Lactic acidosis: a unique presentation of diffuse large B-cell lymphoma

Abstract

An elderly man in the seventh decade of life was brought to the hospital with worsening mental status. Blood tests revealed anaemia and thrombocytopenia with elevated lactate dehydrogenase and serum lactate levels. CT scan showed bulky thoracic and abdominal lymphadenopathy with splenomegaly. A positron emission tomography scan confirmed the above and in addition, revealed bilateral adrenal involvement. Bone marrow biopsy revealed non-germinal centre B-cell-like (non-GCB)-diffuse large B-cell lymphoma (DLBCL). Prompt treatment with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab with intrathecal methotrexate chemotherapy resulted in a dramatic improvement in the patient’s condition. This vignette serves as a reminder to include aggressive lymphomas like DLBCL in the differential diagnoses of patients presenting with metabolic encephalopathy and lactic acidosis. Our patient was moribund at presentation with poor sensorium and failure to thrive. The dilemma was whether to take an aggressive stand and start chemotherapy urgently or whether to stabilise the patient first and then consider the treatment of DLBCL. We make a case for initiating therapy promptly in such patients irrespective of their performance status.

Background

Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma (NHL) in the USA.¹ Although one-third of the patients present with extra-nodal involvement, central nervous system involvement is not uncommon and predicts dismal prognosis. Type B lactic acidosis is a rare life-threatening paraneoplastic phenomenon described more often in association with haematological rather than solid malignancies.² It can manifest as abdominal discomfort, tachypnea, myalgia and altered mental status (AMS) among others. Prompt and accurate diagnosis, immediately followed by aggressive targeted chemotherapy can be lifesaving. Here we report a unique case of DLBCL presenting with AMS from type B lactic acidosis from the lymphoma.

Case presentation

An elderly man with no significant past medical history was brought to the hospital with worsening mental status. He was in good health until a few weeks ago when he began experiencing progressive fatigue and night sweats. He had been to the local emergency room three times in the past month for dizziness, dehydration and weakness and was discharged after hydration and supportive care. His family noted declining sensorium and brought him to the hospital. He had not seen his primary care physician for the past several years and was not on any medications. He had a remote history of left ankle surgery 20 years ago following an injury. Social history included cigarette smoking, social alcohol consumption and prior marijuana use. His father had died of lung cancer several years ago. On admission, he was afebrile with blood pressure 116/66 mm Hg, heart rate 71 beats/min, respiratory rate 14 breaths/min and saturating at 96% on room air. He was agitated and restless but had no signs of head trauma and Glasgow Coma Score was 11(E2V4M5). On neurological examination, he was awake, alert and oriented to place and person but not to time. He had delayed speech response but was able to follow commands. Gross motor and cranial nerves examination were normal. He had no signs of meningeal irritation. Other system examination was essentially normal.

Investigations

Blood tests showed anaemia (haemoglobin 80 g/L) and thrombocytopenia (platelet count 68×10⁹/L) with normal white blood cell (WBC) count. The comprehensive metabolic panel revealed elevated liver enzymes (aspartate aminotransferase 149, alanine aminotransferase 121) and prothrombin time (18.6 s, international normalised ratio 1.68). Lactate dehydrogenase (LDH) was significantly elevated at 12 688 U/L. Blood lactic acid was markedly elevated at 99 (normal range: 8.1–15.3 mg/dL). Blood glucose and serum ammonia were normal. Toxicity screen for alcohol and drugs of abuse was negative. Chest X-ray, urinalysis and ECG were normal. CT brain showed no evidence of intracranial haemorrhage or mass effect. Arterial blood gas analysis showed compensated metabolic acidosis with increased anion gap (pH 7.37, pCo₂ 21, HCO₃ 12). He had no other metabolic derangements. Such marked elevation of LDH level is commonly seen in malignancies like abdominal or lung cancers, lymphomas, severe shock and hypoxia and sometimes in benign haematological conditions like untreated megaloblastic or pernicious anaemia. Although our patient had elevated liver enzymes along with high LDH level, patients with liver diseases commonly have relatively worse derangement of liver function parameters than LDH. His extremely high blood lactic acid (LA) level was also a significant concern. A rapidly progressing infection or malignancy was considered based on history and physical examination and preliminary laboratory testing. Infectious workup including multiple blood and urine cultures and viral studies for HIV and hepatitis B and C were negative. Cerebrospinal fluid (CSF) analysis revealed colourless fluid on gross examination, normal CSF opening pressure, glucose 48 mg/dL, protein 60 mg/dL, LDH 32, WBC 2, red blood cell 1, malignant cells—negative, rapid plasma reagin (RPR) and HSV PCR—negative. The patient was too restless and agitated to undergo a brain MRI during early evaluation. Due to high LDH and LA levels, evaluation for malignancy was undertaken, specifically lymphoma. CT scan showed bulky thoracic and abdominal lymphadenopathy with splenomegaly. A positron emission tomography (PET) scan confirmed the above and also, revealed bilateral adrenal involvement (figure 1A). Bone marrow biopsy revealed non-germinal centre B-cell-like (non-GCB)-diffuse large B-cell lymphoma (DLBCL).

Figure 1.

(A) Pretreatment images on positron emission tomography scan demonstrate fluorodeoxyglucose-avid enlarged cervical and thoracic lymph nodes, adrenal and diffuse spleen involvement consistent with lymphoma.(B) Two cycles of DA-EPOCH-R later, repeated images reveal complete metabolic and radiographic resolution (arrows). DA-EPOCH-R, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab with intrathecal methotrexate.

Differential diagnosis

Here we describe the clinical course of a patient with DLBCL who presented with AMS and high anion gap metabolic acidosis secondary to elevated blood lactate. The absence of any obvious alternative aetiology for AMS and temporal association between normalisation of sensorium and resolution of lactic acidosis with therapy suggests lactic acidosis as the cause of his altered mentation. For this reason, an expensive test like MRI was not pursued at a later point in time as the patient was showed significant clinical improvement. The patient did not have any evidence of infection or hypotension ruling out sepsis or cardiac failure as a cause for type A lactic acidosis from hypoxia. High LDH levels were consistent with massive tumour burden as demonstrated in the imaging studies. Elevated serum lactate has been previously described in patients with leukaemia and lymphoma and is traditionally associated with poor prognosis as it is commonly a terminal event in such cases.^{3 4} It is extremely rare for lactic acidosis to be the presenting feature in haematological malignancies.

Treatment

DLBCL is a high-grade lymphoma with rapid disease progression and typically fatal course without therapy. While chemotherapy is generally deferred in patients with poor performance status, DLBCL is one of those rare malignancies where timely intervention can occasionally salvage a moribund patient and even lead to a cure. Bearing this in mind, after extensive discussion with the family, our patient was promptly started on dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab with intrathecal methotrexate. His mental status deteriorated further during the initial 3 days but then started to recover. By day 8, he had regained normal sensorium which correlated with resolution of lactic acidosis and near-normalisation of serum LDH (figure 2). He was discharged to a subacute rehabilitation unit for steroid-induced proximal myopathy.

Figure 2.

The line graphs depict the return of serum LDH and lactate levels to normal after the start of chemotherapy which correlates with resolution of the clinical findings.

Outcome and follow-up

By the end of cycle 2, he had made a full neurological recovery with interim scan showing near-complete remission (figure 1B). He continued further therapy as an outpatient with a plan to complete six cycles of chemotherapy with curative intent. Unfortunately, he developed a mycotic abdominal aortic aneurysm due to recurrent neutropenia which progressed to fungal sepsis with multiple emboli despite adequate anti-fungal therapy. He died of septic shock and intracranial haemorrhage after cycle 5.

Discussion

A literature search reveals few case reports of patients with lactic acidosis as the ominous manifestation of diffuse large B-cell lymphoma. In one case report, patient with relapsed DLBCL had serially mounting serum lactate levels and died at home after a few weeks following discharge from the rehabilitation centre. In another case, a 61-year-old man with acute onset confusion, anasarca, pancytopenia and lactate levels of 4.9 at admission with no obvious site of malignancy on the initial evaluation, died after developing ventricular tachycardia on day 4 of hospitalisation. The autopsy revealed extensive extranodal site involvement of heart, peripancreatic tissue, liver and subserosa of the digestive tract with CD 20—DCBCL. In one report, a patient with intermittent fever for 1 week on admission was found to have elevated lactate levels pancytopenia, and his bone marrow biopsy revealed hemophagocytosis. He was treated with EPOCH regimen. His lactate levels rapidly reduced and the patient showed significant improvement clinically. In a recently published report, a patient with DLBCL presented abdominal mass and lactic acidosis was found to be thiamine deficient. On treatment with intravenous thiamine, his lactic acid levels rapidly normalised emphasising thiamine deficiency as one of the reasons for elevated lactate levels in patients with DLBCL. Elevated lactate levels have been commonly seen as a terminal event in the disease process. The pathophysiology of increased serum lactate levels in lymphoma is not completely understood. It is possibly secondary to an interplay between multiple factors like preferential aerobic glycolysis by tumour cells (Warburg effect),⁵ hepatic parenchymal dysfunction from tumour infiltration leading to impaired lactate breakdown and, thiamine and riboflavin deficiency causing cessation of oxidative phosphorylation and diverting energy production towards anaerobic glycolysis. Since the symptoms of lactic acidosis are non-specific, a high index of suspicion is needed for appropriate diagnosis and timely therapy.

Learning points.

• This vignette serves as a reminder to include aggressive lymphomas like diffuse large B-cell lymphoma (DLBCL) in the differential diagnoses of patients presenting with metabolic encephalopathy and lactic acidosis.

• Type B lactic acidosis is a rare life-threatening paraneoplastic phenomenon described more often in association with haematological malignancies and is traditionally associated with poor prognosis.

• DLBCL is one of those rare malignancies where timely intervention can occasionally salvage a moribund patient and even lead to a cure.