A case of primary adrenal diffuse large B-cell lymphoma in HIV

Introduction

Primary adrenal lymphoma (PAL) is a rare and highly aggressive disease. In non-HIV patients this is seen in the elderly, especially those with a history of cancer, immunodeficiency or autoimmune disorders. ¹ In around 50% of cases, it presents with symptoms of adrenal insufficiency due to bilateral involvement.^1,2 The most common type of PAL is diffuse large B-cell lymphoma (DLBCL). ³ There is only one previous case reported in the literature in HIV. ⁴

Case report

A 63-year-old man, diagnosed with HIV seven years previously, presented with high-grade fever. He had been poorly compliant with treatment during many years of his diagnosis. He was treated abroad for colorectal lymphoma three years prior to this presentation.

High-grade fever (>38℃) was associated with severe fatigue and shortness of breath. His CD4+ lymphocyte count at presentation was 244 (11%) cells/mm³, and plasma HIV viral load was 44 copies/mL. His antiretroviral therapy comprised tenofovir/emtricitabine (Truvada), darunavir and ritonavir.

He was worked up as a pyrexia of unknown origin (PUO); first line tests revealed moderately impaired renal function with urea 15 mmol/L, creatinine 146 umol/L, eGFR 42 mL/min/1.7 mL/min/1.73 m² and raised C-reactive protein (CRP) 137 mg/L. Whole body, contrast-enhanced CT scan revealed bilaterally enlarged, well-defined homogenous adrenal masses, measuring 50 × 74 mm (normal range: 2.8 × 6.1 mm) on the right and 57 × 83 mm (normal range: 3.0 × 7.9 mm) on the left. There was no evidence of any lymphadenopathy or visceral involvement (Figure 1). A follow-up CT abdomen, two years after treatment of colorectal lymphoma, had revealed normal-sized adrenal glands. OPEN IN VIEWER

Baseline endocrine tests showed normal levels of serum adrenocorticotropic hormone (ACTH), metanephrines, lutenizing hormone (LH)/follicle stimulating hormone (FSH), dehydroepiandrostenedione (DHEA)/testosterone, cortisol, amylase and aldosterone. Serum renin was increased to 294 mU/L (normal range: 3–40 mU/L), and lactate dehydrogenase (LDH) was mildly raised to 361 IU/L (normal range: 90–275 IU/L). Viral polymerase chain reaction (PCR) for cytomegalovirus (CMV), Epstein-Barr virus (EBV) and herpes simplex virus (HSV) were negative in cerebrospinal fluid (CSF). Bone marrow biopsy showed no evidence of lymphoma or histoplasmosis.

He was commenced on broad-spectrum antibiotics for a PUO. Truvada was changed to alternate days and later withheld for a brief period, which led to an improvement of his renal function. CRP improved to <40 mg/L with antibiotics. He was discharged after four weeks awaiting discussion at the adrenal team meeting.

He was readmitted two weeks later with progressive deterioration with temperature >38℃, worsening fatigue and back pain. Repeat endocrine investigations revealed raised serum ACTH of 84 ng/L (normal range: 40 ng/L) and moderately raised LDH of 495 IU/L (normal range: 90–275 IU/L).

Repeat CT scan showed an increase in the size of the adrenal glands with the right adrenal now measuring 76 mm and left adrenal measuring 87 mm, again showing no lymphadenopathy or visceral involvement.

Following endocrine opinion, he underwent CT-guided biopsy which confirmed DLBCL of non-germinal cell type – Stage 4. The neoplastic lymphoid cells were strongly positive for CD20 with moderate positivity for CD79a. The cells were strongly positive for BCL-2, MUM-1 and CD30. EBV (LMP) was expressed in most. The Ki-67 proliferative index was 85%.

The histology of his previous colorectal lymphoma had shown atypical cell population, most likely of lymphoid origin, relatively large atypical cell type with vesicular nuclei and mostly prominent nucleoli and focally weak CD4 expression with almost no CD3, CD5 and CD8 expression. Atypical lymphoid cell population was CD20, CD30, pax5, cycline D1, cam5.2, BCL2 and BCL6 negative.

As the immunostaining of the adrenal biopsy was different from the colorectal biopsy, it was consistent with bilateral DLBCL of the adrenals rather than relapse of his previous colorectal lymphoma to the adrenals.

Over the next few days, he became increasingly confused and disorientated. A repeat MRI brain revealed no new changes. CSF revealed presence of lymphoid cells confirming possible CNS involvement. 41,500 EBV DNA copies/mL were detected in CSF.

He showed mild improvement on steroids but remained confused with poor performance status and was deemed not suitable for chemotherapy. He deteriorated and died within three weeks of tissue diagnosis, three months from the time of his first presentation.

This case posed a diagnostic dilemma as the patient had enlarged bilateral adrenals without lymphadenopathy, visceral involvement or adrenal insufficiency. An important learning message to emphasise would be to pursue early tissue diagnosis and treatment, as it can be fatal within weeks if left untreated.

Discussion

HIV-positive individuals have an increased risk of developing non-Hodgkin lymphoma. After Kaposi’s sarcoma, it is considered to be the most common malignancy in HIV.

The two commonest subtypes are DLBCL and Burkitt’s lymphoma/leukaemia, which are both considered AIDS-defining. ⁵ Since the introduction of highly-active antiretroviral therapy (HAART), the overall incidence of lymphoma is declining, although the AIDS-related lymphomas have increased as a percentage of first AIDS-defining disease.

PAL is extremely rare with only 130 cases reported in the English literature. ⁶ Our patient is only the second case reported in a HIV patient.

Clinical features include fever, weight loss, fatigue, abdominal pain with or without features of adrenal insufficiency, ² which is observed in around 50% of patients;^1,2 its incidence does not correlate with tumour size.^2,7 Adrenocortical insufficiency occurs when there is 90% destruction of the adrenal parenchyma. ⁸

Diagnosis is largely dependent on imaging. On CT and MRI imaging, PALs tend to appear as complex masses of variable density, often with areas of necrosis and/or haemorrhage. ⁹ CT- or ultrasound-guided adrenal gland biopsy is confirmatory. ⁸ Endocrine investigations are supplementary.

Poor prognostic markers include advancing age, tumour size, bilateral involvement, high level of LDH, involvement of other organs and the presence of adrenal insufficiency.^2,10,11

In HIV-positive individuals, a low CD4 count and no prior treatment with HAART also contribute to a poor prognosis. Although our patient was on HAART, he had low CD4 count, bilateral adrenal involvement, raised LDH and compromised endocrine status which possibly led to quick progression of disease.

Treatment includes multiple modalities such as surgery, combination chemotherapy and/or radiotherapy. Commonly used chemotherapy regimes are CHOP ¹² alone or with rituximab. ¹³ The British HIV Association recommends that chemotherapy regimens should be combined with HAART in HIV-positive individuals. ⁵

PAL is a highly aggressive form of lymphoma and, as in this case, is fatal within weeks if left untreated. Full or partial response to treatment is seen in only one-third of cases. ⁹

In conclusion, DLBCL of the adrenals is a rare presentation of an AIDS-defining illness. Early suspicion, diagnosis and treatment are crucial, as the mortality rate is high.