Int J STD AIDS OnlineFirst, published on July 15, 2015 as doi:10.1177/0956462415596301

Case report

Durable survival after chemotherapy in an HIV patient with Burkitt’s lymphoma presenting with massive upper gastrointestinal bleeding

International Journal of STD & AIDS 0(0) 1–7 ! The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0956462415596301 std.sagepub.com

Man F Law1,2, Hay N Chan1, Chun Y Pang3, Ho K Lai1, Chung Y Ha1, Celia Ng1, Rita Ho4, Cheuk K Wong5, Yiu M Yeung1 and Sze F Yip1

Abstract Massive upper gastrointestinal bleeding is an uncommon presentation of Burkitt’s lymphoma in a patient with HIV/AIDS, and is seldom reported in the literature. A 39-year-old homosexual man presented with abdominal pain and massive hematemesis, and a rapid drop in haemoglobin level to 4.8 g/dL. Upper gastrointestinal endoscopy showed a large blood clot in stomach, and emergent laparotomy was performed because of unstable hemodynamics. This showed active bleeding from multiple tumours in the fundus and body of the stomach. The patient underwent gastrectomy and gastric biopsy confirmed Burkitt’s lymphoma. Further tests showed lymphoma involvement in bone marrow and central nervous system. The patient tested positive for HIV, and had a CD4 count of 212/mm3 and viral load of 18,000 copies/mL at diagnosis. He was commenced on a chemotherapy regimen of CODOX-M/IVAC, and highly active antiretroviral therapy consisting of indinavir, stavudine and lamivudine. The major side effect was peripheral neuropathy. Infective complications during chemotherapy were controlled by broad-spectrum antibiotics and anti-fungal agents. Complete remission of the lymphoma was achieved after the chemotherapy and remission was maintained for more than 14 years.

Keywords Burkitt’s lymphoma, massive gastrointestinal bleeding, HIV, AIDS Date received: 8 March 2015; accepted: 18 June 2015

Introduction Patients with human immunodeficiency virus (HIV) infection have a 60 - to 200-fold increased incidence of non-Hodgkin lymphoma (NHL). The most common HIV-associated lymphomas are diffuse large B-cell lymphoma (DLBCL), which includes primary central nervous system lymphoma (PCNSL), and Burkitt’s lymphoma, whereas plasmablastic lymphoma (PBL), primary effusion lymphoma (PEL) and classic Hodgkin lymphoma are less frequent.1 Between 2001 and 2007, the most common acquired immunodeficiency deficiency syndrome (AIDS)-defining NHL was DLBCL with an incidence of 120 cases per 100,000 patient-years, followed by Burkitt’s lymphoma with an incidence of 32 cases per 100,000 patient-years.2 The widespread adoption of highly active antiretroviral therapy (HAART) beginning in 1996 has improved HIV-related immunodeficiency and decreased overall

NHL incidence.3,4 For example, the incidence rate of Burkitt’s lymphoma was 93 per 100,000 AIDS between 1980 and 1989, 64 between 1990 and 1995 and 32 between 2001 and 2007.2 The aetiological factors that contribute to Burkitt’s lymphoma are multifactorial. HIV patients are susceptible to infection by oncogenic viruses, which can alter 1

Department Department Hong Kong 3 Department 4 Department 5 Department 2

of Medicine, Tuen Mun Hospital, Hong Kong of Medicine and Therapeutics, Prince of Wales Hospital, of Pathology, North District Hospital, Hong Kong of Medicine, North District Hospital, Hong Kong of Radiology, Tuen Mun Hospital, Hong Kong

Corresponding author: Man F Law, Department of Medicine and Therapeutics, Prince of Wales Hospital, Shatin 852, Hong Kong. Email: [email protected]

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mechanisms of apoptosis and cell cycle regulation, activate oncogenes, and inhibit tumour suppressor genes.5 Chronic antigenic stimulation of B cells and macrophages induced by the viruses triggers cytokine and growth factor release, which promote B-cell proliferation and the outgrowth of a monoclonal B-cell population.6 PBL and PEL are both oncogenic virus-driven tumours associated mainly with HIV advanced immune depletion. PBL mainly involves extranodal site and is Epstein-Barr virus (EBV)-related in most patients. There is strong correlation between plasma EBV DNA level and therapy progress of PBL.7 Both of these tumours carry a poor prognosis. HIV/AIDS can affect the gastrointestinal (GI) tract by infection or malignancies like lymphoma or Kaposi’s sarcoma. Massive GI bleeding is a rare presentation of Burkitt’s lymphoma in patients with HIV/ AIDS, and only a few case reports have been published. The outcome can be fatal. We report the case of an HIV patient presenting with acute and massive upper GI bleeding who survived for 14 years after intensive chemotherapy for the lymphoma.

Case report A 39-year-old Chinese male with a history of appendectomy for acute appendicitis presented with a one-day history of generalised abdominal pain, which was increasing in severity. There was no radiation of the pain to the back. He reported no NSAID use, fever or vomiting. Physical examination showed epigastric tenderness, but no rebound tenderness or guarding. There was no palpable lymph node, but the patient had moderate splenomegaly. Complete blood picture showed a haemoglobin level of 8.8 g/dL, white cell

count of 6.6  109/L, and platelet 120  109/L. Liver function analysis showed a bilirubin level of 7 mmol/L, aminotransferase 51 U/L and alkaline phosphatase 334 U/L. Lactate dehydrogenase was elevated at 11,390 U/L. The patient developed sudden massive haemetemesis during hospitalisation. Systolic blood pressure dropped to 90 mmHg, and the haemoglobin level to 4.8 g/dL. The patient received fluid replacement and blood transfusion. Upper endoscopy showed a large fresh blood clot in the stomach, masking the field. Emergent laparotomy was performed in view of the patient’s unstable hemodynamics. Multiple tumours were found in the fundus and body of stomach, and there was active bleeding, so the surgeon performed a total gastrectomy. There were also multiple lesions at both lobes of liver. Gastric biopsy showed diffuse infiltration by a monotonous population of medium-sized lymphoid cells with a starry sky pattern and high nuclear to cytoplasmic ratio. Immunohistochemistry revealed that the neoplastic cells expressed CD20, CD79a and CD10. They were negative for bcl-2 and terminal deoxynucleotidyl transferase (TdT) and 100% of the cells were Ki67 positive (Figure 1). The diagnosis was compatible with Burkitt’s lymphoma. Biopsy of the hepatic tissue also showed involvement by Burkitt’s lymphoma (Figure 2). Computerised tomography (CT) scan of the abdomen showed multiple intra-abdominal lymph nodes and splenomegaly. Examination of bone marrow biopsy confirmed lymphoma involvement of bone marrow. Viral screens were negative for hepatitis B and C, but positive for HIV. The patient then revealed that he was homosexual and denied a history of drug abuse. His CD4 count was 212/mm3 and viral load was 18,000 copies/mL at diagnosis. A lumbar puncture was performed and lymphoma cells were present in the cerebrospinal fluid analysis, but there were no parenchymal

Figure 1. (a) Low-power examination of stomach showing transmural involvement by Burkitt’s lymphoma. (b) High-power examination showing squaring of tumour cell border, abundant tangible body macrophages and mitotic figures.

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Figure 2. (a) Low-power examination of liver showing patchy involvement by Burkitt’s lymphoma. (b) High-power examination showing tumour involvement around the central vein and apoptotic bodies are readily seen.

lesions on brain CT. This patient with HIV had stage IV Burkitt’s lymphoma with gastric, bone marrow, hepatic and central nervous system (CNS) involvement. CVP (cyclophosphamide, vincristine and prednisolone) chemotherapy was used for cytoreduction, followed by the intensive chemotherapy regimen CODOX-IVAC (cyclophosphamide, vincristine, doxorubicin, methotrexate/ifosfamide, etoposide and cytarabine). CNS treatment included high-dose intravenous methotrexate and cytarabine, and intrathecal methotrexate, cytarabine and hydrocortisone. HAART consisting of indinavir, stavudine and lamivudine was started concomitantly with chemotherapy. Although the patient was able to tolerate the HARRT, he did develop peripheral neuropathy. The dosage of vincristine was reduced in subsequent cycles of chemotherapy. Prophylactic antibiotics and antifungal agents were given, but his clinical course during chemotherapy was nevertheless complicated by febrile neutropenia, mucositis, bloody diarrhoea and a buttock abscess. He responded well to broad-spectrum antibiotics and antifungal treatment. A total of eight cycles of chemotherapy were given. A follow-up CT scan showed complete resolution of the tumour masses. The bone marrow was free of lymphoma involvement. He has remained well for 14 years since treatment of the lymphoma and there has been no evidence of a relapse of the lymphoma. There has also been no recurrence of GI bleeding. The patient’s latest CD4 count was 300/mm3 with an undetectable viral load.

Discussion Acute upper GI bleeding in patients with HIV/AIDS is a relatively uncommon condition.8 Four cases of acute

GI bleeding have been reported by Lane et al.8 in a series of 85 consecutive AIDS patients. The differential diagnoses of upper GI bleeding in AIDS patients include hematological malignancies like NHL, as well as Kaposi’s sarcoma, ulcerations caused by opportunistic infections such as cytomegalovirus, herpes simplex virus or histoplasmosis. AIDS patients are also prone to thrombocytopenia which will aggravate the GI bleeding. Acute GI bleeding in AIDS patients is associated with significantly reduced survival. Parente et al.9 showed that the estimated survival rate at 12 months was 8% in AIDS patients with GI bleeding vs. 64% in those who did not bleed. The reduced survival can be a consequence of the bleeding itself or of the underlying disease, for which bleeding is a marker of severity. The major presenting symptoms in HIV/AIDS patients with gastric Burkitt‘s lymphoma are abdominal pain and weight loss.9,10 Massive GI bleeding is uncommon. However, NHL that infiltrates the stomach can cause abdominal pain, gastric outlet obstruction and ulcerations, which might be complicated by bleeding and perforation.9,11 The prognosis for patients with HIV-associated NHL of the GI tract is generally poor, with survival after diagnosis of approximately six months on average.11,12 However, survival has improved with the development of chemotherapeutic regimen and antimicrobial prophylaxis, and the usual approach is intensive chemotherapy with CNS prophylaxis, HAART and adequate antibiotic, antifungal and antiviral prophylaxis. The appropriate chemotherapy, antiretroviral therapy, antibiotics and antifungal prophylaxis and rapid recognition and treatment of infections are essential components of treatment for Burkitt’s lymphoma in

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HIV patients.13 In HIV-infected patients with NHL, response to HAART was strongly associated with a better response to chemotherapy and prolonged survival. In AIDS patients with lymphomas, combining HAART with chemotherapy could be a feasible and effective approach.14 Although there is a potential for drug interactions between antiretroviral drugs and chemotherapeutics agents, the use of HAART and chemotherapy is considered to be safe and tolerable.15 However, overlapping side effects are a potential concern, and should be carefully considered when making treatment decisions. For example, zidovudine is associated with severe neutropenia in patients with advanced AIDS. Since cytotoxic chemotherapy regimens are also associated with neutropenia, zidovudine-containing HAART regimens should be avoided and an alternative nucleoside reverse transcriptase inhibitor considered. Similarly, stavudine is frequently associated with peripheral neuropathy, which might be irreversible,16 and peripheral neuropathy is also a side effect of vinca-alkaloids. Dose reduction of vinca-alkaloid may be considered when these two agents are used concomitantly. Vaccher et al.17 observed a higher rate of grade 3/4 autonomic neuropathy in patients with AIDSrelated NHL receiving CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) plus HAART compared with patients receiving CHOP alone in a retrospective study (17% vs. 0%; p ¼ 0.002). The difference may be due to protease inhibitor-mediated inhibition of vincristine metabolism as there was resolution of symptoms following interruption of HAART treatment. Toffoli et al.18 also demonstrated that protease inhibitor-based HAART therapy has no significant effect on doxorubicin pharmacokinetics in HIV patients with NHL treated with chemotherapy. The outcome of HIV-associated Burkitt’s lymphoma has improved since the widespread introduction of HAART. In the pre-HAART era, HIV patients with Burkitt’s lymphoma generally received CHOP-based chemotherapy; methotrexate, etoposide and bleomycin were incorporated in some schedules.19,20 These regimens achieved a complete remission (CR) rate of 32 to 56%, with median survival ranging four to seven months. A little over half (54%) of complete responders relapsed after various chemotherapy regimens.20 Patients with high viral loads, low CD4 counts and CNS involvement usually have a poorer prognosis. Low CD4 count at diagnosis is an independent risk factor for death.21 Patients with baseline CD4 counts of

Durable survival after chemotherapy in a HIV patient with Burkitt's lymphoma presenting with massive upper gastrointestinal bleeding.

Massive upper gastrointestinal bleeding is an uncommon presentation of Burkitt's lymphoma in a patient with HIV/AIDS, and is seldom reported in the li...
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