence of redistribution of marker material. In the present study, we applied the same technique to normal human melanocytes and melanoma cells. Unfixed primary human mixed epidermal cell cultures displayed CF labelling patterns identical to those in guinea pig epidermal cells: on keratinocytes, CF was found in distinct aggregations which, upon prolonged incubation, clustered and were shed. Melanocytes, in contrast, bound CF to the cell surface as a uniform diffuse monolayer. There were no signs of cluster formation or shedding. Melanoma cell cultures were derived from 10 primary (2 lentigo maligna, 1 lentigo maligna melanoma, 4 superficial spreading melanomas, 2 nodular portions of superficial spreading melanomas, 1 nodular melanoma) and from 7 metastatic melanomas (4 cutaneous, 3 lymph node metastases). The CF labelling patterns encountered were heterogeneous. Three out of 10 primary tumors and 5 out of 7 metastases showed alterations of the normal melanocyte labelling pattern: regions of typical CF distribution were irregularly interrupted by stretches of membrane free of marker. In some areas, CF occurred in small globular aggregates. There was considerable heterogeneity of CF labelling patterns in different clones of a given culture. Altered CF binding patterns in melanoma cells appear to be associated with high metastasizing protential of the cell clones and may thus represent an unfavourable prognostic sign.

Binding Sites↗

PubMed2000

Levels of cyclin D1 and D3 in malignant melanoma: deregulated cyclin D3 expression is associated with poor clinical outcome in superficial melanoma.

We examined 172 primary (110 superficial and 62 nodular) and 73 metastatic melanomas, as well as 10 benign nevi, for protein expression of cyclin D1 and cyclin D3 and evaluated the relationship between deregulated protein levels and clinical outcome. For both proteins, a heterogeneous nuclear staining pattern was observed. Cyclin D3 was expressed by 96% of primary and 97% of metastatic melanomas. The corresponding percentages for cyclin D1 were 62% and 29%, respectively. In benign nevi, only rare cyclin D3-positive cells and no cyclin D1-positive cells were observed. High levels of cyclin D3 (>5% of the cells stained) were detected in 26 of 62 (42%) nodular melanomas and in 22 of 110 (20%) superficial tumors, whereas no such difference was observed with respect to cyclin D1. In superficial melanomas, a significant concordant staining pattern was observed between cyclin D1 and cyclin D3 (P = 0.0009), cyclin D1 and Ki-67 (P = 0.0001), cyclin D1 and cyclin A (P = 0.02), cyclin D3 and Ki-67 (P < 0.00001), and cyclin D3 and cyclin A (P = 0.002). Kaplan-Meier analysis revealed that high levels of cyclin D3 were an indicator of early relapse and decreased overall survival for patients with superficial (P = 0.001 and P = 0.009, respectively) but not nodular (P = 0.64 and P = 0.23) melanoma. Cyclin D1 did not have any impact on disease-free and overall survival for either of the subtypes. In conclusion, our results suggest that deregulation of cyclin D3 expression leading to increased proliferation may be a prognostic factor for superficial melanoma, whereas deregulated cell cycle machinery seems to have little impact on disease progression of nodular melanoma.

Biomarkers, Tumor↗