EBV-Positive Intravascular Large B-Cell Lymphoma of the Small Intestine: A Case Report and Literature Review

Intravascular large B-cell lymphoma (IVLBCL) is a rare lymphoma that affects the brain, skin, and bone marrow. We describe the case of a 75-year-old man who was admitted to the hospital after 4 h of stomach aches. A thorough physical examination indicated stomach discomfort and skin discoloration. Laboratory tests revealed thrombocytopenia and elevated lactate dehydrogenase levels. A computed tomography scan of the abdomen revealed that the small intestine wall was thickened, edematous, and necrotic. The necrotic small bowel was surgically removed, revealing many little round, homogenous, and unusual cells in the mesenteric vein. In-situ hybridization revealed that these cells were positive for PAX5, CD20, CD79a, CD10, and BCL2, as well as Epstein-Barr virus-encoded small RNA. After 1 week of hospitalization without treatment, the patient was diagnosed with IVLBCL and died of multiple organ dysfunction syndrome. IVLBCL is a rare illness that affects the small intestine and possibly the gastrointestinal system. It has an insidious start, a fast development, and a dismal prognosis. Knowing its clinicopathologic traits helps in understanding the illness, making an early diagnosis, and preventing rapid worsening.


Introduction
We report a case of intravascular large B-cell lymphoma (IVLBCL) and review the literature.IVLBCL is a rare extranodal large B-cell lymphoma defined by the selective development of lymphocytes in the lumen of blood vessels, particularly capillaries, and rarely in large arteries and veins.The condition manifests itself in a wide age range (13-85 years), mainly in adults, with a median age at diagnosis of 70 years and a male-to-female ratio of 1.1:1. 1,2VLBCL usually affects any organ other than the lymph nodes, and enlarged lymph nodes are uncommon.There are 2 types of clinical manifestations: the first occurs primarily in the nervous system and skin, and the tumor involves the major organs and causes corresponding clinical symptoms; the second type is phagocytosis, which causes corresponding clinical symptoms such as liver failure, hepatosplenomegaly, and pancytopenia.][5] Without treatment, the disease may quickly progress to lethal stages.Histologically, IVLBCL is seen when tumor cells are found in the center of tiny blood vessels in several organs.Immunohistochemistry shows that tumor cells express antigens like CD19, CD20, and CD79a that are found on mature B lymphocytes.
Thirty-eight percent of cases were positive for CD5, and 12% were positive for CD10. 6

Case Report
A 75-year-old man with severe abdominal pain was admitted to the First Affiliated Hospital of Kunming Medical University for 4 h.The examination found stomach pain that spread throughout the abdomen, particularly in the lower right abdomen.The abdominal wall showed high pressure and discomfort, and the skin of the lower right abdominal wall was purple.Yet, without histological evidence of the causes of skin changes.The abdominal computed tomography (CT) examination revealed obvious edema and intestinal wall thickening in the right middle and lower abdomen, blurring surrounding fat space, a filling defect, and the development of emboli in the superior mesenteric vein (Figure 1 A and B).An urgent blood test revealed thrombocytopenia, poor coagulation function, and an increased lactate dehydrogenase level (Table 1).The patient's anti-HIV antibody was negative, and no anti-immunosuppressant had been administered in the recent past.The patient was admitted to the hospital for an operative procedure for small bowel necrosis and mesenteric venous thrombosis.After the operation, approximately 500 mL of bloody ascites were observed in the abdominal cavity, and approximately 40 cm of the intestinal tube showed ischemia necrosis at the intersection of the jejunum and ileum near the ileum segment (Figure 2A to I).
The macroscopic scan revealed a section of the necrotic intestinal tube measuring approximately 58 cm long and 2 to 5 cm wide.The intestinal wall was hemorrhagic and necrotic, and there were no enlarged lymph nodes in the mesentery.
Only the lumens of tiny blood vessels contained cancer cells.In the lumens of the larger blood vessels, there were no tumor cells.Some tumor cells generated a tumor thrombus or totally obstructed the capillary lumen, resulting in an embolism.These tumor cells were found to be positive for CD45, CD20, CD79a, PAX5, CD19, CD5, CD10, BCL2 and MUM1.CD30, cyclin D1, SOX11, and kappa and lambda light chains were negative.It was found that the proliferation index for Ki67 was 80% (Figure 3).In-situ hybridization of Epstein-Barr virus-encoded small RNA detected EBER (Figure 4 and Table 2).The patient was diagnosed with IVLBCL of the small intestine, with mesenteric vein thrombosis and necrosis, based on the observations.One week after the operation, the patient's symptoms rapidly deteriorated, and he died of MODS without receiving chemotherapy.The patient's family declined an autopsy.

Discussion
IVLBCL was described for the first time in 1986. 7At that time, it was included in the fourth edition of the World  Health Organization Classification of Hematopoietic Lymphoid Tumors in 2016, and it was a solid tumor in a mature B-cell tumor. 8The fifth edition of the World Health Organization Classification of Hematopoietic Lymphoid Tumors will continue to follow the classification of the fourth edition.Early diagnosis of IVLBCL is extremely difficult.When there are obvious clinical symptoms, it has almost completely spread throughout the body, and some cases were even diagnosed at autopsy. 9 The clinical symptoms of IVLBCL are heterogeneous.We discovered 3 different types of IVLBCL based on the cases reported.The classic type is more frequent in Western nations and mostly affects the central nervous system and skin. 10The second type, represented by Japan, is characterized by hemophagocytic syndrome, with fever, hepatosplenomegaly, thrombocytopenia, and tumor involvement of the bone marrow. 2 Several researchers compared the clinical symptoms of Japanese and Western patients.They discovered that Japanese patients primarily suffered from the hemophagocytic syndrome, whereas Western patients showed neurological and skin symptoms. 11he third type, called the skin variant, is characterized by showing only skin symptoms without nerve or hemophagocytic symptoms. 12The patient in our case had thrombocytopenia; CT scanning revealed neither an enlarged liver nor spleen, as well as no fever.The patient's chest, abdomen, and bilateral inner thighs have spotted changes.The patient had a cerebral infarction, which we also learned from the patient's family.Unfortunately, no biopsies were performed to determine whether these symptoms were caused by IVLBCL.IVLBCL can affect virtually every organ in the body.The nervous system and the skin are the most commonly affected areas.IVLBCL has been discovered in a growing number of tissues and organs, including the lungs, 13,14 breast, 15 uteri, 16 prostate, 17 liver, 18 kidneys, 19,20 and thyroid, 21 as awareness of the disease has increased.While this disease is uncommon in the gastrointestinal system, certain research has demonstrated that 8% (3 of 38) of IVLBCL patients manifest in the gastrointestinal system. 103][24][25][26][27][28][29][30][31][32] The clinicopathological characteristics of IVLBCL in the gastrointestinal tract are described in Supplemental Table 1.The pathogenesis of IVLBCL in the gastrointestinal tract is complex, and the clinical symptoms almost always present as acute abdominal pain.Similar to our case, most are discovered during surgery or gastrointestinal endoscopy.Pancytopenia was observed in 29% (4 of 14) of the patients, which was important evidence for an early diagnosis of IVLBCL.Similar to IVLBCL in other organs, there could be a slight increase in LDH levels in gastrointestinal IVLBCL.Both arterioles and venules contain tumor cells of the same size.These tumor cells express immunohistochemical markers for B cells (CD20, CD45, and CD79a).MUM1, PAX5, BCL2, and BCL6 are expressed in only a few instances.The clinical symptoms of IVLBCL in the gastrointestinal tract are frequently not restricted to a single body region.Some researchers have performed multisite biopsies on patients with IVLBCL of the gastrointestinal tract, and their findings indicate that patients with gastrointestinal symptoms as the initial symptom may have systemic involvement; therefore, early diagnosis is especially important for these patients. 304][35] One case (1 of 3) was associated with HIV infection, while the other 2 cases (2 of 3) involved elderly adults without EBV infection or acquired immunodeficiency syndrome (AIDS).Burkitt's lymphoma, classic Hodgkin's lymphoma, lymphoma-like granulomatosis, primary exudative lymphoma, plasmablastic lymphoma, and lymphoproliferative diseases after transplantation are primarily associated with EBV infection. 36,37According to multiple articles, EBV-positive diffuse large B-cell lymphoma mainly affects the elderly (median age, 71-75.5)and is associated with a poor prognosis. 38,391][42] EBV + DLBCL demonstrated up regulation of genes involved in NF-κB activity, cell proliferation, cellcycle progression, and cell metabolism. 43,44Previous case reports described EBV-positive IVLBCL in the abdominal  aorta and liver; no EBV-positive cases of gastrointestinal IVLBCL were found, and this is the first report of gastrointestinal EBER-positive IVLBCL.Our case demonstrates that a positive EBV test is associated with a poorer prognosis.Currently, the pathophysiology of IVLBCL is unclear.Other studies have demonstrated that IVLBCL lacks the cell surface proteins (such as CD29 and CD54) of lymphocytes across vascular endothelial cells, 45,46 causing tumor cells to gather within the vascular lumen and become immobile.Multiple researchers have discovered that CXC chemokines cause the concentration of tumor cells in the arterial lumen.They discovered that CXC chemokine receptors 3 and 4 (CXCR3 and CXCR4) are expressed in IVLBCL, as are their ligands, CXC chemokine ligands 9 and 12 (CXCL9 and CXCL12), and that the interaction of receptors and ligands causes tumor cell accumulation in the lumen of blood vessels. 47,48Using next-generation sequencing, multiple researchers have discovered mutations in MYD88 and CD79B in IVLBCL. 49,50We know that EBV drives the NF-κB signaling pathway to promote tumor growth, while lacks the cell surface proteins of lymphocytes across vascular endothelial cells, causing tumor cells to gather within the vascular lumen and become immobile.Therefore, we speculate that the above 2 mechanisms may affect the occurrence of EBV-positive IVLBCL.
IVLBCL needs to be differentially diagnosed with intralymphovascular immunoblastic proliferations.Histopathology showed that tumor cells of IVLBCL gathered in the capillaries, whereas large cells of intralymphovascular immunoblastic proliferations were localized within the lymphatic spaces.IVLBCL was found in the blood vessels as homogeneous large cells with no other types of cells mixed together.Intralymphovascular immunoblastic proliferations' large cells, however, were frequently mixed with smaller lymphocytes or plasma cells.The immunophenotype of IVLBCL is often positive for CD20 (strong positive and diffuse positive), positive for PAX5 and BCL2, positive in certain cases for CD10 and CD5, and negative for CD30, while intralymphovascular immunoblastic proliferations are positive for CD30, polytypic for kappa and lambda light chains, CD20 and PAX5 negative or very marginally positive, and CD10, BCL2, and BCL6 negative.CD20 and CD30 can be used to identify them apart. 51VLBCL can happen in many parts of the body, but the main symptoms are problems with the nervous system and skin, with no obvious lymphadenopathy.The disease is easily misdiagnosed, and if the patient is not diagnosed in a timely manner, the disease will proceed swiftly, resulting in a terrible prognosis for the patient.If symptoms like fever, skin changes, or high LDH levels start to show up, IVLBCL should be thought of as a possible cause.Some researchers think that a random skin biopsy and tests on the bone marrow could help figure out if someone has IVLBCL. 52luorodeoxyglucose-positron emission tomography (FDG-PET)/CT is one of the best ways to find out if someone has IVLBCL if they have a fever that can't be explained or if they think they might have IVLBCL.In contrast to traditional imaging, FDG-PET shows abnormally high metabolism, which may be a sign of IVLBCL.FDG-PET results that were negative at first may become positive in a few months as the illness gets worse. 53urrently, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) is the main treatment for IVLBCL. 54Ferreri et al 55 discovered that by adding Rituximab to CHOP chemotherapy, the prognosis of Western patients was dramatically improved.Japanese researchers discovered that R-CHOP-based chemotherapy patients had a median overall survival time of 135 months and a five-year survival rate of 62%. 11When IVLBCL develops in the gastrointestinal tract, tumor cell clusters frequently embolize blood vessels, which increases the likelihood of ischemia and intestinal wall necrosis.The intestinal tube resection is a vital therapeutic strategy. 56ost IVLBCLs in the digestive system are found by accident and are easy to miss because their symptoms are not clear.IVLBCL that begins in the digestive tract spreads rapidly and frequently begins in one area of the body before moving on to another.To be able to spot it

Figure 1 .
Figure 1.Computed tomography (CT) showed obvious edema and thickening of the small intestinal wall in the middle and lower abdomen: (A) noncontrast CT and (B) contrast-enhanced CT (triangle: necrotic small intestine).

Figure 2 .
Figure 2. Pathological section of lesioned intestine section (hematoxylin-eosin staining): (A) small bowel wall hemorrhage and necrosis, (B) many atypical cells can be seen in the mesenteric vein, 10 × and (C-I) tumor cells mixed with red thrombus plug blood vessel (C-F 20 × and G-I 40 ×).

Figure 4 .
Figure 4. In-situ hybridization of EBV RNA was positive for EBER.In the upper right corner, nasopharyngeal tissue was used as the internal control (40 ×).Abbreviations: EBV, Epstein-Barr virus; EBER, Epstein-Barr virus-encoded small RNA.

Table 1 .
Laboratory Findings on Admission.

Table 2 .
The Summarizing of Immunohistochemistry and In-Situ Hybridization.early and help patients live longer, it's important to know a lot about it.Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.improves outcome in 'Western' patients with intravascular large B-cell lymphoma.Br J Haematol.2008;143:253-257.56.Nakamoto H, Yokota R, Namba H, Yamada K, Hosoda M, Taguchi K. Effectiveness of intraoperative indocyanine green fluorescence-navigated surgery for superior mesenteric vein thrombosis that developed during treatment for intravascular lymphoma: a case report.Am J Case Rep. 2021;22: e929549.doi:10.12659/AJCR.929549