Emanuela Vaccher

Hodgkin's disease and human immunodeficiency virus infection: clinicopathologic and virologic features of 114 patients from the Italian Cooperative Group on AIDS and Tumors.

PURPOSE To describe virologic, clinicopathologic, and therapeutic features of a large series of Italian patients with Hodgkins disease (HD) and human immunodeficiency virus (HIV) infection. PATIENTS AND METHODS From November 1986 to March 1994, 114 cases were observed. The relationship between Epstein-Barr virus (EBV) and HD was determined by an in situ hybridization technique, immunostaining for EBV-encoded latent membrane protein-1 (LMP-1) expression, and Southern blotting. Twenty-six patients were included in a prospective study evaluating the combination of chemotherapy (CT) with zidovudine. RESULTS Combined approach on EBV study revealed that 14 (78%) of 18 patients were EBV-associated. An almost equivalent distribution of EBV subtypes was observed in EBV-carrying cases, indicating that in the HIV setting, type 2 EBV also may be pathogenetically involved in HD development. In comparing these 114 patients with our single-institutional series of 104 HIV-negative patients with HD, we observed at presentation a younger median age (29 v 38 years); a prevalence of males (90% v 56%); and a higher percentage of stage IV disease (52% v 15%), presence of B symptoms (77% v 35%), and extranodal disease (63% v 29%). The complete remission (CR) rate (58%) and median survival (13 months) of patients treated prospectively were similar to that of patients treated with standard CT regimens. The statistically significant favorable prognostic factors for survival being the following: achievement of CR, CD4+ count greater than 250/microL, and no prior diagnosis of AIDS at onset of HD. CONCLUSION Our virologic findings indicate that HIV-related HD is more closely associated with EBV than HD in the general population. The peculiar clinicopathologic findings, the role of some prognostic factors, and the possibility of cure of HIV-related HD have been demonstrated.

Hepatocellular carcinoma in HIV-infected patients: epidemiological features, clinical presentation and outcome.

Objective: Hepatocellular carcinoma (HCC) is an increasing cause of mortality in HIV-seropositive individuals. The aim of the study was to compare the main features of HCC in HIV-seropositive individuals with those in to HIV-negative patients. Patients and methods: All HIV-infected subjects with a diagnosis of HCC included in three cancer registry databases were enrolled in the study as cases. HCC cases that occurred in the province of Brescia, North Italy, in the period 1995–1998 and all cases reported at the Italian Liver Cancer Project were enrolled as controls. All data were collected using a standardized case report form. The main clinical and epidemiological characteristics of patients with HCC and their survival were compared between HIV-positive and uninfected subjects. Results: Forty-one HIV-infected subjects with HCC were identified. Multivariate analysis adjusted for age and sex identified an association between HIV infection and HCV infection [odds ratio (OR), 11; P = 0.005], and infiltrating tumours and/or extranodal metastasis at presentation (OR = 11.8; P < 0.001). HIV infection was independently associated with shorter survival (hazard ratio, 1.63; P = 0.015). Conclusions: HCC in HIV-infected patients is mainly associated with underlying chronic hepatitis C and has a more aggressive clinical course. Thus, preventative strategies (including the treatment of hepatitis C) should be implemented in the management of HIV/HCV-coinfected patients.

Clinical Features and Outcome of Primary Effusion Lymphoma in HIV-Infected Patients: A Single-Institution Study

PURPOSE To describe the clinical features and outcome of HIV-associated primary effusion lymphoma (PEL) and to compare them with those of the other HIV-associated non-Hodgkins lymphomas (NHLs). PATIENTS AND METHODS From April 1987 to June 2002, 277 patients with HIV infection and systemic NHL were diagnosed and treated in our institution. Clinical features and outcome of PEL patients were compared with the features and outcomes of 162 patients belonging to the following histologic subtypes: plasmoblastic lymphoma of oral cavity (PBLOC, n = 11), immunoblastic lymphoma (IBL, n = 76), and centroblastic B-cell lymphoma (CBCL, n = 75). RESULTS Among the 277 NHL patients, PEL was diagnosed in 11 patients (4%). Eight of 11 patients were treated with a cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-like regimen. Complete remission was reached in 42% of patients, with a median survival time of 6 months. When the clinical features and outcome of 11 PEL patients were compared with the other three groups of patients affected by NHL, at the onset of the disease, no statistically significant differences were observed in demographic data, CD4 absolute number, HIV viremia plasma levels, and clinical characteristics. When we compared the outcome of PEL patients with the CBCL group, a statistically significant worse outcome was observed; however, the clinical outcome of PEL patients was not significantly different from the outcome observed in the other two groups (PBLOC and IBL groups). CONCLUSION PEL is a rare HIV-associated NHL type occurring as a late manifestation of HIV infection with a poor clinical outcome and a shorter overall survival compared with CBCL patients.

Concomitant cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy plus highly active antiretroviral therapy in patients with human immunodeficiency virus‐related, non‐Hodgkin lymphoma

The feasibility and efficacy of concomitant chemotherapy and highly active antiretroviral therapy (HAART) is still unknown in patients with human immunodeficiency virus (HIV)‐related malignancies. To evaluate the impact of chemotherapy plus HAART on the clinical course of patients with HIV‐related, systemic, non‐Hodgkin lymphoma (HIV‐NHL), the authors compared retrospectively a group of 24 patients with HIV‐NHL who were treated with the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy regimen plus HAART with a group of 80 patients who were treated with CHOP chemotherapy or a CHOP‐like regimen (i.e., cyclophosphamide, doxorubicin, teniposide, and prednisone with vincristine plus bleomycin) without receiving antiretroviral therapy.

Lung carcinoma in 36 patients with human immunodeficiency virus infection

The current study describes the clinicopathologic characteristics of 36 patients with lung carcinoma and human immunodeficiency virus (HIV) infection observed within the Italian Cooperative Group on AIDS and Tumors (GICAT).

Kaposi’s Sarcoma-Associated Herpesvirus/Human Herpesvirus Type 8-Positive Solid Lymphomas : A Tissue-Based Variant of Primary Effusion Lymphoma

Kaposis sarcoma-associated herpesvirus (KSHV), also termed human herpesvirus type 8, is consistently identified in Kaposis sarcoma, primary effusion lymphoma (PEL), and multicentric Castlemans disease. Here we report four cases of KSHV-bearing solid lymphomas that occurred in AIDS patients (cases 1 to 3) and in a human immunodeficiency virus (HIV)-seronegative person (case 4). The patients presented extranodal masses in the abdomen (cases 1, 3, and 4) or skin (case 2), and nodal involvement, together with Kaposis sarcoma (case 3). The gastrointestinal tract was involved in two patients (cases 1 and 3). The patients did not develop a lymphomatous effusion. KSHV was detected in the tumor cells of all cases by immunohistochemistry and by polymerase chain reaction. Epstein-Barr virus was detected in two of the HIV-related cases. All KSHV-positive solid lymphomas exhibited PEL-like cell morphology. To investigate the relationship of these disorders to PEL and to other AIDS-associated diffuse large cell lymphomas, KSHV-positive solid lymphomas were tested for the expression of a set of genes that were previously shown by gene profiling analysis to define PEL tumor cells. The results showed that expression of this set of genes in KSHV-positive lymphomas is similar to that of PEL but distinct from KSHV-negative AIDS-associated diffuse large cell lymphomas. Because pathobiological features of KSHV-positive solid lymphomas closely mimic those of PEL, our results suggest that KSHV-positive solid lymphomas should be considered as a tissue-based variant of classical PEL, irrespective of HIV status.

Unusual malignant tumours in 49 patients with HIV infection

Between December 1986 and December 1988, the Italian Cooperative Group on AIDS-Related Tumours documented 49 HIV-related tumours other than malignant lymphomas (ML) and Kaposis sarcomas (KS), predominantly among HIV-infected intravenous drug abusers (IVDA). Of 12 germinal testicular tumours collected, six were seminomas, two of which were pure embryonal and the other four embryonal mixed. Cervical carcinoma was observed in nine IVDAs (intraepithelial in eight and advanced, with rapid progression, in one). Lung cancer associated with HIV infection was reported in eight patients, of whom four had an adenocarcinoma, two a small cell carcinoma, one an epidermoid carcinoma and one a mesothelioma. All patients with non-small-cell-lung cancer (SCLC) were at stage III, while those with SCLC and mesothelioma had limited disease. Five out of eight presented with limited disease at onset. The median age was low; lung cancer occurred predominantly in young adults, of whom all but one were smokers. Three patients could not be treated; four died while on treatment because of progression of the neoplasia and one died of an overdose. Acute lymphoblastic leukaemia (ALL) was diagnosed in five patients. The immunophenotype was always Burkitt-like (L3), and acute myeloblastic leukaemia (M2) was diagnosed in one. Of the central nervous system (CNS) tumours, two cases of glioblastoma and one of medulloblastoma were described. Two cases of young adults with multiple myeloma and two cases of colorectal carcinoma were also reported. One case of chronic lymphocytic leukaemia, one anorectal carcinoma, one oral carcinoma, one pancreatic carcinoma, one thymoma, one kidney carcinoma, one malignant melanoma and thyroid carcinoma were also found. Testis carcinoma occurred mainly in patients in an early phase of HIV infection, without adversely affecting full-dose chemotherapy or radiotherapy. In situ cervical carcinoma treated with conization would suggest papanicolaou shear test screening in young IVDA. Lung carcinoma occurred in a young age group with rapid progression and resulted in death within 2 months. Intensive chemotherapy for ALL was not adversely affected by HIV infection and two complete remissions were achieved (11 and 15 months duration). This retrospective study shows that while oral and anorectal tumours were very rarely observed, a wide spectrum of other HIV-related solid tumours and leukaemias were found in this IVDA-based series. The incidence of such tumours is probably underestimated because they are not diagnostic of AIDS. The required therapeutic approaches may not necessarily be influenced by HIV infection, in contrast with the observed pattern for treatment of KS and ML in HIV-infected subjects.

AIDS-Related Kaposi’s Sarcoma: Evaluation of Potential New Prognostic Factors and Assessment of the AIDS Clinical Trial Group Staging System in the Haart Era—the Italian Cooperative Group on AIDS and Tumors and the Italian Cohort of Patients Naïve From Antiretrovirals

PURPOSE To assess potential new prognostic factors and to validate the AIDS Clinical Trials Group (ACTG) for AIDS-related Kaposis sarcoma (AIDS-KS) staging system in the highly active antiretroviral therapy (HAART) era. PATIENTS AND METHODS We collected epidemiologic, clinical, staging, and survival data from 211 patients with AIDS-KS enrolled in two prospective Italian human immunodeficiency virus (HIV) cohort studies. We included in the analysis all patients with the diagnosis of KS made from January 1996, the time at which HAART became available in Italy. RESULTS In the univariate analysis, survival was not influenced by sex, age, level of HIV viremia at KS diagnosis, HAART at KS diagnosis (HAART-naïve v HAART-experienced), or type of HAART combination. Regarding ACTG classification, the 3-year survival rate was 85% for T0 patients and 69% for T1 patients (P =.007), 83% for S0 patients and 63% for S1 patients (P =.003), and 83% for I0 patients and 71% for I1 patients (P =.06). In the multivariate analysis, only the combination of poor tumor stage (T1) and poor systemic disease (S1) risk identified patients with unfavorable prognosis. The 3-year survival rate of patients with T1S1 was 53%, which was significantly lower compared with the 3-year survival rates of patients with T0S0, T1S0, and T0S1, which were 88%, 80%, and 81%, respectively (P =.0001). CONCLUSION In the era of HAART, a refinement of the original ACTG staging system is needed. CD4 level does not seem to provide prognostic information. Two different risk categories are identified: a good risk (T0S0, T1S0, T0S1) and a poor risk (T1S1).

High-dose therapy and autologous peripheral blood stem cell transplantation as salvage treatment for AIDS-related lymphoma: long-term results of the Italian Cooperative Group on AIDS and Tumors (GICAT) study with analysis of prognostic factors.

After the introduction of highly active antiretroviral therapy (HAART), intensive treatment, including high-dose therapy (HDT) and peripheral blood stem cell transplantation (PBSCT), has become feasible in HIV-positive patients with Hodgkin (HL) and non-Hodgkin (NHL) lymphoma. Herein, we report the long-term results, on an intention-to-treat basis, of a prospective study on HDT and PBSCT in 50 HIV-positive HAART-responding patients with refractory/relapsed lymphoma. After debulking therapy, 2 patients had early toxic deaths, 10 had chemoresistant disease, 6 failed stem cell mobilization, 1 refused collection, and 4 progressed soon after PBSC harvest. Twenty-seven actually received transplant. Twenty-one patients are alive and disease-free after a median follow-up of 44 months (OS, 74.6%; PFS, 75.9%). Only lymphoma response significantly affected OS after transplantation. In multivariate analyses both lymphoma stage and low CD4 count negatively influenced the possibility to receive transplant. Median OS of all 50 eligible patients was 33 months (OS, 49.8%; PFS, 48.9%). Low CD4 count, marrow involvement, and poor performance status independently affected survival. PBSCT is a highly effective salvage treatment for chemosensitive AIDS-related lymphoma. It seems rational to explore its use earlier during the course of lymphoma to increase the proportion of patients who can actually receive transplant.

Distribution of human herpesvirus-8 sequences throughout the spectrum of AIDS-related neoplasia

Objective:AIDS frequently associates with certain malignancies, including Kaposis sarcoma, non-Hodgkins lymphoma (NHL), and anogenital neoplasia. In this study we aimed to define the frequency of infection by human herpesvirus (HHV)-8 throughout the spectrum of AIDS-related neoplasia in Europe. Design:A tumour panel representative of the distinct types of AIDS-related neoplasms was tested for the presence of HHV-8 DNA sequences. Autologous uninvolved tissues were also tested in selected cases. Methods:The presence of HHV-8 DNA sequences was assayed by a combination of polymerase chain reaction followed by oligohybridization and Southern blot hybridization of genomic DNA with an HHV-8-specific probe. Results:HHV-8 sequences were detected in 100% of AIDS-related Kaposis sarcoma (all 35 cases). Among AIDS-related NHL, HHV-8 sequences selectively clustered with body-cavity-based lymphomas (BCBL; all three cases), although they were consistently negative in small non-cleaved cell lymphomas (none in 18 cases), diffuse large cell lymphomas (none in seven), or anaplastic large cell lymphomas (none in three). No HHV-8 sequences were found in cases of anogenital neoplasia (out of 14) or Hodgkins disease (out of three). HHV-8 DNA sequences were also positive in the uninvolved skin of all six AIDS-related Kaposis sarcoma patients, but not in the circulating lymphocytes of a BCBL patient. Positivity for HHV-8 sequences occurred in patients belonging to all major AIDS risk categories. Conclusions:These data confirm that HHV-8 sequences associate at high frequency with selected types of AIDS-related neoplasia, namely Kaposis sarcoma and BCBL, although they are consistently absent in other types of AIDS-NHL and AIDS-related anogenital neoplasia.