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Annals of Clinical & Laboratory Science 40:75-79 (2010)
© 2010 Association of Clinical Scientists

Case Report

Primary Testicular Lymphoma and AIDS

Nitin Verma1, Uzair B. Chaudhary1, Luciano J. Costa1, Vinay Gudena1 and John Lazarchick1,2
Departments of 1 Medicine, and 2 Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina

Address correspondence to John Lazarchick, M.D., Department of Pathology and Laboratory Medicine, Medical University of South Carolina, 165 Ashley Avenue, PO Box 250908, Charleston, SC, USA; tel 843 792 0217; fax 843 792 4811; e-mail lazarj{at}musc.edu.


   Abstract
Top
 Abstract
Introduction
 Case Study
 Discussion
 References
 
Immunosuppressed patients have an increased risk for developing extranodal lymphoma, including testicular lymphoma. In AIDS patients, primary testicular lymphoma has been reported as an initial manifestation of the disease. These patients typically present at an early age; their lymphomas usually have aggressive histologic appearance and are associated with poor prognosis. We report a testicular lymphoma consistent with diffuse large B-cell lymphoma (DLBCL) in an AIDS patient and we review the literature on primary testicular lymphoma in AIDS patients.

Keywords: AIDS, primary testicular lymphoma


   Introduction
Top
 Abstract
 Introduction
Case Study
 Discussion
 References
 
Testicular lymphoma is a highly lethal disease, second only to primary CNS lymphoma among extra-nodal lymphomas, with a median survival of 12 to 24 months [1]. It accounts for 1 to 2% of non-Hodgkin’s lymphomas (NHL), with an incidence of 0.26/100,000 persons/year [2]. Before the era of HIV infections, primary testicular lymphomas comprised 3 to 5% of testicular tumors and they generally occured in the elderly. During the current era of HIV infections, primary testicular lymphomas are estimated to comprise 5% of testicular tumors and they tend to occur in patients <50 years of age. In HIV-infected patients, primary testicular lymphoma has been reported as the initial manifestation of the disease [3,4]. We report a testicular diffuse large B-cell lymphoma (DLBCL) with a high proliferative index in an AIDS patient and we review the literature on primary testicular lymphoma in HIV-infected patients.


   Case Study
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 Abstract
 Introduction
 Case Study
Discussion
 References
 
The patient was a 47-yr-old white male with a medical history significant for hepatitis C infection, which was diagnosed in 1997. In 2000, he received interferon and ribavirin therapy for hepatitis C, with minimal response. In March 2005 he was found to be HIV-positive during a routine examination in the hepatology clinic. In May 2005, his CD4 count was 1200/mm3 with a viral load of 145,000 copies/ml. An abdominal ultrasound study, performed for follow-up of hepatitis, disclosed intra-abdominal adenopathy. Further imaging studies revealed mild mediastinal, axillary, and inguinal adenopathy that was attributed to the HIV infection. The patient was not started on antiretroviral therapy at that time.

In September 2005, the patient noted right testicular swelling. He was initially treated with antibiotics with no improvement. He reported night sweats and had 3.6-kg weight loss during a 2-month period. His CD4 count was 573/mm3. A scrotal ultrasound study revealed an enlarged right testis with diffusely hypoechoic parenchyma.

The patient underwent a radical right inguinal orchiectomy. Pathologic examination of the testis showed diffuse infiltration by monotonous intermediate sized lymphocytes with high nuclear:cytoplasmic ratio. There were scattered mitotic figures, plasma cells, and immunoblast-like cells (Fig. 1AGo), positive for CD20 (Fig. 1BGo), positive for Ki-67 in >99% (Fig. 1CGo), and negative for CD3, CD43, and CD79a.


Figure 1
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  		Fig. 1. Morphologic and immunohistochemical features of DLBCL involving the testis. Panel A: The infiltrate is composed of intermediate sized lymphocytes with pleomorphism in nuclear size and shape. Benign appearing macrophages containing cytoplasmic debris are prominent. Panel B: Upon immunohistochemical staining, all of the neoplastic cells are CD20-positive. Panel C: More than 99% of these cells also show nuclear staining with the proliferation marker Ki67.

 
Fluorescent in situ hybridization (FISH) did not reveal c-myc translocation and cytogenetic studies were normal, supporting the diagnosis of DLBCL rather than Burkitt lymphoma, despite the high proliferative index noted on Ki67 staining. Examinations of bone marrow and cerebrospinal fluid were negative for lymphomatous involvement. Imaging studies showed mild mediastinal and retroperitoneal adenopathy, unchanged from the scans performed 6 months before, and hence presumed to be reactive to HIV infection. The final diagnosis was primary testicular DLBCL stage IB.

The patient was treated with the Hyper-CVAD regimen [5] with the addition of rituximab (R-Hyper-CVAD) [6] due to the aggressive nature of the disease. The patient also received prophylactic intrathecal chemotherapy. Due to persistence of elevated serum levels of liver enzymes, antiretroviral therapy was not started until after the second cycle, with Efavirenz and Abacavir/Lamivudine, along with TMP-SMX for Pneumocystis jiroveci prophylaxis. The patient developed worsening liver function due to active hepatitis C, which interrupted further chemotherapy. He was admitted to the hospital with acute pancreatitis and sepsis, from which he died at seven months after the initial diagnosis of lymphoma.


   Discussion
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 Abstract
 Introduction
 Case Study
 Discussion
References
 
In brief, this HIV-positive patient was diagnosed with primary testicular DLBCL. He had liver dysfunction due to hepatitis C, intolerance to antiretrovirals, and prolonged cytopenia from high dose chemotherapy. The patient died of acute pancreatitis and sepsis, seven months after initial diagnosis. Even though testicular lymphomas account for only 4% of all extranodal NHL and 5% of all testicular malignancies, they are the most common testicular malignancy in men >60-yr old [7]. Immunosuppressed patients have increased risk for developing extranodal lymphoma, including testicular lymphoma [8]. This patient subset typically presents at an early age (median age 37 yr) with an aggressive histologic tumor grade (centroblastic or immunoblastic DLBCL, or Burkitt lymphoma) and a poor prognosis [8].

Testicular lymphoma may be the primary and only manifestation of malignant lymphoma, the initial sign of generalized disease, or it may occur during the clinical course of a patient with established lymphoma. Secondary involvement of the testis in patients with lymphoma is far more common than primary testicular lymphoma [8]. Autopsy studies show a high incidence of testicular involvement with systemic lymphoma. Givler [9] reported microscopic involvement of the testis with NHL in 19 of 102 (18.5%) patients. Testicular involvement by DLBCL, compared to nodal lymphoma and extranodal lymphomas of other sites, is associated with increased risks of bone marrow and CNS involvement [8].

Increased incidence of high-grade NHL in HIV patients was first reported in 1984, following the description of NHL in 90 homosexual men with acquired immunodeficiency syndrome (AIDS) [10]. Since 1985, aggressive B-cell lymphoma has been classified as an AIDS-defining illness and is the second most common cancer associated with HIV. Using data obtained by linking AIDS and cancer registries in selected areas of the United States, Cote et al. [11] demonstrated that the relative risk of developing lymphoma within 3 years of an AIDS diagnosis was increased by 165-fold when compared to cohorts without AIDS. The increases in risk were 652-fold for high-grade DLBCL immunoblastic tumors, 261-fold for Burkitt lymphomas, 113-fold for intermediate-grade lymphomas, and 14-fold for low-grade lymphomas [10,11].

The WHO classification of AIDS Related Lymphoma includes Burkitt lymphoma (BL), atypical Burkitt lymphoma, DLBCL, and other more uncommon entities such as primary effusion lymphoma (PEL) and plasmablastic lymphoma [12]. There are multiple possible mechanisms and pathways responsible for the development of lymphomas in HIV patients. These include chronic B-cell stimulation induced by HIV itself as well as other coinfecting viruses such as Epstein-Barr virus (EBV) and human herpes virus 8, genetic aberrations, and cytokine deregulation. Although testicular lymphomas encompass a heterogeneous group of lymphomas, the most common primary testicular lymphoma is diffuse large B-cell lymphoma, which comprises >70% of cases in most reported series. The other subtypes that are reported include follicular lymphoma, plasmablastic, lymphoblastic, and Burkitt’s lymphoma [13–15].

The reported data for a total of 9 HIV patients with testicular lymphoma are listed in Table 1Go [3,4,13,16–20]. In contrast to testicular lymphoma in the non-HIV setting, most patients were <50 years of age, including our patient. The median overall survival after diagnosis was <6 months in these patients. Recently, rituximab as well as HAART has been added to the management of AIDS-related lymphomas. We used the R-Hyper-CVAD regimen in our patient, although there was limited literature available to us due to the rarity of this disease.


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  		Table 1. Summary of clinical data in nine cases of AIDS patients with testicular lymphoma.
 
Retrospective analyses have shown that after locoregional treatment (orchiectomy and radiation therapy) only, relapse is high, ranging from 50 to 80%, with a third of the patients relapsing in the CNS or in the contralateral testis [21,22]. The cause of the consistently observed high rate of extranodal relapses in primary testicular lymphoma remains undefined. A particular pattern of expression of adhesion molecules, resulting in poor adhesion of lymphoma cells to the extracellular matrix, may contribute to this behavior (23). In addition, both testis and CNS have been considered immune privileged sites where lymphoma cells may escape from T lymphocyte–mediated immunosurveil-lance, sanctuary sites where chemotherapy may have reduced efficacy [24]. Clinical staging of testicular cancer in AIDS patients may be less accurate due to benign lymphadenopathy (nonspecific reactive hyperplasia typical of AIDS), infection, and pulmonary lesions. These may be mistaken for metastasis and result in clinical over-staging of pathologically Stage I tumors [25,26]. In our opinion even PET/CT would be of limited utility in the presence of reactive lymphadenopathy secondary to the virus.

The presence of a primary B-cell testicular lymphoma in a patient younger than fifty years may imply a significantly altered immune status and is highly suggestive of AIDS. Because of the poor prognosis, an aggressive treatment approach is warranted. Management of testicular lymphoma in HIV patients presents daunting challenges including aggressive pathology, altered immune status, immune privileged sites of the disease, and intolerance to antiretrovirals to list a few. What is the optimal timing of HAART (during or after chemotherapy) for the best outcome of ARL? What is the role of rituximab in the setting of AIDS-related testicular lymphoma in an immune privileged site? These questions remain unanswered due to the paucity of literature on the treatment of testicular lymphoma in HIV patients. The answers might help to improve the survival of patients with this otherwise dismal disease.


   References
Top
 Abstract
 Introduction
 Case Study
 Discussion
 References
 

  1. Gospodarowicz MK, Sutcliffe SB, Brown TC, Chua T, Bush RS. Patterns of disease in localized extranodal lymphomas. J Clin Oncol 1987;5:875–880.[Abstract/Free Full Text]
  2. Moller MB, d’Amore F, Christensen BE. Testicular lymphoma: a population-based study of incidence, clinicopathological correlations and prognosis. The Danish Lymphoma Study Group. Eur J Cancer 1994; 30A:1760–1764.
  3. Buzelin F, Karam G, Moreau A, Wetzel O, Gaillard F. Testicular tumor and the acquired immunodeficiency syndrome. Eur Urology 1994;26:71–76.
  4. Sokovich RS, Bormes TP, McKiel CF. Acquired immunodeficiency syndrome presenting as testicular lymphoma. J Urology 1992;147:1110–1111.[Medline]
  5. Cortes J, Thomas D, Rios A, Koller C, O’Brien S, Jeha S, Faderl S, Kantarjian H. Hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone and highly active antiretroviral therapy for patients with acquired immunodeficiency syndrome-related Burkitt lymphoma/leukemia. Cancer 2002;94:1492–1499.[Medline]
  6. Thomas DA, Faderl S, O’Brien S, Bueso-Ramos C, Cortes J, Garcia-Manero G, Giles FJ, Verstovsek S, Wierda WG, Pierce SA, Shan J, Brandt M, Hagemeister FB, Keating MJ, Cabanillas F, Kantarjian H. Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer 2006;106: 1569–1580.[Medline]
  7. Zouhair A, Weber D, Belkacemi Y, Ketterer N, Dietrich PY, Villa S, Scandolaro L, Bieri S, Studer G, Delacretaz F, Girardet C, Mirimanoff RO, Ozsahin M. Outcome and patterns of failure in testicular lymphoma: a multicenter Rare Cancer Network study. Int J Radiat Oncol, Biology, Physics 2002;52:652–656.
  8. Shahab N, Doll DC. Testicular lymphoma. Sem Oncology 1999;26:259–269.
  9. Givler RL. Testicular involvement in leukemia and lymphoma. Cancer 1969;23:1290–1295.[Medline]
  10. Ziegler JL, Beckstead JA, Volberding PA, Abrams DI, Levine AM, Lukes RJ, Gill PS, Burkes RL, Meyer PR, Metroka CE, et al. Non-Hodgkin’s lymphoma in 90 homosexual men. Relation to generalized lymphadenopathy and the acquired immunodeficiency syndrome. NEJM 1984;311:565–570.[Medline]
  11. Cote TR, Biggar RJ, Rosenberg PS, Devesa SS, Percy C, Yellin FJ, Lemp G, Hardy C, Geodert JJ, Blattner WA. Non-Hodgkin’s lymphoma among people with AIDS: incidence, presentation and public health burden. AIDS/Cancer Study Group. Int J Cancer 1997;73:645–650.[Medline]
  12. Raphael M, Said J, Borish B, Cesarman E, Harris NL. Lymphoma associated with HIV infection. In: WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues, 4th ed (Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, Eds), IARC Press, Lyon, 2008; pp 340–342.
  13. Al-Abbadi MA, Hattab EM, Tarawneh MS, Amr SS, Orazi A, Ulbright TM. Primary testicular diffuse large B-cell lymphoma belongs to the nongerminal center B-cell-like subgroup: A study of 18 cases. Mod Pathol 2006;19:1521–1527.[Medline]
  14. Paladugu RR, Bearman RM, Rappaport H. Malignant lymphoma with primary manifestation in the gonad: a clinicopathologic study of 38 patients. Cancer 1980;45: 561–571.[Medline]
  15. Turner RR, Colby TV, MacKintosh FR. Testicular lymphomas: a clinicopathologic study of 35 cases. Cancer 1981;48:2095–2102.[Medline]
  16. Mohler JL, Jarow JP, Marshall FF. Unusual urological presentations of acquired immune deficiency syndrome: large cell lymphoma. J Urol 1987;138:627–629.[Medline]
  17. Armenakas NA, Schevchuk MM, Brodherson M, Fracchia JA. AIDS presenting as primary testicular lymphoma. Urology 1992;40:162–164.[Medline]
  18. Wilson WT, Frenkel E, Vuitch F, Sagalowsky AI. Testicular tumors in men with human immunodeficiency virus. J Urol 1992;147:1038–1040.[Medline]
  19. Haddy TB, Sandlund JT, Magrath IT. Testicular involvement in young patients with non-Hodgkin’s lymphoma. Am J Ped Hemat/Oncol 1988;10:224–229.
  20. Perez-Santos LG, Gamboa-Dominguez A, Guzman-Rodriguez H, Salazar-Nando A, Tapia-Rangel B, Sotomayor-de-Zavaleta M, Gabilondo-Navarro F. Testicular lymphoma in two patients with AIDS and two without AIDS. Rev Invest Clin 1998;50:423–427.[Medline]
  21. Duncan PR, Checa F, Gowing NF, McElwain TJ, Peckham MJ. Extranodal non-Hodgkin’s lymphoma presenting in the testicle: a clinical and pathologic study of 24 cases. Cancer 1980;45:1578–1584.[Medline]
  22. Martenson JA Jr, Buskirk SJ, Ilstrup DM, Banks PM, Evans RG, Colgan JP, Earle JD. Patterns of failure in primary testicular non-Hodgkin’s lymphoma. J Clin Oncol 1988;6:297–302.[Abstract]
  23. Drillenburg P, Pals ST. Cell adhesion receptors in lymphoma dissemination. Blood 2000;95:1900–1910.[Abstract/Free Full Text]
  24. Riemersma SA, Jordanova ES, Schop RF, Philippo K, Looijenga LH, Schuuring E, Kluin PM. Extensive genetic alterations of the HLA region, including homozygous deletions of HLA class II genes in B-cell lymphomas arising in immune-privileged sites. Blood 2000;96:3569–3577.[Abstract/Free Full Text]
  25. Logothetis CJ, Newell GR, Samuels ML. Testicular cancer in homosexual men with cellular immune deficiency: report of 2 cases. J Urology 1985;133:484–486.[Medline]
  26. Wilkinson M, Carroll PR. Testicular carcinoma in patients positive and at risk for human immunodeficiency virus. J Urology 1990;144:1157–1159.[Medline]




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