ABSTRACT
BACKGROUND AND AIMS: The impact of biliary invasion on recurrence and survival, after resection of colorectal cancer liver metastases, is not well known as publications are limited to small patient series. The aim was to investigate if biliary invasion in liver resected patients associated with liver relapses and recurrence-free survival. Secondary endpoints included association with other prognostic factors, disease-free survival and overall survival. MATERIALS AND METHODS: All patients with histologically verified biliary invasion (n = 31, 9%) were identified among 344 patients with liver resection between January 2009 and March 2015. Controls (n = 78) were selected from the same time period and matched for, among others, size and number of colorectal cancer liver metastasis. RESULTS: Median liver recurrence-free survival was significantly shorter in patients with biliary invasion than in controls (15.3 months versus not reached; p = 0.031) and more relapses were noted in the liver (61.3% versus 33.3%; p = 0.010), respectively. In univariate analyses for liver recurrence-free survival, biliary invasion was the only significant prognostic factor; p = 0.034. There were no statistical differences in disease-free and overall survival between the groups. CONCLUSION: Biliary invasion was associated with higher liver recurrence rates and shorter liver recurrence-free survival in patients with resected colorectal cancer liver metastasis.
Subject(s)
Biliary Tract Neoplasms/secondary , Biliary Tract Neoplasms/surgery , Colorectal Neoplasms/pathology , Liver Neoplasms/secondary , Liver Neoplasms/surgery , Adult , Aged , Aged, 80 and over , Biliary Tract Neoplasms/diagnostic imaging , Biliary Tract Neoplasms/drug therapy , Biomarkers, Tumor/analysis , Case-Control Studies , Colorectal Neoplasms/diagnostic imaging , Colorectal Neoplasms/drug therapy , Combined Modality Therapy , Female , Hepatectomy/methods , Humans , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/drug therapy , Male , Middle Aged , Neoplasm Invasiveness , Prognosis , Retrospective Studies , Survival Rate , Whole Body ImagingSubject(s)
Thyroglossal Cyst/surgery , Adolescent , Adult , Age Distribution , Aged , Child , Child, Preschool , Female , Humans , Infant , Male , Middle Aged , Postoperative Complications , Recurrence , Retrospective Studies , Sex Distribution , Thyroglossal Cyst/pathology , Treatment OutcomeABSTRACT
The aryl hydrocarbon receptor interacting protein (AIP) is a tumor-suppressor gene underlying the pituitary adenoma predisposition. Thus far, the exact molecular mechanisms by which inactivated AIP exerts its tumor-promoting action have been unclear. To better understand the role of AIP in pituitary tumorigenesis, we performed gene expression microarray analysis to examine changes between Aip wild-type and knockout mouse embryonic fibroblast (MEF) cell lines. Transcriptional analyses implied that Aip deficiency causes a dysfunction in cyclic adenosine monophosphate (cAMP) signaling, as well as impairments in signaling cascades associated with developmental and immune-inflammatory responses. In vitro experiments showed that AIP deficiency increases intracellular cAMP concentrations in both MEF and murine pituitary adenoma cell lines. Based on knockdown of various G protein α subunits, we concluded that AIP deficiency leads to elevated cAMP concentrations through defective Gαi-2 and Gαi-3 proteins that normally inhibit cAMP synthesis. Furthermore, immunostaining of Gαi-2 revealed that AIP deficiency is associated with a clear reduction in Gαi-2 protein expression levels in human and mouse growth hormone (GH)-secreting pituitary adenomas, thus indicating defective Gαi signaling in these tumors. By contrast, all prolactin-secreting tumors showed prominent Gαi-2 protein levels, irrespective of Aip mutation status. We additionally observed reduced expression of phosphorylated extracellular signal-regulated kinases 1/2 and cAMP response element-binding protein levels in mouse and human AIP-deficient somatotropinomas. This study implies for the first time that a failure to inhibit cAMP synthesis through dysfunctional Gαi signaling underlies the development of GH-secreting pituitary adenomas in AIP mutation carriers.
Subject(s)
Adenoma/metabolism , Cyclic AMP/metabolism , GTP-Binding Protein alpha Subunits, Gi-Go/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Pituitary Gland/pathology , Pituitary Neoplasms/metabolism , Signal Transduction , Animals , Cell Line , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology , Fibroblasts/cytology , GTP-Binding Protein alpha Subunits, Gi-Go/genetics , Gene Knockout Techniques , Humans , Mice , Pituitary Gland/metabolismABSTRACT
Neuroendocrine tumors (NETs) arise from disseminated neuroendocrine cells and express general and specific neuroendocrine markers. Neuropeptide S receptor 1 (NPSR1) is expressed in neuroendocrine cells and its ligand neuropeptide S (NPS) affects cell proliferation. Our aim was to study whether NPS/NPSR1 could be used as a biomarker for neuroendocrine neoplasms and to identify the gene pathways affected by NPS/NPSR1. We collected a cohort of NETs comprised of 91 samples from endocrine glands, digestive tract, skin, and lung. Tumor type was validated by immunostaining of chromogranin-A and synaptophysin expression and tumor grade was analyzed by Ki-67 proliferation index. NPS and NPSR1 expression was quantified by immunohistochemistry using polyclonal antibodies against NPS and monoclonal antibodies against the amino-terminus and carboxy-terminus of NPSR1 isoform A (NPSR1-A). The effects of NPS on downstream signaling were studied in a human SH-SY5Y neuroblastoma cell line which overexpresses NPSR1-A and is of neuroendocrine origin. NPSR1 and NPS were expressed in most NET tissues, with the exception of adrenal pheochromocytomas in which NPS/NPSR1 immunoreactivity was very low. Transcriptome analysis of NPSR1-A overexpressing cells revealed that mitogen-activated protein kinase (MAPK) pathways, circadian activity, focal adhesion, transforming growth factor beta, and cytokine-cytokine interactions were the most altered gene pathways after NPS stimulation. Our results show that NETs are a source of NPS and NPSR1, and that NPS affects cancer-related pathways.
Subject(s)
Endocrine Gland Neoplasms/physiopathology , Gastrointestinal Neoplasms/physiopathology , Neuroendocrine Tumors/physiopathology , Receptors, G-Protein-Coupled/physiology , Signal Transduction/physiology , Skin Neoplasms/physiopathology , Adult , Aged , Antibodies, Monoclonal/immunology , Antibody Specificity , Biomarkers, Tumor/immunology , Biomarkers, Tumor/physiology , Cell Proliferation , Endocrine Gland Neoplasms/pathology , Female , Gastrointestinal Neoplasms/pathology , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/pathology , Lung Neoplasms/physiopathology , Male , Middle Aged , Neuroendocrine Tumors/pathology , Neuropeptides/immunology , Neuropeptides/physiology , Receptors, G-Protein-Coupled/immunology , Retrospective Studies , Skin Neoplasms/pathologyABSTRACT
BACKGROUND: Mediator complex participates in transcriptional regulation by connecting regulatory DNA sequences to the RNA polymerase II initiation complex. Recently, we discovered through exome sequencing that as many as 70% of uterine leiomyomas harbour specific mutations in exon 2 of mediator complex subunit 12 (MED12). In this work, we examined the role of MED12 exon 2 mutations in other tumour types. METHODS: The frequency of MED12 exon 2 mutations was analysed in altogether 1158 tumours by direct sequencing. The tumour spectrum included mesenchymal tumours (extrauterine leiomyomas, endometrial polyps, lipomas, uterine leiomyosarcomas, other sarcomas, gastro-intestinal stromal tumours), hormone-dependent tumours (breast and ovarian cancers), haematological malignancies (acute myeloid leukaemias, acute lymphoid leukaemias, myeloproliferative neoplasms), and tumours associated with abnormal Wnt-signalling (colorectal cancers (CRC)). RESULTS: Five somatic alterations were observed: three in uterine leiomyosarcomas (3/41, 7%; Gly44Ser, Ala38_Leu39ins7, Glu35_Leu36delinsVal), and two in CRC (2/392, 0.5%; Gly44Cys, Ala67Val). CONCLUSION: Somatic MED12 exon 2 mutations were observed in uterine leiomyosarcomas, suggesting that a subgroup of these malignant tumours may develop from a leiomyoma precursor. Mutations in CRC samples indicate that MED12 may, albeit rarely, contribute to CRC tumorigenesis.
Subject(s)
Colorectal Neoplasms/genetics , Leiomyosarcoma/genetics , Mediator Complex/genetics , Uterine Neoplasms/genetics , Colorectal Neoplasms/pathology , Exome , Exons , Female , Humans , Leiomyoma/genetics , Leiomyoma/pathology , Leiomyosarcoma/pathology , Mutation , Sequence Analysis, DNA/methods , Uterine Neoplasms/pathologyABSTRACT
OBJECTIVE: Cytology screening for prevention of cervical cancer can reduce incidence and mortality by more than 80% in settings with good organization and rigorous quality control. Audit studies are essential for reaching and maintaining a high quality of screening. The aim of this study was to evaluate variation in performance indicators by screening laboratory and assess the impact on the effectiveness of screening as indicated by cervical intraepithelial neoplasia grade 3 and above (CIN3+) rates after a negative screen. METHODS: Seven cytology screening laboratories operating during 1990-1999 with a total of 953 610 screening tests performed were included in the study. By linking screening and cancer register files, all cases of CIN3+ diagnosed in the screened population were identified. For 395 CIN3+ cases with a preceding negative screen and 787 controls, a re-evaluation of smears was undertaken to uncover false negative screening tests. Performance parameters and rates of CIN3+ after a negative screen were analysed for interlaboratory heterogeneity. RESULTS: The rates of follow-up recommendations and referrals varied by up to 3.6- (2.8-10.2%) and 4.0-fold (0.03-0.12%), respectively. CIN1, CIN2 and CIN3+ screen detection rates differed by up to 8.5- (0.02-0.17%), 5.4- (0.05-0.25%) and 3.3-fold (0.05-0.18%). False negative rates determined by re-evaluation showed up to 2.1-fold differences (29-62%). Rates of CIN3+ after a negative screen (0.023-0.048%) and as a proportion of total CIN3+ (15-31%) in the screened population were low and did not vary significantly. CONCLUSIONS: There were large variations in the sensitivity-specificity trade-off between laboratories, reflected in all performance indicators as well as in the test validity estimates of the re-evaluation phase, but not in screening effectiveness. Even though performance variations do not always have an impact on the effectiveness of screening, they lead to variations in cost, treatment and psychological burden, and should be addressed.
Subject(s)
Early Detection of Cancer/methods , Laboratories/standards , Program Evaluation , Uterine Cervical Dysplasia/diagnosis , Alphapapillomavirus/pathogenicity , Early Detection of Cancer/standards , Early Detection of Cancer/statistics & numerical data , False Negative Reactions , Female , Finland , Humans , Laboratory Proficiency Testing/methods , Laboratory Proficiency Testing/standards , Papillomavirus Infections/diagnosis , Papillomavirus Infections/pathology , Referral and Consultation/statistics & numerical data , Regression Analysis , Sensitivity and Specificity , Vaginal Smears , Uterine Cervical Dysplasia/pathology , Uterine Cervical Dysplasia/prevention & controlABSTRACT
Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy often caused by mutations in complement factor H (CFH), the main regulator of alternative complement pathway. Because CFH is produced mainly by the liver, combined liver-kidney transplantation is a reasonable option in treatment of patients with severe aHUS. We studied complement activation by monitoring activation markers during liver transplantation in two aHUS patients treated extensively with plasma exchange and nine other liver transplantation patients. After the reperfusion, a clear increase in all the activation markers except C4d was observed indicating that the activation occurs mainly through the alternative pathway. Concentration of SC5b-9 was higher in the hepatic than the portal vein indicating complement activation in the graft. Preoperatively and early during the operation, the aHUS patients showed highest C3d concentrations but otherwise their activation markers were similar to the other patients. In the other patients, correlation was found between perioperative SC5b-9 concentration and postoperative alanine aminotransferase and histological changes. This study explains why supply of normal CFH by extensive plasma exchange is beneficial before combined liver-kidney transplantation of aHUS patients. Also the results suggest that perioperative inhibition of the terminal complement cascade might be beneficial if enhanced complement activation is expected.
Subject(s)
Complement Activation , Hemolytic-Uremic Syndrome/surgery , Liver Transplantation , Adolescent , Adult , Humans , Middle Aged , Young AdultABSTRACT
The concomitant existence of a non-malignant neuroendocrine tumor (NET) and membranous glomerulonephritis (MGN) is rare. We report a subject with kidney biopsy proven MGN and nephrotic syndrome in which a computerized scan tomography (CT) examination was performed revealing a pancreatic tumor. A pancreatectomy was performed and the tumor was shown to be a non-malignant NET with a malignant potential. Although treatment with corticosteroids was initiated remission of MGN was observed within the next month after pancreatectomy. The rapid remission observed shortly after pancreatectomy pointed to that tumor removal contributed to, and that neither spontaneous nor corticosteroid treatment alone did induce the rapid remission of the MGN. The coexistence of the two disorders NET and MGN is very rare, however. This is the first report on remission of MGN after pancreatectomy for a NET.
Subject(s)
Glomerulonephritis, Membranous/complications , Kidney/pathology , Neuroendocrine Tumors/surgery , Pancreatectomy , Pancreatic Neoplasms/surgery , Adrenal Cortex Hormones/therapeutic use , Biopsy , Female , Glomerulonephritis, Membranous/drug therapy , Glomerulonephritis, Membranous/pathology , Humans , Middle Aged , Nephrotic Syndrome/etiology , Neuroendocrine Tumors/complications , Neuroendocrine Tumors/diagnostic imaging , Pancreatic Neoplasms/complications , Pancreatic Neoplasms/diagnostic imaging , Remission Induction , Time Factors , Tomography, X-Ray Computed , Treatment OutcomeABSTRACT
Anaplastic thyroid carcinoma (ATC) is one of the most lethal malignancies; poorly differentiated thyroid carcinoma (PDTC) is a new diagnosis for rare aggressive thyroid tumours. Surgery is often considered the only chance for survival, but the benefit of surgery and subsequent multimodal therapy is unclear. We retrospectively analyzed the outcome of 44 ATC and 8 PDTC consecutive patients treated at Helsinki University Central Hospital between 1990 and 2008. All ATC and PDTC cases were re-examined and reclassified histologically. Median survival was only 3.1 months for ATC, but 3.7 years for PDTC. Most patients in both groups eventually died of cancer. ATC patients were older than PDTC patients (74 vs. 66 years). Nodal and distant metastases had a negative impact on survival (ATC; p = 0.038, p = 0.008). Long-term survivors in both groups were stage N0M0 at presentation. Multimodal therapy was successful for 9 (20%) ATC patients, and their median survival was the longest (11.6 months) among treatment groups. Most PDTC patients (88%) underwent total thyroidectomy followed by radioiodine ablation; the only 2 who received chemotherapy survived longest. Although ATC and PDTC are both aggressive thyroid carcinomas, multimodal therapy for both can provide a chance of prolonged survival in patients with locoregional disease.
Subject(s)
Antineoplastic Agents/therapeutic use , Adult , Aged , Aged, 80 and over , Combined Modality Therapy , Disease-Free Survival , Doxorubicin/therapeutic use , Female , Humans , Male , Middle Aged , Neoplasm Metastasis , Paclitaxel/therapeutic use , Prognosis , Retrospective Studies , Thyroid Carcinoma, Anaplastic , Thyroid Neoplasms/pathology , Thyroid Neoplasms/therapy , Treatment OutcomeABSTRACT
Phaeochromocytomas are uncommon tumours of adrenal or extra-adrenal chromaffin tissue. About 2-26% of these have been reported to metastasize, but, on histological criteria, it is virtually impossible to predict malignant behaviour of the tumour. Using immunohistochemistry, we analysed the protein expression of SNAIL, a zinc-finger transcription factor, in a series of 50 phaeochromocytoma specimens from 42 patients. We found that SNAIL-expressing cells are frequent in metastatic primary tumours and their metastases, whereas in tumours without metastases, SNAIL expression is commonly absent. We conclude that the expression of SNAIL may be of use in predicting the metastatic potential of phaeochromocytoma.
Subject(s)
Adrenal Gland Neoplasms/metabolism , Biomarkers, Tumor/metabolism , Pheochromocytoma/metabolism , Transcription Factors/metabolism , Adolescent , Adrenal Gland Neoplasms/secondary , Adult , Aged, 80 and over , Humans , Immunoenzyme Techniques , Middle Aged , Pheochromocytoma/pathology , Prognosis , Retrospective Studies , Snail Family Transcription Factors , Young AdultABSTRACT
AIMS/HYPOTHESIS: It has recently been suggested that the rs738409 G allele in PNPLA3, which encodes adiponutrin, is strongly associated with increased liver fat content in three different ethnic groups. The aims of the present study were as follows: (1) to try to replicate these findings in European individuals with quantitative measures of hepatic fat content; (2) to study whether the polymorphism influences hepatic and adipose tissue insulin sensitivity; and (3) to investigate whether PNPLA3 expression is altered in the human fatty liver. METHODS: We genotyped 291 Finnish individuals in whom liver fat had been measured using proton magnetic resonance spectroscopy. Hepatic PNPLA3 expression was measured in 32 participants. Hepatic and adipose tissue insulin sensitivities were measured using a euglycaemic-hyperinsulinaemic (insulin infusion 0.3 mU kg(-1) min(-1)) clamp technique combined with infusion of [3-(3)H]glucose in 109 participants. RESULTS: The rs738409 G allele in PNPLA3 was associated with increased quantitative measures of liver fat content (p = 0.011) and serum aspartate aminotransferase concentrations (p = 0.002) independently of age, sex and BMI. Fasting serum insulin and hepatic and adipose tissue insulin sensitivity were related to liver fat content independently of genotype status. PNPLA3 mRNA expression in the liver was positively related to obesity (r = 0.62, p < 0.0001) and to liver fat content (r = 0.58, p = 0.025) in participants who were not morbidly obese (BMI < 40 kg/m(2)). CONCLUSIONS/INTERPRETATION: A common variant in PNPLA3 increases the risk of hepatic steatosis in humans.
Subject(s)
Fatty Liver/genetics , Lipase/genetics , Membrane Proteins/genetics , Adult , Aged , Body Mass Index , Fatty Liver/blood , Fatty Liver/metabolism , Female , Genetic Predisposition to Disease , Genotype , Glucose Clamp Technique , Humans , Magnetic Resonance Spectroscopy , Male , Middle Aged , Obesity/genetics , Polymerase Chain ReactionABSTRACT
Germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene were recently observed in patients with pituitary adenoma predisposition (PAP). Though AIP mutation-positive individuals with prolactin-, mixed growth hormone/prolactin-, and ACTH-producing pituitary adenomas as well as non-secreting pituitary adenomas have been reported, most mutation-positive patients have had growth hormone-producing adenomas diagnosed at relatively young age. Pituitary adenomas are also component tumors of some familial endocrine neoplasia syndromes such as multiple endocrine neoplasia type 1 (MEN1) and Carney complex (CNC). Genes underlying MEN1 and CNC are rarely mutated in sporadic pituitary adenomas, but more often in other lesions contributing to these two syndromes. Thus far, the occurrence of somatic AIP mutations has not been studied in endocrine tumors other than pituitary adenomas. Here, we have analyzed 32 pituitary adenomas and 79 other tumors of the endocrine system for somatic AIP mutations by direct sequencing. No somatic mutations were identified. However, two out of nine patients with prolactin-producing adenoma were shown to harbor a Finnish founder mutation (Q14X) with a complete loss of the wild-type allele in the tumors. These results are in agreement with previous studies in that prolactin-producing adenomas are component tumors in PAP. The data also support the previous finding that somatic AIP mutations are not common in pituitary adenomas and suggest that such mutations are rare in other endocrine tumors as well.
Subject(s)
Adenoma/genetics , Carcinoma/genetics , Endocrine Gland Neoplasms/genetics , Mutation , Proteins/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Base Sequence , DNA Mutational Analysis , Female , Humans , Intracellular Signaling Peptides and Proteins , Male , Middle AgedABSTRACT
BACKGROUND: MDM2 acts as a principal regulator of the tumour suppressor p53 by targeting its destruction through the ubiquitin pathway. A polymorphism in the MDM2 promoter (SNP309) was recently identified. SNP309 was shown to result, via Sp1, in higher levels of MDM2 RNA and protein, and subsequent attenuation of the p53 pathway. Furthermore, SNP309 was proposed to be associated with accelerated soft tissue sarcoma formation in both hereditary (Li-Fraumeni) and sporadic cases in humans. METHODS: We evaluated the possible contribution of SNP309 to three tumour types known to be linked with the MDM2/p53 pathway, using genomic sequencing or restriction fragment length polymorphism as screening methods. Three separate Finnish tumour materials (population based sets of 68 patients with early onset uterine leiomyosarcomas and 1042 patients with colorectal cancer, and a series of 162 patients with squamous cell carcinoma of the head and neck) and a set of 185 healthy Finnish controls were analysed for SNP309. RESULTS: Frequencies of SNP309 were similar in all four cohorts. In the colorectal cancer series, SNP309 was somewhat more frequent in women and in patients with microsatellite stable tumours. Female SNP309 carriers were diagnosed with colorectal cancer approximately 2.7 years earlier than those carrying the wild type gene. However, no statistically significant association of SNP309 with patients' age at disease onset or to any other clinicopathological parameter was found in these three tumour materials. CONCLUSION: SNP309 had no significant contribution to tumour formation in our materials. Possible associations of SNP309 with microsatellite stable colorectal cancer and with earlier disease onset in female carriers need to be examined in subsequent studies.
Subject(s)
Carcinoma, Squamous Cell/genetics , Colorectal Neoplasms/genetics , Head and Neck Neoplasms/genetics , Leiomyosarcoma/genetics , Polymorphism, Single Nucleotide , Promoter Regions, Genetic , Proto-Oncogene Proteins c-mdm2/genetics , Adult , Aged , Cohort Studies , Evaluation Studies as Topic , Female , Humans , Male , Middle Aged , Risk , Uterine Neoplasms/drug therapyABSTRACT
CONTEXT: Cortisol secretion is usually under the control of ACTH. However, cortisol secretion occurs in response to gastric inhibitory polypeptide (GIP) in rare cases of food-dependent Cushing's syndrome (CS). OBJECTIVE: We have investigated whether chronic ACTH stimulation or activation of the ACTH signaling pathway might be associated with GIP receptor (GIPR) expression. DESIGN: RT-PCR analysis and primary culture of hyperplastic adrenals. PATIENTS: All patients presented with CS: 20 unilateral adrenal adenomas, five Cushing's disease, one food-dependent CS. RESULTS: RT-PCR revealed GIPR expression in all hyperplastic adrenals studied. No RT-PCR product could be detected in two normal adrenals or 20 hyperfunctioning adrenal adenomas. Primary culture revealed a significant cAMP response to ACTH in all adrenals available for study (EC50, 8.1 x 10(-10) M in normals, 4.7 x 10(-10) M in Cushing's disease, and 4.4 x 10(-10) M in food-dependent disease). However, cultures taken from all four ACTH-dependent and the one food-dependent hyperplastic adrenals studied were also responsive to GIP (EC50 for cAMP, 1.3 x 10(-9) M in Cushing's disease and 4.1 x 10(-10) M in food-dependent disease). Fasting cortisol levels were low in the case of food-dependant Cushing's, rising postprandially as predicted. However, there was no trend toward low fasting or high postprandial cortisol in the other cases, suggesting that the presence of detectable GIPR alone, albeit with definite function in vitro, is not sufficient to cause clinically food-dependent CS. CONCLUSIONS: These data are consistent with the hypothesis that chronic ACTH stimulation or constitutive activation of the ACTH signaling pathway may be associated with aberrant GIPR expression, and suggest one mechanism for the pathogenesis of this phenomenon.
Subject(s)
Adrenal Cortex/pathology , Adrenocorticotropic Hormone/pharmacology , Gene Expression Regulation , Pituitary ACTH Hypersecretion/metabolism , Receptors, Gastrointestinal Hormone/genetics , Adult , Aged , Cells, Cultured , Child , Female , Gastric Inhibitory Polypeptide/pharmacology , Humans , Hydrocortisone/blood , Hyperplasia , Middle Aged , Pituitary ACTH Hypersecretion/pathology , Receptors, Corticotropin/physiology , Signal Transduction , Up-RegulationABSTRACT
Transcription factors GATA-4 and GATA-6 are expressed during normal adrenocortical development in mice and humans, and in vitro studies have linked them to adrenal steroidogenesis. GATA-4 is highly expressed in the adrenocortical tumors of gonadectomized mice, whereas GATA-6 is down-regulated in the tumor area. Based on these findings we studied GATA-4 and GATA-6 expression in 39 human adrenocortical tumors using RT-PCR, Northern analysis and immunohistochemistry. 6/18 adenomas and 4/11 carcinomas were positive for GATA-4 mRNA. GATA-6 mRNA was expressed in 19/19 adenomas and 9/10 carcinomas, and GATA-6 immunoreactivity was remarkably lower in adrenocortical carcinomas than in adenomas (p < 0.05). Some of the steroidogenically active human adrenocortical cells (NCI-H295R) were weakly positive for GATA-4, whereas steroidogenically inactive cells (ACT-1) were totally GATA-4 negative. In contrast, both cell lines expressed GATA-6. GATA expression patterns similar to the animal models can thus be observed in human adrenocortical tumors, but the pathophysiological significance of these findings remains to be elucidated.
Subject(s)
Adenoma/metabolism , Adrenal Cortex Neoplasms/metabolism , Carcinoma/metabolism , DNA-Binding Proteins/metabolism , Transcription Factors/metabolism , Blotting, Northern , Cell Line, Tumor , DNA-Binding Proteins/genetics , GATA4 Transcription Factor , GATA6 Transcription Factor , Humans , Immunohistochemistry , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Steroids/metabolism , Transcription Factors/geneticsABSTRACT
AIMS: The malignancy of phaeochromocytomas is difficult to predict. Traditionally, only a metastasized tumour is considered malignant. The aim of this study was to assess the histopathological and clinical features, as well as the proliferative activity, and to analyse p53 and p21 expression in 105 phaeochromocytomas. METHODS AND RESULTS: All malignant phaeochromocytomas (n = 8) showed at least one of the histologically suspicious features, i.e. over five mitoses/10 high-power fields, necrosis, capsular or vascular invasion. Malignant tumours were larger, but the age and gender of the patients were not significantly different. All benign (n = 33) and most of the borderline (18/21) adrenal phaeochromocytomas had less than 6% Ki67+ tumour cells, while most malignant tumours (6/7) expressed Ki67 in >6% of the cells. p53+ immunohistochemistry was found in two malignant tumours, while p21 expression did not correlate with malignancy. CONCLUSIONS: These data suggest that the lack of histologically suspicious features, low proliferative activity, smaller size, and negative p53 immunostaining point to a benign diagnosis in phaeochromocytomas.
Subject(s)
Adrenal Gland Neoplasms/pathology , Pheochromocytoma/secondary , Tumor Suppressor Protein p53/metabolism , Adolescent , Adrenal Gland Neoplasms/metabolism , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/metabolism , Cell Division , Female , Humans , Immunohistochemistry , Male , Middle Aged , Pheochromocytoma/metabolismABSTRACT
Pheochromocytomas are rare tumors of the adrenal medulla or the paraganglion system. There are no histological or chemical markers available that define the malignant behavior of these tumors; so far only the discovery of metastases reveals malignancy. Cyclooxygenase (Cox) is the key enzyme in conversion of arachidonic acid to PGs, and two isoforms, Cox-1 and Cox-2, have been identified. Cox-2 has been associated with carcinogenesis, and it is overexpressed in many human malignancies. We have now investigated the expression of Cox-2 in normal adrenal gland, in 92 primary pheochromocytomas and in six metastases using immunohistochemistry and Northern blot and Western blot analyses. Cox-2 protein was expressed in the adrenal cortex, whereas the medulla was negative as detected by immunohistochemistry. Interestingly, all malignant pheochromocytomas (n = 8), regardless of the primary location of the tumor, showed moderate or strong Cox-2 immunoreactivity, whereas 75% of the benign adrenal tumors (n = 36) showed no or only weak immunopositivity. The staining was negative or weak in 79% of the adrenal tumors that showed histologically suspicious features (n = 24), but had not metastasized. Most of the pheochromocytoma samples studied also expressed low levels of Cox-2 mRNA. Our data show that normal adrenal medulla does not express Cox-2 immunohistochemically. However, strong Cox-2 protein expression was found in malignant pheochromocytomas, whereas most benign tumors expressed Cox-2 only weakly. To our knowledge, this is the first report on Cox-2 expression in pheochromocytomas and enhanced expression in malignant pheochromocytomas. These findings suggest that negative or weak Cox-2 expression in pheochromocytomas favors benign diagnosis.
Subject(s)
Adrenal Gland Neoplasms/enzymology , Isoenzymes/biosynthesis , Pheochromocytoma/enzymology , Prostaglandin-Endoperoxide Synthases/biosynthesis , Adolescent , Adrenal Gland Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Blotting, Northern , Blotting, Western , Cyclooxygenase 2 , Female , Follow-Up Studies , Humans , Immunohistochemistry , Male , Membrane Proteins , Middle Aged , Pheochromocytoma/pathology , RNA, Messenger/biosynthesisABSTRACT
Tenascin is a significant extracellular matrix glycoprotein, which is upregulated in various neoplasias and pathologic processes. Pheochromocytomas are rare tumors of the sympathoadrenal system, whose malignancy is almost impossible to predict. There are no histologic or chemical markers available that would define the malignant behavior of these tumors, except the discovery of metastases. In our search for new markers, we investigated the immunohistochemical expression of tenascin in a large number of pheochromocytomas and paragangliomas. Seven tumors were metastasized and were thus considered malignant. Normal adrenal medulla was tenascin negative. A striking difference was seen between malignant and benign pheochromocytomas. All malignant pheochromocytomas expressed stromal tenascin strongly or moderately, whereas most benign pheochromocytomas (28 of 37, 70%) showed no or only weak immunopositivity. The staining was strong or moderate also in 13 of 28 (46%) of the tumors that showed histologically suspicious features, here called borderline tumors. Paragangliomas showed a more heterogeneous staining pattern, and no significant difference was found between benign and malignant paragangliomas. To our knowledge, this is the first study to demonstrate the expression of tenascin in pheochromocytomas and particularly the enhanced expression in malignant pheochromocytomas. We therefore suggest that tenascin may be associated with the malignant transformation and metastasis of pheochromocytomas. It is also a potential marker predicting more aggressive behavior in pheochromocytomas.
Subject(s)
Adrenal Gland Neoplasms/metabolism , Pheochromocytoma/metabolism , Tenascin/biosynthesis , Adolescent , Adrenal Gland Neoplasms/pathology , Adrenal Medulla/anatomy & histology , Adrenal Medulla/chemistry , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor , Female , Follow-Up Studies , Humans , Immunoenzyme Techniques , Male , Middle Aged , Pheochromocytoma/secondary , Tenascin/analysisSubject(s)
Abscess/veterinary , Dog Diseases/diagnosis , Splenic Diseases/veterinary , Abscess/complications , Abscess/diagnosis , Animals , Diagnosis, Differential , Dog Diseases/diagnostic imaging , Dog Diseases/pathology , Dogs , Male , Splenic Diseases/complications , Splenic Diseases/diagnosis , Splenomegaly/etiology , Splenomegaly/veterinary , UltrasonographyABSTRACT
Little has been known about the molecular background of familial multiple cutaneous leiomyomatosis (MCL). We report here a clinical, histopathological, and molecular study of a multiple cutaneous leiomyomatosis kindred with seven affected members. This detailed study revealed strong features of a recently described cancer predisposition syndrome, hereditary leiomyomatosis and renal cell cancer (HLRCC). The family was compatible with linkage to the HLRCC locus in 1q. Also, all seven cutaneous leiomyomas derived from the proband and analyzed for loss of heterozygosity displayed loss of the wild-type allele, confirming the association with a susceptibility gene in chromosome 1q. One individual had had renal cell cancer at the age of 35 years. This tumor displayed a rare papillary histopathology, which appears to be characteristic for HLRCC. The derived linkage, loss of heterozygosity, and clinical data suggest that MCL and HLRCC are a single disease with a variable phenotype. The possibility that members of leiomyomatosis families are predisposed to renal cell cancer should be taken into account.