Peripheral T cell lymphoma with cytotoxic phenotype: an emerging disease in HIV-infected patients?

Recently, a 15-fold increased risk of T cell lymphomas has been estimated in HIV-infected populations. This increase has been observed for all T cell lymphoma subtypes. In the present report we describe clinical and pathological features of three consecutive cases of peripheral T cell lymphoma (PTCL) with cytotoxic phenotype in HIV-positive patients that came to our attention in May-September 2002. The diagnosis of PTCL was made in lymph node (two cases) and in needle biopsies from liver and bone marrow of the same patient. The patients were two females (31 and 45 years old) and one male (49 years old). The risk factor for each patient was heterosexual, injecting drug user, and homosexual, respectively. CD4 cell counts were low (79-81 cells/mm3). Two patients were naive for antiretroviral therapy. At histological examination, all the involved tissues were effaced by a neoplastic proliferation of CD3+/CD8+ medium to large pleomorphic cells containing TIA-1+ cytotoxic granules and a few granzyme B+ granules. Neoplastic cells were not infected by EBV or by HHV-8. They were negative for the B cell antigens CD20 and CD79a, for CD30 and for CD56. Clonal T cell receptor-g (TCR-g) rearrangements were demonstrated in the three cases.

B cell clonality in multiple localizations of primary central nervous system lymphomas in AIDS patients.

The aim of our study was to investigate B cell clonality of distinct localizations of primary central nervous system lymphomas (PCNSL) in AIDS patients. We selected seven autoptic cases of AIDS PCNSL with at least two separated localizations of the disease in the central nervous system (CNS). Clonality was investigated by immunoglobulin light chain restriction and by semi-nested PCR for the immunoglobulin heavy chain (IgH). Three cases showed a concordant restriction in the two lesions. In an additional case, an identical IgH sequence was found. The remaining three cases did not provide consistent information because of extensive necrosis in the lesions. Our findings suggest that multifocality of PCNSL is due to dissemination of a single neoplastic clone rather than to a synchronous transformation of multiple B cell clones.

True thymic hyperplasia associated with thymic hemorrhage in an adult patient.

A case of true thymic hyperplasia (TTH) associated with thymic hemorrhage (TH) was observed in a 22-year-old male patient who presented with persistent cough and thoracic pain due to an anterior mediastinal mass. The diagnosis of TTH was supported by the observation that the mediastinal mass was essentially composed of histologically normal thymic lobules with preserved cortico-medullary differentiation. The TTH tissue presented multiple areas of hemorrhage associated with the presence of large, tortuous, abnormal vessels in the thymic stroma. Foci of spindle cell proliferations resembling an epitheliod hemangioma were also seen. This finding raises the possibility that vascular malformations, perhaps due to an abnormal growth of the thymus, may be responsible for some cases of TH associated with TTH.

E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer.

Deregulation of E2F1 activity and resistance to TGFbeta are hallmarks of gastric cancer. MicroRNAs (miRNAs) are small noncoding RNAs frequently misregulated in human malignancies. Here we provide evidence that the miR-106b-25 cluster, upregulated in a subset of human gastric tumors, is activated by E2F1 in parallel with its host gene, Mcm7. In turn, miR-106b and miR-93 regulate E2F1 expression, establishing a miRNA-directed negative feedback loop. Furthermore, upregulation of these miRNAs impairs the TGFbeta tumor suppressor pathway, interfering with the expression of CDKN1A (p21(Waf1/Cip1)) and BCL2L11 (Bim). Together, these results suggest that the miR-106b-25 cluster is involved in E2F1 posttranscriptional regulation and may play a key role in the development of TGFbeta resistance in gastric cancer.

Hepatocyte growth factor (HGF) downregulates thrombospondin 1 (TSP-1) expression in thyroid papillary carcinoma cells.

This study investigates the expression of thrombospondin-1 in papillary carcinoma of the thyroid and the role of Met-HGF interaction in TSP-1 regulation. In tissue sections, immunostaining for TSP-1 was associated with the fibrous tumour stroma, and showed areas of marked intensity adjacent to the basal membrane of tumour cells. Investigation of TSP-1 RNA expression showed that, in 10 of 14 cases, TSP-1 mRNA levels were significantly lower in tumour tissue (20-100% reduction; mean = 55% +/- 20; p = 0.001) than in the corresponding normal thyroid. Since it has been reported that HGF can downregulate the expression of TSP-1 mRNA, TSP-1 mRNA levels were measured in 7 primary cultures, established from thyroid papillary carcinomas (TPC), and in 1 TPC cell line prior to, or after, stimulation with HGF. A marked decrease in TSP-1 mRNA levels was observed after HGF stimulation in 6/7 primary cultures (60-100% decrease (mean = 79 +/- 15%; p = 0.006) and in the TPC cell line; moreover, the decrease in TSP-1 mRNA in cell extracts was associated with a decrease in TSP-1 protein in culture supernatants. The HGF activity was dose dependent and the downregulation lasted for at least 48 h after stimulation. The high-level expression of Met protein, the high-affinity receptor for HGF, in most cases of papillary carcinoma of the thyroid is consistent with the possibility that HGF-Met interaction plays a crucial role in regulating the expression of TSP-1 in this tumour type.

Papillary carcinoma of the thyroid: evidence for a role for hepatocyte growth factor (HGF) in promoting tumour angiogenesis.

The pattern of vascularization of papillary carcinoma was investigated in tumour sections from 31 cases and in primary cultures from 12 cases. Tumour sections were immunostained for von Willebrand Factor (vWF) to visualize blood vessels; for endothelial-specific nitric-oxide-synthase (EC-NOS), as a marker of endothelial cell activation; and for Ki-67 to evaluate endothelial cell proliferation. It was found that endothelial cells lining venous vessels located in peritumoural fibrous tissue were intensely EC-NOS-positive and occasionally Ki-67-positive. Capillary vessels of tumour papillae were not stained for Ki-67 and were weakly EC-NOS-positive. Primary cultures of papillary carcinoma cells were used as a potential source of factors active on endothelial cells. It was found that thyroid tumour cells contain RNAs for angiopoietin, vascular endothelial growth factor (VEGF), and VEGF-C; moreover, they release large amounts of VEGF into culture supernatants and exert chemotactic activity in vitro for the endothelial cell line SIEC. The ability of papillary carcinoma cells to release angiogenic factors could be stimulated in vitro. Hepatocyte growth factor (HGF; 25 ng/ml) induced a 1.2- to 5-fold increase in the amount of VEGF released by tumour cells and a 1.2- to 4.2-fold increase in the amount of chemotactic activity present in culture supernatants. Met protein, the high affinity HGF-receptor, is overexpressed in a large proportion of cases of papillary carcinoma. These findings are consistent with the possibility that HGF-Met protein interaction is one of the molecular mechanisms promoting the vascularization of papillary carcinoma of the thyroid.

Increased expression of Met protein is associated with up-regulation of hypoxia inducible factor-1 (HIF-1) in tumour cells in papillary carcinoma of the thyroid.

Met protein, the high affinity receptor for hepatocyte growth factor (HGF), was highly expressed by the tumour cells of 64 well-differentiated papillary carcinomas of the thyroid. The p145 mature form and the p170 precursor form of the protein were both isolated from the tumours. Enhanced expression of Met protein was associated with a 9.5 +/- 5-fold increase in MET RNA transcript levels, suggesting increased transcription of the gene. In the same tumours, the levels of RNA transcripts for hypoxia inducible factor-1 (HIF-1), a potent stimulator of met gene transcription, were 4.5 +/- 3-fold higher than those present in the surrounding normal thyroid tissues. HIF-1 is generally induced by hypoxia. Histological features suggestive of a hypoxia were observed in 37 of 50 tumours and included coagulative necrosis, psammoma bodies, cystic changes, intratumoural haemorrhage, and hyalinization of the fibrous stroma. Immunostaining for Met protein was particularly intense in some cells located at the tumour periphery which were characterized by an invasive phenotype. Microdissection of tumour cell nests from the invading front revealed that the levels of RNA transcripts for MET/HIF were higher than in the centre of the tumour in four of nine cases. Taken together, the findings of this study suggest that HIF-1, perhaps driven by hypoxia, may be one of the factors leading to the increased transcription of met gene in papillary carcinoma and that this event is often more pronounced at the tumour periphery.