Mexican consensus on Hodgkin's lymphoma.

El linfoma de Hodgkin (LH) se debe a la transformación clonal de células originadas en los linfocitos B, lo que genera las células binucleadas patognomónicas de Reed-Sternberg. El LH es una enfermedad de células B con una distribución bimodal, con mayor incidencia en la adolescencia y la tercera década de la vida y un segundo pico en personas mayores de 55 años. Las células del LH clásico habitualmente sufren una reprogramación de la expresión génica, ya que pierden la expresión de la mayoría de los genes típicos de las células B y han adquirido la expresión de múltiples genes que son típicos de otros tipos de células del sistema inmunitario. El algoritmo de tratamiento dependerá si se trata de LH clásico o de predominio linfocítico, si es un estadio temprano con marcadores de pronóstico desfavorables o no, el esquema inicial de manejo y si existe enfermedad voluminosa, entre las variables más relevantes.Hodgkin's lymphoma (HL) is due to the clonal transformation of cells originating from B lymphocytes, generating the pathognomonic binucleate Reed-Sternberg cells. HL is a B cell disease with a bimodal distribution, with higher incidence in adolescence and the third decade of life, showing a second peak in people over 55 years of age. Classic Hodgkin lymphoma cells routinely undergo gene expression reprogramming, as they lose the expression of most of the typical B-cell genes and acquire the expression of multiple genes that are typical of other types of cells in the immune system. The treatment algorithm will depend on whether it is classic or predominantly lymphocytic HL, if it is early stage with unfavorable prognostic markers or not, the initial management regimen, and whether there is bulky disease, among the most relevant variables.

A lymphomagenic role for HIV beyond immune suppression?

Despite the immune reconstitution promoted by combined antiretroviral therapy (cART), lymphomas still represent the most common type of cancer in HIV-infected individuals. Cofactors related to immunodeficiency such as oncogenic viruses, chronic antigenic stimulation, and cytokine overproduction are thought to be the main drivers of HIV lymphomagenesis, although the current scenario does not convincingly explain the still-high incidence of lymphomas and the occurrence of peculiar lymphoma histotypes in HIV-infected patients under cART. Recent findings are challenging the current view of a mainly indirect role of HIV in lymphoma development and support the possibility that HIV may directly contribute to lymphomagenesis. In fact, mechanisms other than immune suppression involve biologic effects mediated by HIV products that are secreted and accumulate in lymphoid tissues, mainly within lymph node germinal centers. Notably, HIV-infected patients with lymphomas, but not those not affected by these tumors, were recently shown to carry HIV p17 protein variants with enhanced B-cell clonogenic activity. HIV p17 protein variants were characterized by the presence of distinct insertions at the C-terminal region of the protein responsible for a structural destabilization and the acquisition of novel biologic properties. These data are changing the current paradigm assuming that HIV is only indirectly related to lymphomagenesis. Furthermore, these recent findings are consistent with a role of HIV as a critical microenvironmental factor promoting lymphoma development and pave the way for further studies that may lead to the design of more effective strategies for an early identification and improved control of lymphomas in the HIV setting.

The impact of EBV and HIV infection on the microenvironmental niche underlying Hodgkin lymphoma pathogenesis.

The pathogenesis of classical Hodgkin lymphoma (cHL) is still enigmatic, largely because its tumor cells, the so-called Hodgkin and Reed-Stenberg (HRS) cells, invariably reside in a prominent reactive microenvironment, are rare and therefore difficult to analyze. On the other hand, the broadly investigated cHL-derived cell lines are not unequivocally considered as suitable and representative models for this puzzling disease. Based on current knowledge, it appears that the cross talk between the tumor cells and the reactive infiltrate of the microenvironment is complex and that multiple mechanisms occur, making cHL a very heterogeneous disease. In 20-40% of cHL cases, HRS cells carry a monoclonal infection by Epstein Barr virus (EBV), which is considered a tumor-initiating factor. In these cases, EBV shows a latency type II infection pattern with the expression of latent membrane protein-1 (LMP-1), a viral oncoprotein that mimics CD40 activation. This scenario is particularly intriguing for the pathogenesis of cHL arising in HIV-infected patients, which, for still obscure reasons, is invariably EBV-associated with LMP-1 expression in HRS cells. Recent evidences are consistent with the occurrence of different pathogenic pathways variably triggered by virus infections (EBV and HIV), genetic alterations, and interactions with critical microenvironmental components. This review focuses on the different microenvironmental niches that characterize cHL of the general population as well as cases of HIV-infected patients. A more comprehensive understanding of the complex interplay existing between HRS and tumor microenvironment is pivotal for the development of more effective treatments, particularly for relapsed or refractory diseases.

The tumor virus landscape of AIDS-related lymphomas.

Immunodeficiency dramatically increases susceptibility to cancer as a result of reduced immune surveillance and enhanced opportunities for virus-mediated oncogenesis. Although AIDS-related lymphomas (ARLs) are frequently associated with known oncogenic viruses, many cases contain no known transforming virus. To discover novel transforming viruses, we profiled a set of ARL samples using whole transcriptome sequencing. We determined that Epstein-Barr virus (EBV) was the only virus detected in the tumor samples of this cohort, suggesting that if unidentified pathogens exist in this disease, they are present in <10% of cases or undetectable by our methods. To evaluate the role of EBV in ARL pathogenesis, we analyzed viral gene expression and found highly heterogeneous patterns of viral transcription across samples. We also found significant heterogeneity of viral antigen expression across a large cohort, with many patient samples presenting with restricted type I viral latency, indicating that EBV latency proteins are under increased immunosurveillance in the post-combined antiretroviral therapies era. Furthermore, EBV infection of lymphoma cells in HIV-positive individuals was associated with a distinct host gene expression program. These findings provide insight into the joint host-virus regulatory network of primary ARL tumor samples and expand our understanding of virus-associated oncogenesis. Our findings may also have therapeutic implications, as treatment may be personalized to target specific viral and virus-associated host processes that are only present in a subset of patients.

Microenvironment and HIV-related lymphomagenesis.

Patients with HIV infection are at increased risk of developing non-Hodgkin lymphoma and Hodgkin lymphoma. While the pathogenesis of these lymphomas is incompletely understood, evidence indicates that immune deregulation, genetic alterations and cytokine production play an important role in HIV lymphomagenesis. The lymphoma microenvironment in this heterogeneous group of lymphomas plays an equally critical role in their development, growth and progression. Important components of the microenvironment in HIV-related lymphomas include EBV and/or HHV-8 coinfection, reactive inflammatory cells, tumor microvasculature, and soluble factors. This paper provides a brief overview of HIV-related lymphomas and focuses on their lymphomagenesis and microenvironment.

Lung Malignancies in HIV Infection.

Pulmonary malignancies are a major source of morbidity and mortality in HIV-infected persons. Non-AIDS-defining lung cancers (mostly non-small cell lung cancers) are now a leading cause of cancer death among HIV-infected persons. HIV-associated factors appear to affect the risk of lung cancer and may adversely impact cancer treatment and outcomes. HIV infection also may modify the potential harms and benefits of lung cancer screening with computed tomography. AIDS-defining lung malignancies include pulmonary Kaposi sarcoma and pulmonary lymphoma, both of which are less prevalent with widespread adoption of antiretroviral therapy.

The role of microRNAs in the pathogenesis of HIV-related lymphomas.

The incidence of HIV-related lymphomas (HRLs) is increased by 60-100 times in patients with HIV. When compared to the general population, patients with HRLs often present with extranodal lymphoid proliferation, most frequently of the gastrointestinal tract, central nervous system, liver and bone marrow. MicroRNAs (miRs) are non-coding double-stranded RNA molecules of 18-25 nucleotides that regulate post-translational gene expression by inhibiting translation or promoting degradation of messenger RNA complementary sequences. Before their discovery, tumorigenesis was thought to have been caused by the alteration of protein-coding oncogenes and tumor-suppressor genes, but once identified in B-cell chronic lymphocytic leukemia, miRs function as either oncogenes or tumor-suppressor genes was confirmed in different types of malignancies. Since miRs are clearly involved in tumorigenesis in many cancers, their role in HRLs is now receiving attention. A few studies have been conducted thus far in some HRLs on the involvement of miR in the pathogenesis of lymphoid malignancies. Since B-cell lymphomas arise from various stages of B-cell development in both HIV-infected and HIV-naïve patients, investigators have tried to determine the different miR signatures in B-cell development. As classic immunohistochemistry staining is sometimes not enough for the differential diagnosis of HRLs, in the present review, we have described the potential use of miRs in the prognosis and diagnosis of these diseases.

Raising awareness of non-Hodgkin lymphoma in HIV-infected adolescents: report of 2 cases in the HAART era.

Human immunodeficiency virus (HIV) chronically infected patients are at increased risk of developing non-Hodgkin lymphoma compared with the general population. Highly active antiretroviral therapy has had a dramatic effect on the natural history of HIV infection, reducing the incidence of acquired immunodeficiency syndrome-related non-Hodgkin lymphoma and improving overall survival. However, problems related to adherence to treatment, frequently experienced during adolescence, may increase the risk of acquired immunodeficiency syndrome-related cancers. Optimizing highly active antiretroviral therapy and monitoring noncompliant patients with persisting HIV replication should be considered by physicians who take care of these patients. We herein report 2 cases of relapsed/progressive Burkitt lymphoma in HIV vertically infected adolescents.

AIDS-related malignancies.

Cancer remains a significant burden for human immunodeficiency virus (HIV)-infected individuals. Most cancers that are associated with HIV infection are driven by oncogenic viruses, such as Epstein-Barr virus, Kaposi's sarcoma-associated herpesvirus and human papillomavirus. Gaining insight into the epidemiology and mechanisms that underlie AIDS-related cancers has provided us with a better understanding of cancer immunity and viral oncogenesis.

Human retroviruses in the second decade: a personal perspective.

Human retroviruses have developed novel strategies for their propagation and survival. A consequence of their success has been the induction of an extraordinarily diverse set of human diseases, including AIDS, cancers and neurological and inflammatory disorders. Early research focused on their characterization, linkage to these diseases, and the mechanisms involved. Research should now aim at the eradication of human retroviruses and on treatment of infected people.

Epstein-barr virus-infected resting memory B cells, not proliferating lymphoblasts, accumulate in the peripheral blood of immunosuppressed patients.

When Epstein-Barr virus (EBV) infects B cells in vitro, the result is a proliferating lymphoblast that expresses at least nine latent proteins. It is generally believed that these cells are rigorously controlled in vivo by cytotoxic T cells. Consistent with this, the latently infected cells in the peripheral blood of healthy carriers are not lymphoblasts. Rather, they are resting memory B cells that are probably not subject to direct immunosurveillance by cytotoxic T lymphocytes (CTLs). When patients become immunosuppressed, the viral load increases in the peripheral blood. The expansion of proliferating lymphoblasts due to the suppressed CTL response is believed to account for this increase and is considered to be a major risk factor for posttransplant lymphoproliferative disease (PTLD) and AIDS-associated B cell lymphoma. Here we show that there is an increase in the numbers of latently infected cells in the peripheral blood of immunosuppressed patients. However, the cells are not proliferating lymphoblasts. They are all latently infected, resting, memory B cells-the same population of infected cells found in the blood of healthy carriers. These results are discussed in the context of a model for EBV persistence that explains why PTLD is usually limited to the lymph nodes.

Controversies in the treatment of Burkitt lymphoma in AIDS.

PURPOSE OF REVIEW: The success of combined antiretroviral therapy (cART) has transformed HIV infection into a survivable chronic disease in developed countries. Increasingly then, the risks of HIV associated cancers become paramount. Burkitt lymphoma is one of the cancer subtypes highly disproportionately affecting HIV infected patients. RECENT FINDINGS: Recent conference proceedings appear to corroborate early reports that intensive therapy of HIV-Burkitt lymphoma is feasible and effective. An optimal approach is not defined due to the small numbers of patients in current trials and the absence of comparison studies. Moreover, as breakthroughs in the pathogenesis of lymphoma in general and Burkitt lymphoma in particular suggest that HIV infection plays a significant role, the opportunity for targeted therapy based on differences in biology are wholly untapped. SUMMARY: Advances are being made in HIV-Burkitt lymphoma, but future studies need to incorporate our expanding understanding of biology to improve efficacy and reduce toxicity, preferably by integrating a biologic approach to this curable disease.

[The pattern of central nervous system lesions in HIV-infected patients of the specialized unit in infectious disease hospital].

AIM: To define the incidence and features of brain lesion (BL) in HIV-infected inpatients. SUBJECTS AND METHODS: Four hundred and fifty-eight patients with Stage 4B HIV infection (AIDS) and central nervous system (CNS) lesion admitted to Infectious Diseases Hospital Two, Moscow, were followed up in 2003-2009. The authors used cerebrospinal fluid (CSF) microscopic and bacteriological assays for DNA of T. gondii, M. tuberculosis, herpes simplex virus (HSV) types 1 and 2, cytomegalovirus (CMV), HSV type 6, and varicella-zoster virus, Cr. neoformans, C. albicans, C. glabrata, and C. krusei. Blood and CSF were tested for IgM and IgG T. gondii antibodies; brain magnetic resonance imaging was carried out. RESULTS: In patients with late-stage HIV infection, the principal cause of neurological diseases was cerebral toxoplasmosis (34.7% of BL cases) and a generalized process involving the brain, lung, heart, liver, and eyes in 11.5%. There was commonly cerebral toxoplasmosis concurrent with CMV infection with clinical manifestations. 16-32% of the inpatients developed tuberculosis meningoencephalitis that was a manifestation of hematogenous disseminated tuberculosis involving the lung. There was a rise in the incidence of cancers (brain lymphomas, astrocytomas) running with CNS lesion. Mental disorders progressing to dementia were a distinctive property of CMV ventriculoencephalitis, one of the leading factors in the development of AIDS dementia complex. Molecular diagnostic techniques are needed to ascertain the etiology of BL in HIV infection. CONCLUSION: The CSF test for DNA of causative agents is a specific and most sensitive method for diagnosing a relevant CNS lesion.

HIV-Related Lymphoproliferative Diseases in the Era of Combination Antiretroviral Therapy.

HIV-positive patients have a 60- to 200-fold increased incidence of Non-Hodgkin Lymphomas (NHL) because of their impaired cellular immunity. Some NHL are considered Acquired Immunodeficiency Syndrome (AIDS) defining conditions. Diffuse large B-cell Lymphoma (DLBC) and Burkitt Lymphoma (BL) are the most commonly observed, whereas Primary Effusion Lymphoma (PEL), Central Nervous System Lymphomas (PCNSL), Plasmablastic Lymphoma (PBL) and classic Hodgkin Lymphoma (HL) are far less frequent. Multicentric Castleman disease (MCD) is an aggressive lymphoproliferative disorder highly prevalent in HIV-positive patients and strongly associated with HHV-8 virus infection. In the pre-Combination Antiretroviral Therapy (CART) era, patients with HIV-associated lymphoma had poor outcomes with median survival of 5 to 6 months. By improving the immunological status, CART extended the therapeutic options for HIV positive patients with lymphomas, allowing them to tolerate standard chemotherapies regimen with similar outcomes to those of the general population. The combination of CART and chemotherapy/ immuno-chemotherapy treatment has resulted in a remarkable prolongation of survival among HIVinfected patients with lymphomas. In this short communication, we briefly review the problems linked with the treatment of lymphoproliferative diseases in HIV patients. Combination Antiretroviral Therapy (CART) not only reduces HIV replication and restores the immunological status improving immune function of the HIV-related lymphomas patients but allows patients to deal with standard doses of chemotherapies. The association of CART and chemotherapy allowed to obtain better results in terms of overall survival and complete responses. In the setting of HIVassociated lymphomas, many issues remain open and their treatment is complicated by the patient's immunocompromised status and the need to treat HIV concurrently.

CD4 counts and the risk of systemic non-Hodgkin's lymphoma in individuals with HIV in the UK.

Since the introduction of highly active antiretroviral therapy, there has been a decline in the incidence of non-Hodgkin's lymphoma among HIV-infected individuals. We described trends in the incidence of systemic non-Hodgkin's lymphoma in the UK CHIC Study from 1996-2006 and evaluated the association between immunosuppression and development of systemic non-Hodgkin's lymphoma: 286/23,155 (1.2%) individuals developed an AIDS-defining lymphoma (258 systemic). Younger age, receipt of highly active antiretroviral therapy and later calendar year were all independently associated with a reduced risk of systemic non-Hodgkin's lymphoma. A lower latest CD4 count was strongly associated with systemic non-Hodgkin's lymphoma, in patients who had (RR per log(2)(cells/mm(3)) higher: 0.62) and had not (0.70) received highly active antiretroviral therapy. Associations with other measures of immunosuppression, including nadir CD4 count, experience and duration of severe immunosuppression, were generally weaker. Earlier highly active anti-retroviral therapy initiation and wider access to HIV testing is advocated to reduce the risk of systemic non-Hodgkin's lymphoma.

Burkitt's lymphoma nodular cystic hepatosplenic, in HIV patient. Case report / Linfoma de Burkitt hepatoesplénico quístico nodular, en paciente con VIH. Reporte de caso

Background: Patients with human immunodeficiency virus (HIV) are more likely to develop cancer. Malignant lymphomas are the main cancer group seen in these patients. Diffuse large B-cell lymphoma including central nervous system lymphoma and Burkitt's lymphoma account for 90% of HIV-related non-Hodgkin's lymphomas. Clinical case: A 22-year-old man with fever up to 39 ° C, malaise, excessive tiredness and night sweats, loss of 8 kg of weight, abdominal pain in the right hypochondrium, all 5 months before hospitalization. Hemoglobin: 9.5 g/dL, leukocytes 5.13 x 103/mm3, platelets 124 000 cel/mm3; albumin 2.9 g/dL, alanine aminotransferase 28 IU/L, aspartate aminotransferase 105 IU/L; HIV reactive, beta 2 microglobulin: 20 000 ng/mL. Viral load for HIV 100 034 cp/mL, CD4: 76 cel/mcL (5%). It was performed abdominal ultrasound and denoted cysts in the liver and spleen. Abdominal-pelvic computed tomography with hepatosplenomegaly, retroperitoneal and inguinal adenopathies and free fluid in abdominal cavity. Splenectomy was performed and Burkitt's lymphoma was reported in the histopathological study. Conclusion: HIV predisposes patients to any type of cancer. Intra-abdominal findings should be a warning of lymphoma suspicious and may occur from infiltration of the small intestine, solid organ and soft tissues.

Introducción: los pacientes con virus de inmunodeficiencia humana (VIH) son más propensos a desarrollar cáncer. Los linfomas malignos son el principal grupo de cáncer que se observa en estos pacientes. El linfoma difuso de células grandes B, incluido el del sistema nervioso central y el linfoma de Burkitt, constituyen 90% de los linfomas no Hodgkin relacionados con VIH. Caso clínico: hombre de 22 años de edad, con fiebre de hasta 39 °C, malestar general, cansancio excesivo y sudoración nocturna, pérdida de 8 kg de peso y dolor abdominal en hipocondrio derecho, 5 meses previos a su hospitalización. Se reportó hemoglobina de 9.5 g/dL, leucocitos 5.13 x 103/mm3, plaquetas 124 000 cel/mm3; albúmina 2.9 g/dL; alanino aminotransferasa 28 UI/L, aspartato aminotransferasa 105 UI/L; VIH reactivo, beta 2 microglobulina 20 000 ng/mL. Carga viral para VIH 100 034 cp/mL, CD4 76 cel/mcL (5%). El ultrasonido abdominal mostró quistes en hígado y bazo. La tomografía abdominopélvica reportó hepatoesplenomegalia, adenopatías retroperitoneales e inguinal y líquido libre en cavidad abdominal. Se realizó esplenectomía y en el estudio histopatológico se reportó Linfoma de Burkitt. Conclusión: El VIH predispone a los pacientes a cualquier tipo de cáncer. Los hallazgos intraabdominales deben hacer sospechar de linfoma y se puede presentar desde infiltración del intestino delgado, órgano sólido y tejidos blandos.

Malignancies in HIV: the Indian scenario.

PURPOSE OF REVIEW: India has the second largest number of HIV/AIDS patients in the world; however, studies done in the area of HIV-related malignancies are few. With the availability of highly active antiretroviral therapy and treatment and prevention of opportunistic infections, an increase in life expectancy of HIV-infected individuals and an increase in HIV-related malignancies is expected. The purpose of this review is to put forth the Indian scenario of HIV-related malignancies. RECENT FINDINGS: About 2.5 million Indians have HIV/AIDS. Non-Hodgkin's lymphoma and cervical cancer were found to occur in a higher proportion among the HIV-infected individuals in India as compared with non-HIV-infected individuals. The incidence of AIDS-related primary central nervous system lymphoma is low in India. Kaposi's sarcoma is rare in India. Amongst the non-AIDS defining cancers anal cancer, testicular cancer, Hodgkin's disease, colon cancer and certain head and neck cancer sites in men and vaginal cancers among women were found to occur more frequently. SUMMARY: With the availability of highly active antiretroviral therapy an increased mortality and morbidity due to neoplastic diseases is expected in the future. As India is a large country and geographically and culturally diverse, large-scale studies need to be done linking the regional cancer centres with the AIDS centres across the country to evaluate the exact burden of HIV-related malignancies.

Oral malignancies associated with HIV.

Advances in the management of HIV infection have resulted in significant changes in survival and in the prevalence and incidence of oral diseases found in persons infected with HIV (as discussed in other articles in this series). HIV is associated with an increased risk of malignant disease that is related to immunosuppression and the activity of the HIV transactivator of transcription protein, coviral infection and exposure to carcinogens. The presence of oral malignancies varies with the route of the transmission of HIV and varies geographically, based on behaviour, viral cofactors, HIV therapy and genetic variation. Oral health care providers can identify these lesions early.

Acquired immunodeficiency syndrome-related malignancies in the era of highly active antiretroviral therapy.

Since the beginning of the acquired immunodeficiency syndrome (AIDS) epidemic, malignancies have been an important feature of this disease. Several cancers, including Kaposi sarcoma (KS), certain aggressive B-cell lymphomas, and cervical cancer, are considered AIDS-defining when they occur in patients infected with human immunodeficiency virus. Most AIDS-defining tumors are associated with one of 3 DNA viruses: KS-associated herpesvirus, Epstein-Barr virus, or human papillomavirus. With the introduction of highly active antiretroviral therapy (HAART), the incidence of KS and certain lymphomas has decreased, whereas that of other tumors, such as cervical cancer, has undergone little change. Several new drugs and therapies have been developed for KS and AIDS-related lymphomas, and these treatments, plus the development of HAART, have contributed to improvements in morbidity and mortality. At the same time, the improved overall survival of patients with HAART has contributed to an increase in the number of patients living with AIDS in developed countries such as the United States. With the development of HAART and improved prevention and treatment of opportunistic infections, an increasing percentage of the deaths in AIDS patients have been from malignancies. Strategies for prevention, screening, and therapy remain important areas of research in this developing field.