Article Text
PDF
Abstract
A patient was admitted to hospital with splenic rupture, four 4 days after colonoscopy was performed following one month’s intermittent and aggravating abdominal pain. During recovery from splenectomy, the patient developed sudden tachycardic and tachypnoea. A blood sample revealed a very low blood glucose, high lactate and acidaemia.
The patient required high-dose continuous intravenous glucose, while the lactate remained elevated. Decreasing consciousness with signs of acute liver failure necessitated transfer to an advanced intensive care unit. The patient’s clinical status rapidly deteriorated despite therapeutic intervention. The patient died of multiorgan failure eleven days post-splenectomy. Based on the pathology of the spleen and a post-mortem liver specimen, the patient was diagnosed with a primary extra-nodal B-cell hepatosplenic lymphoma (BCHSL) – an extremely rare form of non-Hodgkin lymphomanon.
Splenic rupture followed by lactic acidosis and hypoglycaemia should lead to suspicion of a cancer-mediated Warburg effect, and prompt urgent chemotherapy.
- Haematology (incl blood transfusion)
- Intensive care
- Pathology
- the Warburg effect
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
Statistics from Altmetric.com
Background
Lactic acidosis (LA) with persistent hypoglycaemia is a rare but known complication of haematological malignancies such as lymphoma and leukaemia and may possibly be explained by the Warburg effect. The Warburg effect is caused by a high glucose uptake and glycolysis in cancer cells leading to low blood glucose and lactate acidosis despite aerobic conditions.1–7
Based on two reviews covering 1964–2010, 38 published non-Hodgkin’s lymphoma (NHL) cases with LA were identified, 15 of which also showed hypoglycaemia.1 8 In addition, we identified 15 cases with lymphoma and the Warburg effect published in the period 2011–2023 (table 1).
Case reports of patients with lymphoma and the Warburg effect 2011–2023
The occurrence of LA in patients with cancer is associated with a poor prognosis. Under normal physiological conditions, lactate is a by-product of anaerobic glycolysis and is recycled to glucose, primarily by the liver and partly by the kidneys. Hyperlactataemia is defined as a serum lactate level above 2.0 mmol/L. When combined with acidaemia (pH<7.35), the condition is known as LA. LA typically occurs when a deficit exists between the delivery of, and demand for, oxygen at the cellular level. Hypoperfusion or hypoxia can cause this deficit, in which case the condition is designated LA type A. The less common LA type B is caused by impaired oxidative phosphorylation due to decreased gluconeogenesis, accelerated glycolysis and/or an impaired Krebs cycle as seen secondary to malignancy.2 8
Atraumatic splenic rupture is rare9 and splenic injuries secondary to colonoscopy are extremely rare.10 Atraumatic splenic rupture may be associated with a variety of causes including disorders with a neoplastic, infectious, non-infectious (inflammatory), iatrogenic (drug or treatment related) or mechanical background; or it may occur in an apparently normal spleen. In a series of 845 patients with atraumatic splenic rupture reported in the period 1980–2008, 59 had an underlying lymphoma (NHL, n=55; Hodgkin’s lymphoma, n=4).9
Hepatosplenic lymphoma is a rare, often clinically aggressive lymphoma, without evidence of nodal disease. Almost all cases are derived from γδ T cells. B-cell hepatosplenic lymphoma (BCHSL) is strikingly rare, with only a handful of published cases.11 Splenic rupture is an unusual presenting sign of lymphoma—we only located 29 reported cases12–41 (online supplemental table 1). Given the rarity of BCHSL, it is not surprising that our case is the first report of this lymphoma presenting with splenic rupture and subsequently the Warburg effect.
Supplemental material
Case presentation
A man in his 70s had intermittent epigastric and right-side abdominal pain with increasing intensity and frequency over a period of 1.5 months. Clinically, he had a high performance level and took no medications. Prior medical history included hemithyroidectomy, hip replacement and curative treated malignant melanoma. Under the suspicion of intestinal cancer, a fast-track colonoscopy was performed as an outpatient procedure at the local regional hospital (day 1). No cancer suspicious lesions were found. On day 5, the patient developed sudden, severe abdominal pain with radiation to the right arm and neck, causing near-fainting. The patient was admitted to the emergency department (ED) at the local hospital. No history of trauma was reported and the only mechanical manipulation near the spleen was the colonoscopy performed 4 days earlier. Clinical examination on admission revealed circulatory instability (table 2).
Clinical examination at the time of emergency department admission
The patient was diagnosed with splenic rupture, necessitating a splenectomy. The patient’s condition did not allow for transfer to a specialised hospital to enable endovascular coiling. The spleen was large and measured 18×13×10 cm with a weight of 1200 g.
After a 24-hour admission on the recovery ward, the patient was transferred to the general surgical ward (on day 6 after the colonoscopy), his only symptom being mild nausea that had resulted in a single episode of vomiting. In addition, his urine output had diminished. On the general surgical ward, furosemide was prescribed on day 9 to increase urine production, and discharge from hospital was planned within the near future. However, in the night between day 9 and day 10 the patient’s condition worsened. Increased respiratory rate, tachycardia and dizziness were observed and his urine output was low, despite the administered furosemide. At this point, the patient’s weight had increased by 9 kg. Because of severe hypoglycaemia and LA, the patient was immediately transferred to the intensive care unit (ICU) at the local hospital.
On day 11, the patient presented with confusion and drowsiness. He was transferred to an advanced level ICU at a specialised hospital because of suspicion of severe acute liver failure. An unchanged high-rate infusion of glucose was needed to maintain glucose levels in the normal range while the level of lactate remained elevated.
Based on microscopy of the removed spleen, a preliminary pathological report on day 13 raised the strong suspicion of splenic lymphoma and the case was referred for specialist haematopathological second opinion.
Investigations and differential diagnosis
An acute CT scan at the ED on day 5 revealed intra-abdominal bleeding from a ruptured spleen. Blood examination revealed a lactate of 2.8 mmol/L, base excess of −3, a pH of 7.41, and a haemoglobin of 93.5 g/L (5.8 mmol/L) (table 3). Blood and urine were cultured—no infectious agents were subsequently found.
Timeline with summary of key laboratory findings during hospitalisation
In the night between day 9 and day 10, the blood glucose level was found to be as low as 1.4 mmol/L (25.3 mg/dL; no exogenous insulin had been administered) and the level of lactate had increased to 20 mmol/L with an arterial pH of 7.14.
Based on CT imaging on days 5, 10 and 11, as well as blood samples, differential diagnoses including intestinal ischaemia, cholangitis, pancreatic pathology and peritonitis were ruled out. The CT images revealed no visible cancer and specifically no lymph node enlargement. Jaundice was observed and confirmed by a bilirubin level of 68 µmol/L. Based on increasing bilirubin, alanine transaminase, lactate dehydrogenase and international normalised ratio, acute liver failure was suspected with associated hepatic encephalopathy, as an explanation for the low level of consciousness in the presence of normal neuroimaging (CT). The suspicion of hepatic encephalopathy was supported by an ammonia of 147 µmol/L on day 12 (table 3).
On day 15, a second-opinion pathological diagnosis of CD5-positive, high-grade splenic B-cell lymphoma was made. Microscopy of the spleen revealed widespread, cell-rich infiltration of the splenic parenchyma with lymphoma cells showing positive reactions for CD20, CD79, PAX-5, CD5 and Bcl-2; partial positive reactions for MUM-1, cMYC and Bcl-6; negative reactions for CD3, CD10, CD23, CD21, CD30, cyclinD1, CD38 and ALK (figure 1). The lymphoma showed a high Ki-67 proliferation index with over 90% of lymphoma cells in cycle. ‘A bone marrow biopsy and PET CT scan were not feasible due to the patient’s clinical condition.’ A postmortem histological liver specimen revealed hepatic infiltration with high-grade B-cell hepatic, morphologically and immunophenotypically identical to that seen in the spleen (figure 1). There were no signs of fibrosis or chronic liver disease.
Histological examination of a postmortem needle specimen from the liver. (A) Routine microscopy shows infiltration of a portal tract (upper right) and adjacent liver parenchyma, primarily in liver sinusoids (central), by a high-grade non-Hodgkin’s lymphoma (H&E×20); (B–D) Immunohistochemistry. Lymphoma cells shows positive reactions for (B) CD20 (B-cells; ×10) and (C) CD5 (×10); D: Ki-67 proliferation index is high in the lymphoma cells.
A final diagnosis was made of primary, extranodal BCHSL.
Treatment
The patient was treated with fluid-resuscitation (crystalloids and blood) and broad-spectrum antibiotics at the time of the ED admission on day 5.
When the patient was found to be hypoglycaemic on day 10, treatment was initiated with infusion of 10% glucose at 160 mL per hour together with additional fluid resuscitation. At the advanced level ICU, the level of hypoglycaemia required unchanged glucose infusion to maintain a normal blood glucose level. The infusion was changed to 20% glucose at 80 mL per hour, to reduce the amount of fluid infusion.
On day 12, the patient underwent endotracheal intubation and was ventilated by respirator. In addition, continuous renal replacement therapy (dialysis) was initiated.
When the suspicion of lymphoma was raised, treatment with the anti-inflammatory drug Solu-Cortef (hydrocortisone sodium succinate) was initiated with 100 mg four times per day.
Outcome
Despite treatment, the patient’s condition deteriorated with the development of multiple organ failure, including failure of the respiratory system, circulatory system, the bone marrow, the liver and the kidneys. The patient’s condition did not allow for chemotherapy, nor for further diagnostic investigations such as bone marrow examination or diagnostic imaging. On day 16 after the initial colonoscopy (11 days after the splenectomy), the patient died.
Discussion
This was a highly complex case that gave rise to a number of reflections.
The patient’s spontaneous splenic rupture was most likely caused by the underlying lymphoma disease, rather than the colonoscopy performed 4 days earlier. Although splenic rupture is a relatively unusual presentation for lymphoma, it is well described (Supplemental Table 1). Lymphoma followed by LA and hypoglycaemia, probably caused by the Warburg effect, is relatively rare and has only been reported in a few cases since 19641 8 (table 1). In this case, the presentation of LA and hypoglycaemia is most likely explained by the Warburg effect, possibly accelerated by impaired gluconeogenesis because of liver failure. In light of the clinical presentation, pathology results, imaging findings and laboratory results, no other reasonable explanations for this case seem to exist.
The cornerstone of treatment for lymphoma with an associated Warburg effect is prompt chemotherapy. Based on published case reports, patients with lymphoma who showed evidence of the Warburg effect, all died when not treated with chemotherapy (table 1). Of 30 cases published from 1964 to 2023, only five patients4 41–44 had a positive outcome, all being treated with chemotherapy.
Supportive care consists of haemodialysis, bicarbonate, thiamine and glucose. Haemodialysis can be used supportively while awaiting the effect of chemotherapy, but cannot alone clear the extreme amounts of lactic acid.41 Treatment of acidosis with bicarbonate alone remains controversial but may improve the circulatory system. Bicarbonate can theoretically increase lactate formation and, thereby, potentially worsen the patient’s clinical condition.1 6 8 Administration of thiamine, even in cases with normal serum levels, is thought to drive pyruvate towards the synthesis of acetyl-CoA instead of lactic acid. However, the role of thiamine as a cofactor in the pathway of ribose synthesis, a precursor of DNA, could serve as a counterargument for its use, since it might increase tumour growth.8 Warburg-related hypoglycaemia may be associated with normal cerebral function.4 45 In these cases, a restrictive glucose strategy may seem reasonable,4 42 45 since treatment with glucose infusion might theoretically increase cancer growth with increased lactic acid production. In our case, the patient was tired but relatively alert at the time of the most severe hypoglycaemia at day 10. Whether a reduced infusion rate of glucose could have been tolerated remains unknown.
Unexplainable LA and hypoglycaemia should raise the suspicion of the Warburg effect and should be considered an oncological emergency. Time is a crucial factor for survival of lymphoma patients presenting with the Warburg effect, hence tissue and/or bone marrow biopsies should be considered immediately to achieve a diagnosis as soon as possible. The most effective treatment for lymphoma with LA is chemotherapy, and this should be initiated without delay.
Learning points
Spontaneous spleen rupture is rare, and an underlying pathological aetiology should be suspected.
Lactic acidosis together with hypoglycaemia should lead to suspicion of the Warburg effect.
The only treatment for lactic acidosis caused by cancer cells is immediate chemotherapy.
Ethics statements
Patient consent for publication
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors MM, SH-D, TS and MFG are designated as authors and they meet all four ICMJE criteria for authorship, by having conceptualised the manuscript and by having reviewed, drafted and approved the final manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.