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Malignant lymphomas are neoplastic diseases of the lymphatic system that grow rapidly and aggressively, and lead to death within a few weeks or months if left untreated. Hodgkin's disease (HD) is distinguished from the large group of non-Hodgkin's lymphomas (NHL). In comparison to the normal population, HIV patients are affected significantly more frequently by all types of lymphoma (see Table 1) - the greatest risk is aggressive NHL of B-cell origin. Since the introduction of HAART, the incidence has declined, although not as impressively as with Kaposi's sarcoma or the most OIs (Clarke 2001, Little 2001), so that the relative proportion of AIDS-associated illnesses that are lymphomas is increasing. The reduction is seen principally in the subtypes that mostly occur in the setting of severe immunodeficiency (Kirk 2001).

In some HIV cohorts, malignant lymphomas have already overtaken Kaposi's sarcoma as the most frequent malignancy. In the EuroSIDA study, the proportion of AIDS-defined illnesses that were malignant lymphomas increased from less than 4 % in 1994 to 16 % in 1998 (Mocroft 2000). In France, lymphomas accounted for 11 % of all deaths in HIV infected patients in 2000 (Bonnet 2004).

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Table 1. Relative risk of different lymphomas in HIV patients in comparison to the normal population (adapted from Goedert 2000) Malignant NHL total 165 High-grade malignancy NHL 348 Immunoblastic NHL 652 Burkitt's NHL 261 Not classifiable 580 Primary CNS lymphoma (PCNSL) > 1,000 Low-grade malignancy NHL 14 Plasmocytoma 5 Hodgkin's disease 8 Malignant lymphomas in HIV-infected patients are biologically very heterogenous. The frequency and extent of oncogenic mutations or cytokine dysregulation differ, as does the histogenetic origin of the malignant cells (Porcu 2000). Furthermore, the association with EBV and other oncogenic viruses such as HHV-8 or SV40 is very variable. The extent of immunodeficiency also varies. Whilst Burkitt's lymphoma and Hodgkin's disease frequently occur even when the immune status is good, immunoblastic and especially primary CNS lymphomas (PCNSL) are almost always associated with severe immunodeficiency. However, HIV-associated lymphomas - both NHL and HD - have numerous common clinical features. Characteristics include the usually aggressive growth, diagnosis in the advanced stages with frequent extranodal manifestations, poorer response to treatment, high relapse rates and an overall poor prognosis (Levine 2000). Even in the HAART era, the treatment of malignant lymphoma remains challenging. Although aggressive chemotherapy is possible in many patients with existing immunodeficiency, treatment is complicated and requires a close cooperation between HIV clinicians and physicians with experience in hematology/oncology. The following discusses systemic NHL, PCNSL and Hodgkin's lymphoma separately. Multicentric Castleman's disease will also be mentioned as a distinct entity, although it is not considered a malignant lymphoma. Low-grade (indolent) NHLs are very rare in HIV patients, and will therefore not be discussed here - treatment of such cases in the HAART era should follow the recommendations for HIV-negative patients. Systemic non-Hodgkin lymphomas (NHL) A close association between systemic NHL and AIDS has been described for a long time - the first cases were published only about a year after the first description of AIDS and even before the discovery of HIV (Ziegler 1982). High-grade B-NHLs have been AIDS-defining since 1985. So far, more than 90 % of HIV-associated NHLs are of B-cell origin. They are almost always of high-grade malignancy. Two main histological types dominate: according to the WHO classification these are Burkitt's lymphomas, which comprise 30-40 % of cases, and diffuse large-cell B cell lymphomas, comprising 40-60 %. However, a relatively large proportion of HIV-associated lymphomas (up to 30 %) cannot be classified even by reference pathologists. A small proportion of NHLs (1-3 %) are primary effusion or body cavity-based lymphomas, representing a distinct entity (see below). The prognosis of patients with NHL was poor in the pre-HAART era, being between 6 and 9 months (Levine 2000). Since the advent of HAART, this has changed (see below). Whether the clinical and pathological spectrum of NHL is also changing, is still unclear. Signs and symptoms The main symptom is lymph node enlargement. Lymphomas are firm, immobile or barely mobile and painless. A large proportion of patients have advanced-stage lymphoma at the time of diagnosis. Ann Arbor stages III-IV are almost always the rule, and B symptoms with fever, night sweats and/or weight loss are found in the majority of cases (60-80 %). General asthenia, significant malaise and rapid physical deterioration are also frequently seen. Extranodal involvement is common, and may be to a grotesque extent. In our own cohort of 203 patients, 81 % had at least one extranodal focus (Hoffmann 2003). Whether the orbital cavity, testes, heart, breasts, bladder, kidneys, muscles, or bones - every conceivable region can be affected. The gastrointestinal tract, liver, and bone marrow are affected particularly frequently. Secondary CNS involvement can also occur. With extranodal disease, additional symptoms arise depending on the localization. These include, for example, abdominal pain from hepatosplenomegaly, hemorrhage or ileus symptoms due to intestinal involvement, bone pain with skeletal infiltration, or headache caused by brain involvement. Diagnosis Rapid histological diagnosis is important. If bone marrow biopsy has not secured the diagnosis already, a lymph node (e.g. cervical, axillary or inguinal) should be extirpated. Mere puncture biopsy of a lymph node is often insufficient to identify the subtype. It is important to send the material to a specialized pathology laboratory with extensive experience in HIV lymph node morphology. The basic pathological diagnosis should include information about the subtype (Burkitt?), the proliferation rate and the expression profile (definitely: CD20, and desirably: CD10, CD138, MUM-1) as this may implicate have therapeutic consequences (see below). For the treating physician, it is important not just to accept a pathological diagnosis, but to discuss it with the pathologist, especially if there is any doubt in the clinical picture. All patients with NHL should be "staged" according to the Ann-Arbor classification (Tables 2a, b). Table 2a. Staging according to the updated Ann-Arbor classification I Involvement of a single lymph node region (I) or involvement of a single extralymphatic organ or site (IE) II Involvement of 2 or more lymph node regions on the same side of the diaphragm (II) or localized involvement of an extralymphatic organ or site plus its regional lymph nodes, with or without involvement of other lymph node regions on the same side of the diaphragm (IIE) III Involvement of lymph nodes regions on both sides of the diaphragm (III), can be accompanied by localized extralymphatic organ involvement (IIIE) or spleen involvement (IIIS) or both (IIIE+S) IV Diffuse or disseminated involvement of one or more extralymphatic organs with or without associated lymph node involvement; or isolated involvement of an extralymphatic organ with involvement of distal (non-regional) lymph nodes. Basic diagnostic tests for staging include chest radiography, abdominal ultrasound, bone marrow biopsy (only aspiration is not enough!) and CT scans of the neck, thorax and abdomen. In addition to an updated immune status and viral load, the following should be determined: blood count, erythrocyte sedimentation rate, CRP, uric acid, LDH, liver and kidney parameters and electrolytes. ECG and echocardiography are also important beforehand. The possible cardiotoxicity of chemotherapy (anthracyclines!) during the course of treatment can only be evaluated if these tests have been performed at the start! Pulmonary function should be tested before treatment with regimens containing bleomycin is initiated. Table 2b. Every stage is divided into categories A and B A Asymptomatic B General symptoms: a) unexplained weight loss of more than 10 % in the last six months, and/or b) unexplained persistent or recurring fever with temperatures above 38 °C, and/or c) drenching night sweats After two cycles of chemotherapy, a restaging should evaluate the treatment success. The restaging should be oriented according to the original localization of lymphoma. After completion of the chemotherapy, a complete restaging with bone marrow biopsy (if there was initial involvement) and all CT scans is necessary. With a complete remission, restaging is recommended initially at three-monthly intervals. These intervals can be prolonged to six months after one year and to twelve months after two years. Relapses after more than three years are rare. In advanced stages of the disease (Ann Arbor III-IV), and with ENT involvement, CSF puncture should be performed at the start of systemic chemotherapy to exclude meningeal involvement. At the same time, 15 mg of methotrexate can be administered intrathecally as prophylaxis. Whether and when this (widely accepted by oncologists) action actually has any benefit or not, has never been shown in controlled studies. Therapy Due to rapid generalization, even "early stages" are rarely limited. The real stage of the disease is often underestimated - every aggressive HIV-associated lymphoma should therefore be treated primarily with systemic chemotherapy with curative intent. Surgery or radiation therapy alone are not sufficient in most cases. Treatment must be started rapidly due to the aggressive nature of these lymphomas. In particular, time should not be wasted on staging procedures. The necessary tests should be completed within a week. In Europe, diffuse large-cell NHLs have been treated for many years with CHOP-based regimens (usually 4-6 cycles, see table). CHOP is the abbreviation used for the combination chemotherapy with the cytostatics cyclophosphamide, adriamycin (hydroxydoxorubicin), vincristine (oncovin) and prednisolone. To date, no other chemotherapy regimen has been shown to have better efficacy. CHOP can be administered in ambulatory care and is fairly well tolerated. At least 4 cycles should be administered, and - as far as possible - 2 cycles after reaching complete remission (CR). The standard three-week CHOP regimen ("CHOP-21") is shown in Table 3. Following the success of "CHOP-14" in older HIV-negative patients (Pfreundschuh 2004), "CHOP-21" can also be condensed: in "CHOP-14" (one cycle every two weeks) the use of the growth hormone G-CSF (e.g. Filgastrim 30-48 million units or Neupogen™ 300/480 µg s.c. daily on days 4 to 13) reduces the duration of neutropenia. This approach not only decreases the phase of increased susceptibility to infections, but also increases the dose intensity of chemotherapy. However, there is no comparative data on this yet for HIV infected patients. So far, we have had fairly positive experiences with this approach - in most HIV infected patients, it is possible to shorten the interval. We recommend the administration of co-trimoxazole as an adjuvant therapy, up until one month after completion of the chemotherapy (960 mg three times weekly), independent of the CD4 cell count. Oral mucous membranes should be treated with mouthwashes and topical antimycotics such as amphotericin. Good adherence is an important factor. During chemotherapy, at least twice weekly monitoring of the patient's condition, blood count, liver and kidney parameters is necessary. Treatment is usually continued with the full dose according to protocol if leukocytes are above 3,000/µl again after nadir and platelets more than 80,000/µl on the planned day of treatment. Patients should be advised to carry out daily temperature monitoring and be told to present immediately in case of fever. Table 3: CHOP regimen (4-6 cycles of 3 weeks each, repeat on Day 22) * Cyclophosphamide EndoxanÔ 750 mg/m2 i.v. Day 1 Doxorubicin Doxo-CellÔ, AdriblastinÔ 50 mg/m2 i.v. Day 1 Vincristine VincristinÔ 1.4 mg/m2 (maximum 2 mg) i.v. Day 1 Prednisolone Decortin HÔ 2 tbl. à 50 mg qd p.o., Day 1-5 Mesna UromitexanÔ 20 % of cyclophosphamide dose at hours 0, 4, 8 i.v. (given as a short infusion) or orally * Standard CHOP regimen (CHOP 21). Repeated on Day 22. Alternatively, with CHOP 14, the cycles are tightened with the help of G-CSF (see text). Rituximab in HIV infection? The introduction of the monoclonal CD20-antibody rituximab (MabThera™ or Rituxan™) was one of the biggest advances in oncology in recent years. In numerous lymphomas, this antibody, which binds highly specifically to CD20-positive B-cells (CD20 is expressed on most lymphoma cells), has markedly improved the effectiveness and length of response of conventional chemotherapy. A combination of CHOP and rituximab ("R-CHOP") is now standard in many lymphomas. Rituximab is usually well tolerated, but often leads to a longer lasting B-cell depletion, and occasionally to severe neutropenia (Voog 2003). It is not clear whether rituximab has a similarly large clinical benefit for HIV infected patients as it has for HIV-negative patients with B-cell lymphoma. The results from AMC 010, a multicenter prospective and randomized US study, have at least raised doubts (Kaplan 2005). In total, 143 patients with CD20-positive AIDS-NHL were randomized to CHOP or R-CHOP (rituximab in the usual dose of 375 mg/m² on day 1 with a monthly maintenance therapy for 3 months following chemotherapy). In addition to the chemotherapy, all patients also received G-CSF, a co-trimoxazole prophylaxis and an AZT-free HAART. Both groups had minimal differences at baseline. In the rituximab group, the CD4-cell counts were slightly, but not significantly lower (128 vs 158/µl). With regard to other parameters, such as histology, stage of disease, etc., there were no significant differences. Even the planned CHOP cycles were carried out at the same intensity in both groups, and in both groups only slight dose reductions were necessary. The essential results: neither group differed significantly in the length of response, disease-free or total survival. However, neutropenia and incidence of (especially severe) infection were significantly higher in the rituximab group. Out of a total of 15 patients who died from an infection, 14 had received rituximab. The cause of death was usually septicemia from various bacteria - both gram-negative and gram-positive were identified. Death occurred in the majority (8/15) of the patients during the first two cycles, although 6 cases happened during the rituximab treatment at the end of the chemotherapy. Fatalities occurred in all centers and were therefore not due to a possible lack of expertise in any one location. A further risk factor for death from infection was a low baseline CD4-cell count - 8/13 patients had less than 50 cells/µl. The cause of the high rate of severe infections is still unclear. Pathophysiologically, it is at least possible that in pre-existing T cell defects present in HIV infected patients, a long-lasting rituximab-induced B cell depletion or hypoglobulinemia has particularly negative effects (Miles 2005). According to these data, rituximab seems at first glance to have no significant beneficial effect on HIV infected patients with aggressive lymphomas, and if indeed there is one, this is cancelled by the increased risk of infection. In a further study from Italy, in which rituximab was given with CDE (cyclophosphamide, doxorubicin, etoposide), fatal infectious complications occurred in 8 % of patients (Spina 2005). In contrast, in a French study the infection rate was not increased and the CR-rates were as high as 77 % (Boue 2006). It is our opinion that in HIV lymphomas, rituximab should only be used within clinical trials or on patients with low immunosuppression. In addition, it is imperative that more data is obtained. For this reason, a multicentric cohort study has been set up for Germany starting in 2006, which should incorporate as many patients as possible. Contact the author, IPM study center, telephone + 49 40 4132420. More intensive chemotherapy as standard CHOP After earlier studies showed that intensive chemotherapy led to a disproportionately high risk of infection and toxic complications (Kaplan 1997), the tendency for a long time was to withhold HIV infected patients from therapy and often to treat them with reduced-dose regimens. This seems to be changing in the age of HAART. Prospective studies have shown that the tolerability of chemotherapy is improved through HAART (Powles 2002, Sparano 2004). In the past few years, small pilot studies have been repeatedly published in which HIV infected patients have been treated with CHOP regimens. There are also studies in which doxorubicin has been given as liposomal Caelyx™ (Levine 2004) or where the dose of cyclophosphamide was increased (Costello 2004). In addition, CDE, a regimen which, when given for several days as infusions is supposed to overcome the potential chemotherapy resistance of lymphoma cells, is propagated again and again (Sparano 2004). The CR rates in these studies were between 50 and 75 %. Whether these new attempts, which always cause a stir, are really better than CHOP, remains speculative. In our view, they are not ready for use outside of clinical trials. Even stem cell transplantations are now possible in HIV infected patients - a scenario that was unthinkable earlier. High doses of myeloablative chemotherapy in combination with HAART are well tolerated (Gabarre 2000 + 2004, Kang 2002, Re 2003, Krishnan 2005). In HIV infected patients with Burkitt's lymphoma, intensive protocols that were originally developed for HIV negative patients are also being successfully employed (see below). Today, the decisive question regarding more intensive chemotherapy in HIV patients is, therefore, not whether it can be used, but who actually needs it or will profit from an increased dose. HAART and classic risk factors At first glance, the effect of HAART on the prognosis of HIV-associated NHL seems contradictory. At least four large cohort studies (Conti 2000, Levine 2000, Matthews 2000, Chow 2001) have shown sobering results. These data contradict numerous, mostly smaller, but more closely analyzed and prospective studies. These showed without exception that HAART significantly improved prognosis (Thiessard 2000, Antinori 2001, Besson 2001, Ratner 2001, Powles 2002, Vilchez 2002, Navarro 2003, Vaccher 2003, Sparano 2004). In addition to survival, some studies also showed improved disease-free survival, response rates and even improved tolerability of chemotherapy. While the "classic" NHL risk factors for survival (including Ann Arbor stage, LDH, age, Karnofsky score) are already of lower significance in HIV infected patients than the HIV-relevant factors (CD4-cells, history of AIDS), then the latter presumably lose relevance too when the impact of HAART is also considered (Hoffmann 2003, Lim 2005). In our own multicenter cohort with over 200 patients, the immunologic-virological success of HAART was an important and independent factor for the prognosis (Hoffmann 2003). This was also true for patients who still had a relatively preserved immune status (> 200 CD4 cells/µl at the time of lymphoma). The only additional clinical risk factors were extranodal disease and a history of AIDS, but had relatively weak predictive relevance. However, in a histological analysis, a post germinal centre profile was also associated with a worsened prognosis (Hoffmann 2003). In practical terms, this means: in a treatment-naïve patient, the chances of complete remission are not necessarily poor even with an otherwise poor starting condition (advanced lymphoma or HIV). Every patient should start HAART as rapidly as possible, even with only moderate immunodeficiency. Chemotherapy with curative intent should follow and, if possible, doses should not be reduced. In order to obtain more data, all patients in the German cohort studies should be included (see above for telephone/contact). Which HAART when? Already existing, adequate HAART should be continued during chemotherapy if possible. Depending on the resistence situation, replacement of AZT (myelotoxicity!) and d4T/ddI (polyneuropathy, especially in combination with vincristine!) should be considered. In treatment-naïve patients, the first one or two CHOP cycles can be completed before starting HAART. Some clinicians prefer to complete all six cycles out of concern for interactions and cumulative toxicities (Little 2003). In our opinion, this is not necessary. The choice of antiretroviral drugs is not easy, however. d4T, ddI and AZT should be avoided because of their toxicities. The abacavir hypersensitivity reaction (malaise, fever!) can cause problems with differential diagnoses during chemotherapy; the kidneys have to be very closely monitored on tenofovir. Little is known of the possible interactions between PIs and NNRTIs with cyclophosphamide and other cytostatic agents. The effect on doxorubicin seems to be limited (Toffoli 2004). In treatment-naïve patients without signs of resistance and pre-existing renal disease, we favor a combination of tenofovir, 3TC/FTC and an NNRTI. This is well tolerated in most cases, has a low number of pills and low risk of interactions. As long as a boosted PI regimen is being used, the plasma PI levels should be regularly controlled. Special entities of lymphoma Burkitt's or Burkitt-like lymphomas (BL/BLL): the particularly high proliferative capacity and aggressiveness of BL/BLL is a problem even in HIV-negative patients. In this case, CHOP is insufficient (Trümper 2001). Although it is still unclear whether this is also true for HIV infected patients, many clinicians have tended to treat such patients more intensively. A modified dose-adapted protocol of the German multicenter study group for adult acute lymphoblastic leukemia (GMALL) is usually used for the treatment of HIV-negative cases of Burkitt-NHL/B-ALL, and consists of four to six short, intensive 5-day polychemotherapy cycles, alternating A and B cycles. A cytoreductive pretreatment with cyclophosphamide and prednisone, each for 5 days, was given before the first cycle. During cycle A, fractionated doses of ifosphamide for 5 days, intermediate- or high-dose methotrexate 500-3,000 mg/m2, VM26, cytarabine (ara-C), vincristine, and dexamethasone are given. During cycle B, ara-C, VM26 and ifosphamide are replaced by doxorubicin and cyclophosphamide (Hoelzer 1996). The preliminary data show better responses than with CHOP (Hoffmann 2006) and rates comparative to those of HIV-negative patients (Oriol 2003). However, the GMALL protocol is a very intensive chemotherapy, which cannot be administered on an outpatient basis. Strict monitoring of patients in hospital for several weeks is essential. Centers without experience in this intensive protocol should not administer it to HIV-infected patients. As well as the B-ALL-protocol, other intensive therapies have been reported (Cortes 2002, Wang 2003). A significant problem with most of the studies is that there is no control group. There is no randomized study. However, there is increasing evidence that conventionally treated patients with Burkitt's lymphoma also have a worse prognosis even in the era of HAART (Conti 2000, Lim 2005, Spina 2005). Although this has not been confirmed by all investigators (Bower 2005), intensive therapy should be considered for every patient with Burkitt's lymphoma. A poor immune status and even the existence of a concurrent opportunistic infection does not necessarily have to be an obstruction (Lehmann 2005). Plasmablastic lymphomas: are a relatively "new" entity in HIV infected patients. These lymphomas probably belong to the diffuse large-cell NHLs, but have characteristic immunophenotype, which usually indicates a post-germinal center cell origine - markers for the B-cell antigen CD20 are negative, whereas the plasma-cell reactive antibodies VS38c and CD138 are positive (Brown 1998, Teruya-Feldstein 2004). The oral cavity is the site of involvement (Gaidano 2002), although extra-oral manifestations do occur (Chetty 2003). There is a close association with HHV-8 infection. Like Burkitt's lymphoma, plasmablastic lymphomas have a very high rate of proliferation and are extremely aggressive. More recent data shows that the earlier very poor prognosis is markedly improved by HAART (Teruya-Feldstein 2004, Lester 2004). In a study on 89 NHL, we were able to show that a post germinal center profile, as often occurs in plasmablastic lymphomas, is independently associated with a worse prognosis (Hoffmann 2005). It is our opinion that in these patients, a more intensive treatment than CHOP should be considered. Primary effusion lymphoma (PEL): a further therapeutic problem is the relatively rare entity of the so-called primary effusion lymphoma which is also termed body cavity lymphoma (Carbone 1997, 2000). These lymphomas are often very difficult to diagnose histologically. A visible tumor mass is usually absent, so that malignant cells can only be found in body cavities (e.g. pleural, pericardial, peritoneal). There are histological similarities to immunoblastic and anaplastic cells with a non-B-, non-T phenotype. Every pleural or pericardial effusion occurring in an HIV infected patient and containing malignant cells, is suspicious of PEL. The involved pathologist should always be informed about this suspicion. There is a characteristic close association with the herpes virus HHV-8, which can be detected in the malignant cells, and which provides a relatively typical gene expression profile (Simonelli 2005, Fan 2005). Recently, a solitary variant has been reported, which is neither morphologically nor immunophenotypically distinguishable from the classical PEL types (Chadburn 2004). The response to CHOP is usually poor and poorer than that of centroblastic NHL (Simonelli 2003). Case studies with complete remission on HAART alone have been described (Boulanger 2001, Hocqueloux 2001). We have, however, seen two PEL patients who have also died of progression despite CHOP and HAART after only a few months. Recently, a combined chemotherapy with high dose methotrexate has been reported, with which, in at least 3/7 patients, a lasting complete remission could be achieved - a notable achievement in view of the otherwise poor prognosis, and an approach that should be followed up (Boulanger 2003). On the other hand, there are reports in which even intensive treatment regimens were unsuccessful (Waddington 2004). Relapse therapy, stem cell transplantation At the moment, no general recommendations for treatment of recurrent NHL can be given. The prognosis of recurrent NHL is poor overall. A team from the USA reported their positive experiences using the ESHAP protocol (etoposide, methylprednisolone, ara-C and cisplatin) - the frequently used DHAP regimen appears to have no effect in this case (Bi 2001). Salvage monotherapies with mitoguazon or liposomal daunorubicin are well tolerated, but purely palliative (Levine 1997, Tulpule 2001). It should therefore always be checked whether a patient with recurrent lymphoma qualifies in principle for an autologous stem cell transplant (ASCT). In ASCT, the intensity of the chemotherapy can be markedly increased by the preceding gain of stem cells (own cells: autologous; foreign cells: allogenic). Following the myeloablative chemotherapy, the patients are re-infused with the stem cells. Over 70 cases have been described so far worldwide (Gabarre 2000 + 2004, Re 2003, Krishnan 2005, Serrano 2005, Hoffmann 2006), including even a few allogenic SCT (Kang 2002). The critical problem in many hematological centers is above all a logistical one, namely the complicated storage of stem cells, which has to conform to strict safety regulations. The storage of potentially infectious HIV material together with stem cells from non-infected patients in the normal cooling tanks is not allowed - an extra (expensive) tank is required. References 1. Antinori A, Cingolani A, Alba L, et al. 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Distinct subsets of primary effusion lymphoma can be identified based on their cellular gene expression profile and viral association. J Virol 2005, 79:1244-51. http://amedeo.com/lit.php?id=15613351 20. Gabarre J, Azar N, Autran B, Katlama C, Leblond V. High-dose therapy and autologous haematopoietic stem-cell transplantation for HIV-1-associated lymphoma. Lancet 2000, 355:1071-2. http://amedeo.com/lit.php?id=10744095 21. Gabarre J, Marcelin AG, Azar N, et al. High-dose therapy plus autologous hematopoietic stem cell transplantation for HIV-related lymphoma: results and impact on HIV disease. Haematologica 2004, 89:1100-8. http://amedeo.com/lit.php?id=15377471 22. Gaidano G, Cerri M, Capello D, et al. Molecular histogenesis of plasmablastic lymphoma of the oral cavity. Br J Haematol 2002,; 119: 622-628. http://amedeo.com/lit.php?id=12437635 23. Goedert JJ. The epidemiology of AIDS malignancies. Semin Oncol 2000, 27:390-401. http://amedeo.com/lit.php?id=10950365 24. Hocqueloux L, Agbalika F, Oksenhendler E, Molina JM. Long-term remission of an AIDS-related primary effusion lymphoma with antiviral therapy. AIDS 2001, 15:280-2. 25. Hoffmann C, Repp R, Schoch R, et al. Successful autologous stem cell transplantation in a severely immunocompromised patient with relapsed AIDS-related B-cell Lymphoma. Eur J Med Res 2006, 11:73-6. http://amedeo.com/lit.php?id=16504964 26. Hoffmann C, Tiemann M, Schrader C, et al. AIDS-related B-cell lymphoma (ARL): correlation of prognosis with differentiation profiles assessed by immunophenotyping. Blood 2005, 106:1762-9. http://amedeo.com/lit.php?id=15905193 27. Hoffmann C, Wolf E, Wyen C, et al. AIDS-associated Burkitt or Burkitt-like lymphoma: short intensive polychemotherapy is feasible and effective.Leuk Lymphoma 2006, 47:1872-80. http://amedeo.com/lit.php?id=17065000 28. Hoffmann C, Wolf E, Fatkenheuer G, et al. Response to highly active antiretroviral therapy strongly predicts outcome in patients with AIDS-related lymphoma. AIDS 2003, 17:1521-9. http://amedeo.com/lit.php?id=12824790 29. Kang EM, de Witte M, Malech H, et al. Nonmyeloablative conditioning followed by transplantation of genetically modified HLA-matched peripheral blood progenitor cells for hematologic malignancies in patients with AIDS. Blood 2002, 99:698-701. http://amedeo.com/lit.php?id=11781257 30. Kaplan LD, Lee JY, Ambinder RF, et al. Rituximab does not improve clinical outcome in a randomized phase III trial of CHOP with or without rituximab in patients with HIV-associated non-Hodgkin's lymphoma: AIDS-malignancies consortium trial 010. Blood 2005, 106:1538-43. http://amedeo.com/lit.php?id=15914552 31. Kaplan LD, Straus DJ, Testa MA, et al. Low-dose compared with standard-dose m-BACOD chemotherapy for non-Hodgkin's lymphoma associated with HIV infection. N Engl J Med 1997, 336:1641-8. http://www. amedeo.com/lit.php?id=9171066 32. Kirk O, Pedersen C, Cozzi-Lepri A, et al. Non-Hodgkin lymphoma in HIV-infected patients in the era of HAART. Blood 2001, 98: 3406-3412. http://amedeo.com/lit.php?id=11719381 33. Krishnan A, Molina A, Zaia J, et al. Durable remissions with autologous stem cell transplantation for high risk HIV-associated lymphomas. Blood 2005, 105:874-8. http://amedeo.com/lit.php?id=15388574 34. Lehmann C, Wyen C, Hoffmann C, Fatkenheuer G. Successful administration of aggressive chemotherapy concomitant to tuberculostatic and highly active antiretroviral therapy in a patient with AIDS-related Burkitt's lymphoma. HIV Med 2005, 6:51-3. 35. Lester R, Li C, Galbraith P, et al. Improved outcome of human immunodeficiency virus-associated plasmablastic lymphoma of the oral cavity in the era of HAART: a report of two cases. Leuk Lymphoma 2004, 45:1881-5. http://amedeo.com/lit.php?id=15223650 36. Levine AM, Seneviratne L, Espina BM, et al. Evolving characteristics of AIDS-related lymphoma. Blood 2000, 96: 4084-4090. http://amedeo.com/lit.php?id=11110677 37. Levine AM, Tulpule A, Espina B, et al. Liposome-encapsulated doxorubicin in combination with standard agents (cyclophosphamide, vincristine, prednisone) in patients with newly diagnosed AIDS-related non-Hodgkin's lymphoma: results of therapy and correlates of response. J Clin Oncol 2004; 22:2662-70. http://amedeo.com/lit.php?id=15226333 38. Levine AM, Tulpule A, Tessman D, et al. Mitoguazone therapy in patients with refractory or relapsed AIDS-related lymphoma: results from a multicenter phase II trial. J Clin Oncol 1997;15:1094-103. http://amedeo.com/lit.php?id=9060550 39. Levine AM. AIDS-related lymphoma: clinical aspects. Semin Oncol 2000, 27:442-53. http://amedeo.com/lit.php?id=10950371 40. Lim ST, Karim R, Nathwani BN, AIDS-related Burkitt's lymphoma versus diffuse large-cell lymphoma in the pre-highly active antiretroviral therapy (HAART) and HAART eras: significant differences in survival with standard chemotherapy. J Clin Oncol 2005, 23:4430-8. http://amedeo.com/lit.php?id=15883411 41. Lim ST, Karim R, Tulpule A, Nathwani BN, Levine AM. Prognostic factors in HIV-related diffuse large-cell lymphoma: before versus after highly active antiretroviral therapy. J Clin Oncol 2005, 23:8477-82. http://amedeo.com/lit.php?id=16230675 42. Little RF, Gutierrez M, Jaffe ES, et al. HIV-Associated non-Hodgkin lymphoma: incidence, presentation, and prognosis. JAMA 2001, 285:1880-1885. http://amedeo.com/lit.php?id=11308402 43. Little RF, Pittaluga S, Grant N, et al. Highly effective treatment of AIDS-related lymphoma with dose-adjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology. Blood 2003, 101:4653-9. http://amedeo.com/lit.php?id=12609827 44. Matthews GV, Bower M, Mandalia S, et al. Changes in AIDS-related lymphoma since the introduction of HAART. Blood 2000, 96:2730-2734. http://amedeo.com/lit.php?id=11023505 45. Miles SA, McGratten M. Persistent panhypogammaglobulinemia after CHOP-Rituximab for HIV-related lymphoma. JCO 2005;23:247-8. 46. Mocroft A, Katlama C, Johnson AM, et al. AIDS across Europe, 1994-1998: the Eurosida study. Lancet 2000, 356:291-296. http://amedeo.com/lit.php?id=11071184 47. Navarro JT, Ribera JM, Oriol A, et al. Improved outcome of AIDS-related lymphoma in patients with virologic response to highly active antiretroviral therapy. J AIDS 2003, 32: 347-8. 48. Oriol A, Ribera JM, Esteve J, et al. Lack of influence of human immunodeficiency virus infection status in the response to therapy and survival of adult patients with mature B-cell lymphoma or leukemia. Results of the PETHEMA-LAL3/97 study. Haematologica 2003, 88:445-53. http://amedeo.com/lit.php?id=12681972 49. Pfreundschuh M, Trumper L, Kloess M, et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood 2004, 104:634-41. http://amedeo.com/lit.php?id=15016643 50. Porcu P, Caligiuri MA. AIDS-related lymphomas: future directions. Sem Oncology 2000, 4:454-62. http://amedeo.com/lit.php?id=10950372 51. Powles T, Imami N, Nelson M, Gazzard BG, Bower M. Effects of combination chemotherapy and HAART on immune parameters in HIV-1 associated lymphoma. AIDS 2002, 16:531-6. http://amedeo.com/lit.php?id=11872995 52. Ratner L, Lee J, Tang S et al. Chemotherapy for HIV-associated non-Hodgkin's lymphoma in combination with HAART. J Clin Oncol 2001, 19: 2171-8. http://amedeo.com/lit.php?id=11304769 53. Re A, Cattaneo C, Michieli M, et al. High-dose therapy and autologous peripheral-blood stem-cell transplantation as salvage treatment for HIV-associated lymphoma in patients receiving HAART. JCO 2003, 21:4423-7. http://amedeo.com/lit.php?id=14581441 54. Serrano D, Carrion R, Balsalobre P, et al. HIV-associated lymphoma successfully treated with peripheral blood stem cell transplantation. Exp Hematol 2005, 33:487-94. http://amedeo.com/lit.php?id=15781340 55. Simonelli C, Spina M, Cinelli R, et al. Clinical features and outcome of primary effusion lymphoma in HIV-infected patients: a single-institution study. J Clin Oncol 2003, 21:3948-54. http://amedeo.com/lit.php?id=14581418 56. Simonelli C, Tedeschi R, Gloghini A, et al. Characterization of immunologic and virological parameters in HIV-infected patients with primary effusion lymphoma during antiblastic therapy and highly active antiretroviral therapy. Clin Infect Dis 2005, 40:1022-7. http://amedeo.com/lit.php?id=15824995 57. Sparano JA, Lee S, Chen MG, et al. Phase II trial of infusional cyclophosphamide, doxorubicin, and etoposide in patients with HIV-associated non-Hodgkin's lymphoma: an Eastern Cooperative Oncology Group Trial (E1494). J Clin Oncol 2004, 22:1491-500. http://amedeo.com/lit.php?id=15084622 58. Spina M, Jaeger U, Sparano JA, et al. Rituximab plus infusional cyclophosphamide, doxorubicin and etoposide (R-CDE) in HIV-associated non-Hodgkin's lymphoma: pooled results from three phase II trials. Blood 2005, 105:1891-7. http://amedeo.com/lit.php?id=15550484 59. Spina M, Simonelli C, Talamini R, Tirelli U. Patients with HIV with Burkitt's lymphoma have a worse outcome than those with diffuse large-cell lymphoma also in the highly active antiretroviral therapy era. J Clin Oncol 2005, 23:8132-3. 60. Stebbing J, Gazzard B, Mandalia S, et al. Antiretroviral treatment regimens and immune parameters in the prevention of systemic AIDS-related non-Hodgkin's lymphoma. J Clin Oncol 2004, 22:2177-83. http://amedeo.com/lit.php?id=15169806 61. Stebbing J, Mandalia S, Palmieri C, Nelson M, Gazzard B, Bower M. Burkitt's lymphoma and previous AIDS-defining illnesses are not prognostic factors in AIDS-related non-Hodgkin's lymphoma. J Clin Oncol 2005, 23:8538-40. 62. Teruya-Feldstein J, Chiao E, Filippa DA, et al. CD20-negative large-cell lymphoma with plasmablastic features: a clinically heterogenous spectrum in both HIV-positive and -negative patients. Ann Oncol 2004, 15:1673-9. http://amedeo.com/lit.php?id=15520070 63. Thiessard F, Morlat P, Marimoutou C et al. Prognostic factors after non-Hodgkin lymphoma in patients infected with the HIV: Aquitaine cohort, France, 1986-1997. Cancer 2000, 88:1696-1702. http://amedeo.com/lit.php?id=10738229 64. Toffoli G, Corona G, Cattarossi G, et al. Effect of highly active antiretroviral therapy (HAART) on pharmacokinetics and pharmacodynamics of doxorubicin in patients with HIV-associated non-Hodgkin's lymphoma. Ann Oncol 2004, 15:1805-9. http://amedeo.com/lit.php?id=15550586 65. Trümper L, Möller P, Neubauer A. Non-Hodgkin-Lymphome. Lehrbuch der Klinischen Onkologie (Hrsg. Hiddemann W, Bartram C, Huber H), Springer Verlag. 66. Tulpule A, Rarick MU, Kolitz J, et al. Liposomal daunorubicin in the treatment of relapsed or refractory non-Hodgkin's lymphoma. Ann Oncol 2001;12:457-62. http://amedeo.com/lit.php?id=11398876 67. Vaccher E, Spina M, Talamini R, et al. improvement of systemic human immunodeficiency virus-related non-hodgkin lymphoma outcome in the era of highly active antiretroviral therapy. Clin Infect Dis 2003, 37: 1556-1564. http://amedeo.com/lit.php?id=14614680 68. Vilchez RA, Jorgensen JL, Kroll MH. Systemic non-Hodgkin lymphoma in HIV-infected patients in the era of highly active antiretroviral therapy. Blood 2002, 99: 4250-1. 69. Voog E, Morschhauser F, Solal-Celigny P. Neutropenia in patients treated with rituximab. N Engl J Med 2003, 348:2691-4. 70. Waddington TW, Aboulafia DM. Failure to eradicate AIDS-associated primary effusion lymphoma with high-dose chemotherapy and autologous stem cell reinfusion: case report and literature review. AIDS Patient Care STDS 2004, 18:67-73. http://amedeo.com/lit.php?id=15006181 71. Wang ES, Straus DJ, Teruya-Feldstein J, et al. Intensive chemotherapy with cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC) for HIV-associated Burkitt lymphoma. Cancer 2003, 98: 1196-205. http://amedeo.com/lit.php?id=12973843 72. Ziegler JL, Drew WL, Miner RC, et al. Outbreak of Burkitt's-like lymphoma in homosexual men. Lancet 1982, 2:631-3. http://amedeo.com/lit.php?id=6125777 Primary CNS lymphoma Primary CNS lymphomas (PCNSL) are a late complication of HIV infection and used to occur in up to 10 % of AIDS patients. The incidence of PCNSL has decreased significantly in the last years in comparison to systemic lymphomas. PCNSL are EBV-associated in almost 100 % of cases (Camilleri-Broet 1997), and histologically are mainly diffuse, large-cell non-Hodgkin's lymphomas. The CD4 cells are almost always below 50/µl at the time of diagnosis. In the pre-HAART era, PCNSL had the poorest prognosis of all the AIDS-defining illnesses, with a median survival of less than three months (Fine and Maher 1993). In the last years, this bleak picture, often characterized by therapeutic nihilism, has changed significantly. In the HAART-era, survival may be several years and even complete remissions have become possible (Hoffmann 2001). Signs and symptoms Different neurological deficits occur depending on the localization and the size. Epileptic seizures may be the first manifestation of disease. Personality changes, changes in vigilance, headache and focal deficits such as paresis are also frequent. Fever is usually absent. However, as patients are almost always severely immunocompromised, constitutional symptoms may mask the actual problem. Diagnosis Cranial CT or (better) MRT scan should be performed rapidly. The usually single masses absorb contrast medium, show a small to moderate edema, and often take up very little room. The most important differential diagnosis is cerebral toxoplasmosis. A solitary mass with a small edema is usually more indicative of PCNSL. However, 2-4 lesions may be present, which are usually fairly large (more than 2 cm in diameter). More than four lesions of a PCNSL are rarely found. In addition to an updated toxoplasmosis serology, which - if negative - makes toxoplasmosis rather unlikely, a recent CD4 cell count should be available. The better the immune status, the less likely the diagnosis of PCNSL. In our own cohort, less than 20 % of patients had more than 50 CD4 cells/µl at the time of diagnosis. At over 100 cells/µl, however, cerebral toxoplasmosis is also less likely. In addition to the physical examination, a minimal diagnostic program (chest radiography, abdominal ultrasound) should clarify whether the CNS involvement is secondary to systemic lymphoma. This should always include fundoscopy to exclude ocular involvement (up to 20 %). Besides cerebral toxoplasmosis, differential diagnoses include abscesses, glioblastoma and cerebral metastasis of solid tumors. In the absence of increased intracranial pressure, lumbar puncture is advised in order to detect malignant cells. With a positive EBV-PCR of CSF, the suspicion of PCNSL becomes more likely. In such cases, cerebral lymphomatous granulomatosis has to be considered, which shows a very complex picture on MRT (Wyen 2006, Patsalides 2006). In most cases, a treatment attempt for toxoplasmosis can be made initially, without steroids wherever possible. If this is unsuccessful, PCNSL is more likely. In such cases, stereotactic brain biopsy is essential to secure the diagnosis. This, however, only makes sense if steroids have not been given previously - even low doses of steroids make histopathological diagnosis impossible. Treatment For many years, cranial radiation therapy has been the only option for patients with PCNSL, independent of the HIV status. In HIV-negative patients, using the combination of radiation therapy and steroids, a remission of 12-18 months duration is usually achieved. In HIV patients in the pre-HAART era, radiation only improved survival from 0.9 to 3.0 months (Fine 1993). Survival of more than one year was rare. The prognosis for HIV-negative patients has improved in the last years due to the combination of methotrexate-based (MTX) chemotherapies and radiation. Smaller studies have indicated that monotherapy with high doses of MTX is effective, thereby reserving radiation therapy for relapses (De Angelis 2001). Whether this is also applicable in HIV infected patients is not clear. In addition, the incidence of HIV-associated PCNSL is now diminishing to such an extent that no prospective studies are expected in the forseeable future. A clear recommendation for treatment can therefore not be made. Some clinicians still favor cranial radiation therapy alone in HIV infected patients (fractionated, 40 Gy total dose). In our experience, a treatment attempt with intravenous MTX is justified (3 g/m2 every 14 days with leucovorin rescue) - in order to avoid possible neurological damage from radiation. A small study in HIV infected patients has shown that this approach is practical (Jacomet 1997). However, the decisive factor always - independent of the specific therapy chosen - is the best possible immune reconstitution. Under HAART, survival of several years has become realistic. Complete remissions have even been described after treatment with HAART alone (McGowan 1998, Corales 2000). In our own cohort of 29 patients with histologically diagnosed PCNSL, all four patients who experienced an increase in CD4 T cells survived longer than 18 months. Three out of four patients reached complete remission. One patient has now lived for over six years without evidence of relapse (Hoffmann 2001). In a multivariate analysis, HAART was shown to be the only factor associated with a prolonged survival in addition to cranial radiation therapy. Two of these patients, however, died after about three years of a progressive neurological syndrome, which was probably a long-term sequela of radiation therapy in both cases. In view of the better prognosis for patients today, radiation toxicity should therefore be considered more than in the past. Three further studies from France, the USA and Australia have since shown a survival of several years due to HAART (Rigolet 2001, Skiest 2003, Newell 2004). All patients with PCNSL should therefore be treated intensively with HAART, to achieve the best possible immune reconstitution. If only a moderate immune reconstitution is possible, additional immunomodulatory or antiviral therapies should be evaluated. The partially positive reports about ganciclovir and interleukin-2 (Raez 1999, Aboulafia 2002) or hydroxyurea (Slobod 2000) should, however, be interpreted with care. "Between the lines" of these publications, in which either individual or hardly more than 2-4 patients were described, HAART was almost always a factor. With signs of raised intracranial pressure, rapid administration of steroids (e.g. dexamethasone 8 mg tid, decreasing the dose rapidly after resolution of edema) is indicated, even if diagnostic testing is more difficult as a result. References 1. Aboulafia DM. Interleukin-2, ganciclovir, and high-dose zidovudine for the treatment of AIDS-associated primary central nervous system lymphoma. Clin Infect Dis 2002, 34: 1660-2. 2. Camilleri-Broet S, Davi F, Feuillard J, et al. AIDS-related primary brain lymphomas: histopathologic and immunohistochemical study of 51 cases. Hum Pathol 1997, 28:367-74. http://amedeo.com/lit.php?id=9042803 3. Corales R, Taege A, Rehm S, Schmitt S. Regression of AIDS-related CNS Lymphoma with HAART. XIII International AIDS-Conference, Durban, South Africa, 2000, Abstract MoPpB1086. 4. DeAngelis LM. Primary central nervous system lymphomas. Curr Treat Options Oncol. 2001, 2:309-18. http://amedeo.com/lit.php?id=12057111 5. Fine HA, Mayer RJ. Primary central nervous lymphoma. Ann Intern Med 1993, 119:1093-1104. http://amedeo.com/lit.php?id=8239229 6. Hoffmann C, Tabrizian S, Wolf E et al. Survival of AIDS patients with primary central nervous system lymphoma is dramatically improved by HAART-induced immune recovery. AIDS 2001, 15:2119-2127. http://amedeo.com/lit.php?id=11684931 7. Jacomet C, Girard PM, Lebrette MG, Farese VL, Monfort L, Rozenbaum W. Intravenous methotrexate for primary central nervous system non-Hodgkin's lymphoma in AIDS. AIDS 1997, 11:1725-30. http://amedeo.com/lit.php?id=9386807 8. Levine AM. AIDS-related lymphoma: clinical aspects. Semin Oncol 2000, 27:442-53. http://amedeo.com/lit.php?id=10950371 9. McGowan JP, Shah S. Long-term remission of AIDS-related PCNSL associated with HAART. AIDS 1998, 952-954. 10. Newell ME, Hoy JF, Cooper SG, et al. Human immunodeficiency virus-related primary central nervous system lymphoma: factors influencing survival in 111 patients. Cancer 2004, 100:2627-36. http://amedeo.com/lit.php?id=15197806 11. Patsalides AD, Atac G, Hedge U, et al. Lymphomatoid granulomatosis: abnormalities of the brain at MR imaging. Radiology 2005, 237:265-73. http://amedeo.com/lit.php?id=16100084 12. Raez L, Cabral L, Cai JP, et al. Treatment of AIDS-related primary central nervous system lymphoma with zidovudine, ganciclovir, and interleukin 2. AIDS Res Hum Retroviruses 1999, 15:713-9. http://amedeo.com/lit.php?id=10357467 13. Rigolet A, Bossi P, Caumes E, et al. Epidemiological features and incidence trends of primary cerebral lymphomas observed in 80 HIV-infected patients from 1983 to 1999. Pathol Biol (Paris) 2001, 49:572-5. http://amedeo.com/lit.php?id=11642021 14. Skiest DJ, Crosby C. Survival is prolonged by highly active antiretroviral therapy in AIDS atients with primary central nervous system lymphoma. AIDS 2003, 17:1787-93. http://amedeo.com/lit.php?id=12891064 15. Slobod KS, Taylor GH, Sandlund JT, Furth P, Helton KJ, Sixbey JW. Epstein-Barr virus-targeted therapy for AIDS-related primary lymphoma of the central nervous system. Lancet 2000, 356:1493-94. 16. Wyen C, Stenzel W, Hoffmann C, Lehmann C, Deckert M, Fatkenheuer G. Fatal cerebral lymphomatoid granulomatosis in an HIV-1-infected patient. J Infect. 2006 Dec 11. http://amedeo.com/lit.php?id=17169433 Hodgkin's disease (HD) The incidence of HD is elevated in HIV infected patients by a factor of 5-10 compared to the HIV-negative population. For particular subtypes of HD, such as lymphocyte-depleted and mixed-cellularity HD, the relative risk is presumably much higher (Frisch 2001). Despite this and the growing realization that these subtypes at least are clearly associated with immunodeficiency, HIV-HD is not considered as an AIDS-defining illness. HAART does not appear to reduce the incidence of HD. On the contrary: it seems to be increasing (Biggar 2006, Engels 2006). In our experience, the patients that develop HD frequently have a well-suppressed viral load and good immune status. The reasons for it are still unclear. An advanced stage of disease at diagnosis is typical for HIV-HD, as is frequent extranodal involvement and a trend towards prognostically poorer subtypes (Tirelli 1995, Rapezzi 2001, Thompson 2004). Mediastinal disease is less frequent than in HIV-negative patients. A further difference to HD in seronegative patients is the predominance of cases with Reed-Sternberg cells, as well as the clear association with EBV infection, which is 80-100 %, and is an important etiologic factor for development of HIV-HD. In comparison to HIV negative HD, which is one of the most highly treatable tumors overall, the prognosis of HIV-HD in the pre-HAART era was poor with a median survival of only 15-20 months (Andrieu 1993, Errante 1999, Levine 2000, Tirelli 1995). The response to chemotherapy was also moderate. Complete remission rates were between 40-80 %, and hematological and infectious complications were frequent. Even if there is much evidence to support that this is changing in the era of HAART, as with NHL, there is little data so far. In our own cohort of 56 patients, the median survival was 40 months. In patients with adequate HAART, the two-year survival rate was 84 %, which is encouraging (Hoffmann 2004). Other groups have also reported better prognoses with HAART (Ribera 2002, Gérard 2003). Signs and symptoms B symptoms occur in the majority of cases. Extranodal and advanced stages are also frequent. Lymphomas are firm, immobile or hardly mobile and painless, and clinical distinction from HIV lymphadenopathy or tuberculous lymphadenitis is not possible. Diagnosis Staging is necessary as for non-Hodgkin lymphoma (see NHL section). Diagnostic lymph node extirpation is even more important here than with NHL, as puncture only rarely allows diagnosis of Hodgkin's disease. Single accurate diagnostics are better than half-heartedly bothering the patient with repeated punctures and losing time unnecessarily! Extirpation is usually possible as an outpatient. As with NHL, specimens should be sent to reference laboratories if possible. Since bleomycin will be administered, a lung function test should always precede the first chemotherapy. Treatment As for HIV-negative HD, treatment should depend on the Ann-Arbor staging and possible risk factors such as extranodal involvement, more than three affected lymph nodes or a large mediastinal tumor. Thus the distinction can be made between limited (I-II without risk factors), intermediary (I-II with risk factors), and advanced (III-IV) stages. The classical ABVD regimen (four double cycles) with follow-up radiotherapy is recommended for limited or intermediary stages. ABVD is the abbreviation for the combination chemotherapy with the cytostatics adriamycin, bleomycin, vinblastine and DTIC (dacarbazine). Ambulatory treatment is possible. Table 4: ABVD regimen (4 double cycles, repeat on Day 29)* Adriamycin (= doxorubicin) Doxo-CellÔ, Adriblastin™ 25 mg/m2 i.v. Day 1 + 15 Bleomycin Bleomycin™, Bleo-Cell™ 10 mg/m2 i.v. Day 1 + 15 Vinblastine Velbe™, Vinblastin Hexal™ 6 mg/m2 i.v. Day 1 + 15 Dacarbazine (DTIC) Detimedac™ 375 mg/m2 i.v. Day 1 + 15 *ABVD regimen. Due to strong emetogenicity of dacarbazine, 5HT3-receptor blocker anti-eme-tics should always be administered, e.g. granisetron (Kevatril™), or ondansetron (Zofran™). In HIV negative patients with advanced stages (as is often the case for HIV-HD) the escalating BEACOPP regimen of the German Hodgkin Study Group has been used in the last years. This has proven to be significantly more effective, both with regard to response rates and long-term survival. But, the BEACOPP regimen is more toxic, and whether these positive results can be seen in HIV-HD is still not clear. However, based on initial reports and our experience, BEACOPP seems to be possible (Hartmann 2003). There is also growing experience to date with the Stanford V protocol, for which there have recently been promising reports (Spina 2002). Patients are preferably treated within a prospective study. A stage-adapted protocol has been developed for Germany (Study leader: Dr. M. Hentrich, Munich; information via hiv.net). References 1. Andrieu JM, Roithmann S, Tourani JM, et al. Hodgkin's disease during HIV-1 infection: the French registry experience. French Registry of HIV-associated Tumors. Ann Oncol 1993, 4:635-41. http://amedeo.com/lit.php?id=8240994 2. Biggar RJ, Jaffe ES, Goedert JJ, et al. Hodgkin lymphoma and immunodeficiency in persons with HIV/AIDS. Blood 2006, 108:3786-91. 3. Engels EA, Pfeiffer RM, Goedert JJ, et al. Trends in cancer risk among people with AIDS in the United States 1980-2002. AIDS 2006, 20:1645-54. http://amedeo.com/lit.php?id=16868446 4. Errante D, Gabarre J, Ridolfo AL, et al. Hodgkin's disease in 35 patients with HIV infection: an experience with epirubicin, bleomycin, vinblastine and prednisone chemotherapy in combination with antiretroviral therapy and primary use of G-CSF. Ann Oncol 1999, 10:189-95. http://amedeo.com/lit.php?id=10093688 5. Frisch M, Biggar R, et al. Association of Cancer with AIDS-related immunosuppression in Adults. JAMA 2001, 1736-1745. http://amedeo.com/lit.php?id=11277828 6. Gérard L, Galicier L, Boulanger E, et al. Improved survival in HIV-related Hodgkin's lymphoma since the introduction of highly active antiretroviral therapy. AIDS 2003;17:81-7. http://amedeo.com/lit.php?id=12478072 7. Hartmann P, Rehwald U, Salzberger B, Franzen C, Sieber M, Wohrmann A, Diehl V. BEACOPP therapeutic regimen for patients with Hodgkin's disease and HIV infection. Ann Oncol 2003;14:1562-9. http://amedeo.com/lit.php?id=14504059 8. Hoffmann C, Chow KU, Wolf E, et al. HIV-associated Hodgkin's Disease in the era of HAART - is there an improvement in survival? Abstract 504, DGHO München 2002. 9. Levine AM, Li P, Cheung T, et al. Chemotherapy consisting of doxorubicin, bleomycin, vinblastine, and dacarbazine with granulocyte-colony-stimulating factor in HIV-infected patients with newly diagnosed Hodgkin's disease: a prospective, multi-institutional AIDS clinical trials group study (ACTG 149). JAIDS 2000, 24:444-50. http://amedeo.com/lit.php?id=11035615 10. Powles T, Bower M. HIV-associated Hodgkin's disease. Int J STD AIDS 2000, 11:492-4. http://amedeo.com/lit.php?id=10990330 11. Rapezzi D, Ugolini D, Ferraris AM, Racchi O, Gaetani GF. Histological subtypes of Hodgkin's disease in the setting of HIV infection. Ann Hematol 2001, 80:340-4. http://amedeo.com/lit.php?id=11475147 12. Re A, Casari S, Cattaneo C, et al. Hodgkin disease developing in patients infected by HIV results in clinical features and a prognosis similar to those in patients with HIV-related non-Hodgkin lymphoma. Cancer 2001, 92:2739-45. http://amedeo.com/lit.php?id=11753946 13. Ribera JM, Navarro JT, Oriol A, et al. Prognostic impact of highly active antiretroviral therapy in HIV- related Hodgkin's disease. AIDS 2002, 16: 1973-6. 14. Spina M, Gabarre J, Rossi G, et al. Stanford V regimen and concomitant HAART in 59 patients with Hodgkin disease and HIV infection. Blood 2002, 100:1984-8. http://amedeo.com/lit.php?id=12200356 15. Spina M, Vaccher E, Nasti G, Tirelli U. HIV-associated Hodgkin's disease. Semin Oncol 2000, 27:480-8. http://amedeo.com/lit.php?id=10950375 16. Thompson LD, Fisher SI, Chu WS, Nelson A, Abbondanzo SL. HIV-associated Hodgkin lymphoma: a clinicopathologic and immunophenotypic study of 45 cases. Am J Clin Pathol. 2004, 121:727-38. http://amedeo.com/lit.php?id=15151213 17. Tirelli U, Errante D, Dolcetti R, et al. Hodgkin's disease and HIV infection: clinicopathologic and virologic features of 114 patients from the Italian Cooperative Group on AIDS and Tumors. J Clin Oncol 1995, 13:1758-67. http://amedeo.com/lit.php?id=7541452 Multicentric Castleman's Disease (MCD) Although rare, multicentric Castleman's disease (MCD) is a highly problematic illness for those affected - not only due to the (in HIV infection) rather poor prognosis, but also because many clinicians and pathologists are not very familiar with this entity. It is not rare for the usually severely ill patients, who experience the disease in impulses, to be subjected to long diagnostic procedures. In comparison to the benign, localized hyperplasia of lymphatic tissue, first described by the American pathologist Benjamin Castleman in 1956, HIV-associated MCD, although neither a lymphoma nor AIDS-defining illness, is a malignant lymphoproliferative disease. In the pre-HAART era, the median survival time was just 14 months (Oksenhendler 1996). The pathogenesis of MCD is not well understood. There is an almost obligatory association to HHV-8, and approximately half of the patients have Kaposi's sarcoma. Cytokine dysregulation, possibly due to viral interleukins, seems to be crucial. In particular IL-6 and IL-10 are elevated with close association to the HHV-8 viral load (Oksenhendler 2000). The extent of CD4 cell depletion varies significantly - we have seen patients with a normal immune status and low HIV plasma viremia. "Progression" to malignant lymphoma (often HHV-8-associated subtypes such as primary effusion lymphoma) is frequent. Out of 60 MCD cases, 14 patients developed malignant lymphoma after a median observation period of 20 months (Oksenhendler 2002). Signs and symptoms The main signs are the often impressive lymph node enlargements, which can be soft (as in tuberculosis) to rock hard (as in lymphoma) on palpation. These are almost always combined with considerable B symptoms including fever, night sweats and weight loss. Almost all patients complain of weakness and significant malaise. There is always massive splenomegaly. Hepatomegaly (70 %), respiratory symptoms (65 %) and edema with hypoalbuminemia (55 %) are also seen in the majority of cases. The illness typically proceeds in impulses, which can last for a few days to weeks and during which patients have a high fever and are very ill. These impulses are interrupted by long phases, sometimes lasting for several months, in which the patients feel relatively well. Without any intervention, the lymph nodes can return to normal. With prolonged duration of the illness, the acute phases become more frequent. Diagnosis Ultrasound reveals hepatosplenomegaly. Laboratory tests show elevated CRP, hypergammaglobulinemia and hypoalbuminemia. There is often significant anemia (may be hemolytic, often reflecting pancytopenia). The diagnosis is made histologically from an extirpated lymph node - providing that the pathologist knows what HIV-associated multicentric Castleman's disease looks like. The germinal centers of the lymph nodes are layered like an onion and have vessels running through them. Hyaline-vascular and plasma cell types of Castleman's disease can be distinguished. Clinicians should explicitly indicate their suspicion. It is possible that many cases are never correctly diagnosed. In the presence of an impulsive course of disease with B symptoms, splenomegaly, high CRP, and fluctuating lymph node swellings, the pathological diagnosis of HIV-associated lymphadenopathy should not be simply accepted. HIV infection alone never causes illness as severe as MCD! Treatment At present, there is no clear recommendation for a specific treatment for MCD. HAART should be given whenever possible, although it doesn't always help (Dupin 1997, Lanzafame 2000, Aaron 2002, de Jong 2003, Sprinz 2004). Some cases have even been described to occur or worsen after starting HAART, leading to the suspicion that the inflammatory component of MCD may be increased by immune reconstitution (Zietz 1999). Apart from HAART, there are many diverse forms of therapy, which unfortunately means that so far none of them is particularly convincing. The problem lies also within the countless case reports, where a probable positive "publication bias" has to be taken into account. On the other hand, something has to be done quickly in HIV infected patients with MCD: the course of disease can be fulminant. In our experience, CRP is a useful parameter aside from symptoms and signs, for measuring the course of disease and observing the success of MCD treatment. Virostatics - because of the association with HHV-8, several antiviral substances have been tried, including ganciclovir, which was successful on at least one patient (Caspar 2004). We have observed improvement in two patients on valganciclovir. In contrast, the use of foscarnet or cidofovir had no benefit (Coty 2003, Senanayake 2003, Berezne 2004). Chemotherapies - well-tolerated drugs such as vincristine (2 mg i.v. as a bolus at 14-day intervals), vinblastin, or oral etoposide (50 mg daily) have proven effective according to several reports as well as our own experience (Scott 2001, Kotb 2006). Even CHOP chemotherapy can help, but does not seem to significantly prolong survival. Rituximab: this monoclonal antibody against CD20-expressing cells, which is also used in B cell lymphomas (see above), has been successfully tried in several patients (Corbellino 2001, Marcelin 2003, Casquero 2006). In a French study, 16 to 24 patients achieved a complete remission after one year and four courses of rituximab (Gèrard 2006). The overall survival after one year was approximately 92 %; for disease free survival, the rate was 74 %. The mode of action is not clear, but is probably due to the fact that HHV-8 primarily infects the B cells coating the lymph node. These B cells are eliminated by rituximab. It should be noted that an accompanying Kaposi's sarcoma can progress on rituximab. Other immunotherapies: positive as well as negative cases exist for interferon (Coty 2003, Nord 2003). From Japan, there are data on seven HIV-negative patients, who were treated successfully with IL-6 receptor antibody (Nishimoto 2000). Thalidomide is a new approach, which suppresses cytokine dysregulation or the inflammatory component, and for which case studies are available (Lee 2003, Jung 2004). In contrast, steroids have no effect on MCD. Splenectomy - may be appropriate in severe cases. In 40 patients, the median survival following splenectomy was 28 versus 12 months (Oksenhendler 2002). According to a US team, the symptoms were improved in 10/10 patients following splenectomy (Coty 2003). 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