Extracavitary primary effusion lymphoma associated with hemophagocytic lymphohistiocytosis
Authors: Narendranath Epperla, Alexandra M. Harrington, Kathleen Hemauer, Nirav N. Shah
Journal: American Journal of Hematology (2016)

A 44-year-old African American male with history of human immunodeficiency virus (HIV) on antiretroviral therapy (ART), chronic hepatitis B, Kaposi sarcoma, and squamous cell cancer (SCC) of the anus was hospitalized with fevers and diarrhea of 2 months duration. He had a documented 30-pound weight loss over the past 6 months and reported intermittent hematuria, but denied abdominal pain, nausea, dysuria, melena, and hematochezia. The patient was diagnosed with HIV in 1989 and was on tenofovir disoproxil fumarate plus emtricitabine (TDF/FTC), darunavir and dolutegravir at the time of presentation. On examination, the patient was febrile (102.0) with an otherwise unremarkable physical exam. Initial blood work was notable for anemia (hemoglobin of 9.4 g/dL, normal 13.7–17.5 g/dL) and thrombocytopenia (platelet count of 59 × 103/uL, normal 163–369 × 103/uL). His absolute CD4 count was 144 cells/uL (normal 410–1540 cells/uL) and HIV viral load was undetectable. Additional work up including chest X-ray, cultures, as well as stool studies was negative. To further evaluate his fevers, the patient underwent Computed Tomography (CT) of head, chest, abdomen and pelvis that demonstrated opacification of the left maxillary sinus with infiltration into the nasal cavity along with mild splenomegaly and widespread lymphadenopathy involving the parotid, supraclavicular, and mediastinal nodes. Additionally, nodularity along the right lateral bladder wall was noted [Fig. 1]. Imaging was concerning for malignancy. CT of the head (above left) revealed complete opacification of the left maxillary sinus. CT abdomen and pelvis (above right) demonstrated nodularity of the right bladder wall. [Color figure can be viewed at wileyonlinelibrary.com] Patients with HIV are at higher risk of developing certain malignant conditions. This patient has a history of two HIV-associated malignancies: SCC of the anus previously treated with 5-Fluorouracil/Mitomycin with radiation and Kaposi sarcoma managed with ART. Human papilloma virus has been associated with HIV related SCC of the anus whereas human herpesvirus 8 (HHV8) has been associated with Kaposi sarcoma. In addition, HHV8 has been related to other lymphoproliferative disorders including primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD)-associated plasmablastic lymphoma and MCD-unrelated plasmablastic lymphoma 1. With his previous diagnosis of Kaposi sarcoma, this patient was at risk for developing other HHV8-related complications. Otolaryngology performed endoscopic maxillary antrostomy with biopsy. The bladder lesion was biopsied by cystoscopy. Both biopsies revealed extensive necrosis and a highly cellular tumor composed of medium to large sized cells with variably condensed chromatin, prominent nucleoli, and abundant amphophilic cytoplasm. The neoplastic cells were strongly positive for CD30, variably positive for CD45 and CD138 and negative for CD3, CD20, CD10, PAX-5, CD79a, and BCL-6. They were strongly positive for EBV in situ hybridization studies and LANA-1 stain (HHV-8 immunohistochemistry), with a very high proliferation rate (Ki-67 close to 100%). A diagnosis of extracavitary PEL was rendered [Fig. 2]. HHV-8 polymerase chain reaction was positive with 4,500,000 DNA copies/mL in the peripheral blood. An EBV nuclear acid amplification test on the blood did not detect any EBV DNA. Sinus biopsy. (A) Hematoxylin & Eosin (H&E)-stained sections reveal necrosis and sinonasal mucosa with underlying tumor (40×), (B) High power magnification of tumor cells (200×), (C) CD30 immunohistochemistry staining in subset of tumor cells (200×), (D) EBV positivity in tumor cells (100×), (E) CD138 positivity in tumor cells (200×), and (F) LANA-1 positivity in all tumor cells (100×). [Color figure can be viewed at wileyonlinelibrary.com] PEL is an aggressive HHV8- associated, B-cell non-Hodgkin lymphoma seen almost exclusively in patients with HIV [It has been described in non-HIV patients as well rarely]. While HHV8 positivity is mandatory for the diagnosis, EBV positivity is variable 2. The typical presentation of classic PEL includes malignant effusions involving the pleural, peritoneal, and/or pericardial cavities without a tumor mass 3. A rare form, extracavitary or solid variant PEL, can present with tumor masses in absence of cavity effusions, as is the case in our patient 2. The PEL variants (both - classical and extracavitary/solid), show similar histopathology, immunophenotype and genotype as well as HHV8 viral status. The tumor cells express CD45 antigen in greater than 90% of cases, but lack expression of B-cell and T-cell associated antigens consistent with a null phenotype 1. Immunostaining of neoplastic cells with LANA-1 stain confirms the presence of HHV8 DNA. The patient continued to have daily fevers to 103.6 degrees through the hospital stay. His ferritin was elevated to 3,997 ng/mL (reference range 30–400 ng/mL), with normal liver enzymes. Staging bone marrow biopsy (BMBx) showed focal lymphomatous lesions consistent with PEL (variable cellularity <5% to 80%). Additionally there was histiocytic hyperplasia with hemophagocytosis seen [Fig. 3]. Thus, due to the constellation of features (fevers, cytopenias, elevated ferritin, splenomegaly and evidence of hemophagocytosis on BMBx), the patient was diagnosed with hemophagocytic lymphohistiocytosis (HLH) felt to be secondary to malignancy and HHV-8. Dexamethasone 10 mg (10 mg/m2) twice daily was started to halt the aggressive inflammation associated with HLH. Bone marrow biopsy. (A) H&E-stained core biopsy showing tumor aggregates with alternating areas of hypocellularity and histiocytic proliferation (100×), (B) Wright-stained aspirate smear demonstrating a hemophagocytic histiocyte (1000×). [Color figure can be viewed at wileyonlinelibrary.com] HLH is an aggressive systemic inflammatory syndrome that leads to end organ damage and frequently death 4, 5. It can be a primary, genetic condition or a secondary, acquired illness as a result of viral infections, hematological malignancies, or autoimmune disorders. It can present in patients with advanced HIV or AIDS, triggered by an opportunistic infection, but it can also occur in those with acute HIV infection or as a manifestation of immune reconstitution syndrome 6-8. Although rare, HHV-8 may be associated with HLH in HIV-infected patients 9. In our patient, HHV-8 in conjunction with PEL was felt to be the trigger for HLH after ruling out other causes including other infectious (with multiple cultures and imaging studies as mentioned above) and medication mediated etiologies. Treatment for HLH involves identification and treatment of underlying etiology, as well as immunosuppression to dampen the exaggerated immune response and prevent end organ damage 5. In this case, the patient was started on steroids initially as a bridge to definitive therapy with chemotherapy aimed at the underlying driving malignancy. Staging Positron emission tomography (PET)/CT revealed increased fluorine-18 fluorodeoxyglucose uptake in the nodal (supraclavicular region, mediastinum, and upper abdomen) and extranodal sites (left maxillary sinus, liver, stomach, bladder and bone) [Fig. 4]. As the patient was on TDF/FTC for HIV which is also the treatment for Hepatitis B, rituximab was felt to be safe with ongoing monitoring of liver function. Patient was started on treatment with the HIV dose adjusted R-EPOCH (rituximab, etoposide, vincristine, cyclophosphamide, doxorubicin) regimen with alternating intrathecal methotrexate and cytarabine each cycle. Fevers resolved after the initiation of chemotherapy. The patient developed new bilateral lower extremity edema after cycle 2 and echocardiogram demonstrated anthracycline-induced cardiomyopathy, so patient received subsequent cycles 3–6 without doxorubicin. Vincristine was also dose reduced for peripheral neuropathy after cycle 3. Follow-up PET/CT after cycle 2 indicated a complete remission (CR) [Fig. 4]. His end of treatment PET/CT confirms an ongoing CR. HHV-8 and ferritin levels were measured and down trended with corresponding treatment. Anterior projection from volume rendered MIP (maximum intensity projection) views of PET during initial staging prior to treatment (A), after cycle 2 of R-EPOCH (B), and after cycle 5 of R-EPOC (C), respectively. Patient showed complete remission after cycle 5 of R-EPOC. Both HLH and PEL have high mortality rates. PEL has a reported median survival less than 6 months 10. Historically, chemotherapy treatment of PEL has consisted of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. However, recently the favored treatment for HIV patients with aggressive non-Hodgkin lymphoma has shifted to R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) 5, 10, 11 given the impressive outcomes in phase II clinical trials. Our patient received R-EPOCH. Despite a CD20 negative neoplasm, rituximab was given as the cell of origin in PEL is a B-cell and due to clinical evidence of benefit in both PEL and other HHV8 driven malignancies such as HIV-associated MCD 12, 13. PEL is an aggressive non-Hodgkin lymphoma that is seen in approximately 4% of all HIV-related lymphomas 14. The majority of patients present with lymphomatous involvement of serous cavities including, peritoneal, pericardial and pleural cavities (classic PEL) 15. However, few patients present with the involvement of extranodal sites most commonly gastrointestinal tract, lung, central nervous system or skin without effusion (extracavitary/solid variant PEL) 16, 17. Clinically, these two variants of PEL seem to have different biological behavior, in that HIV patients with extracavitary/solid PEL appear to have a better survival when compared to patients with classical PEL 16. HHV-8 is strongly associated with PEL and HHV-8 positivity is mandatory for diagnosis of the disease. Plasma levels of HHV8 DNA have been shown to correlate with relapse of other HIV-associated lymphoproliferative disorders, such as MCD 21. HHV8 DNA levels in the peripheral blood were followed and correlated with remission of PEL in this case. PEL can be associated with HLH, another life-threatening disorder, which if not recognized and treated promptly can lead to fatal outcome. HLH is diagnosed when 5 out of 8 criteria are fulfilled—fever, splenomegaly, cytopenias, hypertriglyceridemia and/or hypofibrinogenemia, low or absent NK cell activity, hemophagocytosis in the bone marrow, spleen or lymph nodes, ferritin >500 ng/ml and soluble CD25 >2,400 U/mL 18. It can be a primary, genetic condition or a secondary, acquired illness as a result of viral infections, hematological malignancies, medications or autoimmune disorders. Both PEL and HLH have been associated with HHV8 and tend to have poor prognoses. Patients with poor performance status and lack of ART before diagnosis can result in worse outcome 10. Thus a high index of suspicion is needed especially in patients with HIV and HHV-8- related conditions for early diagnosis and treatment. PEL has traditionally been treated with CHOP chemotherapy with a median survival of 6 months 10. Even though PEL is not a CD20 positive neoplasm, there are reports of the utility of rituximab (monoclonal antibody directed against CD20) in the treatment of this malignancy 11, 12. The addition of rituximab to CHOP therapy has previously been validated in HIV-associated lymphoma (both in newly diagnosed and relapsing disease) 12, 19. In addition, CD30 targeting therapy, including brentuximab vedotin, has demonstrated tumor regression and prolonged survival in mice with PEL tumors derived from HHV-8 and EBV PEL cell lines 20. R-EPOCH was chosen for our patient given the benefit shown in HIV-associated B-cell non-Hodgkin lymphoma and the potential benefit of etoposide for his concurrent HLH 5, 11. ART was continued throughout treatment. The patient achieved complete remission with this regimen. Early recognition of PEL in the HIV population, especially those with documented HHV8 infection, is very important. We recommend following HHV-8 levels as an additional marker for disease remission and monitoring for potential relapse in this patient population. Though rare, clinicians should be aware of the association of PEL and HLH to initiate early treatment for better outcomes.