HIV-related lymphomas: Clinical manifestations and diagnosis

INTRODUCTION — Human immunodeficiency virus (HIV) infection causes impaired cellular immunity, which predisposes to development of lymphomas and other malignancies. In people living with HIV (PLWH), diagnosis of Kaposi sarcoma, advanced cervical cancer, or certain types of lymphoma (ie, systemic high-grade B cell non-Hodgkin lymphoma, primary central nervous system (CNS) lymphoma, primary effusion lymphoma) is acquired immunodeficiency syndrome (AIDS)-defining. Other types of lymphoma (eg, Hodgkin lymphoma, follicular lymphoma) and other cancers in people living with HIV are not considered AIDS-defining. The clinical presentation of HIV-related lymphomas (HRLs) differs in important ways from lymphomas in HIV-negative patients.

Clinical manifestations and diagnosis of HRLs are reviewed in this topic, with an emphasis on features that distinguish HRLs from those in HIV-seronegative patients.

Epidemiology, risk factors, pathogenesis, and treatment of HRLs; HIV-related primary CNS lymphoma; and primary effusion lymphoma are discussed separately.

●(See "HIV-related lymphomas: Epidemiology, risk factors, and pathobiology".)

●(See "HIV-related lymphomas: Treatment of systemic lymphoma".)

●(See "HIV-related lymphomas: Primary central nervous system lymphoma".)

●(See "Primary effusion lymphoma".)

CLINICAL MANIFESTATIONS — The clinical presentation of HIV-related lymphomas (HRLs) varies with the histologic category of lymphoma and the sites and extent of disease (ie, stage). Categories of lymphomas that are encountered in the HIV-infected patient and disease staging are described separately. (See "HIV-related lymphomas: Epidemiology, risk factors, and pathobiology", section on 'Epidemiology'.)

Distinguishing features — Compared with lymphomas in the HIV-negative population, HRLs are more likely to present with advanced-stage disease, constitutional symptoms ("B" symptoms; ie, fever, weight loss, night sweats), extranodal involvement, or have disease involving unusual locations (eg, body cavity, soft tissue) [1,2]. Because aggressive histologies and extranodal disease are common with HRLs, there is an increased risk for oncologic emergencies (eg, tumor lysis syndrome, airway or gastrointestinal [GI] tract obstruction, involvement of the brain or meninges).

Clinical manifestations of extranodal HRLs are described below. (See 'Extranodal manifestations' below.)

General presentation — The clinical manifestations are protean, but HRLs often present with lymphadenopathy, organomegaly, and/or constitutional symptoms. Some patients present with unexplained cytopenias, fever of unknown origin, tumor lysis syndrome (eg, lactic acidosis, hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, elevated lactate dehydrogenase), or other isolated laboratory abnormalities (eg, hypercalcemia) [3]. General clinical manifestations of lymphoma are discussed separately. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Clinical presentation' and "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors".)

Lymphomas may present at any time after HIV infection, but their emergence can vary by histologic subtype. Diffuse large B cell lymphoma and primary central nervous system (CNS) lymphoma tend to occur when immunosuppression is most pronounced, whereas Burkitt lymphoma (BL) generally occurs earlier in the course of the illness when CD4 counts are better preserved [4]. In contrast, Hodgkin lymphoma (HL) occurs with relatively high frequency in the first months of antiretroviral therapy (ART) therapy, as CD4 counts are rising [5].

Extranodal manifestations — Extranodal manifestations (ie, disease involving sites other than lymph nodes, spleen, thymus, and pharyngeal lymphatic tissue) are more common with HRLs than with lymphomas in the HIV-negative population [1,6].

GI tract and liver — Any region of the gastrointestinal (GI) tract may be involved with an HRL, but clinical manifestations vary with the histologic type and site(s) of disease. GI involvement may be a manifestation of a primary GI lymphoma, such as a mucosa-associated lymphoid tissue (MALT) lymphoma, or it may reflect secondary involvement from a systemic lymphoma. A retrospective study reported GI involvement in 14 percent of 399 patients with HRLs but did not distinguish between those who had primary GI lymphomas versus secondary involvement from a systemic lymphoma [7].

Symptoms of GI involvement may include abdominal or perianal pain, diarrhea, weight loss, bleeding, or symptoms related to perforation or obstruction [8-13]. Physical examination may reveal a mass at the involved site but is often normal. Liver involvement may be asymptomatic, or it may present with pain, ascites, weight loss, nausea, jaundice, abdominal fullness, hepatomegaly, and/or abnormal liver function tests. (See "Clinical presentation and diagnosis of primary gastrointestinal lymphomas".)

Virtually any area of the GI tract may be involved, including the oral cavity, esophagus, bile duct, liver, pancreas, mesentery, small bowel, perianal area, and anal canal [1,8,9,11,14]. In one series of 48 patients with HIV-associated GI lymphoma, involvement was multifocal in 23 percent, and areas of involvement included [8]:

●Stomach – 50 percent

●Duodenum – 25 percent

●Perianal/anal – 15 percent

●Oropharynx – 10 percent

●Small bowel – 8 percent

●Esophagus – 6 percent

●Liver, cecum, and rectum – Each <5 percent

Lung and pleura — Pleuro-pulmonary involvement is common with HRLs. Most pulmonary involvement is a manifestation of a systemic lymphoma, but the lungs and/or pleura can also be primary sites of disease. As an example, an autopsy series from 1982 to 1991 reported isolated pulmonary lymphoma in 6 percent of 38 patients, but the lungs were involved secondarily by systemic lymphoma in 70 percent [15]. Most primary pulmonary lymphomas are large cell lymphoma, but follicular lymphoma, BL, primary effusion lymphoma, and MALT lymphoma are also seen [16,17].

Clinical manifestations of pulmonary involvement include cough, dyspnea, hemoptysis, chest pain, constitutional symptoms, and crackles on auscultation [18-22]. In one report of HIV-infected patients, pulmonary manifestations of non-Hodgkin lymphoma (NHL) included constitutional symptoms (95 percent), tachypnea (74 percent), cough (71 percent), and dyspnea (63 percent) [16]. Approximately 20 percent of patients with HRLs have endobronchial involvement of MALT tissue, which can invade adjacent pulmonary parenchyma, cause atelectasis, and occasionally result in life-threatening airway narrowing or occlusion [16,23-26]. Pleural effusions develop in up to two-thirds of patients with pulmonary involvement by HIV-associated NHL [18,27]. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Chest and lungs'.)

Primary effusion lymphoma is a high-grade NHL of B cell origin. Evaluation and management of primary effusion lymphoma is discussed separately. (See "Primary effusion lymphoma".)

Bone marrow — Bone marrow involvement by an HRL may be asymptomatic, or it may be manifest as cytopenias (ie, anemia, neutropenia, and thrombocytopenia) or with related symptoms (eg, weakness, fatigue, fever, infections, and/or bleeding). Various studies report bone marrow involvement in approximately 20 to 30 percent of patients with HRLs [28-31]. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Abnormal laboratory results'.)

Central nervous system — CNS involvement may be due to a primary CNS lymphoma (an AIDS-defining disease), or it may reflect secondary involvement of the brain or leptomeninges from a systemic lymphoma. Lymphomatous meningitis has been reported in 5 to 20 percent of patients with HIV-associated systemic NHL at the time of presentation, but the incidence varies with the histologic category; the risk of lymphomatous meningitis appears to have decreased with routine use of ART [32-35]. It is not clear if the relatively high incidence of leptomeningeal involvement is an inherent property of HRLs or if it is related to the greater frequency of risk factors for CNS involvement, such as extranodal disease or Burkitt histology [33,36]. There is not a substantial risk of CNS involvement with HL.

Clinical findings of CNS involvement can include headache; back, neck, or radicular pain; focal weakness or sensory loss; cranial nerve palsies; and mental status changes [37]. Nearly one-quarter of patients with leptomeningeal involvement by HRLs are asymptomatic; however, even in symptomatic patients, only a minority have meningeal signs (eg, nuchal rigidity, Kernig sign, Brudzinski sign) [32]. (See "Secondary central nervous system lymphoma: Clinical features and diagnosis".)

Clinical manifestations, diagnosis, and management of primary CNS lymphoma are discussed separately. (See "HIV-related lymphomas: Primary central nervous system lymphoma".)

EVALUATION

General — Evaluation of the patient with a suspected HRL includes a history and physical examination, laboratory studies, and imaging. Because aggressive lymphoma histologies and extranodal disease are common with HRLs, there is an increased risk for oncologic emergencies, including tumor lysis syndrome and other metabolic emergencies; pericardial tamponade; obstruction of the airway, gastrointestinal (GI) tract, or ureters; brain or meningeal involvement; and others. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Oncologic emergencies'.)

The history must include assessment for B symptoms, HIV-related complications, comorbid illnesses (eg, diabetes, heart disease), infections (eg, hepatitis B, hepatitis C, opportunistic infections), and medications, including antiretroviral therapy. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'History'.)

Physical examination should evaluate all lymph node regions, liver, spleen, neurologic examination, and potential sites of extranodal involvement, as described separately. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Physical examination'.)

Laboratory studies should include complete blood count with differential count, chemistries (including electrolytes, liver and renal function tests, lactate dehydrogenase [LDH], uric acid, phosphate), infectious disease screening (CD4 count, HIV viral load, screening for hepatitis B and C), and pregnancy test. Pretreatment evaluation and staging, including bone marrow examination, lumbar puncture (LP), cardiac testing, and imaging are described separately. (See "HIV-related lymphomas: Treatment of systemic lymphoma", section on 'Pretreatment evaluation'.)

Tissue evaluation — A tissue biopsy is required to diagnose an HRL and determine the histologic category.

The biopsy specimen should be obtained from a site that is suspected of involvement based on physical examination and/or imaging. An excisional/incisional biopsy or multiple core biopsies are preferred. In general, we suggest not using fine needle aspiration (FNA) unless other biopsy methods are judged to be too risky (eg, a patient with a severe bleeding disorder); FNA generally yields only limited pathologic material and disrupts nodal architecture so that histologic classification may not be possible. Whenever possible, tissue should be obtained prior to treatment with steroids because their lympholytic effects may obscure the diagnosis. A portion of the biopsy specimen should be set aside as fresh tissue (ie, not fixed in formalin) for flow cytometry and molecular studies. Selection of a lymph node or other tissue for biopsy and the required histologic, immunophenotypic, and molecular studies are discussed separately. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Lymph node and tissue biopsy'.)

GI tract evaluation — When gastrointestinal (GI) involvement is suspected, the patient should be evaluated to determine the sites(s) and extent of involvement and the possibility of life-threatening complications, such as obstruction, perforation, or bleeding. GI evaluation should include a history, physical examination, imaging, endoscopy, and biopsy. Laparoscopy or laparotomy are typically performed only when complications such as perforation or obstruction are suspected. Clinical findings that suggest GI involvement are described above. (See 'GI tract and liver' above.)

●Imaging – Computed tomography (CT) and/or contrast radiography are typically used to evaluate suspected GI involvement; plain radiographs of the abdomen are generally unrevealing [14,38,39]. The utility of positron emission tomography (PET) for detecting lymphoma in the GI tract varies with the histologic category, but most HRLs are PET-avid.

●Endoscopy – Endoscopy may reveal mucosal abnormalities (eg, erythema, erosions, ulceration, nodules, polyps, masses), submucosal masses, or obstruction. Endoscopic ultrasound may reveal submucosal lesions, depth of involvement, or associated lymphadenopathy. Multiple biopsies should be obtained of suspicious lesions.

Further discussion of evaluation of the GI tract for involvement by lymphomas is presented separately. (See "Clinical presentation and diagnosis of primary gastrointestinal lymphomas".)

Pulmonary evaluation — Suspected pleuro-pulmonary involvement by lymphoma should be evaluated by history, physical examination, and imaging. In many cases, CT is performed to characterize the extent and pattern of involvement and identify possible sites for biopsy. For the patient with an isolated pleural effusion or other pleural abnormalities, thoracentesis and/or pleural biopsy can provide diagnostic material. Patients with a combination of lung, pleural, and/or mediastinal disease may require sampling of all affected sites, as more than one process may be present in HIV-infected patients. Thoracoscopic or open lung biopsy is generally only performed when less invasive procedures have not provided a diagnosis. Clinical findings that suggest pleuro-pulmonary involvement are described above. (See 'Lung and pleura' above.)

Evaluation for pleuro-pulmonary involvement by an HRL may include:

●Imaging – Pulmonary abnormalities should be evaluated with CT and/or PET. Parenchymal involvement may appear as an isolated mass, multiple nodules, and/or diffuse opacities, and CT can guide a transthoracic needle biopsy to diagnose lymphoma in this setting [18,40]. Most HRLs are PET-avid, except mucosa-associated lymphoid tissue (MALT) lymphomas. However, it is important to recognize that CT and/or PET generally cannot distinguish an HRL from other diagnoses, such as opportunistic infection or other malignancies [41-43]. (See "Evaluation of pulmonary symptoms in persons with HIV", section on 'Imaging studies'.)

Pleural involvement with non-Hodgkin lymphoma (NHL) can present on CT as a pleural effusion, plaque, nodule, or a combination of these abnormalities [18,41]. Pleural effusions are bilateral in approximately 60 percent. Pleural involvement by primary effusion lymphoma is almost always a free-flowing effusion and is often accompanied by pericardial and peritoneal effusions. (See "Primary effusion lymphoma".)

●Bronchoscopy – For HIV-infected patients with pulmonary parenchymal lesions, bronchoscopy should be performed to evaluate for the patient for an infection or malignancy with a transbronchial biopsy. Bronchoalveolar lavage (BAL) and bronchial brushings generally have a low yield for diagnosing lymphoma; these techniques are more useful for evaluating for infection or lung cancer [16,40]. Although flow cytometry of BAL fluid can detect a monoclonal population of lymphocytes of MALT and other lymphomas, its sensitivity and specificity in this setting are not known [44,45]. (See "Evaluation of pulmonary symptoms in persons with HIV", section on 'Invasive tests'.)

●Thoracentesis/pleural biopsy – For patients with pleural abnormalities, thoracentesis and/or pleural biopsy can confirm lymphoma and exclude other causes such as infection and other malignancies. The fluid associated with pleural lymphoma is exudative, with high concentrations of LDH, and a lymphocyte-predominant pleocytosis [16,46]. In one study in HIV-infected patients, the yield of pleural fluid cytology and pleural biopsy for lymphoma involvement was reported to be 75 percent [16]. Evaluation of pleural fluid for lymphomatous involvement is described separately. (See "Primary effusion lymphoma".)

Central nervous system evaluation — For clinical findings that are suspicious for involvement of the central nervous system (CNS) by HRLs, we suggest evaluation with history, neurologic examination, neuroimaging, and LP. We also evaluate all patients with HIV-related Burkitt lymphoma (BL) and selected patients with diffuse large B cell lymphoma (DLBCL) who are at higher risk for CNS involvement. (See 'Central nervous system' above.)

Our approach to selection of patients for routine CNS evaluation (with or without suspicious clinical findings) follows:

●BL – All patients with HIV-related BL should have an LP and magnetic resonance imaging (MRI) to evaluate potential CNS involvement.

●DLBCL – For patients with HIV-related DLBCL, we perform routine LP and MRI with either of the following:

•Patients with involvement of paranasal sinuses, bone marrow, renal/adrenal, testis, or epidural disease, or ≥2 extranodal sites [47].

•Patients with 4 to 6 risk factors (high risk) in the CNS-International Prognostic Index (CNS-IPI): age >60 years, LDH greater than the upper limit of normal, Eastern Cooperative Oncology Group performance status >1 (table 1), stage 3 or 4 disease, >1 extranodal site, or renal or adrenal involvement [48]. The CNS-IPI has not been specifically validated in the setting of HIV-associated lymphomas. (See "Secondary central nervous system lymphoma: Treatment and prognosis", section on 'Diffuse large B cell lymphoma'.)

We suggest the following evaluation for CNS involvement:

●Imaging – Contrast-enhanced MRI is the preferred imaging modality for potential CNS involvement. Contrast-enhanced CT is an acceptable alternative for patients with contraindications to MRI. If possible, imaging should be obtained before performing an LP, to detect a possible mass effect or midline shift and to avoid meningeal irritation and leptomeningeal enhancement caused by LP. Radiographic findings that suggest primary CNS involvement are described separately. (See "Primary central nervous system lymphoma: Clinical features, diagnosis, and extent of disease evaluation".)

●CSF analysis – Evaluation of the cerebrospinal fluid (CSF) should include cell counts, protein and glucose levels, cytology, flow cytometry, immunoglobulin heavy-chain gene (IgH) rearrangement studies, and polymerase chain reaction for Epstein-Barr virus (EBV) and JC virus. The CSF in lymphomatous meningitis often reveals an elevated protein concentration and a lymphocyte-predominant pleocytosis, and glucose concentration is usually normal or low [49,50]. One study of CSF analysis in 50 patients with systemic HIV-related NHL reported that detection of EBV-DNA in CSF was 90 and 100 percent sensitive and specific, respectively, for CNS involvement by lymphoma [36]. (See "Secondary central nervous system lymphoma: Clinical features and diagnosis", section on 'Lumbar puncture'.)

DIAGNOSIS — HRL should be suspected in people living with HIV infection (PLWH) with adenopathy, B symptoms (fever, weight loss, night sweats), possible extranodal involvement, or other clinical findings that may be attributable to a lymphoma. In some cases, an HRL is the first manifestation of HIV-associated illness in a patient who was not known to have HIV infection. Clinical manifestations of HRLs and methods for diagnosing HIV infection are described above and separately. (See 'Clinical manifestations' above and "The natural history and clinical features of HIV infection in adults and adolescents".)

Diagnosis of an HRL requires detection of malignant lymphoid cells by morphologic, immunophenotypic, and/or molecular criteria. Detection of a clonal population of malignant lymphoid cells distinguishes a non-Hodgkin lymphoma (NHL) from Hodgkin lymphoma (HL). In contrast, HL typically displays diagnostic Hodgkin/Reed-Sternberg (HRS) cells in an inflammatory background of small lymphocytes, eosinophils, neutrophils, macrophages, plasma cells, and fibroblasts, often associated with collagen deposition and fibrosis. Details of the diagnosis of NHL and HL are presented separately. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Lymph node and tissue biopsy' and "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults", section on 'Diagnosis'.)

Important considerations for obtaining an optimal diagnostic specimen are discussed above. (See 'Tissue evaluation' above.)

The most common categories of lymphoma in HIV-infected patients are:

●Burkitt lymphoma (BL) – BL accounts for approximately one-quarter of HIV-associated lymphomas [51]. The GI tract is the most common site of presentation, but in patients with HIV, BL can present in unusual sites, including bone marrow. Histologically, there is a monotonous pattern of intermediate-sized cells with round nucleoli and basophilic cytoplasm that resemble small noncleaved cells found in germinal centers, frequent mitoses, and a characteristic "starry-sky" appearance [52]. Tumor cells are positive for CD20, CD10, and BCL6, but negative for BCL2, and the proliferation index (eg, by Ki67 staining) approaches 100 percent. The cells are generally positive for MYC by immunohistochemistry, and MYC rearrangements can be demonstrated by cytogenetics or fluorescence in situ hybridization. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of Burkitt lymphoma".)

●Diffuse large B cell lymphoma (DLBCL) – DLBCL usually presents with advanced-stage (ie, stage III-IV) or extranodal disease, most often involving the CNS, GI tract, bone marrow, or liver; nodal presentation of DLBCL is less common than in immunocompetent patients [51]. Most DLBCL consists of a diffuse pattern of centroblasts (large cells with round or oval nuclei and ≥2 nucleoli). Mitoses may be frequent, but they lack a starry-sky pattern seen with BL. Some DLBCL is immunoblastic, with larger cells, deeply basophilic cytoplasm, the nucleus contains a prominent central nucleolus, and the cells may appear plasmacytoid. Primary CNS lymphomas are usually immunoblastic in appearance [53]. The tumor cells typically express CD19, CD20, and have immunophenotypes that resemble DLBCL in the general population. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma".)

●Plasmablastic lymphoma (PL) – PL is a rare disorder in PLWH [54]. Extranodal presentation is common, especially in the oral cavity or jaw; other sites include the GI tract, skin, abdomen, retroperitoneum, and soft tissues of the extremities [55-57]. Patients usually present with advanced-stage disease, B symptoms, and bone marrow involvement. Histologically, the tumors reveal sheets of large cells with immunoblastic or plasmablastic appearance, round or oval nuclei, prominent nucleoli, and moderately abundant amphophilic cytoplasm; there are frequent apoptotic cells, but a starry-sky pattern is rare [54]. The malignant cells are usually negative or weakly positive for CD45 and are usually negative for CD19, CD20, and PAX5. Most cases are positive for CD79a, IRF4 (also called MUM1), PRDM1 (also called BLIMP1), CD38, and CD138. There may be aberrant expression of T cell markers (eg, CD2, CD4), and Ki67 proliferation index is almost 100 percent. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma".)

●Classic Hodgkin lymphoma (cHL) – Presentation of cHL in PLWH may have atypical manifestations, such as advanced-stage disease, involvement of bone marrow or liver, and noncontiguous spread to multiple nodal groups [58]. Approximately one-half of HIV-associated cHL is the nodular sclerosis subtype. Diagnosis requires the presence of HRS cells or variants in an inflammatory background, with a variable number of small lymphocytes, eosinophils, neutrophils, histiocytes, plasma cells, fibroblasts, and collagen fibers. HRS cells typically express CD15 and CD30, uncommonly express CD20, and do not express CD3 or CD45. In HIV-associated cHL there may be decreased nodal CD4 T cells and Reed-Sternberg (RS) cells are positive for Epstein-Barr virus (EBV)-encoded RNA (EBER) in 80 to 100 percent of cases [59]. (See "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults", section on 'Diagnosis'.)

Other categories of lymphoma that may be found in HIV-infected patients are discussed separately. (See "HIV-related lymphomas: Epidemiology, risk factors, and pathobiology", section on 'Epidemiology'.)

Additional diagnostic testing that is required for pretreatment evaluation and staging of lymphoma is described separately. (See "HIV-related lymphomas: Treatment of systemic lymphoma", section on 'Pretreatment evaluation'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis includes various infections, malignancies, inflammatory conditions, or drug reactions that may present with lymphadenopathy, organomegaly, unexplained B symptoms, or other clinical manifestations that are seen with HRLs. (See 'Clinical manifestations' above.)

Infections — Various infectious diseases are associated with fever, lymphadenopathy, organomegaly, weight loss, or other clinical findings that may be indistinguishable from a lymphoma in an HIV-infected patient. Disseminated mycobacterial or fungal infections may be particularly difficult to distinguish from lymphoma in this setting. Diagnostic material from an involved site is required to distinguish an infection from an HRL. It is important to recognize that a person living with HIV may have both a lymphoma and an infection. Examples of clinical manifestations of infectious diseases that may mimic lymphoma include:

●Respiratory symptoms – Cough, dyspnea, pleuritic chest pain, hemoptysis, or radiographic opacities should be investigated with stains and culture of sputum for viral, bacterial, fungal, protozoal, and parasitic testing. Evaluation of the immunocompromised patient with respiratory findings and/or radiologic abnormalities of the lungs or pleura is described separately. (See "Pleural effusions in HIV-infected patients" and "Epidemiology of pulmonary infections in immunocompromised patients".)

●Gastrointestinal (GI) manifestations – Unexplained nausea/vomiting, abdominal pain, diarrhea, weight loss, bleeding, perforation, and/or obstruction in the immunocompromised patient should be investigated for a variety of infectious diseases with stool culture, staining for ova and parasites, endoscopic examination, and/or tissue biopsy, as described separately. (See "AIDS-related cytomegalovirus gastrointestinal disease".)

●Constitutional symptoms – Unexplained fever, weight loss, and/or drenching sweats may require blood cultures, bone marrow examination, or evaluation of other sites including special stains, culture, and/or imaging (eg, echocardiogram) to identify an infectious cause, as described separately. (See "Fever of unknown origin in adults: Evaluation and management", section on 'Persistent fevers'.)

●Skin – Rash, pruritus, or ulceration may be investigated with special stains, culture, and/or biopsy to identify an infectious cause, as described separately. (See "Fever and rash in patients with HIV".)

●Central nervous system – Neurologic findings in a patient with HIV infection should be investigated for infectious causes with imaging and/or lumbar puncture, as described separately. (See "Approach to the patient with HIV and central nervous system lesions".)

The natural history and clinical features of the HIV-infected patient is discussed separately. (See "The natural history and clinical features of HIV infection in adults and adolescents".)

Malignancies — Various malignancies can cause lymphadenopathy, organomegaly, extranodal findings (eg, lung, GI tract, skin), constitutional symptoms, and laboratory abnormalities that may be indistinguishable from lymphoma. Numerous malignancies are associated with HIV infection, including Kaposi sarcoma, cervical cancer, basal cell or squamous cell cutaneous malignancies, Merkel cell tumor, lung cancer, hepatocellular cancer, and others. Distinguishing these cancers from HRLs requires a tissue biopsy, which is informed by clinical manifestations, such as a radiographic opacity, enlarged lymph node, or other finding. (See "HIV infection and malignancy: Management considerations".)

Inflammatory conditions — Inflammatory conditions that may mimic clinical manifestations of HRLs include multicentric Castleman disease (MCD) and sarcoidosis.

●MCD presents with lymphadenopathy in multiple lymph node regions, hepatosplenomegaly, constitutional symptoms, cytopenias, organ dysfunction, and cutaneous manifestations. The diagnosis of MCD in a patient with HIV infection requires pathologic confirmation of plasmablastic cells on lymph node biopsy, enlargement of multiple lymph node regions, and detection of human herpesvirus 8 (HHV-8) in the lymph node or peripheral blood. (See "HHV-8/KSHV-associated multicentric Castleman disease", section on 'Diagnostic evaluation'.)

●Sarcoidosis may manifest as fever, lymphadenopathy, rash, laboratory abnormalities, radiographic abnormalities, and other findings that resemble lymphoma. The diagnosis of sarcoidosis requires compatible clinical and radiographic manifestations, exclusion of other diseases, and histopathologic detection of noncaseating granulomas. (See "Clinical manifestations and diagnosis of sarcoidosis" and "Overview of extrapulmonary manifestations of sarcoidosis".)

Drug reactions — Drug reactions may cause fever, lymphadenopathy, rash, and other findings that can resemble clinical manifestations of a lymphoma. Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare, drug-induced hypersensitivity with a prolonged course and frequent relapses. Diagnosis of DRESS is based on a history of exposure to high-risk medication; morbilliform, confluent, or extensive exfoliative dermatitis; eosinophilia and/or atypical lymphocytosis; fever; lymphadenopathy; and other characteristic systemic symptoms and organ involvement, as discussed separately. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

Immune reconstitution inflammatory syndrome (IRIS) — Immune reconstitution inflammatory syndrome (IRIS) describes a collection of inflammatory disorders associated with paradoxical worsening of preexisting infectious processes following the initiation of antiretroviral therapy (ART) in HIV-infected individuals. IRIS typically begins within one week to a few months after the initiation of ART and the clinical features are related to the type and location of the preexisting opportunistic infection. The clinical presentation, diagnosis and management of IRIS is discussed separately. (See "Immune reconstitution inflammatory syndrome".)

SUMMARY

●Description – HIV infection impairs cellular immunity and is associated with an increased risk for lymphomas and other malignancies in people living with HIV (PLWH).

Examples of HIV-related lymphomas (HRLs) include:

•Burkitt lymphoma

•Diffuse large B cell lymphoma

•Plasmablastic lymphoma

•Primary central nervous system (CNS) lymphoma

•Primary effusion lymphoma

•Hodgkin lymphoma

●Presentation – Clinical manifestations of HRLs vary with the histologic subtype, sites of involvement, and stage of disease. HRLs may present with lymphadenopathy, organomegaly, and/or constitutional symptoms, but some manifest unexplained cytopenias, fever of unknown origin, tumor lysis syndrome (TLS), or other laboratory abnormalities. (See 'Clinical manifestations' above.)

●Distinguishing features of HRLs – Compared with lymphomas in the HIV-negative population, HRLs are more likely to present with advanced-stage disease, B symptoms (ie, fever, weight loss, night sweats), extranodal involvement (eg, spleen, thymus, pharynx), or disease affecting unusual locations (eg, body cavities, soft tissue). There is an increased risk for TLS, airway or gastrointestinal (GI) tract obstruction, involvement of the brain or meninges, or other oncologic emergencies. (See 'Distinguishing features' above.)  

●Extranodal involvement – The most common extranodal presentations of HRLs involve (see 'Central nervous system evaluation' above):

•GI tract (see 'GI tract and liver' above)

•Pulmonary/pleural (see 'Lung and pleura' above)

•Bone marrow (see 'Bone marrow' above)

•CNS (see 'Central nervous system evaluation' above)

●Evaluation

•Clinical – History/physical examination and laboratory studies. (See 'General' above.)

•Pathology – Excisional/incisional biopsy or multiple core biopsies from a lymph node or other involved site. (See 'Tissue evaluation' above.)

•Imaging – CT and/or positron emission tomography to define nodal and extranodal involvement.

•CNS – Lumbar puncture and MRI for all patients with Burkitt lymphoma and high-risk diffuse large B cell lymphoma, as discussed above. (See 'Central nervous system evaluation' above.)

●Diagnosis – HRL should be suspected in PLWH who have adenopathy, constitutional symptoms, possible extranodal involvement, or other lymphoma-associated clinical findings. (See 'Diagnosis' above.)

Diagnosis and classification require pathologic confirmation by morphology, immunophenotype, and molecular studies in PLWH. Details of diagnostic criteria for specific HRLs are discussed in disease-specific topics:

•Burkitt lymphoma (see "Epidemiology, clinical manifestations, pathologic features, and diagnosis of Burkitt lymphoma")

•Diffuse large B cell lymphoma and plasmablastic lymphoma (see "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma")

•Primary CNS lymphoma (see "HIV-related lymphomas: Primary central nervous system lymphoma")

•Primary effusion lymphoma (see "Primary effusion lymphoma")

•Hodgkin lymphoma (see "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults")

●Differential diagnosis – Other conditions to be excluded include infectious diseases, malignancies, and inflammatory conditions that present with constitutional symptoms, adenopathy, extranodal manifestations, and related findings in PLWH. (See 'Differential diagnosis' above.)