Author: Li Chunyan, Chang Xing, Huang Aiping, Tang Shanhong
Unit: Department of Gastroenterology, General Hospital of the Western Theater of Operations
Editor's note: In order to help clinical hepatologists broaden their horizons, enrich their practice, and cultivate their clinical thinking skills, International Liver Disease specially invited the team of Professor Tang Shanhong from the Department of Gastroenterology of the Western Theater General Hospital to jointly create a column of "Liver Difficult Cases". This column brings together the "classic cases" encountered by Professor Tang Shanhong's team in clinical diagnosis and treatment for many years, and will also regularly collect complex or rare clinical cases published in well-known academic journals, focusing on the diagnosis and treatment of various liver diseases, and providing valuable clinical reference for the majority of colleagues.
Thematic review
The etiology of hepatosplenomegaly, cholestasis and splenic infarction is variable, and clinical diagnosis and treatment are difficult. The diagnosis and treatment of the above three symptoms at the same time is more challenging. Diffuse large B cell lymphoma (DLBCL) is the most common histological type of non-Hodgkin lymphoma, and its lesions invade various systems and organs of the body and lack specificity. DLBCL with hepatosplenomegaly, splenic infarction, and cholestasis as the main manifestations is relatively rare in clinical practice. This article mainly reports a case of DLBCL with hepatosplenomegaly, splenic infarction, and cholestasis as the main manifestations, and then the condition deteriorates sharply and develops into lymphoma-related hemophagocytic syndrome, liver failure, and intestinal failure, so as to provide some new ideas for clinicians to diagnose and treat this type of disease.
Summary of medical records
The patient was a male and was admitted to the hospital with recurrent neck pain for more than 3 months, abdominal pain and bloating for 8 days. More than 3 months ago, the patient developed cervical lymphadenopathy and pain, and was treated outside the hospital, and after symptomatic treatment (specifics unknown), the patient's neck swelling and pain were reduced, and the self-reported enlarged lymph nodes disappeared. During hospitalization (8 days ago), there was no obvious cause of abdominal pain, abdominal distention, persistent vague pain, radiating to the back of the lower back, accompanied by dizziness, fatigue, yellow staining of the skin and sclera, nausea, vomiting, anorexia, and was transferred to two hospitals.
2024-04-15院外查肝功能：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。 腹部CT提示：1）肝脾明显增大，脾脏实质密度团片状稍低密度影；2）肝前间隙区结节影；3）腹腔内及腹膜后淋巴结增多，部分增大。 给予对症治疗（具体不详）后患者腹痛较前加重，于2024-04-16入我院。
Physical examination after admission: T 36.5°C, P 50 times/min, R 21 times/min, BP 129/73 mmHg, conscious, severe yellow staining of the skin and sclera; Bilateral axillary palpable enlarged lymph nodes, nontender, slightly hard, and sliding; The abdomen is slightly distended, the abdominal muscles are soft, the epigastric tenderness is obvious, there is no rebound tenderness, muscle tension, the whole abdomen has no palpable mass, 6 transverse fingers from the lower edge of the liver to the lower costal margin, 4 transverse fingers from the lower border of the spleen to the inferior costal margin, no obvious abnormality in the gallbladder, Murphy's sign (-), moving dullness (-), percussion pain in the liver region (-), percussion pain in the bilateral renal region (-). Bowel sounds 2 times/min, no vibrating water sounds and vascular bruits were heard.
辅助检查：血常规+CRP：WBC 8.92×1012/L、RBC4.46 ×109/L 、HCT 40.7%、PLT 27×109/L↓、N 4.50×109/L、N% 50.5%、L 3.32×1012/L↑、CRP 27.10 ng/L↑；凝血功能+D-二聚体：PT 13.1 S↑、APTT 38.9 S↑、TT 36.5 S ↑、INR 1.14、D-二聚体 5.85 ng/L↑；肝功能：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↑、TBA94 μmol/L↑；肝炎病毒: HBsAg（+）、HBsAb（+）、HBeAb（+）、HBcAb（+），其余阴性；HCV Ab（±）；HBV DNA < 2.0×102 IU/mL；HCV RNA<5.0×102 IU/mL；肿瘤标志物：CA125 493.20 U/mL↑、CA199 242.90 U/mL↑；尿常规：胆红素3+、尿胆原4+、尿蛋白+-。
Abdominal CT with enhanced abdomen showed (Fig. 1) :(1) The soft tissue density shadow of the mass in the descending-horizontal segment junction area of the duodenum was consistent with the intestinal tract after enhancement, and the intestinal aggregation was considered. (2) Hepatosplenomegaly, intrasplenic patches and wedge-shaped hypodense shadows, unclear enhancement, considering the possibility of splenic infarction; (3) Multiple swollen lymph nodes in the prehepatic space, left diaphragmatic angle, hepatogastric space, abdominal cavity and retroperitoneum; (4) Intestinal pneumosis above the rectal-sigmoid junction, effusion dilation, and partial air-fluid level formation.
Figure 1. Abdominal CT with contrast showed that the volume of the spleen increased significantly, and there were multiple patches and wedge-shaped hypodense shadows in the parenchyma, which were not obvious after enhancement (A sagittal artery stage, C was coronary artery stage), and nodular soft tissue hypodense shadows with a diameter of about 2.5 cm were seen at the splenic hilum (B was the sagittal portal stage, D was the coronary portal stage)
Anti-infection, laxative, hepatoprotective, yellowing, maintenance of electrolyte balance and nutritional support were not effective, and the patient's abdominal pain and bloating were not relieved. Further improvement of superficial lymph node ultrasound showed that bilateral neck II-IV multiple swollen lymph nodes, bilateral axillary lymphadenopathy enlarged.
后完善骨髓穿刺涂片示：有核细胞形态不清，胞核及胞膜结构模糊，呈溶解状态，无法确定细胞属性。 骨髓活检病理示（图2）：<骨髓>红骨髓大部分出血、坏死，背景B细胞淋巴瘤细胞侵犯。 瘤细胞：Bcl-2(灶+)、CD20(+)、CD3(-)、CD5(-)、CD79a(灶+)、CD99(-)、Cyclin D1(-)、PAX-5(灶+)、TdT(-)。 淋巴结活检病理示：结合免疫标记检查支持弥漫大B细胞淋巴瘤，生发中心细胞亚型（GCB)。 瘤细胞：Bcl-2(+，60%)、Bcl-6(+,60%)、CD10(-)、CD20(+)、Ki-67(+，60%)、Lambda(-)、MUM-1(-)、PAX-5(+)、TdT(-)。 原位杂交：EBER(-)。 诊断：弥漫性大B细胞淋巴瘤。
Fig. 2.(A) Bone marrow biopsy with magnification of 10×10x, the nucleated cell capacity of bone marrow tissue is about 90%-100%, trilineage proliferative inhibition with hemorrhage and necrosis, and diffuse infiltration of a large number of lymphocytes in the background. (B) Axillary lymph node biopsy with magnification of 1×20x, and the microscope showed diffuse and uniform distribution of medium-sized lymphocytes. (C) Lymph node biopsy immunoassay immunoassay CD20 with magnification of 10×20x
住院的第5天开始出现连续发热，最高体温39.5℃，住院的第9天发生肝性脑病，第11天出现消化道出血。 2024-04-27复查血常规：WBC 0.49×109/L↓↓、PLT 5×109/L↓↓、L 0.39×109/L↓↓、N 0.04×109/L↓↓、HB 99 g/L、RBC3.20×1012/L；CRP 97.72 mg/L；肝功：ALB 25.7 g/L↓、pre-Alb 26 mg/L、TBIL 327.6 μmol/L↑、DBIL230.9 μmol/L↑、IBIL96.7 μmol/L、ALT 84.8 IU/L、AST 513.1 IU/L↑、GGT 754.2 IU/L↑ 、ALP 1044.4 IU/L↑、TBA242.9 μmol/L↑；凝血功能：TT 26.2 S↑、APTT 45.0 S↑、INR 1.47↑、PT 16.7 S↑；PCT 13.187 ng/mL↑↑。 病情急剧加重，出现噬血细胞综合征、急性肝衰竭、肠道功能衰竭、重症感染、酸碱平衡紊乱等，建议重症ICU进一步多器官支持治疗，患者家属拒绝，自动出院，出院后死亡。
Case discussion
Splenic infarction is avascular necrosis due to occlusion of the splenic artery or its branches or veins, and its clinical manifestations are diverse and nonspecific, with the most common symptom being pain in the left upper quadrant, and other common symptoms including fever, chills, malignant vomiting, and radiating pain in the left shoulder. It is often confused with gastrointestinal diseases and cardiovascular diseases, and is easily misdiagnosed as intestinal obstruction and acute myocardial infarction [1]. The most common causes of splenic infarction are benign and malignant diseases of the hematologic system and thromboembolic diseases. At present, the hematologic diseases that cause splenic infarction include thalassemia, leukemia, lymphoma, myelofibrosis, myeloproliferative diseases, essential thrombocythemia, etc., and the most common are thalassemia and malignant tumors such as leukemia and lymphoma. Thromboembolic diseases are common in atrial fibrillation, endocarditis, patent foramen ovale, prosthetic heart valves, etc. Pancreatic disease, infectious disease, iatrogenic disease, and trauma are rare causes. Cholestasis is caused by dysfunction of bile production in hepatocytes or bile ducts, inhibition of bile secretion or obstruction of excretion, and is often characterized by fatigue, pruritus, jaundice, and abnormal liver function. Cholestasis can be divided into intrahepatic cholestasis and extrahepatic cholestasis according to the lesion location, and the etiology is complex and diverse.
The patient was a middle-aged male, with acute onset and rapid progression, with abdominal pain and abdominal distension as the main clinical manifestations, and physical examination: yellow staining of the skin and sclera, swollen lymph nodes on the body surface, and hepatosplenomegaly. Laboratory examination showed increased ALP, GGT, TBA, TBIL, and imaging showed that there were patches and wedge-shaped low-density shadows in the spleen, and the enhancement was unclear, and splenic infarction was considered; Multiple enlarged lymph nodes in the abdominal cavity and retroperitoneum. After improving superficial lymph node biopsy + bone marrow aspiration and flow cytometry, the diagnosis of DLBCL was supported, and the germinal center cell subtype (GCB) was supported. The patient presents with abdominal distension, decreased bowel sounds, and abdominal CT with contrast suggests intestinal aggregation, intestinal pneumosis above the recto-sigmoid junction, effusion dilation, and partial air-fluid level formation, and the possibility of lymphoma infiltrating intestinal lymph nodes is not ruled out. Intestinal obstruction leads to translocation of gut microbiota and related bacterial products, further impairing liver function through pathogen-associated molecular patterns (PAMPs). In the course of the disease, the patient's blood trilogy decreased sharply, the inflammatory index progressively increased, liver failure, and the symptomatic treatment effect of active anti-infection, liver protection, and yellowing was not good, and then the patient developed hepatic encephalopathy, gastrointestinal bleeding, and the condition aggravated sharply, and it was recommended that the intensive care unit for further treatment was recommended, and the patient's family refused, and was automatically discharged from the hospital, and died after discharge.
The clinical manifestations of DLBCL are diverse, depending on the tissues, organs, and tumor burden involved. Painless lymphadenopathy is common in the initial stages of the disease, but DLBCL can affect any tissue or organ, and extranodal lesions can range from 40 to 60 percent [2]. In this case, DLBCL has invaded extranodal organs such as liver, spleen, and intestine. Among the many clinical manifestations of DLBCL, splenic infarction is a rare extranodal lesion. Hypercoagulability caused by tumor cells and occlusion of blood vessels in lymphoma; Tumor burden, excessive splenic growth, resulting in local tissue hypoperfusion leading to splenic infarction [3]. As early as 1901, William Osler described the clinical features of early splenic infarction as a triad of left upper quadrant pain, tenderness in the splenic area on examination, and mild enlargement of the spleen (Osler's triad). However, Lawrence et al. [4] retrospectively analyzed 26 patients with splenic infarction and found that about 50% of patients had left-sided abdominal pain, 36% had left-sided abdominal tenderness, 31% had no symptoms or signs in the splenic region, and 21 of these 26 patients were diagnosed with previously unrecognized underlying diseases due to the diagnosis of splenic infarction. Therefore, most of the splenic infarction can cause pain in the left abdomen, but the absence of abdominal pain cannot completely exclude splenic infarction, and the cause of splenic infarction should be actively sought for the diagnosis of patients. Cholestasis in lymphoma patients is due to the retention of tumor cells in the liver and the compression of the hepatic sinusoids, which may block the blood vessels of the liver and affect the blood supply. Secondly, tumor cells invade the intrahepatic bile ducts, resulting in large-scale cholangitis and bile duct necrosis; The progressive exacerbation of the patient's condition and the subsequent development of liver failure in this patient may be related to the excessive inflammatory response caused by abnormal immune activation in the later stage, and a large number of inflammatory cytokines further damage liver function.
DLBCL is the most common subtype of lymphoma in mainland China, highly aggressive and highly heterogeneous. When the positive rate of C-MYC is ≥40%, the positive rate of BCL2 is ≥50%, and/or the positive rate of BCL6 is ≥50%, i.e., "double-hit" lymphoma or "triple-hit" lymphoma is classified as high-grade B-cell lymphoma with a poor prognosis [5]. Immunohistochemistry found tumor cells: Bcl-2 (+, 60%), Bcl-6 (+, 60%), but C-MYC was not examined, and the possibility of high-grade B-cell lymphoma was considered to be high in combination with the patient's disease progression. The patient had persistent fever, progressive deterioration of liver function indicators, a sharp decrease in blood trilineage, and an increase in inflammatory markers, and it was very likely that hemophagocytic lymphohistiocytosis (HLH) was considered.
According to the Chinese Expert Consensus on the Diagnosis and Treatment of Lymphoma-related Hemophagocytic Syndrome (2022 Edition), HLH should be suspected in patients with lymphoma who have clinically unexplained persistent fever, cytopenias, splenomegaly, or abnormal liver function [6]. Hemophagocytic syndrome is a syndrome of hyperinflammation caused by primary or secondary immune abnormalities, which are mainly caused by abnormal activation and proliferation of lymphocytes, monocytes, and macrophage systems, and a series of inflammatory responses caused by the secretion of large amounts of inflammatory cytokines [7]. Serum ferritin ≥ 500 micrograms/L, elevated soluble CD25 (sCD25), triacylglycerol >3 mmol/L, and low fibrin <1.5 g/L are diagnostic criteria for HLH [8]. Although cytokine profiling has not been included in the diagnostic criteria for HLH, abnormal elevations of cytokines such as interleukin 6 (IL-6), IL-10, and γ interferon-γ (IFN-γ) suggest the possibility of HLH [9].
Patients with stage III and IV DLBCL are treated with R-CHOP as the first-line chemotherapy regimen[2]. Our team reported a case of DLBCL with hepatosplenomegaly and severe cholestasis as the main manifestations, and when the diagnosis was clear, the patient was admitted to the gastroenterology ICU due to severe jaundice (TBIL460.2 μmol/L, DBIL: 433.7 μmol/L), and the chemotherapy treatment of R-CHOP regimen was started in time, and the liver function indexes improved rapidly after the first chemotherapy, and the chemotherapy sensitivity was good, and the liver function indexes basically returned to normal after 2 weeks, and the morphology of the liver and spleen basically returned to normal. Eight rounds of chemotherapy have been completed so far, and there is no abnormality in liver function indexes in the follow-up, and the size and density of liver and spleen have returned to normal. Therefore, the early diagnosis of DLBCL and early chemotherapy have a better prognosis. However, the patient had serious complications such as severe hemophagocytic syndrome, liver failure, and intestinal failure at the time of diagnosis, and the patient's family refused to receive organ support treatment in the ICU, and died soon after being discharged from the hospital.
In summary, the common causes of pathological splenic infarction include thromboembolic diseases and benign and malignant blood diseases, while thalassemia, leukemia and lymphoma are the most common causes of splenic infarction among hematologic diseases. Splenic infarction should be considered when left upper quadrant pain is present, and abdominal CT shows a patchy or wedge-shaped hypodense unenhanced area with a base proximal to the outer edge of the spleen and a tip pointing toward the hilum of the spleen. Painless superficial lymphadenopathy is the main clinical manifestation of lymphoma, and hepatosplenomegaly, splenic infarction, and cholestasis are rare, so it is easy to miss and misdiagnose. In clinical practice, the physical examination should be careful, in addition to ruling out thromboembolism and hypercoagulability and other possible causes of splenic infarction, it is necessary to consider whether there are hematologic diseases, and timely complete bone marrow and lymph node biopsy. Early diagnosis of DLBCL and prompt chemotherapy have a better prognosis. For patients with DLBCL whose disease progresses rapidly, it is necessary to consider whether they have high-grade B-cell lymphoma and lymphoma-related hemophagocytic syndrome.
Bibliography:
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9. Davis, EJ, Salem, JE, Young, A, et al. Hematologic Complications of Immune Checkpoint Inhibitors. ONCOLOGIST. 2019; 24 (5): 584-588.doi: 10.1634/theoncologist.2018-0574.
Writer
Li Chunyan is a graduate student of the Department of Gastroenterology of the General Hospital of the Western Theater and a master's student of Chengdu University of Traditional Chinese Medicine. He is mainly engaged in clinical research on liver diseases.
Writer
Chang Xing, attending physician of the Department of Gastroenterology, Master of Medicine, has been engaged in the diagnosis and treatment of digestive diseases for a long time.
Writer
Huang Aiping, attending physician of the Department of Pathology of the General Hospital of the Western Theater Theater, member of the Clinical Pathology Branch of Chengdu High-tech Medical Association, and member of the Precision Medicine Branch of Sichuan Bioinformatics Society. He has been engaged in clinical pathology for nearly 10 years, and has been engaged in liver pathology subspecialty work for nearly 6 years, and is familiar with the pathological diagnosis and differential diagnosis of common liver diseases.
Reviewers
Tang Shanhong, Director of the Department of Gastroenterology, Western Theater General Hospital