Expression of TCL1 and CD27 in primary cutaneous B-cell lymphomas.

AIMS: To investigate by immunohistochemical analysis the expression of the TCL1 oncogene product and of CD27 in 25 cases of primary cutaneous B-cell lymphomas (PCBCL) classified according to the World Health Organization-European Organization for Research and Treatment of Cancer classification of cutaneous lymphomas. In B-cell ontogenesis TCL1 is mainly expressed by 'naive' B lymphocytes and by a subset of germinal centre B cells, whereas CD27 is expressed by a subset of germinal centre B cells, 'memory' B lymphocytes and plasma cells, suggesting that their expression in physiological conditions is mutually exclusive. METHODS AND RESULTS: Overall, TCL1 was expressed in 5/25 cases (20%) and CD27 in 15/25 cases (60%). Furthermore, 7/25 cases (28%) were TCL1- and CD27- and 2/25 cases (8%) were TCL1+ and CD27+. In particular, primary cutaneous follicle-centre lymphomas (10 cases) showed a variable expression of both TCL1 and CD27, whereas primary cutaneous marginal-zone B-cell lymphomas (eight cases) showed, with the exception of a single case, a definite CD27+/TCL1- profile. CONCLUSIONS: These findings indicate: (i) the TCL1 oncogene product is uncommonly expressed in PCBCL (20% of cases, mainly of the follicle-centre subtype); (ii) in contrast, CD27 is often expressed in PCBCL (60% of cases), mainly of the marginal-zone subtype; (iii) the coexpression of TCL1 and CD27 may be seldom observed in PCBCL (8% of cases); (iv) PCBCL does not seem to show, in terms of either TCL1 or CD27 expression, significant differences compared with its systemic counterparts.

[The Haemolymphopathology Italian Group (H.I.G.): an essential resource for the new technical and organization problems troubling modern haemolymphopathology diagnostics]. / II Gruppo Italiano di Emolinfopatologia (G.I.E.): una esigenza per le nuove e complesse problematiche tecnico-organizzative della moderna diagnostica emolinfopatologica.

Recently, many progresses have been recorded in the molecular and histogenetic characterization of the haematopoietic and lymphoid tumours, resulting in important classifying changes. As a consequence, the exact definition of lymphoma subtype requires an integration between traditional morphologic "expertise" and several bio-functional data obtained from advanced and complex ancillary techniques (immunohistochemistry, molecular biology and cytogenetics). At the same time, the data provided by gene expression profiling studies are going to deeply modify the therapies in haematological cancers. These studies are expected to allow the achievement of single-patient-tailored genic therapy; for this reason it is necessary to get biological samples of good quality. Indeed, while these progresses contribute to highlight the pathologist's diagnostic role, they should make us reflect on the state of the art of the Italian haemolymphopathology diagnostics and on its ability to cope up with the new challanges. The aim of this article is to outline a realistic picture of the present condition, and to explain the reasons for setting up, inside SIAPEC-IAP, the Haemolymphopathology Italian Group (H.I.G.). The purpose of H.I.G. will be twofold: first of all, scheduling of a series of projects so as to the haemolymphopathological diagnostic standardization; secondly, building a national network among all the pathologists involved in this exciting and complex field of the anatomic pathology.

Laminin alpha2 chain (merosin M chain) distribution and VEGF, FGF(2), and TGFbeta1 gene expression in angiogenesis of supraglottic, lung, and breast carcinomas.

The prognostic significance of vessel quantification in human solid tumours is still debated, due to the presence of multiple factors modulating neoangiogenesis and the invasiveness of neoplastic cells. This study examined ten supraglottic squamous carcinomas, ten non-small cell lung carcinomas (three squamous, five bronchioloalveolar, two adenocarcinomas), and nine classic (NOS) invasive ductal breast carcinomas. The properties studied in these tumours were vascularity; the immunohistochemical distribution of adhesion molecules such as alpha2beta1, alpha3beta1, alpha4beta1, alpha5beta1, alpha6beta4, and ICAM-1 in endothelial cells; extracellular matrix proteins (ECMPs) and laminin alpha2 chain (merosin M chain) in basal membranes of vessels; and gene expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF2), and transforming growth factor beta1 (TGFbeta1), by in situ hybridization. Independently of tumour type and vascularity, laminin alpha2 chain expression was observed in the basal membranes of a limited proportion of vessels. In vitro experiments demonstrated laminin alpha2 chain expression mainly in early endothelial cell cultures, suggesting that laminin alpha2 chain expression in vivo can be considered a marker of early angiogenesis. Stromal and parenchymal vascularity was associated with laminin alpha2 chain expression in supraglottic carcinomas, whereas in the other tumours, laminin alpha2 chain-positive vessels were observed only in the stroma. In supraglottic carcinomas, VEGF-positive cells were mainly represented by neoplastic cells, whereas in the other tumours, the great majority of VEGF-positive cells were macrophages and fibroblasts. FGF2- and TGFbeta1-positive cells were macrophages and fibroblasts in all tumours. These observations suggest that in addition to the quantification and distribution of vessels, evaluation of their maturation may contribute to a better understanding of the role of angiogenesis in the growth and spread potential of solid tumours. In this regard, in supraglottic carcinomas, parenchymal angiogenesis seems to be regulated mainly by neoplastic cells, which may help to explain their high metastatic potential; in solid tumours of different histogenesis, different cells might be responsible for modulating tumour angiogenesis.

p53 over-expression identifies a subset of nodal peripheral T-cell lymphomas with a distinctive biological profile and poor clinical outcome.

Peripheral T-cell lymphomas (PTCL) are usually characterized by aggressive clinical behaviour and poor clinical outcome, but their biological background has not been extensively investigated to date, due to their low incidence, about 10% of all non-Hodgkin's lymphoma cases in Western countries, and also to the paucity of specific molecular-genetic abnormalities. Neverthless, there is increasing biological and clinical evidence that primary nodal PTCL should be considered separately from extra-nodal cases, but little is known about biological factors of possible clinical and prognostic impact. This immunohistochemical study has analysed the expression of p53, Mdm2, p21(WAF1), BCL-2 and p-glycoprotein (MDR-1 gene product) in a series of 45 cases of nodal peripheral T-cell lymphomas (PTCL) with 'high-grade' histology. The immunohistochemical findings were then correlated with proliferative activity and clinical outcome. p53 was over-expressed in 13 cases (28.9%). p53 positive cases showed significantly higher proliferative activity (p<0.01), more frequent expression of Bcl-2 (p<0.01) and less frequent expression of p21(WAF1) than p53 negative cases. Mdm2 and p-glycoprotein were expressed in 4/13 (30.8%) and 8/13 (61.5%) p53 positive cases respectively, and in none (0%) of the p53 negative cases (p<0.01). Analysis of the survival curves showed that p53 positive cases were associated with a significantly poorer clinical outcome than p53 negative cases, in terms of both overall survival (p=0.0032) and event-free survival (p=0.0004). Furthermore, multivariate analysis showed that p53 expression was the most important independent prognostic variable. These findings indicate that p53 over-expression identifies a subset of nodal PTCL cases with a distinctive biological profile (higher proliferative activity, less frequent expression of p21(WAF1) and more frequent expression of Bcl-2, Mdm2 and p-glycoprotein than p53 negative cases) and poor clinical outcome. The immunohistochemical analysis of p53 expression is a simple, rapid and low-cost method which may provide information of potential clinical and prognostic value in nodal peripheral T-cell lymphomas.

Interleukin-12-related cytokine gene expression in carcinomas of the breast, lung, and larynx: a study at tissue level.

Tumor-infiltrating lymphocytes (TIL) consist of T helper 1 (Th1) and T helper 2 (Th2) cells producing interferon-gamma (IFN-gamma) and interleukin4 (IL-4), respectively. Interleukin-12 (IL-12) induces Th1 and Th2 differentiation. Therefore, IL-12, IFN-gamma, and IL-4 gene expression were evaluated by reverse transcriptase-polymerase chain reaction in carcinomas of the breast (n = 10), lung (n = 17), and larynx (n = 13) to investigate whether TIL activation is IL-12-related. IL-12 and IFN-gamma were codistributed in breast carcinomas, and IL-4 was demonstrated in three instances. IL-12 and IFN-gamma were detected in 15 and 13 lung carcinomas, respectively, and were codistributed in 11 cases; IL-4 was observed in 9 cases and was codistributed with IL-12 and IFN-gamma in 7 instances. IL-12 and IFN-gamma expression was observed in five and nine larynx carcinomas, respectively, and were codistributed in four cases; IL-4 was detected in five instances. These data indicate that breast, lung, and larynx carcinomas are characterized by different patterns of IL-12, IFN-gamma, and IL4 gene expression and suggest that Th1 activation may be induced, at least in part, by the neoplastic microenvironment.

Hodgkin/Reed-Sternberg cells and Hodgkin's disease in patients with B-cell chronic lymphocytic leukaemia: an immunohistological, molecular and clinical study of four cases suggesting a heterogeneous pathogenetic background.

We report the immunohistological, molecular and clinical findings in four patients affected by B-cell chronic lymphocytic leukaemia (CLL) who developed "Richter's syndrome with Hodgkin's disease (HD) features" or "CLL with Hodgkin's transformation", all characterised by the presence of typical Hodgkin/Reed-Sternberg (H/RS) cells in lymph node biopsies. In three cases the nodal involvement by CLL was demonstrated both by the presence of a predominant background of CD5/CD19/CD23+ small lymphocytes and an IgH monoclonal rearrangement revealed by PCR analysis. Conversely, in the remaining case there was neither immunohistological nor molecular evidence of lymph node involvement by CLL. In all four cases H/RS cells were Epstein-Barr virus (EBV) latent membrane protein (LMP-1) positive. These findings suggest that the presence of H/RS cells in the first three patients, who had CLL/HD nodal involvement, might be related to transformation or clonal evolution of CLL cells in H/RS cells, which is in keeping with use of the term "CLL with Hodgkin's transformation". In the fourth case a de novo HD may be postulated, representing a second malignancy presumably not clonally related to CLL. In all cases a key pathogenetic role of EBV is suggested by the expression of LMP-1 in H/RS cells. Our findings indicate that the presence of typical H/RS cells in lymph node biopsies in CLL patients may reflect a heterogeneous pathogenetic background. The different clinico-pathologic settings should be taken into consideration because of their possible implications for patients' treatment and prognosis.

Interleukin-12 related cytokine gene expression at a tissue level in carcinomas of the larynx.

Head and neck squamous cell carcinomas are highly immunogenic tumors in which tumor-infiltrating lymphocytes (TIL) consist largely of CD4, Th1, and Th2 lymphocytes and a minor proportion of other immune effector cells, such as macrophages and B cells. Interleukin (IL)-12 release and antigen presentation from macrophages induce Thl and Th2 differentiation. Gene expression for IL-12, interferon (IFN)gamma, IL-4, and other cytokines was studied by reverse transcriptase-polymerase chain reaction in tissue sections from laryngeal carcinomas to evaluate the mechanisms of Th1 and Th2 lymphocyte differentiation. Local effects of cytokines were probed evaluating immunohistochemically the presence of inducible nitric oxide synthase positive tumor-infiltrating macrophages in 13 cases of laryngeal carcinomas. IL-12 gene expression was observed in five cases and that for IFNgamma in nine cases. These cytokines were coexpressed in four specimens. IL-4 and transforming growth factor-beta1 were detected in 5 and 11 cases, respectively. These findings show that IL-12, IFNgamma, IL-4, and IL-6 in laryngeal carcinomas have different patterns of gene expression, suggesting distinct pathways of Th1 and Th2 lymphocyte differentiation to indicate that their exogenous modulation might be utilized in adoptive immunotherapy.

Regulation of TCL1 expression in B- and T-cell lymphomas and reactive lymphoid tissues.

Chromosomal rearrangements observed in T-cell prolymphocytic leukemia involve the translocation of one T-cell receptor gene to either chromosome 14q32 or Xq28, deregulating the expression of cellular protooncogenes of unknown function, such as TCL1 or its homologue, MTCP1. In the human hematopoietic system, TCL1 expression is predominantly observed in developing B lymphocytes, whereas its overexpression in T cells causes mature T-cell proliferation in transgenic mice. In this study, using a newly generated monoclonal antibody against recombinant TCL1 protein, we extended our analysis mainly by immunohistochemistry and also by fluorescence-activated cell sorting and Western blot to a large tumor lymphoma data bank including 194 cases of lymphoproliferative disorders of B- and T-cell origin as well as reactive lymphoid tissues. The results obtained show that in reactive lymphoid tissues, TCL1 is strongly expressed by a subset of mantle zone B lymphocytes and is expressed to a lesser extent by follicle center cells and by scattered interfollicular small lymphocytes. In B-cell neoplasia, TCL1 was expressed in the majority of the cases, including lymphoblastic lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma, follicular lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma (60%), and primary cutaneous B cell lymphoma (55%). TCL1 expression was observed in both the cytoplasmic and nuclear compartments, as confirmed by Western blot analysis. Conversely, TCL1 was not expressed in Hodgkin/Reed-Sternberg cells, multiple myelomas, marginal zone B-cell lymphomas, CD30+ anaplastic large cell lymphoma, lymphoblastic T-cell lymphoma, peripheral T-cell lymphoma, and mycosis fungoides. These data indicate that TCL1 is expressed in more differentiated B cells, under both reactive and neoplastic conditions, from antigen committed B cells and in germinal center B cells and is down-regulated in the latest stage of B-cell differentiation.

Cystic lymphoepithelial lesions of the parotid gland in HIV-1 infection.

The benign cystic lymphoepithelial lesion (BLL) of the parotid gland is a rare disorder affecting HIV-1-infected patients. Here we describe the clinical and histopathological features of 10 cases of BLL, who presented to our observation between November 1992 and December 1996, before the combination antiretroviral therapy was introduced.

alpha5 integrin distribution and TGFbeta1 gene expression in supraglottic carcinoma: their role in neoplastic local invasion and metastasis.

BACKGROUND: Head and neck carcinomas are characterized by tumor-infiltrating lymphocytes (TIL) producing cytokines. Adhesion molecules, extracellular matrix proteins (ECMPs), and cytokines regulate cell-cell and cell-ECMPs interactions. We investigated the distribution of these proteins to contribute to better understanding of their role in local tumor invasion and metastasis. METHODS: Distribution of integrins, laminin, type IV collagen, tenascin, and fibronectin was immunohistochemically evaluated in 13 supraglottis carcinomas. Cytokines gene expression was assessed by reverse-transcriptase-polymerase chain reaction (RT-PCR). RESULTS: Neoplastic cells were alpha2beta1, alpha3beta1, alpha4beta1, alpha5beta1 and alpha6beta1 positive. Normal and metaplastic epithelium was alpha5beta1 negative; the stroma of primary and metastatic tumors was tenascin and fibronectin positive. TGFbeta1 and IFNgamma gene expression was observed in the majority of tumors. CONCLUSIONS: Because TGFbeta1 is known to down-modulate immune processes and to increase alpha2beta1, alpha5beta1, and tenascin distribution, we propose that their expression in neoplastic cells of supraglottis carcinoma might represent an immune-related process able to help tumor growth and progression.

"Composite" lymphoma, lymphoplasmacytoid and diffuse large B-cell lymphoma of the spleen: molecular-genetic evidence of a common clonal origin.

We describe here the first well-characterized case of "composite" lymphoma of the spleen in which the two components were a low-grade and a high-grade B-cell non-Hodgkin's lymphomas. The patient was an elderly man with prominent splenomegaly and multiple hypoechogenic lesions of the spleen. A splenectomy was performed, and the macroscopic and histological findings showed the simultaneous presence of a "low-grade" B-cell lymphoma, lymphoplasmacytoid (immunocytoma) and a "high-grade" B-cell lymphoma (immunoblastic), which were spatially separated. The two lesions expressed the same immunoglobulin light chain (lambda), but the Southern blot analysis showed different patterns of immunoglobulin heavy chain (IgH) clonal rearrangement. PCR analysis followed by direct sequencing of the IgH-amplified rearrangement products provided molecular-genetic evidence that the two components of the composite lymphoma had the same clonal origin. Since both EBV LMP-1 and p53 were negative by immunohistochemistry, it is unlikely that EBV and p53 were involved in the neoplastic progression in this case. PCR analysis and direct sequencing of IgH-amplified rearrangement products are useful tools to investigate clonality in cases in which Southern blot analysis cannot be performed or does not provide conclusive findings.

The benign cystic lymphoepithelial lesion of the parotid gland is a viral reservoir in HIV type 1-infected patients.

The presence of HIV-1 in cystic fluid aspirates from six cases of benign cystic lymphoepithelial lesion (BLL) of the parotid gland, a rare disorder affecting HIV-1-infected patients, has been investigated. HIV-1 p24 protein was present at a concentration ranging from 3 to 15 ng/ml, while it was undetectable in the peripheral blood of the same patients. The number of RNA copies of HIV-1 in the cystic fluids was high, ranging from 0.5 x 10(7) to 7.2 x 10(7) RNA copies/ml. BLL cystic fluid aspirates, despite the high level of HIV-1 RNA, were found to contain only a few infectious virions. The low infectivity correlated with the infrequent detection by electron microscopy of complete HIV-1 particles. The pathogenic mechanism leading to virus accumulation in the cystic fluid was studied by immunohistochemistry of tissue sections. p24 protein was associated with DRC-1+/S-100+ follicular dendritic reticulum cells, which were also present within the cystic cavities. Our findings are consistent with the possibility that the large amounts of virus present in the fluid derive from continuous shedding of HIV-1-infected cells from the surrounding lymphoid tissue.

Expression of p53 and retinoblastoma gene in high-grade nodal peripheral T-cell lymphomas: immunohistochemical and molecular findings suggesting different pathogenetic pathways and possible clinical implications.

The expression of p53 and the retinoblastoma gene has been investigated by immunohistochemical and molecular analysis in 45 cases of nodal peripheral T-cell lymphoma with high-grade histology. Most cases (73.3 per cent) were primary nodal lymphomas without any extra-nodal site involvement. Most of them (75.6 per cent) were histologically classified as pleomorphic, small, medium, and large cell type. Immunohistochemistry detected p53 in nine cases (20 per cent). In each of these cases, the polymerase chain reaction (PCR)/heteroduplex analysis did not show the presence of mutations, this finding being consistent with an alteration of the p53 functional pathway, in the presence of a wild-type protein. The retinoblastoma gene product was detected by immunohistochemistry in 35 cases (77.8 per cent) and not detected in ten cases (22.2 per cent). In the latter cases, the reverse transcription (RT)-PCR analysis showed the presence of a specific retinoblastoma gene transcript in six cases and was negative in the remaining four cases. The immunohistochemical and molecular findings seem to be consistent with abnormalities of retinoblastoma gene expression at either the transcriptional or the post-transcriptional level. Since all nine p53-positive cases by immunohistochemical analysis were also retinoblastoma gene product-positive, and all ten retinoblastoma gene product-negative cases were also p53-negative, two different and mutually exclusive pathways of possible pathogenetic significance may be suggested, the former involving abnormalities of the functional pathway of p53 in the absence of mutations and the latter abnormalities of retinoblastoma gene expression at the transcriptional and/or post-transcriptional level. Finally, the clinico-pathological correlations showed that p53 immunohistochemical expression is significantly associated with a poorer response to intensive chemotherapy.

The risk of acute leukemia in patients treated for Hodgkin's disease is significantly higher aft [see bined modality programs than after chemotherapy alone and is correlated with the extent of radiotherapy and type and duration of chemotherapy: a case-control study.

BACKGROUND AND OBJECTIVE: Patients treated for Hodgkin's disease have an increased risk of developing subsequent acute leukemia. This co-operative study was conducted to assess the relative risk associated with several candidate factors including age, splenectomy, combined modality therapy and cumulative drug dose including alkylating agents and nitrosurea derivatives. DESIGN AND METHODS: This study evaluated the risk of acute leukemia according to pretreatment variables and therapy modalities among 1659 patients treated for Hodgkin's disease and followed for a median time of 10 years. Both case-control and actuarial risk studies were performed. Median age was 34 years (range: 12-83); 53% of patients were splenectomized. As to the overall therapy, 348 patients (21%) were given radiotherapy (RT) alone, 375 (23%) chemotherapy (CT) alone (including MOPP, MOPP + ABVD or MOPP + ABVD + lomustine); 936 (56%) received both CT and RT, either as primary or salvage treatment. RESULTS: The overall 15-year actuarial risk of leukemia was 4.2%; the hazard function curve showed two peaks of risk at the 3th and the 8th year from the initiation of therapy and no leukemia beyond the 12th year of follow-up. Risk of leukemia was 0.3% after RT alone, 2.8% after CT alone (2.2% after MOPP; 4.4% after MOPP + ABVD + lomustine), and 5.4% in patients given combined modality therapy (10.2% for RT + MOPP; 15.6% for RT + MOPP + lomustine). No leukemia occurred after ABVD alone and the risk was low (0.6%) when neither mechlorethamine nor lomustine were utilized. Patients who had received extended radiotherapy including abdomen and pelvis in addition to MOPP showed a significantly higher risk of leukemia compared to those given limited RT + MOPP (P = 0.01). Case-control analysis indicated advanced stage, type and duration (> 8 months) of CT and extension of RT as significant risk factors for leukemia. Compared to RT alone, the odds ratio was 5.9 after MOPP + extended RT, and 8 when a lomustine-containing regimen was used, as well. Neither age nor splenectomy were independent risk factors for leukemia; splenectomy was influential only when patients had been given MOPP chemotherapy, as well. INTERPRETATIONS AND CONCLUSIONS: Both case-control and actuarial analyses indicated that: a) combined modality therapy with MOPP and extensive RT (including abdomen and pelvis), and the use of lomustine added to the leukemogenic risk of MOPP alone; b) programs without mechlorethamine, procarbazine and lomustine were almost devoid of leukemogenic risk.

Detection of infectious simian immunodeficiency virus in B- and T-cell lymphomas of experimentally infected macaques.

An increasing frequency of malignant lymphomas occurs among patients infected by human immunodeficiency virus. Because of the close similarities to human malignancies, we used a nonhuman primate model to study the pathogenesis of simian immunodeficiency virus (SIV)-associated malignancies. Specifically, we investigated (1) the presence of the SIV genome in tumor cells, (2) the presence of coinfecting viruses, and (3) the presence of a rearrangement of the immunoglobulin and c-myc genes. We observed 5 cases of non-Hodgkin's lymphomas (4 of B- and 1 of T-cell origin) among 14 SIV-infected cynomolgus monkeys. No c-myc translocation was observed in the tumors, whereas B-cell lymphomas were characterized either by a monoclonal (in 2 of 4) or by an oligoclonal (in 2 of 4) VDJ rearrangements of the immunoglobulin heavy chain gene. Molecular, biological, and immunological analyses did show the presence of infectious SIV in the tumor cells of 1 T-cell and 2 oligoclonal B-cell lymphomas. Neither Simian T-lymphotropic nor Epstein-Barr viruses were detectable, whereas Simian herpes virus Macaca fascicularis-1 was detectable at a very low copy number in 3 of 4 B-cell lymphomas; however, only 1 of these also harbored the SIV genome. These results support the possibility that SIV may be directly involved in the process of B or T lymphomagenesis occurring in simian acquired immunodeficiency syndrome.

Presence and cellular distribution of HIV in the testes of seropositive subjects: an evaluation by in situ PCR hybridization.

Cellular distribution of HIV-1 proviral DNA has been studied, by in situ PCR hybridization, in the testes of infected men who died at various stages of the disease. In seropositive asymptomatic subjects, HIV-1 proviral DNA was present in the nuclei of germ cells at all stages of their differentiation. The presence of provirus did not induce germ cell damage, was associated with normal spermatogenesis, and was not accompanied by morphologic signs of immune response. The observed HIV hybridization pattern of germ cells suggests clonal infection. Mechanisms responsible for HIV penetration in testicular germ cells remain to be clarified; however, the possibility of a direct infection of the germ cells by cell-free virus is suggested. In the testes of AIDS-deceased men, histologic features of hypoplasia with arrested spermatogenesis were evident, and few infected spermatogonia and spermatocytes were observed. The whole of these data demonstrates that the testis is a site of early viral localization that fails to elicit an immunological response, and that HIV-seropositive men produce infected spermatozoa that are released in the genital tract.

Testicular germ cells of HIV-seropositive asymptomatic men are infected by the virus.

In situ PCR hybridization studies in the testis of infected asymptomatic subjects detected the presence of HIV-1 proviral DNA in the nuclei of germ cells at all stages of differentiation suggesting that HIV-seropositive men produce infected spermatozoa that are released in the genital tract. In all subjects studied spermatogenesis was normal, the presence of provirus was not associated with germ cell damage and a very mild local immune response was observed. The HIV hybridization pattern observed in germ cells supports the hypothesis of a clonal infection. It is suggested the possibility of a direct infection of the germ cells by cell-free virus and that the testis might represent a site of early viral localization, well tolerated because of the immune privilege of this organ.

Expression of Met protein and urokinase-type plasminogen activator receptor (uPA-R) in papillary carcinoma of the thyroid.

Met protein encoded by MET oncogene is the high affinity receptor for hepatocyte growth factor (HGF)/scatter factor (SF). HGF/SF has to be cleaved in its heterodimeric form by the urokinase-type plasminogen activator (uPA) to become active as a ligand for Met receptor. The expression of Met protein and of the high affinity receptor for uPA (uPA-R) was investigated in 39 samples of papillary carcinoma using immunohistochemistry. Reactivity for Met protein was present in 33 of 34 tumours, mostly with a diffuse pattern of staining. Reactivity for uPA-R was present in 78 per cent of papillary tumours and exhibited a pattern of staining similar to that of Met protein. Staining for uPA-R was present in 23 of 25 cases (92 per cent) of papillary carcinoma with prominent sclerosis, and in only 1 of 7 cases (14 per cent) without sclerosis. Peritumoural normal thyroid, follicular adenomas, and follicular carcinomas were negative for Met protein and for uPA-R. Hyperfunctioning tall thyroid cells showed weak membrane reactivity for uPA-R and for Met protein. The findings of immunohistochemistry were confirmed at the mRNA level using in situ hybridization, since the signal for uPA-R and Met RNAs was detected in most tumour cells of five cases of papillary carcinoma.