Anaplastic large-cell lymphoma in AIDS

Abstract

AIDS-related malignancies may alter clinical courses and result in death in critically ill patients. We present a case of a newly diagnosed AIDS patient with Pneumocystis jiroveci pneumonia, Epstein-Barr virus, and cytomegalovirus infections who was found to have widely metastatic kinase-negative anaplastic large-cell lymphoma. This case demonstrates the diversity in the malignant presentation of HIV-infected patients, outside of the more commonly observed non-Hodgkin lymphomas.

Anaplastic large-cell lymphoma (ALCL) is rarely associated with HIV-infected patients. We describe a case of a newly diagnosed HIV-positive man with pathology-confirmed ALCL and a co-occurring Pneumocystis jiroveci pneumonia, Epstein-Barr virus, and cytomegalovirus infection.

CASE PRESENTATION

A 55-year-old man with newly diagnosed HIV presented to the hospital for a recent onset of fever and a 1-month history of shortness of breath, fatigue, nonproductive cough, night sweats, dysphagia, and a 20-lb unintentional weight loss. He had only received 2 days of highly active antiretroviral therapy prior to presentation. His CD4 cell count was 5/mm³, with a viral load of 609,639 copies/mL on admission. On physical exam, the patient was tachypneic, with evidence of thrush but no lymphadenopathy or splenomegaly initially noted. He was pancytopenic; his white blood cell count was 4.3 K/uL, with 77% neutrophils and 12% monocytes, his hemoglobin level was 8.7 g/dL, and his platelet count was 124/mcL. He had a lactate of 4.3 mmol/L and an elevated lactate dehydrogenase (LDH) of 900 IU/L and was hypoxic, with arterial oxygen of 40 mm Hg. On admission, a two-view chest x-ray showed a subtle increased density in the right infrahilar region, with no evidence of pleural effusion, adenopathy, or consolidation (Figure 1a). The patient was initially treated for P. jiroveci pneumonia with steroids, Bactrim, and then with addition of pentamidine after limited clinical improvement and persistent elevation in LDH, bandemia, and ongoing lactic acidosis.

Figure 1.

(a) Posterioanterior chest x-ray showing subtle increased density in the right infrahilar region, with no evidence of pleural effusion, adenopathy, or consolidation. (b) Anaplastic large-cell lymphoma, hematoxylin and eosin, 400×. (c) Pneumocystis jiroveci, Gomori methenamine silver stain, 1000×. Special thanks to Joseph Manuel Guileyardo, MD, for providing the autopsy images.

Over the next few days, he made modest improvement in respiratory function and was able to be weaned from bilevel positive airway pressure to high-flow nasal canula. A cytomegalovirus PCR test was positive, and he was started on valganciclovir. On hospital day 10, the patient had an acute worsening hypoxia and became tachycardic and febrile, requiring emergent intubation. He also had a new finding of enlarged inguinal lymph nodes. He was more edematous, precluding appreciation of any additional lymphadenopathy. Abdominal ultrasound at that time showed two hepatic masses and splenomegaly. The patient continued a rapidly progressive decline, with worsening multiorgan failure attributed to sepsis despite negative cultures and precluding additional diagnostic studies due to his hemodynamic instability. All blood cultures obtained had no bacterial growth. He died on hospital day 14. An autopsy was performed.

At autopsy, the right and left lungs weighed 1475 and 1175 g, respectively. The lung parenchyma was diffusely consolidated. The pleural surfaces were indurated, with nodules averaging 0.5 cm in diameter. There was splenomegaly (1050 g), hepatomegaly (2000 g), and widespread lymphadenopathy within the chest and abdomen (up to 4.0 cm in greatest diameter). Microscopic evaluations of the lymph nodes revealed architectural effacement, composed of large, atypical lymphoid cells, with prominent nucleoli. Tumor cells were also present in the large upper lobe nodule and the smaller blood vessels throughout the lungs and pleural space (Figure 1b). The bone marrow was devoid of neoplastic cells.

Neoplastic lymphoid cells were diffusely immunohistochemically positive for CD30 and focally positive for CD3 (a T-cell marker) and epithelial membrane antigen. Cells were strongly positive by Epstein-Barr virus–encoded RNA (EBER) in situ hybridization. The tumor cells were negative for anaplastic lymphoma kinase (ALK) protein, B-cell markers (BCL6 and CD20), T-cell markers (CD56, TIA-1, CD4, CD5, CD7, CD43), and HHV-8, PAX5, and CD10. Mitotic activity, or Ki-67, measured 20% to 25%, with focal areas of 60% to 65%. T-cell receptor gamma gene rearrangement and IgH receptor gene rearrangement were unable to yield results due to the poor quality of DNA present in the sample.

The final diagnosis was ALK-negative ALCL arising in a setting of HIV. There was widespread lymphomatous involvement of liver, gallbladder, spleen, kidney, lung, stomach, and heart. Other findings included right and left ventricular dilatation, Pneumocystis pneumonia (Figure 1a), bilateral cytomegalovirus adrenalitis, and an incidental appendiceal carcinoid tumor. Postmortem blood cultures were positive for vancomycin-resistant Enterococcus spp.

DISCUSSION

The World Health Organization (WHO) classification scheme classifies lymphoid neoplasms based on their cell of origin. Peripheral T-cell lymphoma (PTCL) arises from and resembles the phenotype of a mature T cell (1). PTCL accounts for about 5% to 10% of non-Hodgkin lymphomas in the general US population, with an incidence of <1 per 100,000 people (2, 3). PTCL is further subdivided into nodal, extranodal, and leukemic subgroups. ALCL is the least common subtype within the nodal subgroup, representing 12% of the PTCL cases worldwide (4, 5). ALCL is distinguishable based on the strong and diffuse CD30-positive staining of the malignant cells compared to scattered CD30 staining in the more commonly identified PTCL-not otherwise specified (25.9% of PTCL cases).

In 2008, the WHO classification further subdivided ALCL based on the presence or absence of an ALK protein (1). On presentation, ALK-negative ALCL is more likely than ALK-positive tumors to be found in older patients, with more advanced (stage 3 or 4) disease and with increased involvement of extranodal sites, including lung, liver, and skin. ALK-negative ALCL is a more aggressive and less responsive disease, with studies suggesting 5-year overall survival rates of 49% vs. 70% for ALK-positive ALCLs (4).

In HIV-infected patients, non-Hodgkin lymphoma is the most prevalent malignancy. PTCL is less common, occurring in only 12% to 15% of HIV-affected individuals with lymphoma, of which ALCL only accounts for 28% of cases (6, 7). Thus, with the limited available data, most of our knowledge on ALCL in the HIV patient population is based on a comprehensive review of 37 HIV-associated ALCL patients. This case review demonstrated that ALCL was predominantly ALK negative, with an average patient age of 38 years and a mean CD4 count of 83 cells/mm³. Among the cases studied, one-third were EBER positive and 78% of patients presented with advanced lymphoma (stage 3/4), with all showing extranodal involvement including lungs, liver, bone marrow, spleen, and myocardium.

The present case furthers the knowledge of HIV-associated ALCL. The patient had a unique presentation, including newly diagnosed HIV. He also had an AIDS-defining illness of P. jiroveci pneumonia on the onset of presentation, along with cytomegalovirus infection and Epstein-Barr virus. In Perez and colleagues' (2010) review, they found that only 11 of the 37 case reports of ALCL in HIV patients had another underlying AIDS-defining illness.

Regarding treatment, chemotherapy options are usually based around CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CHOP-like therapies. For relapsed/refractory T-cell lymphomas, preliminary data support the use of autologous stem-cell transplantation to increase progression-free survival (8). Additional promising research is focused on anti-CD30 monoclonal antibodies, with positive preliminary response in previously treated ALK-negative patients (9, 10). Undoubtedly, the emergence of novel and targeted therapies will increase our ability to treat and manage ALCL in the future.