Authors: Chunyan Li, Xing Chang, Aiping Huang, Shanhong Tang
Institution: Department of Gastroenterology, General Hospital of Western Theater Command
Editorial Note: To help clinical hepatologists broaden their horizons and enrich their practical experience, the Hepatology Digest journal has invited Professor Shanhong Tang's team from the Department of Gastroenterology at General Hospital of Western Theater Command to create the "Liver Challenging Cases" column. This column compiles classic cases encountered by Professor Tang’s team over years of clinical practice and will periodically include complex or rare cases from renowned academic journals. The focus is on elucidating diagnostic and therapeutic approaches for various liver diseases, providing valuable clinical insights for colleagues.Case Review
Hepatosplenomegaly, cholestasis, and splenic infarction have diverse etiologies and present significant diagnostic and therapeutic challenges. Managing cases that simultaneously present these symptoms is even more difficult. Diffuse large B-cell lymphoma (DLBCL) is the most common histological type of non-Hodgkin lymphoma, affecting multiple organ systems and often lacking specificity. Clinical presentation of DLBCL with hepatosplenomegaly, splenic infarction, and cholestasis is rare. This article reports a case of DLBCL primarily manifesting as hepatosplenomegaly, splenic infarction, and cholestasis, which rapidly progressed to lymphoma-associated hemophagocytic syndrome, liver failure, and intestinal failure, providing new diagnostic and therapeutic insights for clinicians.
Case Summary
The patient, a middle-aged male, was admitted due to “recurrent neck pain for more than three months, abdominal pain, and distension for eight days.” Three months prior, the patient experienced neck lymphadenopathy and pain, treated symptomatically (details unspecified) at an external hospital, resulting in reduced neck pain and self-reported lymph node regression. Eight days before admission, the patient developed unexplained abdominal pain and distension, with persistent dull pain radiating to the lower back, accompanied by dizziness, fatigue, jaundice, nausea, vomiting, and poor appetite, seeking treatment at two hospitals.
On April 15, 2024, liver function tests at an external hospital showed: ALB 35.2 g/L, ALT 36 IU/L, AST 148 IU/L, TBIL 121.12 μmol/L, DBIL 90 μmol/L, IBIL 31.12 μmol/L, γ-GGT 489 IU/L, ALP 591 IU/L, TBA 94 μmol/L. Abdominal CT indicated: 1) significant hepatosplenomegaly with patchy low-density areas in the splenic parenchyma; 2) nodules in the anterior hepatic space; 3) increased and enlarged abdominal and retroperitoneal lymph nodes. Symptomatic treatment (details unspecified) led to worsened abdominal pain, prompting admission to our hospital on April 16, 2024.
Physical Examination on Admission:
- T: 36.5°C, P: 50 bpm, R: 21 breaths/min, BP: 129/73 mmHg
- Consciousness: clear
- Skin and sclera: severely jaundiced
- Axillary lymph nodes: palpable, enlarged, non-tender, firm, and mobile
- Abdomen: slightly distended, soft muscles, significant tenderness in the upper abdomen without rebound tenderness or rigidity, no palpable masses, liver edge 6 finger-widths below the costal margin, spleen edge 4 finger-widths below the costal margin, no obvious gallbladder abnormalities, negative Murphy’s sign, negative shifting dullness, negative hepatic and renal percussion tenderness, bowel sounds: 2 times/min, no splash or vascular murmurs.
Auxiliary Examinations:
- Blood count + CRP: WBC 8.92×10^12/L, RBC 4.46×10^9/L, HCT 40.7%, PLT 27×10^9/L↓, N 4.50×10^9/L, N% 50.5%, L 3.32×10^12/L↑, CRP 27.10 ng/L↑
- Coagulation + D-dimer: PT 13.1 S↑, APTT 38.9 S↑, TT 36.5 S↑, INR 1.14, D-dimer 5.85 ng/L↑
- Liver function: TBIL 143.1 μmol/L↑, DBIL 90.9 μmol/L↑, IBIL 52.4 μmol/L, ALT 36.1 IU/L, AST 197.6 IU/L↑, GGT 824.3 IU/L↑, ALP 591 IU/L↑, TBA 94 μmol/L↑
- Viral hepatitis: HBsAg(+), HBsAb(+), HBeAb(+), HBcAb(+), others negative; HCV Ab(±); HBV DNA < 2.0×10^2 IU/mL; HCV RNA < 5.0×10^2 IU/mL
- Tumor markers: CA125 493.20 U/mL↑, CA199 242.90 U/mL↑
- Urinalysis: bilirubin 3+, urobilinogen 4+, protein ±
Abdominal enhanced CT revealed: (1) soft tissue mass density at the duodenum transition, with enhancement consistent with the intestine, likely due to intestinal aggregation; (2) hepatosplenomegaly with patchy and wedge-shaped low-density areas in the spleen, unclear enhancement, suggesting possible splenic infarction; (3) multiple enlarged lymph nodes in the anterior hepatic space, perihepatic area, abdominal cavity, and retroperitoneum; (4) gas and fluid distention with partial gas-fluid levels in the upper rectosigmoid colon.
Symptomatic treatment including anti-infection, bowel movement regulation, liver protection, jaundice reduction, electrolyte balance maintenance, and nutritional support was ineffective, with no relief of abdominal pain and distension. Further superficial lymph node ultrasound showed multiple enlarged lymph nodes in the bilateral neck II-IV regions and axillae.
Subsequent bone marrow aspiration smear revealed: unclear nucleated cell morphology, blurred nuclear and membrane structures, appearing dissolved and undetermined. Bone marrow biopsy pathology indicated: <bone marrow> extensive hemorrhage and necrosis with B-cell lymphoma cell infiltration. Tumor cells: Bcl-2(focal+), CD20(+), CD3(-), CD5(-), CD79a(focal+), CD99(-), Cyclin D1(-), PAX-5(focal+), TdT(-). Lymph node biopsy pathology supported DLBCL, germinal center B-cell subtype (GCB). Tumor cells: Bcl-2(+60%), Bcl-6(+60%), CD10(-), CD20(+), Ki-67(+60%), Lambda(-), MUM-1(-), PAX-5(+), TdT(-). In situ hybridization: EBER(-). Diagnosis: diffuse large B-cell lymphoma.
On the fifth day of hospitalization, the patient developed continuous fever, with a maximum temperature of 39.5°C. On the ninth day, hepatic encephalopathy occurred, and on the eleventh day, gastrointestinal bleeding ensued. On April 27, 2024, blood tests revealed: WBC 0.49×10^9/L↓↓, PLT 5×10^9/L↓↓, L 0.39×10^9/L↓↓, N 0.04×10^9/L↓↓, HB 99 g/L, RBC 3.20×10^12/L; CRP 97.72 mg/L; liver function: ALB 25.7 g/L↓, pre-Alb 26 mg/L, TBIL 327.6 μmol/L↑, DBIL 230.9 μmol/L↑, IBIL 96.7 μmol/L, ALT 84.8 IU/L, AST 513.1 IU/L↑, GGT 754.2 IU/L↑, ALP 1044.4 IU/L↑, TBA 242.9 μmol/L↑; coagulation: TT 26.2 S↑, APTT 45.0 S↑, INR 1.47↑, PT 16.7 S↑; PCT 13.187 ng/mL↑↑. The condition rapidly deteriorated, leading to hemophagocytic syndrome, acute liver failure, intestinal failure, severe infection, and acid-base imbalance. ICU multi-organ support was recommended, but the family refused, leading to discharge and subsequent death.
Case Discussion
Splenic infarction, caused by ischemic necrosis due to obstruction of the splenic artery, its branches, or veins, presents with diverse and non-specific clinical manifestations, most commonly left upper abdominal pain, fever, chills, vomiting, and referred pain to the left shoulder. It is often confused with gastrointestinal or cardiovascular diseases, leading to misdiagnosis as intestinal obstruction or acute myocardial infarction. The most common causes of splenic infarction include hematologic malignancies and thromboembolic diseases. Currently, hematologic diseases causing splenic infarction include thalassemia, leukemia, lymphoma, myelofibrosis, myeloproliferative disorders, and primary thrombocythemia, with thalassemia and malignancies like leukemia and lymphoma being most common. Thromboembolic diseases frequently occur in atrial fibrillation, endocarditis, patent foramen ovale, and artificial heart valves. Pancreatic diseases, infections, and iatrogenic or traumatic causes are rarer. Cholestasis results from impaired bile production by hepatocytes or cholangiocytes, bile secretion inhibition, or bile excretion obstruction, typically presenting as fatigue, pruritus, jaundice, and abnormal liver function. Cholestasis is categorized into intrahepatic and extrahepatic based on the site of the lesion, with diverse and complex causes.
The patient, a middle-aged male, presented with acute onset and rapid progression of symptoms primarily characterized by abdominal pain and distension, jaundice, and lymphadenopathy. Laboratory tests showed elevated ALP, GGT, TBA, and TBIL levels. Imaging revealed patchy and wedge-shaped low-density areas in the spleen, suggesting splenic infarction, along with multiple enlarged abdominal and retroperitoneal lymph nodes. Lymph node and bone marrow biopsies confirmed DLBCL, germinal center B-cell subtype (GCB). Abdominal distension, reduced bowel sounds, and CT findings of intestinal aggregation and gas-fluid levels indicated potential intestinal obstruction, possibly due to lymph node infiltration by lymphoma. The intestinal obstruction led to bacterial translocation, further damaging liver function through pathogen-associated molecular patterns (PAMPs). The patient’s condition rapidly worsened with marked reductions in blood cell counts, elevated inflammatory markers, liver failure, and ineffective symptomatic treatment, eventually developing hepatic encephalopathy, gastrointestinal bleeding, and severe complications, leading to the family’s refusal of ICU treatment and patient’s subsequent death.
DLBCL exhibits varied clinical manifestations depending on the affected tissues, organs, and tumor burden. It initially presents with painless lymphadenopathy, but DLBCL can involve any tissue and organ, with extranodal involvement in 40%-60% of cases. This case of DLBCL involved the liver, spleen, and intestines. Among the many clinical manifestations of DLBCL, splenic infarction is a rare extranodal lesion. Lymphoma-induced hypercoagulable state, vascular obstruction by tumor cells, and splenomegaly leading to local tissue perfusion insufficiency can cause splenic infarction. Early descriptions by William Osler in 1901 identified the classic triad of left upper abdominal pain, splenic tenderness, and mild splenomegaly. However, a retrospective analysis by Lawrence et al. of 26 splenic infarction cases found left abdominal pain in about 50% of patients, left abdominal tenderness in 36%, and absence of symptoms or signs in the splenic region in 31%, with 21 patients diagnosed with previously unrecognized underlying diseases. Thus, splenic infarction should be considered even without abdominal pain, and the underlying cause should be actively investigated. Cholestasis in lymphoma patients can result from tumor cells compressing hepatic sinusoids, obstructing liver blood vessels, or infiltrating intrahepatic bile ducts, leading to extensive cholangitis and biliary necrosis. The patient’s progressive liver failure may be related to immune dysregulation and excessive inflammatory response in the later stages, further damaging liver function.
DLBCL is the most common lymphoma subtype in China, with aggressive behavior and high heterogeneity. When immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) reveal C-MYC positivity ≥40%, BCL2 positivity ≥50%, or/and BCL6 positivity ≥50%, it is classified as “double-hit” or “triple-hit” lymphoma, representing high-grade B-cell lymphoma with poor prognosis. In this case, immunohistochemistry showed tumor cells positive for Bcl-2 (60%) and Bcl-6 (60%), but C-MYC was not tested. Given the rapid disease progression, high-grade B-cell lymphoma is highly suspected. Persistent fever, progressive liver dysfunction, pancytopenia, and elevated inflammatory markers suggest a high likelihood of concomitant hemophagocytic lymphohistiocytosis (HLH), but further testing was not possible due to the patient’s family’s decision.
The “Chinese Expert Consensus on the Diagnosis and Treatment of Lymphoma-Associated Hemophagocytic Syndrome (2022 Edition)” states that HLH should be suspected in lymphoma patients with unexplained persistent fever, cytopenia, splenomegaly, or liver dysfunction. HLH is an excessive inflammatory response syndrome caused by primary or secondary immune dysregulation, mainly involving abnormal activation and proliferation of lymphocytes, monocytes, and macrophages, secreting large amounts of inflammatory cytokines. Serum ferritin ≥500 μg/L and elevated soluble CD25 (sCD25), triglycerides >3 mmol/L, and low fibrinogen <1.5 g/L are diagnostic criteria for HLH. Cytokine profile testing, though not included in HLH diagnostic criteria, also suggests HLH if interleukin-6 (IL-6), IL-10, and interferon-gamma (IFN-γ) are elevated.
For stage III and IV DLBCL patients, R-CHOP is the first-line chemotherapy regimen. Our team previously reported a case of DLBCL with hepatosplenomegaly and severe cholestasis. Upon diagnosis, the patient was admitted to a specialized ICU for severe jaundice (TBIL 460.2 μmol/L, DBIL 433.7 μmol/L). Immediate R-CHOP chemotherapy led to rapid improvement in liver function indicators, with good chemotherapy sensitivity, and liver function and morphology normalized within two weeks. The patient has completed eight chemotherapy cycles with normal liver function and spleen size on follow-up. Therefore, early diagnosis and chemotherapy significantly improve prognosis in DLBCL. However, in this case, the patient presented with severe HLH, liver failure, intestinal failure, and other serious complications at the time of diagnosis. The family refused ICU support, leading to the patient’s rapid decline and death after discharge.
In summary, common causes of pathological splenic infarction include thromboembolic diseases and benign or malignant hematologic diseases, with thalassemia, leukemia, and lymphoma being the most frequent hematologic causes. Left upper abdominal pain with CT findings of patchy or wedge-shaped low-density areas with non-enhancement, with the base near the splenic margin and apex pointing to the splenic hilum, suggests splenic infarction. Lymphoma typically presents with painless superficial lymphadenopathy, and cases manifesting as hepatosplenomegaly, splenic infarction, and cholestasis are rare, leading to misdiagnosis. Clinical examination should be thorough, and after excluding thromboembolic and hypercoagulable states, hematologic diseases should be considered, with timely bone marrow and lymph node biopsy. Early diagnosis and chemotherapy in DLBCL improve prognosis. Rapid disease progression in DLBCL should raise suspicion for high-grade B-cell lymphoma and concomitant HLH.
