1 MRI scan showing frontal PCNSL in a person living with HIV (PLWH) 

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... are the most common AIDS-related lymphomas and occur in both HIV- infected and HIV-uninfected individuals. In patients with HIV infection, DLBCLs were originally divided based on cellular morphology into centroblastic ( Fig. 1.1a ) and immunoblastic ( Fig. 1.1b ) categories and based on location into systemic and primary central nervous system lymphomas (CNS). The immunoblastic type is mostly seen in people with AIDS and is more frequently associated with EBV infec- tion, with reported rates of positivity by this virus as high as 80-90 % [ 17 ]. Immunoblastic lymphomas have also been shown to frequently have an unrestricted EBV latency (type III) [ 17 , 105 ]. This subtype includes most AIDS-related primary CNS lymphomas. However, immunoblastic lymphomas are less frequently seen in the era of CART, at least in the US and Europe, as this type of DLBCL occurs in the context of severe immunodefi ciency, because the EBV proteins expressed in these tumors are not only oncogenic but also immunogenic [ 20 , 75 ]. EBV is most com- monly detected in diagnostic pathology laboratories using in situ hybridization for EBERs ( Fig. 1.1c ), which are abundantly expressed, noncoding viral RNAs. Cases with centroblastic morphology occur regardless of HIV infection. These lympho- mas are subdivided into germinal center and non-germinal center subtypes (non-GC or ABC) in both HIV-positive and HIV-negative patient populations. However, in people with AIDS, the clinical signifi cance of this subclassifi cation is more contro- versial and may be dependent of treatment [ 23 , 25 , 40 ]. DLBCLs in patients with E. Cesarman and A. ...

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... are the most common AIDS-related lymphomas and occur in both HIV- infected and HIV-uninfected individuals. In patients with HIV infection, DLBCLs were originally divided based on cellular morphology into centroblastic ( Fig. 1.1a ) and immunoblastic ( Fig. 1.1b ) categories and based on location into systemic and primary central nervous system lymphomas (CNS). The immunoblastic type is mostly seen in people with AIDS and is more frequently associated with EBV infec- tion, with reported rates of positivity by this virus as high as 80-90 % [ 17 ]. Immunoblastic lymphomas have also been shown to frequently have an unrestricted EBV latency (type III) [ 17 , 105 ]. This subtype includes most AIDS-related primary CNS lymphomas. However, immunoblastic lymphomas are less frequently seen in the era of CART, at least in the US and Europe, as this type of DLBCL occurs in the context of severe immunodefi ciency, because the EBV proteins expressed in these tumors are not only oncogenic but also immunogenic [ 20 , 75 ]. EBV is most com- monly detected in diagnostic pathology laboratories using in situ hybridization for EBERs ( Fig. 1.1c ), which are abundantly expressed, noncoding viral RNAs. Cases with centroblastic morphology occur regardless of HIV infection. These lympho- mas are subdivided into germinal center and non-germinal center subtypes (non-GC or ABC) in both HIV-positive and HIV-negative patient populations. However, in people with AIDS, the clinical signifi cance of this subclassifi cation is more contro- versial and may be dependent of treatment [ 23 , 25 , 40 ]. DLBCLs in patients with E. Cesarman and A. ...

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... are the most common AIDS-related lymphomas and occur in both HIV- infected and HIV-uninfected individuals. In patients with HIV infection, DLBCLs were originally divided based on cellular morphology into centroblastic ( Fig. 1.1a ) and immunoblastic ( Fig. 1.1b ) categories and based on location into systemic and primary central nervous system lymphomas (CNS). The immunoblastic type is mostly seen in people with AIDS and is more frequently associated with EBV infec- tion, with reported rates of positivity by this virus as high as 80-90 % [ 17 ]. Immunoblastic lymphomas have also been shown to frequently have an unrestricted EBV latency (type III) [ 17 , 105 ]. This subtype includes most AIDS-related primary CNS lymphomas. However, immunoblastic lymphomas are less frequently seen in the era of CART, at least in the US and Europe, as this type of DLBCL occurs in the context of severe immunodefi ciency, because the EBV proteins expressed in these tumors are not only oncogenic but also immunogenic [ 20 , 75 ]. EBV is most com- monly detected in diagnostic pathology laboratories using in situ hybridization for EBERs ( Fig. 1.1c ), which are abundantly expressed, noncoding viral RNAs. Cases with centroblastic morphology occur regardless of HIV infection. These lympho- mas are subdivided into germinal center and non-germinal center subtypes (non-GC or ABC) in both HIV-positive and HIV-negative patient populations. However, in people with AIDS, the clinical signifi cance of this subclassifi cation is more contro- versial and may be dependent of treatment [ 23 , 25 , 40 ]. DLBCLs in patients with E. Cesarman and A. ...

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... HIV itself appears not directly implicated in lymphomagenesis, the virus indirectly creates an environment in which chronic antigen stimulation, cyto- kine dysregulation, and coinfection with oncogenic viruses, such as the Epstein- Barr virus (EBV), in the background of genetic abnormalities and impaired immunity, can lead to the emergence of monoclonal B cells (Fig. 3.1 ) [ 2 , 21 ]. Particularly impaired T-cell immunity toward EBV, a ubiquitous gamma herpes virus, is strongly implicated in lymphomagenesis of the immunoblastic variant of DLBCL, which occurs generally in the more immunosuppressed host compared to the centroblastic variant of DLBCL [ 22 , 23 ]. While EBV is identifi ed in neoplastic S.K. Barta et al. pan_papas@yahoo.com [ 2 , 20 , 24 , 25 ]. The immunoblastic immunophenotype is furthermore characterized by plasmacytoid features with upregulation of plasma cell markers and downregulation of mature B-cell markers [ 26 , 27 ]. Generally it is thought that immunoblastic DLBCL carries S.K. Barta et al. pan_papas@yahoo.com a poorer prognosis, but whether this is related to the more immunosuppressed host or lymphoma-specifi c features remains unclear [ 28 ...

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... epidemiologic subtypes of BL are recognized: endemic, sporadic, and AIDS related. The typical histological appearance of BL is the presence of cohesive sheets of malignant cells that are small to intermediate in size and contain moderately abundant basophilic cytoplasm and round, regular nuclei possessing two to fi ve distinct nucleoli. The presence of abundant mitotic fi gures, and numerous, evenly distributed tingible body macrophages with abundant clear cytoplasm are character- istic and have led to a description of BL having a "starry-sky" appearance ( Fig. 1.2 ). However, BL occurring in individuals with AIDS may have atypical features, such as some cases showing plasmacytoid differentiation and others exhibiting greater nuclear polymorphism [ 103 ]. The immunophenotype of BL includes positivity for B-cell antigens, CD10, and BCL6 and negativity or only weak positivity for BCL2. Ki67 immunohistochemistry will be positive in >95 % of the tumor cells, as BL is one of the fastest growing tumors in ...

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... is a rare lymphoma subtype, accounting for less than 5 % of all HIV-related NHLs. It can also occur in individuals without HIV infection but is extremely rare in this latter context. PEL is characterized by the presence of KSHV (also called HHV-8) within the tumor cells, and this virological association is considered a diag- nostic criterion [ 21 , 88 , 103 ]. It presents most commonly as a lymphomatous effu- sion involving one or more of the pleural, peritoneal, and pericardial spaces. However, about one third of the cases can show dissemination to extracavitary sites. Some rare cases of AIDS-related NHL are associated with KSHV infection but without evidence of body cavity involvement. These have been designated solid or extracavitary PEL and represent approximately 5 % of all AIDS-NHLs. They typi- cally have the morphology of DLBCL, frequently with immunoblastic features, but like PELs, they frequently lack of expression of B-cell antigens and are commonly co-infected with EBV [ 24 ]. In addition to the presence of KSHV, the vast majority of PEL cases are co- infected with EBV. While PEL is a tumor of B-cell origin, it is characterized by the lack of expression of B-cell-associated antigens and immunoglobulins (Ig). This lack of B-cell antigens in a neoplastic cell of B-cell origin is not unique to PEL and can be seen in other B-cell malignancies, such as the Reed-Sternberg cells of CHL. Morphologically, it is composed of large tumor cells, with features that can be immunoblastic or anaplastic. However, the lack of B-cell antigen expression can make these diffi cult to identify by immunohistochemistry, and a tumor other than lymphoma may be suspected ( Fig. 1.3 ), particularly since PELs are often positive for antigens such as CD138 and EMA (epithelial membrane antigen), which can be seen in other entities including plasma cell myeloma and some carcinomas. The presence of KSHV is most easily assessed by immunohistochemistry for the KSHV nuclear antigen LANA (encoded by ORF73), which is commercially available ( Fig. 1.3 ...

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... is a rare lymphoma subtype, accounting for less than 5 % of all HIV-related NHLs. It can also occur in individuals without HIV infection but is extremely rare in this latter context. PEL is characterized by the presence of KSHV (also called HHV-8) within the tumor cells, and this virological association is considered a diag- nostic criterion [ 21 , 88 , 103 ]. It presents most commonly as a lymphomatous effu- sion involving one or more of the pleural, peritoneal, and pericardial spaces. However, about one third of the cases can show dissemination to extracavitary sites. Some rare cases of AIDS-related NHL are associated with KSHV infection but without evidence of body cavity involvement. These have been designated solid or extracavitary PEL and represent approximately 5 % of all AIDS-NHLs. They typi- cally have the morphology of DLBCL, frequently with immunoblastic features, but like PELs, they frequently lack of expression of B-cell antigens and are commonly co-infected with EBV [ 24 ]. In addition to the presence of KSHV, the vast majority of PEL cases are co- infected with EBV. While PEL is a tumor of B-cell origin, it is characterized by the lack of expression of B-cell-associated antigens and immunoglobulins (Ig). This lack of B-cell antigens in a neoplastic cell of B-cell origin is not unique to PEL and can be seen in other B-cell malignancies, such as the Reed-Sternberg cells of CHL. Morphologically, it is composed of large tumor cells, with features that can be immunoblastic or anaplastic. However, the lack of B-cell antigen expression can make these diffi cult to identify by immunohistochemistry, and a tumor other than lymphoma may be suspected ( Fig. 1.3 ), particularly since PELs are often positive for antigens such as CD138 and EMA (epithelial membrane antigen), which can be seen in other entities including plasma cell myeloma and some carcinomas. The presence of KSHV is most easily assessed by immunohistochemistry for the KSHV nuclear antigen LANA (encoded by ORF73), which is commercially available ( Fig. 1.3 ...

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... most common causes of cerebral mass lesions in PLWH are toxoplasmosis and primary cerebral lymphoma, and the differential diagnosis often proves diffi cult [ 19 ]. Both diagnoses occur in the context of advanced immunodefi ciency and pres- ent with headaches and focal neurological defi cits. The features that favour PCNSL include a more gradual onset of symptoms over 2-8 weeks and the absence of a fever. CT and MRI scanning usually show solitary or multiple ring-enhancing lesions with prominent mass effect and oedema ( Fig. 7.1 ). Again these fi ndings occur in both diagnoses although PCNSL lesions are frequently periventricular, whilst toxoplasmosis more often affects the basal ganglia [ 20 -23 ]. Hence, clinical fi ndings and standard radiological investigations, whilst suggestive, cannot provide a defi nitive diagnosis (see Table 7.1 ). Moreover, toxoplasma serology (IgG) is falsely negative in 10-15 % of patients with cerebral toxoplasmosis. Over 85 % patients with cerebral toxoplasmosis will respond clinically and radiologically to 2 weeks of anti-toxoplasma ...

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... epidemiologic studies in the United States and Italy do not indicate an increased standard incidence rate (SIR) of AML in HIV-infected persons, studies from France showed that the risk of AML in HIV-positive patients is twice that of the general population [ 43 , 102 , 121 ]. Acute myeloid leukemia can occur in patients of any HIV-risk group including sexually transmitted, transfusion-related, and drug use-risk groups and at any stage of HIV disease [ 2 , 61 ]. AML can develop at any age in HIV-positive patients, including children; however, the mean and median age at diagnosis is approximately 40 years [ 2 , 44 , 61 , 119 , 121 , 128 ]. Although many of the cases are classifi ed as acute myeloid leukemia, not otherwise specifi ed, cases of acute myeloid leukemia from all categories in the 2008 WHO classifi cation, including cases of acute myeloid leukemia with recur- rent genetic abnormalities, such as t(8;21), t(15;17), inv(16)(p13.1q22), and t(3;3), acute myeloid leukemia with myelodysplasia-related changes, and ther- apy-related myeloid neoplasms have been described ( Fig. 1.7 ) [ 2 , 10 , 44 , 61 , 82 , 121 ]. There appears, however, to be relatively large number of cases which are classifi ed morphologically as acute myeloid leukemia with maturation (FAB M2) and acute myelomonocytic leukemia (FAB M4), with or without the associated genetic alterations of t(8;21) and inv(16) [ 2 , 61 , 121 ]. Cases of myeloid sarcoma have also been reported [ 32 , 81 , 107 ]. The majority of the HIV-positive patients with AML who are treated with induc- tion chemotherapy go into clinical remission, but many subsequently relapse. Although in general the prognosis for HIV-positive AML patients is poor, long-term clinical remissions (approximately 10 years) have been reported in the literature. As with diffuse large B-cell lymphoma, the level of immunosuppression as refl ected by the CD4 count appears to be an important prognostic indicator. Patients with CD4 counts less than 200/dL have much shorter survival times than those with a CD4 count greater than 200/dL at diagnosis [ 2 , 44 , 121 ]. In addition, AMLs with an unfavorable karyotype are associated with a worse prognosis [ 44 ...

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... French-American-British (FAB) classifi cation system divides AML into eight subtypes, M0 through to M7, based on the type of cell from which the leuke- mia developed and its degree of maturity (Table 10.2 ). This is done by examining the appearance of the malignant cells with light microscopy and/or by using cytoge- netics to characterize any underlying chromosomal abnormalities (see Fig. 10.1a-d ). ...

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... is a very aggressive malignancy that was fi rst reported in the oral cavity of HIV-infected individuals [ 37 ] but subsequently was shown to occur in other sites, as well as in conjunction with other immunodefi cient states [ 31 ]. This lymphoma sub- type seems to be particularly common in HIV-infected patients in India, so there may be a particular geographic distribution [ 57 ]. The vast majority of cases in the oral cavity are EBV positive, but in other sites, up to 25 % of cases are EBV nega- tive. The immunophenotype of these lymphomas resembles that of plasma cells, with expression of plasma cell antigens including MUM1 and CD138, but usually no expression of B-cell antigens like CD20 and CD79a. There is expression of monotypic cytoplasmic immunoglobulin in the majority of cases, which can be use- ful to distinguish PBL from PEL. The stringency of the criteria used for classifi ca- tion of these lesions has varied over time, with some studies using a very strict defi nition (such as presentation in the oral cavity and presence of EBV), which results in PBL being an extremely rare entity. However, a more general defi nition, provided by the 2008 WHO, includes both EBV-negative cases and extraoral pre- sentation, as long as the morphology (as illustrated in Fig. 1.4 ) and immunopheno- type are that of B immunoblasts or plasma cells [ 120 ], and thus according to these criteria, PBL is less rare. A recent report of fi ve cases with a review of the literature identifi ed 248 PBL cases, out of which 157 were in HIV-positive patients, 43 % were outside the oral cavity, and 86 % were EBV positive [ 33 ]. This is a highly aggressive tumor that responds poorly to all available therapies, with a median sur- vival of around 14 months in HIV-positive patients. Approximately half of the cases have been shown to have a MYC translocation [ 129 ], and, at least according to this molecular study, there are no translocations as evidenced by fl uorescent in situ hybridization (FISH) in the other common lymphoma-associated genes ( BCL2 , BCL6 , MALT1 , PAX5 ), although gains of some of these loci were found in over a third of the ...

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... cases of CML, chronic phase, in HIV-positive patients show similar fi ndings as seen in HIV-negative patients, both in the peripheral blood (including leukocytosis with a leftward shift and basophilia) and in the bone mar- row (hypercellularity with myeloid hyperplasia, increased myeloblasts, and megakaryocytic hyperplasia) [ 114 ]. Conventional cytogenetics and/or FISH shows t(9;22) with or without additional abnormalities [ 61 , 95 , 114 ]. In most cases the HIV-positive patients are in the chronic phase at diagnosis; however, some are in the accelerated phase or blast phase at diagnosis [ 95 ]. It is thought Fig. 1.7 Acute myeloid leukemia. This acute myeloid leukemia in a HIV-positive patient was myelo- peroxidase, CD13, CD33, CD15, CD34, and CD117 positive and exhibited a complex karyotype (hematoxylin and eosin, 40? original magnifi cation; insert Giemsa 100? original magnifi cation) E. Cesarman and A. Chadburn pan_papas@yahoo.com that CML may behave more aggressively in HIV-positive patients, as reported in a relatively large series from South Africa, presenting with greater splenomegaly, more advanced disease based on the Sokal score and a higher incidence of accel- erated/blast phase than their HIV-negative counterparts [ 95 ]. The treatment of CML in all patients, including those that are HIV positive, has been transformed with the introduction of tyrosine kinase inhibitors (TKIs). However, drug-drug interactions between antiretroviral medications and TKIs, therapies that may use the same enzymes in metabolism, are thought to be important [ 36 ]. Although TKIs have improved outcomes in HIV-positive patients with CML, there are reports of poorer responses to TKIs compared to HIV-negative patients as well as indications that some patients on CART and imatinib who have achieved a major response with respect to the their CML have experienced a decrease in their CD4 count [ 95 , 114 ]. In addition, in some HIV+ patients on CART, TKIs can be associ- ated with anemia [ 114 ...