EBV-positive intravascular large B-cell lymphoma of the small intestine: a case report and literature review

doi:10.21203/rs.3.rs-2210505/v1

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Case Report

EBV-positive intravascular large B-cell lymphoma of the small intestine: a case report and literature review

https://doi.org/10.21203/rs.3.rs-2210505/v1

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published 11 Jul, 2023

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Background: Intravascular large B-cell lymphoma is a rare lymphoma that causes symptoms in the central nervous system, skin, and bone marrow.

Case presentation: We report a 75-year-old man who was admitted to the hospital with abdominal pain for four hours. Physical examination revealed abdominal pain and mottled skin. Laboratory tests revealed thrombocytopenia and elevated levels of lactate dehydrogenase.Abdominal CT examination showed thickening, edema, and necrosis of the small intestine wall. Surgical excision of the necrotic small bowel revealed numerous small rounds, consistent, atypical lymphocytes in the mesenteric vein. These cells were positive for CD20, CD79a, CD10, and BCL-2, and were positive for Epstein Barr virus-encoded small RNA (EBER) by in situ hybridization. The patient was diagnosed with IVLBCL and died of MODS after a week of hospitalization without chemotherapy.

Conclusions: IVLBCL that occurs in the small intestine and even in the gastrointestinal tract is an exceedingly rare disease with insidious onset, rapid disease progression and poor prognosis. Fully understanding its clinicopathological features is helpful to understand the disease, make an early diagnosis, and prevent the rapid deterioration of the disease.

Intravascular large B cell lymphoma

IVLBCL

small intestine

case report

We report an intravascular large B cell lymphoma (IVLBCL) and review the literature. IVLBCL is an uncommon extranodal large B-cell lymphoma, that is characterized by the selective growth of lymphocytes in the lumen of blood vessels, especially in the lumen of capillaries, and rarely in large arteries or in the lumen of capillaries. The disease has a wide range of onset ages (range: 13–85 years), mainly in adults, with a median age of onset of 70 years and a male-to-female ratio of 1.1:1^{[1, 2]}. IVLBCL usually occurs in any organ other than the lymph nodes, and swollen lymph nodes are rarely found. The clinical manifestations are mainly in two forms, one of which is that the tumor mainly involves the main organs and shows corresponding clinical symptoms, mainly the nervous system and skin; the other is that the pattern is hemophagocytic cells and shows corresponding clinical symptoms, such as liver failure, hepatosplenomegaly, and pancytopenia. Most patients are already in the terminal stage when they are diagnosed, and some scholars have reported that the disease is usually found at autopsy^[3–5]. The disease can quickly become fatal without treatment.

The histological manifestations of IVLBCL are mainly that the tumor cells are mainly located in the small blood vessel lumen of different organs. Immunohistochemical tumor cells express mature B cell-related antigens, such as CD19, CD20, and CD79a. Thirty-eight percent of cases were positive for CD5, and 12% were positive for CD10^[6].

Table 1

Laboratory Findings on Admission
Cell counts	Test results	Reference value	Unit	Coagulation	Test results	Reference value	Unit
WBC	9.30	3.50–9.50	10⁹/L	APTT	47.6	31.5 ~ 43.5	s
BASO	0.05	< 0.06	10⁹/L	ATIII	56	80 ~ 120	%
EO	0.01	0.02–0.52	10⁹/L	DD2	9.4	< 0.50	mg/L
IG	1.33	1.1–3.2	10⁹/L	FDP	40.3	< 5.0	mg/L
NEUT	7.05	1.8–6.3	10⁹/L	FIB	0.89	2 ~ 4	g/L
RBC	5.08	4.30–5.80	10¹²/L	PT	16.7	11.0 ~ 13.7	s
HGB	162	130–175	g/L	PTA	64	75 ~ 120	%
PLT	53	125–350	10⁹/L	PTR	1.26	~	%
NRBC	0.01	≤ 0	10⁹/L	TT	25.5	< 21.0	s

Biochemistry	Test results	Reference value	Unit
A/G	1	1.2 ~ 2.4	~
ALB	28.8	40 ~ 55	g/L
TP	57.1	65.0 ~ 85.0	g/L
LDH	1173	120 ~ 250	IU/L
WBC: White Blood Cells, BASO: basophil, EO: eosinophil, IG: immature granulocyte, NEUT: neutrophilic granulocyte, RBC: red blood cell, HGB: hemoglobin, PLT: platelets, NRBC: nucleated red blood cell,, APTT: activated partial thromboplastin time, ATI II angiotensin Ⅱ, DD2:, FDP: fibrinogen degradation products, FIB: fibrinogen, PT: prothrombin time, PTA: prothrombin activity, PTR: Prothrombin time rate, TT: thrombin time, A/G: albumin-globulin ratio, ALB: albumin, TP: total protein, LDH: lactate dehydrogenase.

A 75-year-old man was admitted to the First Affiliated Hospital of Kunming Medical University, Yunnan, China, for four hours with acute abdominal pain. Physical examination showed abdominal pain, which spread to the whole abdomen, especially in the right rib area. The abdominal wall had high pressure and tenderness, and the skin of the abdominal wall in the right rib area was purple. Abdominal CT examination showed obvious edema and thickening of the small intestinal wall in the right middle and lower abdomen, blurred surrounding fat space, filling defect and emboli formation in the superior mesenteric vein. Emergency blood examination revealed thrombocytopenia, abnormal coagulation function, and elevated lactate dehydrogenase (Table 1). The patient was admitted to the hospital for surgical treatment of mesenteric venous thrombosis with small bowel necrosis. During the operation, approximately 500 ml of bloody ascites was seen in the abdominal cavity, and approximately 40 cm of intestinal tube showed ischemic necrosis at the junction of the jejunum and ileum near the ileum segment. The patient's condition progressed rapidly, and he died of MODS one week after the operation.

Macroscopic appearance revealed a section of necrotic intestinal tube with a length of 58 cm and a diameter of 2–5 cm. The intestinal wall was in a state of hemorrhage and necrosis, and no enlarged lymph nodes were found in the mesentery.

Histopathologic analysis showed hemorrhage and necrosis in the full thickness of the intestinal wall of the small intestine, small intestine congestion and edema, many extravasations of red blood cells in the intestinal wall, and vasodilation and congestion (Fig. 1A). Many cell clusters composed of uniform tumor cells can be seen in the vessels in the adipose tissue of the serous small intestine, and the tumor cells are approximately 3–5 times that of the normal lymphocytes (Fig. 1B-F). The tumor cells were found only in the lumen of small blood vessels, and no such tumor cells were found in the lumen of larger vessels. Some tumor cells form a tumor thrombus or completely plug the capillary lumen together with the thrombus, forming an embolism. Immunohistochemical results indicated that BCL-2, CD10, CD20, CD79a, LCA, and MUM-1 were positive in these tumor cells, while BCL-6, CD68, PAX-8 and C-MYC were negative. In situ hybridization of EBV RNA was positive for EBER.

Based on the above findings, the patient was diagnosed with intravascular large B cell lymphoma of the small intestine, secondary to mesenteric vein thrombosis and small intestine necrosis. Regrettably, the patient's condition progressed rapidly one week after the operation, and he died of secondary mods, and did not receive chemotherapy.

Table 2

Summary of immunohistochemistry
IHC	Results	Company
CD20	Positive	MXB Biotechnologies
CD10	Positive	MXB Biotechnologies
CD79a	Positive	MXB Biotechnologies
BCL-2	Positive	MXB Biotechnologies
MUM-1	Positive	MXB Biotechnologies
PAX-8	Positive	MXB Biotechnologies
LCA	Positive	MXB Biotechnologies
CKPan	Negative	MXB Biotechnologies
BCL-6	Negative	MXB Biotechnologies
CD21	Negative	MXB Biotechnologies
CD23	Negative	MXB Biotechnologies

Intravascular large B cell lymphoma (IVLBCL) was first reported in 1986^[7]. In 2016, the fourth edition of the World Health Organization classification of haematopoietic lymphoid tumours included it for the first time, and it was included in the classification of mature B-cell tumours and was a separate solid tumours^[8], The fifth edition of the WHO will continue the classification of the fourth edition. IVLBCL is difficult to diagnose at an early stage. When there are obvious clinical symptoms, it has almost spread to the whole body, and some cases are even found at autopsy^[9]. The clinical manifestations of IVLBCL are heterogeneous. From the cases reported, we found that there are three main types of IVLBCL. The first type is the classic type, which is more common in Western countries, mainly involving the central nervous system and skin^[10]. The second type, represented by Japan, mainly manifests as hemophagocytic syndrome, which in most cases manifests as bone marrow involvement, fever, hepatosplenomegaly, and thrombocytopenia^[1]. Some researchers compared the clinical manifestations of Japanese and Western cases and found that Japanese patients mainly presented with hemophagocytic syndrome, while Western patients’ symptoms were neurological and skin symptoms^[11]. The third type, the skin variant, mainly manifests only with skin symptoms, without neurological symptoms and symptoms of hemophagocytic syndrome. The case we reported showed thrombocytopenia, no liver or spleen enlargement was found on imaging, and the patient had no fever. The patient's anterior chest, abdomen, and bilateral inner thigh skin showed piebal-like changes. At the same time, we asked the patient for a history of cerebral infarction. Unfortunately, no biopsy was performed to confirm whether these symptoms were caused by IVLBCL.

IVLBCL can occur in almost all organs of the body. The most common sites are the nervous system and skin. However, with the gradual deepening of the understanding of the disease, IVLBCL has been found in an increasing number of tissues and organs, such as the lung^{[12, 13]},breast^[14],uterus^[15],prostate^[16],liver^[17],kidney^{[18, 19]}, and thyroid^[20]. This disease is relatively rare in the gastrointestinal tract, but some studies have found that 8% (3/38) of IVLBCL case appear in the gastrointestinal tract^[10]. According to the literature we collected, there are 12 literature reports of IVLBCL occurring in the gastrointestinal tract, including 15 cases, of which 5 cases occurred in the small intestine^{[10, 21–31]}. The clinicopathological features are shown in Table 3. The clinical symptoms of IVLBCL in the gastrointestinal tract almost always manifest as acute abdomen, and the pathogenesis is insidious. Most of them are found during surgery or gastrointestinal endoscopy, which is similar to our case. Twenty-nine percent (4/14) of patients had pancytopenia, which may provide a diagnostic basis for early diagnosis. Similar to IVLBCL that occurs in other organs, an increase in lactate dehydrogenase (LDH) levels can also be detected in IVLBCL that occurs in the gastrointestinal tract. The histological manifestations of gastrointestinal IVLBCL are tumor cells of uniform size that aggregate in the lumen of arterioles or venules. These tumor cells express B cell immune markers (CD20, CD45, CD79a), and there are a few cases. MUM-1, Pax-5, BCL-2, and BCL-6 are expressed. In previous literature reports, no EBER-positive cases of gastrointestinal IVLBCL were found, and we are the first to report the occurrence of gastrointestinal EBER-positive IVLBCL. We found that the clinical manifestations of IVLBCL in the gastrointestinal tract are often not limited to one part of the body. Some scholars have performed multisite biopsies on patients with IVLBCL in the gastrointestinal tract ^[27]. This shows that patients with gastrointestinal symptoms as the first onset may have developed systemic metastases, so early diagnosis is particularly important for such patients.

The pathogenesis of IVLBCL is currently unknown. Some researchers have found that IVLBCL lacks the cell surface proteins (such as CD29 and CD54) of lymphocytes across vascular endothelial cells^{[32, 33]}, which causes tumor cells to aggregate into the vascular lumen and cannot migrate. Other scholars have found that CXC chemokines cause tumor cells to accumulate in the vascular lumen. They found that CXC chemokine receptors 3 and 4 (CXCR3, CXCR4) are expressed in IVLBCL, their ligands, CXC chemokine ligand 9 and 12 (CXCL9, CXCL12) are expressed in blood vessels, and the binding of receptors and ligands leads to the accumulation of tumor cells in the lumen of blood vessels^{[34, 35]}. At the molecular level, many scholars have found that IVLBCL has mutations in MYD88 and CD79B through next-generation sequencing^{[36, 37]}.

IVLBCL can appear in various parts of the body, the clinical manifestations are mainly neurological symptoms and skin changes, and there is no obvious lymphadenopathy. Therefore, it is easily missed, and a delay in diagnosis can lead to rapid deterioration of the disease and poor prognosis. If symptoms such as fever, skin changes, and elevated LDH levels occur, a differential diagnosis should be made with IVLBCL. Some scholars have proposed that random skin biopsy and bone marrow examination are helpful for the diagnosis of IVLBCL^[38]. If unexplained fever is found or IVLBCL is suspected, FDG-PET/CT is one of the main methods for diagnosing IVLBCL. The abnormal hypermetabolism on FDG-PET contrasts with conventional imaging, which can indicate IVLBCL; initially, negative FDG-PET results may turn positive in a few months as the disease progresses^[39].

At present, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) is the main treatment for IVLBCL^[40]. Andres et al. ^[41] found that the addition of rituximab to CHOP chemotherapy significantly improved the prognosis of Western patients. Japanese scholars found that the median overall survival time of patients receiving R-CHOP-based chemotherapy was 135 months, and the five-year survival rate was 62%^[11]. For IVLBCL occurring in the gastrointestinal tract, tumor cell clusters often embolize blood vessels, and symptoms of ischemia and necrosis of the intestinal wall are more likely to occur. Resection of necrotic intestinal tubes is a necessary treatment method. Some scholars have found that intraoperative ICG fluorescence imaging can be used to assess intestinal blood flow during venous thrombosis to prevent short bowel syndrome due to excessive resection^[42].

Most IVLBCLs that occur in the gastrointestinal tract are diagnosed incidentally and are easily missed due to their nonspecific clinical manifestations. IVLBCL that occurs in the gastrointestinal tract progresses rapidly, often with systemic metastases at onset. It is necessary to fully understand it, to be able to diagnose it early and to prolong the survival time of patients.

Ethical Approval

Informed consent was obtained from the patient's relatives, consent to publish all information about the patient's case, including pathological and imaging data. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

C.P. wrote and edited the paper. Y.Y. and X.M. generated the tables and figure. C.W. revised the paper. All authors have read and agreed to the published version of the manuscript.

Funding

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Table 3 is available in the Supplementary Files section.

No competing interests reported.

table3.xlsx

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EBV-positive intravascular large B-cell lymphoma of the small intestine: a case report and literature review

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