HIV and Malignancy Alaka Deshpande, Himanshu Soni
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1 HIV and Malignancy Alaka Deshpande, Himanshu Soni Emergence of new infectious disease was documented in Within a short span of time it became a pandemic. It was Acquired Immunodeficiency Syndrome (AIDS) caused by a retrovirus named Human immuno deficiency virus. Earlier two lymphotropic retroviruses were identified but they were oncogenic namely HTLV-1 causing adult T cell lymphoma Leukemia and HTLV-2 associated with adult hairy cell leukemia. However, this new lymphotropic retrovirus is cytopathic. It targets CD4 lymphocytes and results into progressive deficiency of cell mediated immunity. The course of this HIV disease was characterized by progressive immune deficiency presenting with various opportunistic infections. In the early stages of the disease, apart from OIs, a large number of cases of Kaposi Sarcoma were reported from the western world. Soon it was realized that immuno deficient patients also presented with Primary CNS lymphoma. Along with OIs, various malignancies were related to HIV infection. The CDC definition of 1985, includes Kaposi Sarcoma, Primary CNS lymphoma in pts under 60 years of age and squamous cell intraepithelial cervical cancer as AIDS indicator diseases. A review of AIDS and Cancer registry revealed the relative risk of following malignancies compared to controls without AIDS as follows: Relative risk Kaposi Sarcoma 545 NHL 24.6 Hodgkin s lymphoma 13.1 Anal Cancer 8.2 Leukemia 2.4 Lung cancer 1.9 Intraepithelial Cervical Cancer 9.00 (Further reading JAIDS 5003, 32:527) Anal Cancer - Common in MSM with anal sex, is associated with human papilloma virus infection. The MSMs have 42 times higher risk of anal cancer than the general population. Patient with rectal bleeding should be carefully examined along with cytology and high resolution anoscopy. Management comprises of surgery, chemo+ radiotherapy. Cervical Cancer - is also associated with HPV infection. Regular pap-smear examination is recommended for HIV infected women. As there is several fold increase in rates of squamous cell intraepithelial lesions, aggressive testing is recommended by CDC. With HPV vaccine and aggressive screening, cervical cancer is disappearing from the developed world. In last 6 years of ART, we had 4 cases of Ca Cx who were detected to be HIV infected after diagnosis of Ca Cx. Our patients seek the medical help very late. Kaposi s Sarcoma - It presents as purple to brown macule, nodule or a patch without pain or itching seen on legs, face, oral cavity, GI tract and genitalia. Diagnosis is confirmed by biopsy. It is common in MSM. In India, very few cases have been reported in either sex. It is associated with HHV-8 infection. HAART and antiviral treatment with cidofovir, ganciclovir etc against HHV-8 is recommended. There was not a single case of Kaposi Sarcoma at our centre.
2 496 Medicine Update-2011 Lymphomas The first case of lymphoma in an AIDS patient was reported in 1982 in Lancet by Doll DC. HIV associated lymphoma was first incorporated into the U.S. Centers for Disease Control and Prevention s (CDC) case definition of AIDS in Etiopathogenesis and classification of lymphoma There is an epidemic of NHL worldwide.there are a number of possible contributing factors to the increased incidence of lymphoma worldwide which also probably play a role in the etiology of these neoplasms. 1. Chromosomal translocations and oncogenes: Non random chromosomal abnormalities, most commonly translocations, are present in the majority of lymphomas. As given below, many specific rearrangements are associated with particular neoplasms, suggesting a critical role in their genesis. (Table I) 2. Infectious agents: Of all the viruses, Epstein-Barr virus has the most striking association with lymphomagenesis. Others such as human T-cell leukemia virus-1(htlv-1), Kaposi sarcoma herpesvirus/ human herpesvirus-8(kshv/hhv-8), HIV, H.Pylori, and Hepatitis C virus have also been implicated as causative agents. (Table II) AIDS related Lymphoma: Lymphomas occur with an increased frequency in patients with congenital or acquired T cell immunodeficiencies. AIDS is no exception; at least 6% of all patients with AIDS develop lymphoma at some time during the course of their illness. The risk of lymphoma is 120- to 150- fold higher among HIVinfected patients as compared to the general population. Lymphoma is a late manifestation of HIV infection, generally occurring in patients with CD4+ T cell counts < 200/µl. Gradually as HIV disease progresses, the risk of lymphoma increases. In contrast to Kaposi s sarcoma, which occurs at a relatively constant rate throughout the course of HIV disease, the attack rate for lymphoma increases exponentially with increasing duration of HIV infection and decreasing level of immunologic function. Table I. Recurring chromosomal translocations in NHL Table II. Infectious agents assoc. with lymphoid malignancies
3 Medicine Update Classification of AIDS related Lymphoma: In an effort to standardize the nomenclature, improve diagnostic accuracy, and promote international consensus, the World Health Organization (WHO) has developed a different classification of lymphomas. Categories of AIDS related lymphoma (ARL): 1. Lymphomas also occurring in immunocompetent patients: Burkitt's lymphoma: Classic With plasmacytoid differentiation Atypical. Diffuse Large B cell Lymphoma: Centroblastic Immunoblastic Extranodal marginal zone lymphoma of MALT type Peripheral T cell lymphoma (rare) Classic Hodgkin's lymphoma 2. Lymphomas occurring more specifically in HIV patients: Primary effusion lymphoma Plasmablastic lymphoma of the oral cavity 3. Lymphomas occurring in other immunodef states: Polymorphic B cell lymphoma AIDS related lymphomas are almost exclusively of B-cell type. The above mentioned classification is based on the histological patterns seen in AIDS related lymphomas. These patterns are representative of aggressive lymphomas and fall in two main groups: (1) large-cell lymphoma, which includes intermediate-grade large-cell and high-grade immunoblastic lymphoma, and (2) high-grade, small noncleaved lymphoma (often classified as Burkitt's lymphoma). Low-grade lymphomas rarely occur in patients with HIV infection and are not AIDS defining according to the Centers for Disease Control (CDC) criteria. Of 327 cases reported from five centers, 73% of the lymphomas were high grade; 24%, intermediate grade; and 3%, low grade.the large-cell NHLs make up approximately two thirds of all NHLs, whereas approximately 25% are small, noncleaved lymphomas. Reports rarely describe T-cell lymphomas. ARL differs from NHL in general population in the following ways propensity for advanced disease presence of B symptoms Extranodal disease including BM affection Leptomeningeal disease Disease in unusual body sites Less responsiveness to chemotherapy Frequent assoc. with EBV and HHV-8 CLINICALLY, ARLs can be divided into three groups on the basis of their location: Systemic NHL Primary CNS NHL(PCNSL) Primary effusion lymphoma(pel) Systemic NHL: Studies have demonstrated that the relative risk of developing lymphoma within 3 years of an AIDS diagnosis was increased by 165-fold compared to people without AIDS. Clinical manifestations: Extranodal disease is the rule in persons with HIV-associated systemic NHL in a variety of clinical situations. Patients with HIV-NHL frequently present with advanced stage 3 or 4 disease. The majority presents with a rapidly growing mass or development of group B symptoms i.e. fever, night sweats, unexplained weight loss. The clinical presentation is dependent on the site of involvement which include the bone marrow, G I tract, and CNS. Involvement of the small bowel and rectum is also prevalent, particularly in those with the large cell variety. Special attention should be paid to the patient with advanced HIV who presents with confusion, memory loss, and lethargy, as these may be the presenting symptoms of CNS lymphoma. Diagnosis: Unexplained constitutional symptoms (B group) in an HIV patient lasting more than a fortnight, should be evaluated by imaging chest, abdomen and pelvis for non palpable, pathology. Biopsy of newly developed lymph nodes, pathologically enlarged (typically> 2cm), or progressively enlarging nodes should be carried out. In patients without lymphadenopathy, biopsy of the liver, nodules in various organs or the bone marrow may also lead to a diagnosis of lymphoma. Clinicians should be vigilant even if patient is on HAART. Biopsy is preferred to fine needle aspiration as it is required to sub classify the lymphoma. Tests to help stage ARL include bone marrow biopsy, lumbar puncture, CT scans (chest, abdomen, and pelvis), gallium scans, and/or positron emission tomography to assess for the presence and extent
4 498 Medicine Update-2011 of malignant disease. Immunophenotypic and genotypic analysis: Immunophenotypic analysis is done by using antibodies of variable specificity to detect cellular antigens (surface, cytoplasmic or nuclear) in cell suspensions (flow cytometry) or in paraffin embedded tissue sections. Immunophenotyping is often invaluable as it helps in precisely classifying the lymphomas and to demonstrate the lineage of the neoplastic cell (B cell, T cell or NK cell). In ideal circumstances flow cytometry is the preferred technique as it permits rapid analysis of large number of cells, however it requires viable cell populations. In Indian settings usually immunohistochemical studies are run on paraffin embedded tissues, the major limitation of which is the loss of many lymphocyte antigens during tissue processing. Genotypic analysis can be done using PCR techniques, and more recently fluorescence in situ hybridization (FISH) has been applied to paraffin embedded tissue for detection of critical translocations in lymphomas. Staging of AIDS related lymphoma: Staging evaluation of patients with ARL is similar to that for patients without HIV. The initial evaluation of a patient with Hodgkin disease and NHL is similar. In both situations the determination of an accurate anatomic stage is an important part of the evaluation. The staging system is the Ann Arbor staging system originally developed for Hodgkin s disease in Anatomic staging in non-hodgkin Lymphoma can be done using history, physical examination, laboratory studies, and images, in addition to definitive proof of involvement of a particular site from biopsy. As a practical point, most patients are assigned their stage based on the results of noninvasive studies rather than having biopsies to document each apparent site of involvement. The designation E is used when localized, solitary involvement of extra lymphatic tissue, excluding liver and marrow, is seen. The above stages can be sub classified into A or B categories. Prognostic features: Conventionally, the prognosis of patients with NHL is best assigned using the International Prognostic Index (IPI), which is a powerful predictor of outcome in all subtypes of NHL. Primary CNS lymphoma: In the WHO classification the HIV related PCNSL fall in the category of Diffuse large B cell lymphoma; they are usually of the immunoblastic type. In contrast to systemic NHL, primary CNS lymphoma in the setting of HIV infection occurs almost exclusively in persons who are severely immunedeficient. The median CD4 lymphocyte count in persons with PCNSL in HIV disease is usually <50 cells/ul. Clinical features: Single or multiple discrete lesions are the most common findings on computed tomographic (CT) or magnetic resonance imaging (MRI) scans of the brain. The lesions are frequently hypodense and contrast enhancing. SPECT imaging can distinguish between the neurotoxo. and PCNSL as PCNSL is metabolically active and toxoplasmosis is metabolically inactive. Diagnosis is established by brain biopsy, positive CSF cytology, EBV viral DNA in CSF. Primary effusion lymphoma: Primary Effusion lymphoma is a rare subset of large B-cell Table III. The Ann Arbor staging system
5 Medicine Update lymphoma that mainly occurs in AIDS patients. Primary effusion lymphoma (PEL) is a peculiar clinicopathological entity characterized by human herpes virus 8 (HHV-8) infection of tumor clone and by a peculiar tropism of the serous body cavities. HHV-8 occurs in 100% of patients and is frequently, although not always, associated with Epstein- Barr virus infection. PEL, which generally occurs in patients with low CD4 count and advanced HIV disease, presents with pericardial and pleural effusions or ascites. Diagnosis is made by cytological examination of the aspirated fluid and immunohistochemical evaluation. AIDS related Hodgkin lymphoma: The association between Hodgkin s lymphoma and HIV has been supported by multiple studies. Recent data from The National Cancer Institute s AIDS Cancer Match Registry, has demonstrated an approximately 10-fold increase in the risk of Hodgkin s disease in this patient population. The relative risk of Hodgkin s disease in the setting of HIV disease is lower than the relative risk for non-hodgkin s lymphoma. Hodgkin lymphoma in HIV-infected patients exhibits clinical and pathological features different from those of Hodgkin lymphoma in the general population. Characteristics of AIDS related Hodgkin lymphoma: frequent presentation with group B symptoms advanced disease (stage 3 or 4) at the time of diagnosis frequent involvement of extranodal sites (60%), including marrow, liver and spleen high incidence of non-contiguous spread of disease There is a preponderance of unfavorable histologic subtypesmixed cellularity is the most frequent histology, accounting for 41 to 100% of cases, whereas nodular sclerosis is the least frequent, accounting for 0 to 40% of cases. Unlike patients with NHL, Hodgkin lymphoma develops in patients who have higher CD4 counts, ranging from 275 to 306 cells/mm3. Pathogenesis of AIDS related lymphoma: Pathogenesis probably involves sustained polyclonal B-cell activation, followed by the emergence of monoclonal or oligoclonal B-cell populations. It is believed that during the frenzy of proliferation, some clones undergo mutations or chromosomal translocations involving oncogenes or tumor suppressor genes, and subsequent neoplastic transformation. There is morphologic evidence of B-cell activation in lymph nodes, and it is believed that such triggering of B cell is multifactorial. Patients with AIDS have high serum levels of several cytokines which include IL-6, IL-10, scd23, scd27, scd30. Many of these cytokines are potent growth and antiapoptotic factors for B cells. In addition there seems to be a role for EBV, known to be a polyclonal mitogen for B cells. The EBV genome is found in approx 50% of the systemic B-cell lymphomas and in virtually all Primary CNS lymphomas. The rare body cavity-based B cell lymphomas are uniformly associated with the presence of the KSHV genome. Genetic factors also play a role in the development of NHL. Patients who are heterozygotes for the CCR5delta32 are less likely to develop lymphoma, whereas those with stromal cell-derived factor1 mutations are more likely to develop lymphoma. Table IV shows the number and types of lymphoma at various ranges of CD4 counts. Over past four years we had 61 cases of AIDS related lymphomas at our centre. Table 4 shows the range of CD4 counts and types of lymphomas. They were distributed in Table IV. CD4 count ranges and types of lymphoma
6 500 Medicine Update-2011 all age groups based on the immunodeficiency. There were 54 males and 7 females. The diagnosis was made by relevant biopsies, and immunohistochemistry particularly in NHL cases. Brain biopsy could not be done in PCNSL. Treatment: The response to standard chemotherapy, including MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) and ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine), is lower than that of patients without HIV infection. CD4 counts tend to fall during chemotherapy, and leukopenias make standard doses of chemotherapy difficult to administer. The median overall survival of patients is approximately 1.5 years. Because majority of patients have widespread disease, there are no data on the impact of radiation therapy in treatment of AIDS related Hodgkin lymphoma. In past 20 years the author has seen only 2 cases of T cell lymphoma-leukemia and 1 case of chronic lymphocytic leukemia.
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