Forum (Genoa, Italy)最新文献

The presented classification of astrocytic gliomas follows the system adopted by the WHO which was last published in 1993. The nosographic position of each tumour type is discussed in relation to previous positions and the rationale of changes is provided. The biology and pathology of anaplasia, leading from astrocytoma to glioblastoma, are discussed briefly. The increasing genotypic and phenotypic heterogeneity is described in its progressive stages. A series of genetic changes are associated with the main histologic features of malignancy , such as TP53 mutations, EGFR amplification, CDKN2 deletion, etc. The genetic differences between primary and secondary glioblastomas are emphasised. Tumour-associated biological events are presented: cell invasion and spread, necrosis and apoptosis and angiogenesis are all discussed in some detail. Of each event a short survey on the principal phenotypic and molecular features is given with emphasis on their significance to pathogenesis. Each tumour type is briefly summarised from epidemiological, clinical and pathological standpoints.

The evolution of gastric mucosa-associated lymphoid tissue (MALT) lymphoma is a multi-stage process, comprising the sequential development of chronic H. pylori-associated gastritis, low grade and high grade lymphoma. The genesis of MALT lymphoma embodies the mechanisms of both physiological immune responses and the acquisition of genetic abnormalities. The tumour probably originates from an autoreactive MALT marginal zone B cell, which is generated during H. pylori infection. As a consequence of a genotoxic insult induced by H. pylori infection, the progenitor tumour cell may become genetically unstable and develop genetic abnormalities such as the t(11;18) translocation, trisomy three, c-myc and p53 mutations during a phase of expansion, which lead to partial transformation. With the growth help from H. pylori specific T cells, this abnormal B cell clone may undergo clonal expansion and gradually form a low grade MALT lymphoma. Additional genetic abnormalities including the t(1;14) translocation and other uncharacterised events could completely transform this abnormal B cell clone and result in escape from T cell dependency. Finally, further genetic events such as complete inactivation of the tumour suppressor genes p53 and p16, and possible activation of c-myc oncogene by translocation or other undetermined abnormalities can result in high grade transformation

In recent years major research findings have revealed a strong correlation between the genes involved in the pathogenesis of renal tumours and the histopathological and clinical behavioural features. This new genetic information has provided the basis for the recent Heidelberg and Mayo Clinical Classifications for renal tumours. WilmsO tumour has been shown to arise from abnormalities in one of at least three genes. The first WilmsO tumour gene identified WT1, located on chromosome 11p13, encodes a zinc finger binding protein which is important in regulating the formation of the early nephron. Although the second WilmsO tumour gene, WT2, has not been formally identified it is known to be involved in the Beckwith Weideman Syndrome and in the WilmsO tumours which arise from that disease. Other WilmsO tumour genes have been implied from cytogenetic and familial data but their precise location and identification remains. In adult renal tumours there have also been considerable advances. The majority of conventional or clear cell renal carcinomas are associated with losses of chromosome 3p and mutation in the von Hippel Lindau (VHL) gene which is located on that portion of the genome. These mutations affect familial renal cancers arising as part of the VHL syndrome and the majority of sporadic renal carcinomas. There has been an energetic search for genetic abnormalities which may be involved in the progression of these tumours and data revealing the importance of chromosome 14q and other chromosomal sites have been generated. Papillary renal cancer is associated with different genetic abnormalities, in particular mutations of the c-met proto-oncogene and abnormalities of chromosome 7 with a small subgroup of familial papillary renal carcinomas showing evidence of abnormalities of the X chromosome. The less common renal carcinomas have shown cytogenetic abnormalities although the precise genes involved in their formation remain to be identified. These genetic advances have allowed a more accurate classification of renal carcinoma and WilmsO tumour and it is envisaged that they will lead to a better understanding of the biological behaviour with opportunities for therapeutic intervention in this large group of important human neoplasms.

The growth of solid tumours beyond a certain mass is strictly dependent on the formation of a vascular bed from a pre-existing host vasculature. This process has been termed OangiogenesisO and its importance in the process of tumour growth and metastasis has recently gained wide acceptance. Studies have been reported in several kinds of human cancers in which the number of microvessels in the most intense areas of neo-vascularisation (Ohot spotsO) have been shown to be strictly related to the development and progression of the tumour. In the majority of these studies highly vascularised tumours showed a poor prognosis and the influence of tumour angiogenesis proved to be independent of conventional prognostic indicators. The evaluation of tumour angiogenesis by quantitative pathology may represent an important prognostic indicator in human cancers and will be increasingly important in the investigation of new therapies directed to inhibiting angiogenesis or targeting tumour vasculature. This review will briefly summarise the current knowledge on the prognostic impact of tumour angiogenesis in human cancers with a final reference to angiogenesis inhibitors which are currently used in phase I/II and III clinical trials.

Breast involvement by non-Hodgkin lymphoma is uncommon. Differences between primary and secondary breast lymphoma have been well-defined. However, histopathological features, therapeutic approach and outcome are still debated. We report the clinical and pathological features of 5 cases of malignant lymphoma primarily involving the breast. The literature is extensively reviewed paying particular attention to pathological features, therapeutic approach and survival analysis. All patients were women; the median age was 63.2 yr. The clinical course was indistinguishable from that of breast carcinoma. High-grade lymphoma was found in 4 cases; T cell lineage antigens were expressed in one case. All patients were in stage I or II. Treatment consisted of chemotherapy and/or radiotherapy. The follow-up period ranged from 20 to 54 months (mean, 33.2). All patients are still in complete clinical remission. Analysis of the literature showed that about 80% of cases are high grade lymphoma. In this group, stage I at presentation statistically gives the best survival rate; surgery does not appear to have a role in high-grade lymphoma treatment.

Although temporal trends and regional-racial variations in gastric cancer incidence have led to the formulation of different hypotheses, no definite association has been seen between this disease and any behavioural or genetic determinant. In fact, several aetiological factors have been associated with risk of gastric cancer, but not without controversy. Various studies have suggested that genetic factors might be of importance in the pathogenesis of gastric tumours. In fact, stomach carcinoma occurs more frequently among close relatives of affected individuals than in the general population and some of the most common pre-cancerous lesions seem to be genetically determined. In the light of this circumstantial evidence, we decided to investigate the role of various genetic alterations in gastric cancer in order to study their relationship with aetiopathogenesis and disease progression and their value as indicators of risk and prognosis. Our main areas of interest were: i. c-Ha-ras locus polymorphism; ii, truncated c-myc gene variant; iii. loss of heterozygosity, iv. p53 gene mutations; v. oncogene amplification; vi. oncogene amplification proliferative activity and their relation to prognosis in gastric cancer.

Multiple Endocrine Neoplasia (MEN) syndromes are inherited diseases characterised by endocrine tumours occuring as autosomal dominant genetic diseases with high penetrance. In MEN1, most tumours affect the parathyroids, endocrine pancreas, anterior pituitary, and adrenal glands. The MEN1 gene has been cloned recently and encodes a nuclear protein without known function so far. More than 200 germline mutations have been identified in MEN1 patients throughout the entire coding sequence and no genotype-phenotype correlation has been found. Now, MEN1 gene screening is a powerful tool in pre-symptomatic diagnosis for MEN1 patients and those with inherited MEN1 related syndromes. MEN2 refers to the inherited forms of medullary thyroid carcinoma (MTC) which is associated with phaechromocytoma and parathyroid tumours in MEN2A, phaechromocytoma and mucosal neuromas in MEN2B. Familial isolated MTC is characterised by MTC only, and the three variants of MEN2 are related to germline missense mutations of the RET proto-oncogene, which encodes a tyrosine-kinase receptor. Germline RET mutations in MEN2 patients are related to the two main functionnal domains in the RET protein, the extracellular ligand binding domain (MEN2A and FMTC) and the intracellular catalytic domain (MEN2A, MEN2B and FMTC). Genotype-phenotype correlations have been established but must be used carefully in clinical practice. RET mutation analysis is now available for patients and prophylactic thyroidectomy in gene-carriers could be the most reliable way to cure the patients. Mechanisms of tumourigenesis induced by MEN2-related RET germline mutations have been analysed by in vitro studies and the generation of transgenic mice which develop true bilateral MTC. Recent insights on MEN syndrome pathogenesis and related inherited endocrine disorders have a major clinical impact and fundamental studies are now in progress in order to identify all genetic events leading from a normal endocrine tissue towards a fully malignant phenotype.

The liver plays a central role in haemopoiesis and synthesis of coagulation proteins; liver disease is associated with a broad range of haematological abnormalities. Anaemia arises through multiple mechanisms, haem metabolism is disturbed, and liver disease causes alterations in red cell lipid metabolism. Defects of platelet number and function arise due to the effects of liver disease, immune mechanisms and hypersplenism. Coagulation disturbances are due to impaired vitamin K metabolism, defective synthesis of coagulation factors and regulatory proteins, impaired clearance of activated coagulation factors and increased fibrinolysis. Treatment, including blood component therapy, is discussed. Recent data indicate an emerging role for disturbances in Epo, cytokines (TNF, IL-6) and thrombopoietin in causing haematological changes in liver disease.

Impaired arterial oxygenation, ranging from an increased alveolar-arterial oxygen gradient to severe hypoxaemia, is commonly reported in patients with advanced liver disease. Hepatopulmonary syndrome is defined by the clinical triad of liver disease, alveolar-arterial oxygen gradient of >15 mmHg, evidence of intrapulmonary vascular dilatations. Three methods are available for detecting intrapulmonary vascular dilatations: contrast-enhanced echocardiography, technetium 99m-labelled macroaggregated albumin scanning and pulmonary arteriography. A recent hypothesis that assigns to nitric oxide the crucial role as mediator of abnormal pulmonary vasodilatation and oxygen is discussed; the measurement of nitric oxide in the exhaled air may represent a possible marker of gas exchange abnormalities in liver disease. The therapeutic options to relieve the hepatopulmonary syndrome are discussed. While no pharmacological treatment has proved to be clinically useful, liver transplantation was reported to cure the response to transplantation is discussed. The response of hypoxaemia to 100% oxygen breathing appears to be the most important prognostic factor of perioperative death rate.