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
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 . 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 . Monosomy 7 has been described in hematological disorders [3–8], including acute myeloid leukemia, myelodysplastic syndromes, myeloproliferative neoplasms, CMML, and other nonmyeloid malignancies .
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 .
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 . 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 .
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 . As mentioned earlier, rituximab had to be added to the regimen due to improved clinical outcomes in patients treated with rituximab . 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 .
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 . After further clinical improvement, the patient was discharged to a rehabilitation facility.