There are 3 types of acquired immune deficiency syndrome (AIDS)-related lymphomas: systemic non-Hodgkin lymphoma (NHL), primary central nervous system lymphoma, and primary effusion ("body cavity") lymphomas. Diffuse large B-cell lymphoma (DLBCL) is the most common histological type making up approximately 30% of all cases of NHL and is the most commonly encountered aggressive lymphoma.1,2 Diffuse large B-cell lymphoma can occur at any time from adolescence to old age. It is slightly more common in men than in women, generally presents in the middle ages, and usually arises in AIDS patients when CD4 count is less than 100 cell/μL. In non-human immunodeficiency virus (HIV)-infected individuals, the first sign of the condition is a painless swelling in the neck, axilla, or groin caused by enlarged lymph nodes or a rapidly enlarging symptomatic mass due to involvement of nodes often times in the neck or abdomen. However, in HIV-infected individuals extranodal presentation without involvement of other anatomical site is the common presentation. Systemic B symptoms such as night sweats, unexplained high temperatures, and weight loss are observed in 30% of patients with an elevation of lactate dehydrogenase in half of those patients.3,4 In HIV-infected individuals with fever of unknown origin, lymphoma was the primary cause 6.5% of time.5
A 66-year-old Hispanic man with a recent (3-month) diagnosis of HIV/AIDS with latest CD4 count of 0.050 × 109/L (50/μL) and viral load of 130,000 copies/mL was admitted for evaluation of persistent fever of 4 weeks' duration and a 2-day history of diffuse umbilical abdominal pain which localized to the right lower quadrant the next day. The fever is persistent and responds to antipyretic. There is no history of headaches or vision changes. However, there is history of decreased appetite and increased fatigue; per his partner, patient has been slightly forgetful and not quite himself lately. His medical history is significant for high cholesterol level, gastroesophageal reflux disease, and Parkinson disease. The patient is bisexual; there is no history of intravenous drug abuse and no alcohol history; the patient quit smoking 30 years ago. Three months before admission, the patient had presented to his dermatologist with a rash on the chest area, and it was suggested that he get HIV testing; he was found to have AIDS. Medications on admission included atorvastatin, aspirin, carbidopa/levodopa, trimethoprim/sulfamethoxazole, pramipexole, tamsulosin, lansoprazole, and azithromycin. Highly active antiretroviral therapy (HAART) had been delayed because of fevers.
His vital signs showed temperature of 101.1°F, pulse rate of 101/min, respiratory rate of 20/min, and blood pressure of 115/70 mm Hg. On physical examination, the patient was alert and oriented times three and not in acute distress; there was no lymphadenopathy, no oral lesion, and no thrush. His neck was supple, and his lungs were clear bilaterally; his heart has regular rate and rhythm. The abdomen was soft and has normal bowel sounds with mild diffuse periumbilical tenderness, no organomegaly, and no peritoneal signs; cranial nerves II to XII were intact, and no focal deficits were noted. Rectal examination was nontender, and there was good rectal tone; perianal sensation was intact. Chest radiograph was normal. Laboratory values were the following: white blood cell count of 3.8 × 109/L, with a differential count of 63% segmented neutrophils, 1% band forms, 18% lymphocytes, 14% monocytes, 2% eosinophils, 1% basophils, and 1% atypical lymphocytes; hematocrit of 31.7%; hemoglobin level of 11 g/dL, and platelet count of 224 × 109/L. The lymphocyte count was 1.75 × 109/L. The CD4-positive T-cell count was 0.050 × 109/L (50/μL) with the CD8-positive T-cell count of 0.081 × 109/L (81/μL). Serum chemistry was remarkable for serum lactate dehydrogenase level of 665 U/L. Serum cryptococcal antigen was negative. Toxoplasmosis immunoglobulin G was high; rapid plasma reagin was nonreactive, and blood and urine cultures showed no growth.
Considering the history and physical examination, differential diagnosis of lymphoma versus opportunistic infection was suspected. Patient had abdominal computed tomography (CT) that showed acute appendicitis with marked dilatation of the appendix of up to 1.8 cm, with only minimal regional inflammatory changes. Laparoscopic appendectomy was performed, and specimen was sent for pathology that revealed DLBCL of the appendix. The lymphoma cells were positive for CD20, CD45RB, BCL-2, and Ki-67 (Figs. 1-4). They were negative for CD3, CD5, CD10, and BCL-6. Bone marrow biopsy showed no evidence of lymphoma. Follow-up chest, abdomen, and pelvis CT after appendectomy showed no significant mediastinal or hilar lymphadenopathy. However, benign cystic lesions suggestive of metastatic disease were found in the liver. Patient subsequently had bone marrow biopsy that was negative for any malignancy and underwent chemotherapy with rituximab, cyclophosphamide, hydroxydaunomycin (doxorubicin), Oncovin (vincristine), and prednisone (R-CHOP) and HAART was started, and the patient has been doing well clinically. Three months posttreatment, CD4 count was 155/μL, and viral load was <50 copies/mL. Imaging studies posttreatment showed resolution and no sign of recurrence of the disease. The patient is currently disease-free for 15 months since diagnosis of lymphoma.
A 44-year-old man with HIV since 1981 and diagnosis of AIDS in 1995, with CD4 count nadir at less than 10/μL and recent count on admission of 0.7 × 109/L (700/μL), and with a viral load of 31,525 copies/mL, presented to his physician with lower abdominal pain of 2 weeks that radiated to the right side, fever, nausea and vomiting, and no bowel movement for 3 days. Patient denied any chest pain, shortness of breath, diarrhea, and headache. Medications included nelfinavir, nevirapine, stavudine, lamivudine, azithromycin, trimethoprim/sulfamethoxazole, and venlafaxine.
On physical examination, temperature was 102°F (rectal); blood pressure, 129/68 mm Hg; pulse rate, 79/min; and respiration rate, 20/min. The patient was alert and oriented times three and not in acute distress; no lymphadenopathy appreciated. Lungs were clear to auscultation, and the heart has regular rate and rhythm; there was no murmur, and no gallop appreciated. Abdominal examination showed hypoactive bowel sounds and right lower quadrant tenderness with guarding. The patient also had right-sided costovertebral angle tenderness. Laboratory values showed white blood cell count of 11.2 × 109/L, with a differential count of 79.6% segmented neutrophils, 1% band forms, 10.7% monocytes, 0.3% eosinophils, 9.4% lymphocytes, 0% basophils; hematocrit of 34.3%, hemoglobin level of 11 g/dL, and platelet count of 440 × 109/L. The patient had CT of the abdomen that showed inflammatory changes beneath the right kidney in the right iliopsoas area and retroperitoneum, but no abscess was seen. It was consistent with right iliopsoas myositis. Repeat CT showed marked right flank soft tissue inflammation, marked enlargement of iliopsoas muscle, multiple hypodense lesions in liver and spleen, and extensive retroperitoneal adenopathy. Computed tomography-guided right iliopsoas biopsy was done. Immunohistochemical study showed that tumor cells were positive for CD45RB and CD20 and negative for CD3, CD30, keratin, HMB-45, melan A, and S-100 protein. These results were consistent with extranodal malignant B-cell lymphoma-large cell type-involving skeletal muscle. Bone marrow biopsy showed no evidence of malignancy. The patient subsequently received R-CHOP treatment and tolerated the treatment well. Four months posttreatment, CD4 count was 783/μL, and viral load was less than 50 copies/mL; the patient is disease-free, without recurrence for 16 months since diagnosis.
Human immunodeficiency virus-infected individuals have higher risk of developing malignancies compared with the general population. Kaposi sarcoma was the first one to be included in AIDS-defining illness; in 1993, NHL was added as an AIDS-defining illness in the definition of Centers for Disease Control and Prevention guidelines.6
The great majority of AIDS-related lymphomas are high-grade B-cell lymphomas, namely Burkitt lymphoma and DLBCLs with centroblastic and with immunoblastic features.3,4 There are also unusual lymphomas like primary effusion lymphoma and plasmablastic lymphoma of oral cavity as well as primary central nervous system lymphomas.3 Our 2 patients with acquired immunodeficiency syndrome-one with clinical presentation consistent with appendicitis together with CT finding (Fig. 5) and the other with clinical symptoms of appendicitis and CT finding of inflammation of psoas muscle (Fig. 6)-were found to have DLBCLs of the appendix and right psoas muscle, respectively. Both patients were at higher risk of developing lymphoma-one was not on HAART therapy with very low CD4 count and high viral load, and the other was on HAART therapy but had a history of prolonged period of low CD4 count and was failing therapy because of resistance. In both cases, the differential diagnosis of lymphoma was included, and diagnosis was made by immunohistochemical staining. In both cases, the disease was classified as stage IAE because clinical staging did not reveal any other anatomical site involvement.
The pathogenesis of DLBCL is complex and heterogeneous and involves multiple steps including accumulation of multiple genetic and molecular lesions that lead to the survival of malignant clone.5,7 Numerous cases of DLBCL has been reported in the past.8-11 Most cases of NHL of B-cell origin are high grade, aggressive, diffuse, and multiorgan; most of the time, the gastrointestinal system is involved where the terminal ileum and stomach are involved frequently as well as the colon and the rectum, sometimes with the manifestations of perforation, ascites, obstruction, and intussusception.12-14 However, in HIV-infected individuals, extranodal presentation of the disease without involving other anatomical site is the common presentation as seen in the above 2 cases. Hence, lymphoma should be considered in the differential diagnosis in HIV-infected individuals who present with appendicitis or psoas myositis. Recurrences of NHL in psoas muscles have been reported in the past but not as a primary tumor.15
The choice of diagnostic tools depends on the suspected organ site. Biopsy of the involved organ is the criterion standard, followed by imaging studies. Demonstration of CD45 (also known as leukocyte common antigen), critical requirement for T- and B-cell antigen receptor-mediated activation and CD 20 antigens, would classify it as B cell in origin, as was found in both cases. The histological finding of DLBCL as shown in Figure 1 from the first case shows that there is a diffuse growth pattern with large cells (5× normal lymphocytes) resembling immunoblasts (amphophilic cytoplasm, eccentric nuclei with 1 central nucleoli) or centroblasts (pale or basophilic cytoplasm, vesicular chromatin due to chromatin margination, 2-3 nucleoli, often near membrane) associated with neutrophils16; and may have plasmacytic differentiation or epithelioid granulomas.17
The standard of treatment for patients with DLBCL is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); recent studies have shown that treatment with CHOP plus rituximab, compared with CHOP alone, in elderly patients, have shown increased response rate and prolonged event rate and survival.18,19 However, recent report has shown that the use of R-CHOP in AIDS patients causes marked neutropenia and more infection, but the study was criticized from many point of views-one being not accounting for CD4 count. Another issue with regard to survival is the prediction of survival in terms of the expression of certain genes. Genes that were the strongest predictors for survival were LMO2, BCL6, FN1, CCND2, SCYA3, and BCL2; two of these were present in the first case report.20, 21 Although none of these genes were present in the second case, the patient is doing clinically well almost 3 years after chemotherapy.
In conclusion, we report 2 cases of AIDS patients with extranodal presentation of diffuse large-B cell lymphoma which originally presented as acute appendicitis.
1. Straus DJ. Human immunodeficiency virus-associated lymphomas. Med Clin North Am
2. Bower M. Acquired immunodeficiency syndrome-related systemic non-Hodgkin's lymphoma. Br J Haematol
3. Carbone A, Gloghini A. AIDS-related lymphomas: from pathogenesis to pathology. Br J Haematol
4. Cote TR, Biggar RJ, Rosenberg PS, et al. Non-Hodgkin's lymphoma among people with AIDS: incidence, presentation and public health burden. AIDS/Cancer Group. Int J Cancer
5. Lossos IS. Molecular pathogenesis of diffuse large B-cell lymphoma. J Clin Oncol
6. Mbulaiteye SM, Biggar RJ, Goedert JJ, et al. Immune deficiency and risk for malignancy among persons with AIDS. J Acquir Immune Defic Syndr
7. Carbone A. Emerging pathways in the development of AIDS-related lymphomas. Lancet Oncol
8. Muller G, Dargent JL, Duwel V, et al. Leukaemia and lymphoma of the appendix presenting as acute appendicitis or acute abdomen: four case reports with a review of the literature. J Cancer Res Clin Oncol
9. Randin DR, Esplin JA, Levine AM, et al. AIDS-related non-Hodgkin's lymphoma: abdominal CT finding in 112 patients. AJR Am J Roentgenol
10. Pickhardt PJ, Levy AD, Rohrmann CA Jr, et al. Non-Hodgkin's lymphoma of the appendix: clinical and CT finding with pathologic correlation. AJR Am J Roentgenol
11. Liu JK, Kan P, Schmidt MH. Diffuse large B-cell lymphoma presenting as a sacral tumor. Report of two cases. Neurosurg Focus
12. Sheikh RA, Yasmeen S, Prindiville TP, et al. Intestinal perforation and peritonitis in AIDS: case series and review of the literature. JK Pract
13. Heise W, Arasteh K, Mostertz P, et al. Malignant gastrointestinal lymphomas in patients with AIDS. Digestion
14. Malicki DM, Suh YK, Fuller GN, et al. Angiotropic (intravascular) large cell lymphoma of T-cell phenotype presenting as acute appendicitis in a patient with acquired immunodeficiency syndrome. Arch Pathol Lab Med
15. Connor SE, Chavda SV, West R. Recurrence of non-Hodgkin's lymphoma isolated to the right masticator and left poses muscles. Eur Radiol
16. Badve S, Blumstein A, Wiernik P, et al. Non-Hodgkin malignant lymphoma with tissue neutrophilia: a report of 3 cases. Arch Pathol Lab Med
17. Kojima M, Nakamura S, Ichimura K, et al. Centroblastic and centroblastic/centrocytic lymphoma associated with a prominent epithelioid granulomatous response: a clinicopathologic study of 50 cases. Mod Pathol
18. Navarro JT, Lloveras N, Ribera JM, et al. The prognosis of HIV-infected patients with diffuse large B-cell lymphoma treated with chemotherapy and highly active antiretroviral therapy is similar to that of HIV-negative patients receiving chemotherapy. Haematologica
19. Souhami A, Tannock I, Hohenberger P, et al. Oxford Textbook of Oncology.
2nd ed. UK: Oxford University Press; 2002.
20. Kramer MH, Hermans J, Wijburg E, et al. Clinical relevance of BCL2, BCL6, and MYC rearrangements in diffuse large B-cell lymphoma. Blood
21. Lossos IS, Czerwinski DK, Alizadeh AA, et al. Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. N Engl J Med
© 2007 Lippincott Williams & Wilkins, Inc.