Abstract
Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of non-Hodgkin lymphoma. It is characterized by the proliferation of cancerous cells into the intraluminal space of the blood vessels. It has a low incidence rate of 0.095 cases per 1,000,000. The clinical presentation is insidious and unspecific, often delaying the diagnosis. IVLBCL can be diagnosed through body images and histopathology analysis. This neoplasm averages a 60% response rate to current chemotherapy treatment, favoring rituximab, and doxorubicin-based regimen if it is diagnosed in time. Here, we present the case of a 56-year-old man admitted to our hospital with a fever who was eventually diagnosed with IVLBCL. He presented to the consultation with anemia, fever, and splenomegaly. An infection panel, a bone marrow biopsy, and a PET-CT scan were performed and ruled out the possibility of infections and neoplasms. The patient later developed edematous syndrome. As a result, a renal biopsy was performed which tested positive for intravascular large B-cell lymphoma. Currently, the patient has been in complete remission for 33 months. Along with presenting this specific case, we also reviewed previously published cases of IVLBCL to illustrate the renal involvement of this pathology.
1. Introduction
Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of large cell lymphoma that is characterized by the proliferation of cancerous cells into the intraluminal space of small to medium blood vessels while sparing the surrounding tissue, lymph nodes, and reticuloendothelial system. IVLBCL’s incidence rate is 0.095 cases per 1,000,000 in the United States [1]. IVLBCL patients have a median age at diagnosis of 70 years (the age range is from 40 to 90 years old). IVLBCL affects both males and females without a predilection for one or the other [2]. Also, IVLBCL has a heterogeneous clinical presentation depending on the organ that is compromised. The majority of patients present with systemic symptoms such as fever of an unknown origin, pain, weight loss, and rapid deterioration [3]. Usually, the central nervous system (CNS) and the skin are commonly affected [4]. This pathology is classified into three main variants: classical, cutaneous, and hemophagocytic [5].
A diagnosis is made by conducting a surgical biopsy in the affected organ to determine if there has been infiltration by cancerous cells. Intravascular lymphoma (IVL) is positive in 91% of cases for B-cell phenotype (CD19, CD20, CD22, and CD79a) and has occasionally shown expression of CD5 with this last marker being associated with a poor prognosis [6]. Vieites et al. and Yamamoto et al. [7, 8] described segmental tandem triplication of the 18q21 and q22q25 of chromosome 11 as genetic alterations of IVL.
The treatment consists of anthracycline-based chemotherapy regimens which have a nearly 60% response rate and a 3-year overall survival rate higher than 30% [3]. CNS-directed therapy, such as rituximab-cyclophosphamide, vincristine, and doxorubicin, is recommended for patients with neurologic symptoms. Prednisone regimens do not penetrate the CNS [4]. However, this information comes from a small series of cases, and given the rare nature of this disease, there are no randomized controlled trials that compare these treatment regimens [9]. The analysis of a small sample size of patients favors rituximab and doxorubicin-based treatments when adjusting for age and poor prognosis factors such as elevated lactate dehydrogenase serum levels [10]. Notably, patterns of recurrence seem to indicate that the same organ becomes compromised if it recurs. However, the small number of case reports available is not enough for statistical analysis [10].
2. Case Report
In 2017, a 56-year-old man arrived at the emergency room with fever, chills, dyspnea, arthralgia, and headache that he had been experiencing for 20 days before the medical consultation. He had mild anemia with a hemoglobin level of 9.7 g/dL (reference range (RR): 14-18 g/dL), lactate dehydrogenase with levels of 506 U/L (RR: 98-192 U/L), C-reactive protein levels of 18,904 mg/dL (RR: 0.000-0.748 mg/dL), beta 2 microglobulin levels of 5620.0 ng/mL (RR: 1000.0-3000.0 ng/mL), and albumin levels of 1.8 g/dL (RR: 3.50-4.80 g/dL). A physical examination showed fever, diaphoresis, tachypnea, blood oxygen saturation level of 76%, lung noises, and a palpable spleen one centimeter below the costal margin.
Because the patient presented with a fever, infectious disease panels were performed including IgM and IgG antibodies against Cytomegalovirus, rubella virus infection, Treponema pallidum, anti-Epstein-Barr virus-IgG and IgM, hepatitis B and C, and tropical diseases (thick drop test). He was also tested for central nervous system infections using cerebrospinal fluid analysis. All panels and tests were negative.
The patient also presented anemia and a high level of lactate dehydrogenase; therefore, a hematological malignancy was suspected. A bone marrow biopsy was conducted. The bone marrow biopsy tested negative for hemophagocytosis. However, it showed grade II fibrosis. Therefore, a second bone marrow biopsy was performed, which did not show fibrosis; thus, the fibrosis from the first biopsy was interpreted as an inflammatory condition. Also, an autoimmune panel (Anas, rheumatoid factor, C3 and C4 levels, anti-DNA, and anti-neutrophil cytoplasmic antibody) was performed. The autoimmune panel was also negative.
Additionally, bone marrow cultures for detecting bacterial and fungal infections were performed. Cultures for fungal and bacteria (aerobic and anaerobic) were negatives after 48 days and 6 days of incubation, respectively. A polymerase chain reaction for Mycobacterium detection was negative.
A positron emission tomography-computerized tomography (PET-CT) scan was conducted to rule out infectious disease, neoplasms, and inflammatory diseases; it showed a focal hypermetabolic lesion in the colon and an augmented signal in both the spleen and the bone marrow (Figure 1).
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A colonoscopy found grade 1 internal hemorrhoids and sigmoid diverticulitis with focal edema of the mucosa and small angiodysplasia without signs of bleeding. No tumors or polyps were observed. A biopsy was taken from edematous mucosa. Due to the possibility of insidious diverticulitis, a control CT scan was also ordered. The results of the colon biopsy, alpha-fetoprotein test, CA-19-9 blood test, and carcinoembryonic antigen test were negative for malignancy. The control CT scan showed an enlarged liver along with splenomegaly, and thus, a liver biopsy was performed which showed no alterations. Ten days after admission, the patient developed edematous syndrome along with low serum albumin, elevated serum triglycerides, and elevated urine protein levels. A renal biopsy was performed; it was positive for monoclonal B-lymphocyte (CD20+, CD5+, BCL2+ and BCL6+, CD3-, GRANZYME-, MUM1-, and CD10- KI67 80%) infiltration inside the peritubular capillaries which is compatible with an intravascular large B-cell lymphoma (Figure 2).
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The patient was classified with a poor prognosis and considered high risk according to the Revised International Prognostic Index (R-IPI) due to a compromised extranodal site, an ECOG performance status higher than 2, high levels of lactate dehydrogenase, and an Ann Arbor clinical stage of IV. The karyotype analysis was normal, and the cytogenetic FISH assessment was negative for BCL2, MYC, and EBV.
After the diagnosis was made, the patient received 6 cycles of chemotherapy treatment (1 every 21 days) with rituximab, cyclophosphamide, vincristine, doxorubicin, prednisone, intrathecal cytarabine, and methotrexate. This treatment resulted in improvements in his blood test (Figure 3). By the end of the treatment, the patient had achieved complete metabolic response evidenced by the PET-CT scan, normal hemoglobin levels of 14.2 gr/dL, normalized renal function with a creatinine level of 1.01 mg/dL, and regular levels of urine protein. Currently, the patient remains in complete metabolic response after 33 months.
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3. Discussion
IVLBCL has been commonly characterized as an aggressive disease with a poor overall survival rate, and many diagnoses were determined during postmortem analysis. Even though medical advances have been made in the field of hematological malignancies, intravascular lymphomas continue to be a diagnostic challenge due to the undefined symptoms, variable clinical presentations, and inconclusive imaging studies [8]. Not all patients can be categorized under the three variants of clinical manifestation. Additionally, PET-CT scans of patients with IVLBCL are difficult to analyze due to renal excretion of the radioisotope [6]. This difficulty shows the importance that histopathological studies in patients with compromised organs have in diagnosing and characterizing the disease.
This pathology is considered a rare disease; most of the information about it comes from case reports, small case series, and expert opinions [1]. After conducting a literature review, we found 9 cases of renal IVLBCL [11–19] with a higher presentation in female patients and a median age of presentation of 58. The main clinical manifestations in these cases were fever, renal failure, proteinuria, and edema. In imaging studies, a majority of these patients had enlarged kidneys on CT scans and PET-CT exams that were negative for malignancy. Regarding their histopathology, bone marrow biopsies were normal in almost all the patients, and kidney biopsies showed atypical lymphocytes located primarily in the glomerulus, followed by peritubular and interstitial infiltrates (Table 1). In another study, Törnroth et al. [20] reported 44 cases of bilateral renal lymphoma in 2013. Imaging studies revealed that 40 out of the 44 patients in their study had bilateral enlargement of their kidneys without proteinuria in the nephrotic range. Six patients had bone marrow involvement while 16 had another organ compromised. The mortality rate for these cases was approximately 54.5%.
Our patient presented with nonspecific symptoms and without neurological alterations or skin lesions, which led to extended laboratory testing, a late diagnosis, and the delayed initiation of chemotherapeutic treatment. Notable inconclusive tests, in this case, include a bone marrow biopsy which was negative for neoplasm and hemophagocytic syndrome as well as CT scans and PET-CT scans that did not show any findings regarding the neoplasm. This case presents itself as atypical because the PET-CT scan performed was negative for hypermetabolic lesions in the renal parenchyma. Even upon retroactive revision of the images after the full diagnosis was reached, we were unable to identify suspicious images in the kidneys. This absence of findings comes as a surprise given the current opinion of some experts that positions a PET-CT scan as an important tool for diagnosis and follow-up for IVLBCL, especially in patients with renal compromise [21]. Finally, elevated urine proteins along with the presentation of the edematous syndrome were the sole manifestations that indicated the organ was compromised by the disease.
The introduction of novel agents, such as rituximab, into cancer treatment protocols, has led to a paradigm shift in the treatment of lymphomas, making an early diagnosis and consequent treatment of intravascular lymphoma even more important than ever to secure a better response to therapy [7]. In the small series of cases reviewed in the literature, we found 46% of the subjects were treated with rituximab-based chemotherapy regimens, and all of them reached a complete response with only 1 subject experiencing a relapse of his hematological disease. Also, the mortality rate of IVLBCL has decreased from 54% to 10% [11–19]. It is important to perform, in certain specific cases, a histopathological diagnosis in patients with a fever of unknown origin and/or long duration and organ dysfunction. In this case, the patient did not have any infectious or autoimmune disease or any classical clinical presentation of malignancies. Even though the patient’s imaging tests were negative, the presence of hematooncological conditions was determined by renal biopsy.
Ethical Approval
The case report has been approved by our local research ethics committee.
Consent
The patient signed an informed consent form for case reports.
Conflicts of Interest
The authors have no conflicts of interest to declare.
Authors’ Contributions
GEQV, DO, DRF, and JADLHV contributed equally to this work.