Stage IV advanced diffuse large B-cell lymphoma in human immunodeficiency virus infection with achieving cure by using highly active antiretroviral therapy alone: a case report

Introduction

For decades, notable increases in the incidence of non-Hodgkin lymphoma (NHL) have been documented worldwide.^1–3 In recent SEER data, 5.9% of total NHL cases were HIV-infected. ⁴ Among them, the most common subtype of HIV-infected NHL cases were diffuse large B-cell lymphoma (DLBCL). ⁴ Use of highly active antiretroviral therapy (HAART) has contributed to a decline in the incidence of NHL and also a decrease in the overall incidence of AIDS-related lymphoma. ⁵ Much of the focus on the impact of HAART on HIV-related lymphomas has been on epidemiology and prognosis when used together with chemotherapy. ⁵ We describe a remarkable case of an HIV-infected patient with stage IV DLBCL, an aggressive lymphoma, which regressed completely with the use of HAART alone. Written informed consent was obtained from the patient.

Case report

On February 2008, a 48-year-old heterosexual man was evaluated because of dysphagia, odynophagia, and weight loss of 5 kg during the last 2 months. There was no specific finding on physical examination. On endoscopic examination, multiple small or large variable-sized round ulcers were seen in the esophagus. These ulcerative lesions showed cytomegalovirus (CMV) esophagitis from the immunohistochemical staining positivity for CMV antibody. An HIV test was positive (enzyme-linked immunosorbent assay confirmed by Western blot). The patient’s initial CD4 cell count was 69 cells/uL (6%) and the HIV viral load was 510,327 copies/mL. The laboratory examination showed a hemoglobin of 14.3 g/dL, white blood cells of 6620/uL, an LDH of 386 IU/L (the upper limit of normal: 480 IU/L), alanine transaminase 21 U/L, aspartate transaminase 24 U/L, and total bilirubin 0.47 mg/dL. Rapid plasma reagin testing was negative. Hepatitis B surface antigen and hepatitis C virus antibody were negative. Computed tomography (CT) of the neck, chest, and abdomen showed multiple areas of lymphadenopathy and intrahepatic masses. A fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan revealed multiple hypermetabolic lesions at right parotid, liver, and right gluteus medius muscle, and multiple lymph nodes (SUVmax = 6.8) (Figure 1a). Biopsy of the hepatic mass showed large, pleomorphic tumor cells with the following immunohistochemical stains for LCA(+), CD3(–), CD20(+), Pan CK(–), SMA(–), CD34(–), CD15(–), S-100(–). Biopsy findings were compatible with the diagnosis of high-grade malignant lymphoma of B-lineage. The tumor cells were mostly large B cell and negative for CD5. The above-described findings were most compatible with the diagnosis of DLBCL (Figure 2). Unfortunately, there were no available data with additional immunohistochemical stains for CD10, BCL2, and BCL6 and FISH study for MYC, BCL2, and BCL6. An EBV test in tumor cells with EBER or LMP-1 also was not performed. After staging work-up, the patient was finally diagnosed with stage IVB DLBCL, high-intermediate risk with international prognostic index (IPI). OPEN IN VIEWER

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Figure 2.

Liver biopsy. (a) Core needle biopsy (400 H&E) showing a large lymphoid cell population; 400× original magnification. (b) Core needle biopsy (400) Showing diffuse population of CD20-positive B-cells; 400× original magnification.

A HAART regimen of lamivudine, zidovudine, and lopinavir/ritonavir was started as well as prophylactic trimethoprim–sulfamethoxazole against Pneumocystis jiroveci. When the initial biopsy results became available, the patient was advised to return to the hospital for further evaluation and treatment. But, he finally returned to the clinic 8 weeks later and at that time he was asymptomatic, and had gained 3 kg. His CD4 cell count was 194 cells/uL and his HIV viral load was undetectable. He absolutely refused chemotherapy for the lymphoma, but agreed to continue receiving HAART. Follow-up CT scans revealed decreased number and size of hepatic masses and lymph nodes after 6 months of diagnosis. One year after diagnosis, his hepatic masses and multiple areas of lymphadenopathy had disappeared on CT scans. PET scan conducted at 18 months after HAART initiation showed no abnormal FDG uptake (Figure 1b) and his CD4 cell count was 426 cells/uL. His HAART regimen was not changed until April 2012. At that time lamivudine/zidovudine was switched to abacavir/lamivudine to reduce pill burden.

He underwent PET and CT scans regularly. His image studies revealed there was no evidence of recurrence up until 10 February, 2016. His CD4 cell count is 430 cell/uL and his HIV viral load remains undetectable. He has remained adherent to lopinavir/ritonavir and abacavir/lamivudine.

Discussion

Through a MEDLINE search utilizing the following key words: ‘HIV, diffuse large B cell lymphoma, remission and antiretroviral therapy,’ we identified 30 additional reports of HIV-infected patients who were diagnosed with DLBCL and who achieved remission with HAART. Although several cases of low-grade lymphoma with complete regression were reported, we can find only 10 systemic DLBCL cases (except primary CNS lymphoma) that showed remission in patients receiving HAART without chemotherapy or radiotherapy.^6–10

Six out of 10 patients had localized disease and four patients presented with advanced stage (three were stage III and the other was stage IVB) and all of them showed low to low-intermediate risk with IPI (Table 1). The follow-up periods of 9 of the 10 reported cases were less than 5 years (from 9 months to 39 months). One case had a follow-up period over 5 years with a disease-free period of 191 months, but had no information of disease stage and IPI ¹⁰ (Table 1). For diffuse large B-cell NHL patients with complete remission, the guidelines propose follow-up every 3 months for 24 months then every 6 months for 36 months. ¹¹ Few recurrences occur beyond that point for patients with diffuse large-cell NHL or Hodgkin's lymphoma. ¹¹ We have followed him up over 8 years; he has had no evidence of recurrence. According to the definition, our case achieved cure because he remained in complete remission for 5 years or more. Several of the above-noted patients also achieved complete remission of systemic DLBCL by HAART alone (without chemotherapy). However, our case is unique in its noteworthy particulars: stage-IVB disease with multiple-extra-nodal involvement; high-intermediate risk on IPI; and long-term follow-up without relapse. To the best of our knowledge, this is the first case of DLBCL with stage IV, achieving cure with the use of HAART alone.

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Table 1.

Cases of spontaneous regression with HAART alone of HIV–related advanced diffuse large B-cell lymphoma.

References	Stage	Age/Sex	CD4 count at lymphoma diagnosis (cells/µl)	HIV load at lymphoma diagnosis (copies/mL)	Concomitant OIs	HAART	IPI	Length of follow-up	Length of disease-free follow-up	Outcome
Baraboutis et. al. 7	III	48/male	131	302,000	Wasting illness	Tenofovir, emtricitabine, efavirenz	U	U	34 months	Died from recurrence
Koszyk-Szewczyk et.al. 8	III	56/male	288	116,944	Wasting illness	U	Low-intermediate	36 months	26 months	Alive
Griffin et. al. 10	IIIA	40/male	125	3,110,000	U	U	Low	U	39 months	Alive
Griffin et. al. 10	IVB	65/male	70	227,466	U	U	Low-Intermediate	U	24 months	Alive
Griffin et. al. 10	U	21/female	163	57,018	U	U	U	U	191 months	Alive
Our case	IVB	44/male	69	510,327	Wasting illness Cytomegalovirus esophagitis	Lopinavir/ritonavir, lamivudine, zidovudine,	High-intermediate	96 months	78 months	Alive

Multiple immunodeficiency-related factors such as oncogenic viruses, chronic antigenic stimulation, and cytokine overproduction are thought be the main manifestations of lymphomatogenesis in HIV patients. ¹² Recent findings support the possibility that mechanisms other than immune suppression are important, HIV, especially HIV p17 protein, may directly contribute to lymphomatogenesis with enhanced B-cell clonogenic activity. ¹³

As HAART became available, the survival of patients with HIV-DLBCL improved and has become comparable to that of HIV-negative patients.^14,15 These results came from combination systemic chemotherapy and HAART in HIV-DLBCL and there are no survival data using HAART alone for treatment in patients with this aggressive lymphoma subtype. It is clear that the use of HAART protects against the development of HIV-related NHL and improves outcomes.^5–10,14,15 Lymphoma immune reconstitution inflammatory syndrome (IRIS) in AIDS under HAART was reported in one retrospective cohort study. ¹⁶ They reported that patients infected with HIV have increased incidence of malignant lymphoma during the first 6 months after HAART (median 2.2 months). This may be due to IRIS, which is well described for opportunistic infections and Kaposi’s sarcoma. ¹⁷ Detailed lymphoma IRIS studies may explain immunologic control of lymphoma. Immunotherapy for human cancer by tumor-specific T lymphocyte activation is a promising new therapeutic strategy. Immune check-point blockade with inhibitors of programmed death 1 (PD-1) and antibodies to cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) indicate broad and diverse opportunities to enhance anti-tumor immunity and produce clinical response in many human cancers.^18–24 Therefore, the immune reconstitution with HAART might have played a major role in the unexpected regression of the malignant lymphoma. The standard treatment for HIV-associated aggressive lymphoma remains systemic chemotherapy combined with HAART. In light of the results of the present case however, HAART treatment alone, and watchful waiting, may be considered to be an alternative treatment option for HIV-DLBCL with low CD4 count, especially in patients with poor performance status who cannot receive systemic cytotoxic chemotherapy or refuse it. Further data are needed to define the characteristics and predictive parameters of HIV-associated lymphoma that responds to HAART alone.

Conclusion

In conclusion, we report a rare case of spontaneous complete regression of stage IV DLBCL with HAART alone in an HIV-infected patient who achieved eventual cure. It emphasizes the important role of prompt initiation of antiretroviral therapy with careful monitoring of its success. This is an extreme example of the significance of HAART in improving survival and cure in HIV-NHL.