A unifying diagnosis for pancytopenia, fever, hypoglycemia, and lactic acidosis


  • Conflict of interest: None of the authors have any conflicts of interest to declare.

  • A physician or group of physicians considers presentation and evolution of a real clinical case, reacting to clinical information and data (boldface type). This is followed by a discussion/commentary

A 71-year-old Caucasian man from the upper Midwest was transferred from an outside hospital for evaluation of new-onset mental status alterations, diaphoresis, and persistent hypoglycemia of 5 days duration in the setting of recurrent fevers and pancytopenia over the past 5 months. His past medical history was significant for coronary artery disease status post four-vessel coronary artery bypass grafting, hypertension, hyperlipidemia, restless legs syndrome, obstructive sleep apnea, and gastric banding for obesity. Of note, CBC was normal 1 year prior to presentation. Vital signs upon arrival include temperature 36.8°C, heart rate 100 beats per minute, blood pressure 135/78 mmHg, respiratory rate 30 breaths per minute, and oxygen saturation 97% on room air. He was oriented to place and person but not to time. Physical examination was remarkable for splenomegaly.1, 2

Figure 1.

Lymphoma cells in bone marrow trephine biopsy touch prep, Wright-Giemsa, 400× magnification (A). Bone marrow trephine biopsy with intrasinusoidal infiltrate of large neoplastic lymphocytes, hematoxylin and eosin, 200× magnification (B). CD20 stains of neoplastic B-cells which fill intrasinusoidal lumina, L26 antibody to CD20; 200× magnification (C). Bone marrow trephine biopsy with extensive crush artifact, hematoxylin and eosin; 200× magnification (D).

Figure 2.

PET/CT scan [three-dimensional maximum-intensity projection imaging (A) and fusion images at the liver/spleen level (B)] showing profound glucose sequestration in liver, spleen, bone marrow, and brain.

At this point, the differential remains broad. In the absence of any additional data, the most important differential to consider is infection, including bacterial, viral, fungal, or tick borne infection. The protracted time course of his illness makes bacterial etiologies less likely. The authors had to include noninfectious causes such as malignancies, primary bone marrow disorders, liver disease, rheumatologic, and autoimmune disorders in our differential.

Initial work-up at our institution was notable for pancytopenia. Laboratory evaluation showed hemoglobin 11.8 g/dL, leucocyte count 1.9 × 109/L, and platelet count 26 × 109/L. Differential white count was remarkable for neutrophils 56%, lymphocytes 30%, monocytes 13%, metamyelocytes 1%, and few nucleated red blood cells. Absolute neutrophil count was 1,060/L. A peripheral smear showed dacrocytes (red blood cells shaped like teardrops; can be seen in myelofibrosis). He had mild coagulopathy with prothrombin time 16.6 sec, INR 1.4, and aPTT 33 sec. Serum chemistry was notable for direct hyperbilirubinemia (total bilirubin 2.1 mg/dL, direct bilirubin 1.6 mg/dL), elevated liver enzymes (alkaline phosphatase 508 U/L, AST 178 U/L, ALT 56 U/L), hypercalcemia (serum calcium 10.4 mg/dL, with albumin of 3.2 g/dL), hypophosphatemia (serum phosphorus 1.1 mg/dL), anion-gap metabolic acidosis (anion gap 20, bicarbonate 16 mmol/L) and elevated lactate (8.8 mmol/L). Creatinine was normal at 0.6 mg/dL. Blood glucose level at the outside hospital was very low at 26 mg/dL, and he received an intravenous bolus of dextrose 50% prior to transfer. Blood glucose on presentation to our hospital was 82 mg/dL.

As the first step, this patient had to be resuscitated, ideally in an intensive care environment given the degree of lactic acidosis (LA). Infection still remains high on the differential. Further work-up had to include blood and urine cultures, chest X-ray, and possibly a computed tomography (CT) of chest, abdomen, and pelvis. Tick-borne illnesses such as anaplasmosis and ehrlichiosis can present similarly and, therefore, serology had to be obtained. A lumbar puncture with cerebrospinal fluid (CSF) cultures would be desirable, but its safety is questionable given the marked thrombocytopenia [1]. Bone marrow biopsy had to be strongly considered to evaluate pancytopenia.

The patient had a bone marrow biopsy at the referring hospital. Per the outside interpretation, the diagnosis was myelofibrosis with normal trilineage hematopoiesis and complex cytogenetics, including monosomy 7, on cytogenetic analysis.

Splenomegaly, pancytopenia, fevers, and night sweats are certainly features consistent with primary myelofibrosis. Dacrocytes in the peripheral blood smear are also a feature of bone marrow fibrosis. However, a diagnosis of myelofibrosis does not completely explain abnormalities in the liver function tests, unless the liver was involved with extramedullary hematopoiesis; notably, the degree of abnormalities in liver function tests is out of proportion to what is generally seen in extramedullary hematopoiesis involving the liver. In addition, it would also be unusual to see persistent hypoglycemia as well as LA with myelofibrosis. Given the unusual features of this case, I would seek a second opinion from a hematopathologist for an interpretation of the bone marrow biopsy. Monosomy 7 is the most frequent chromosomal abnormality in hematologic malignancies (about 80% of all isolated monosomies) according to analysis of a large unselected cohort of patients with suspected or confirmed hematological malignancies [2]. Monosomy 7 has been described in hematological disorders [3–8], including acute myeloid leukemia, myelodysplastic syndromes, myeloproliferative neoplasms, CMML, and other nonmyeloid malignancies [2].

Shortly after admission to the general medicine floor, the decision was made to transfer the patient to a higher level of care (medical intensive care unit), where he was started on broad-spectrum antibiotics after blood and urine cultures were obtained. Continuous glucose infusion was administered for persistent symptomatic hypoglycemia. A chest X-ray showed mild scattered fibrosis of the left lower lobe with otherwise clear lungs. CT of head and abdomen/pelvis was normal except for splenomegaly. A CT scan of the chest was available from the outside hospital showing small bilateral pleural effusions and atelectasis in the lung bases. Further laboratory evaluation revealed a reticulocyte percentage of 1.19, absolute reticulocyte count of 46.4 × 109/L, lactate dehydrogenase (LDH) of 1,485 U/L and uric acid of 15.1 mg/dL. Vitamin B12 and folate levels were normal. Iron panel showed total iron binding capacity of 222 mcg/dL and ferritin of 883 mcg/L. Creatinine kinase level was normal.

The combination of LA, persistent hypoglycemia, elevated LDH, and uric acid levels make me wonder about high cell turnover and an increase in metabolic rate; as could be observed in leukemia and lymphoma. Myelofibrosis has a significant potential of transformation into an acute, aggressive leukemia [9].

Review of the bone marrow biopsy slides became available on hospital day #5 and revealed significant extensive crush artifact and insufficient sample for analysis, and the hematopathologist recommended a repeat biopsy which was performed on hospital day #6. Results of the repeat bone marrow biopsy became available on hospital day #8 (see image 1) and were diagnostic for intravascular large B-cell lymphoma (IVLBCL) involving 40% of the marrow cellularity. Flow cytometry revealed B cells positive for CD19, CD20, CD 22, and CD5. No expression of CD10 and CD23 was noted. About 60% of nuclei had an unbalanced BCL6 gene rearrangement and a 14q deletion. Nineteen out of 20 metaphases were found to have a complex clone with multiple numeric and structural abnormalities, including monosomy 7.

The diagnosis of IVLBCL provides a unifying explanation for the patient's severe LA and LDH elevation (high cell turnover) as well as hypoglycemia (utilization by lymphoma cells). The next step in management should include staging with a PET/CT scan. Since the central nervous system is involved in 27–39% IVLBCL cases at diagnosis, this patient should also have CSF analysis as a part of the staging workup [10, 11]. Involvement of the CNS will significantly alter therapy as well as prognosis. IVLBCL is usually treated with anthracycline-containing regimen. Since the lymphoma cells are CD20+, rituximab had to be a part of the treatment regimen [12]. Serology for infectious hepatitis had to be obtained prior to therapy with rituximab.

The very high LDH and elevated uric acid are worrisome for spontaneous tumor lysis. I would treat with rasburicase and aggressive intravenous fluid therapy prior to chemotherapy initiation to reduce the risk of end-organ damage [13].

A PET/CT scan on hospital day #8 showed profound glucose sequestration in the liver, spleen, and bone marrow with dramatically decreased cerebral glucose metabolism (see image 2). Spleen was enlarged at 16.7 cm, and there was no lymphadenopathy. CSF analysis was negative for lymphoma cells. Serology was negative for hepatitis.

I would treat this patient with an anthracycline-based regimen, such as CHOP [14]. As mentioned earlier, rituximab had to be added to the regimen due to improved clinical outcomes in patients treated with rituximab [12]. Unfortunately, his liver dysfunction precludes use of standard-dose CHOP chemotherapy. Mechloramine (nitrogen mustard), high dose corticosteroids, and rituximab are not metabolized by the liver and have been shown to improve outcomes when used as a bridge to conventional chemotherapy in patients with lymphoma and significant liver dysfunction [15].

Treatment was started with intravenous methylprednisolone (1,000 mg on hospital day #9, #10, and #11) and rituximab (800 mg on hospital day #9). Mechloramine was not included due to the nation-wide shortage of this drug. After the third dose of methylprednisolone, the patient's mental status significantly improved and the LA and hypoglycemia resolved. Liver function tests were normalized, and, therefore, he was able to receive treatment with standard-dose cyclophosphamide, vincristine, and doxorubicin on hospital day #12. Because IVLBCL has a significant risk of CNS relapse, the authors decided to include prophylactic high-dose intravenous methotrexate as part of the chemotherapy regimen, which may have better efficacy than intrathecal methotrexate therapy in preventing CNS relapse in patients with aggressive lymphoma, although data is limited [16]. After further clinical improvement, the patient was discharged to a rehabilitation facility.


The initial presentation of this gentleman steered the investigations toward an infectious etiology. An added difficulty was the misleading bone marrow biopsy report of myelofibrosis. The patient's first bone marrow biopsy showed extensive crush artifact involving approximately half of the trephine core. Additionally, the finding of a complex karyotype with monosomy 7 was erroneously used to provide further evidence of a myeloid-lineage neoplasm. A second biopsy clearly showed neoplastic B-cells with an intravascular distribution pattern. Flow cytometric and paraffin immunohistochemical immunophenotyping demonstrated a mature, B-lineage immunophenotype. Given the lack of evaluable morphology in the initial biopsy, the repeat biopsy was crucial to establish the proper diagnosis. This case highlights the importance of avoiding premature closure, which can be triggered by over-interpretation of inadequate sample specimens. The initial crush artifact was likely read as myelofibrosis due to the “supporting evidence” of splenomegaly and monosomy 7 on cytogenetics.

IVLBCL belongs to the more aggressive subtypes of Non-Hodgkin lymphomas and usually has a poor prognosis related to a significant delay in diagnosis of most cases. It is characterized by massive proliferation of lymphoma cells within the lumina of small blood vessels (predominantly capillaries). According to the most recent WHO classification, IVLBCL attained the status of an independent disease entity [17] after initially being classified as a rare form of extranodal diffuse large B-cell lymphoma [18]. A series of 96 IVLBCL patients reported the following clinicopathologic features at diagnosis: anemia/thrombocytopenia (84%), hepatosplenomegaly (77%), B symptoms (76%), bone marrow involvement (75%), and hemophagocytosis (61%) [11]. Most patients have an intermediate-high or high score on the International Prognostic Index [11]. Treatment outcomes have significantly improved with the addition of rituximab to standard anthracycline based chemotherapy. Shimada et al. [12] compared treatment outcomes for IVLBCL in Asian patients using chemotherapy with and without rituximab and noted a significantly higher complete response rate (82% rituximab group versus 51% nonrituximab group) and progression-free/overall survival at 2 years (56%/66% rituximab group; 27%/46% nonrituximab group). Similar results were achieved in a report from Ferreri et al. [19] using immunochemotherapy in Western patients. Addition of rituximab to conventional chemotherapy improved complete remission (90% vs. 50%), event-free survival at 3 years (89% vs. 35%), and overall survival at three years (89% vs. 38%). The CNS is not infrequently involved (from 27% [11] to 39% [10]), either during the initial presentation or in relapse. Some groups have treated patients with high-dose chemotherapy followed by autologous stem-cell transplantation either in first remission [20] or in the relapsed setting [21], which may lead to long-term remission [22], although widespread use of this approach is often limited by patient's performance status.

Since chemotherapeutic agents commonly used for IVLCBL have insufficient CNS penetration, some groups recommended the addition of methotrexate or cytarabine [23–25]. This is a controversial area, particularly in light of a recent analysis of CNS relapse in DLBCL patients that did not show a benefit from prophylactic intrathecal methotrexate [16]. There is limited evidence to support the use of high-dose intravenous methotrexate in those considered to be at high risk of CNS relapse, and this is an area that requires prospective evaluation.

LA is a rare complication of hematologic malignancies and even less commonly encountered in conjunction with hypoglycemia. A helpful conceptual framework makes a distinction between type A LA, related to tissue hypoxia/ischemia, and type B LA secondary to underlying disease (B1), drugs or toxins (B2), or inborn errors of metabolism (B3) [26]. Sepsis is one of the most common causes for type A LA while hematologic malignancies, as seen in this case, produce a type B1 LA, presumably by increased glycolysis in tumor cells and decreased lactate clearance secondary to impaired organ function (mainly liver and kidney which account for 90% and 10% of lactate clearance, respectively) [27].

In a case series of 53 patients with LA and underlying hematologic malignancies, 43 had neoplastic involvement of the liver. Hypoglycemia was present in 20 of the 53 patients [28]. Both LA and hypoglycemia can be attributed to a high rate of glycolysis in tumor cells. The intense glucose uptake in the liver, spleen, and bone marrow on the PET scan of our patient can very well be explained by high rate of glucose utilization by neoplastic cells in these tissues. Decreased availability of glucose to vital organs such as the brain led to a correspondingly low uptake in the brain.

Production of lactate results in anion-gap metabolic acidosis, thereby triggering a respiratory compensation that manifests as tachypnea. This can be easily misinterpreted as respiratory distress from a more ominous process such as sepsis or adult respiratory distress syndrome. Both hypoglycemia and uncompensated metabolic acidosis can lead to mental status changes, as seen in our patient. Although sodium bicarbonate can be using as a temporizing measure for LA, early cytoreduction with initiation of chemotherapy is crucial [29]. Presence of LA with hematologic malignancies heralds a poor prognosis, especially for patients who do not receive or do not respond to chemotherapy [28].

This case highlights the importance of time-sensitive diagnosis of IVLBCL but also shows that many of the life-threatening metabolic derangements can be directly related to lymphoma burden and may respond to treatment of the underlying disease. The discovery of unexplained refractory hypoglycemia and/or LA without signs of sepsis or cardiorespiratory dysfunction in a patient with constitutional symptoms should prompt consideration of a hematological malignancy.