Hiding in (not so) plain sight: Spontaneous tumor Lysis syndrome due to intravascular large B cell lymphoma
Authors: Matthew Ho, Saurabh Zanwar, Patrick Duggan, Ryan Carr, Thomas Habermann, Patrick J. Navin, Mohamed E. Salama, Sameer A. Parikh
Journal: American Journal of Hematology (2021)

A 76-year-old female with known history of coronary artery disease, dyslipidemia, and alcohol use disorder, presented to the emergency department with 2 weeks of generalized weakness and confusion. She had fever, night sweats, and a 10 lb (12.5%) weight loss over the preceding 3 months. She denied headache, chest pain, dyspnea, nausea, vomiting, diarrhea, rash, easy bruising, bleeding, or arthralgia. Prior to admission, she was taking aspirin 81 mg, sertraline 25 mg, and over-the-counter vitamin supplements. Her temperature was 36.8 °C, heart rate 90/min, respiratory rate 16/min, blood pressure 119/51 mmHg, and SpO2 91% on room air. On exam, she was oriented only to person. There was no palpable lymphadenopathy, hepatosplenomegaly, focal neurologic deficits, or stigmata of chronic liver disease. Complete blood count (CBC) was significant for thrombocytopenia (platelet count 98 × 109/L). Hemoglobin (Hb) was 14 g/dL and white blood cells (WBC) were 6.8 × 109/L. The manual differential revealed elevated metamyelocytes (3%; reference range [RR] < 1%) and myelocytes (1%; RR < 0.5%), along with decreased lymphocytes (16%; RR 18–42%). The manual absolute neutrophil count (ANC) was normal (4.96 × 109/L; RR 1.56–6.45 × 109/L). The metabolic panel revealed mild hyponatremia (sodium 130 mmol/L), hyperkalemia (potassium 5.3 mmol/L), hypercalcemia (corrected calcium 10.9 mg/dL), hyperuricemia (uric acid 15.6 mg/dL), and stage I oliguric acute kidney injury (AKI, Cr 1.18 mg/dL; baseline 0.78 mg/dL). Serum phosphorus was normal (3.9 mg/dL); and serum lactate dehydrogenase (LDH) was markedly elevated at 1507 U/L (RR 122–222 U/L). Renal ultrasound was unremarkable. Hyperuricemia and hyperkalemia in a patient presenting with B symptoms, and markedly elevated LDH are concerning for tumor lysis syndrome (TLS) secondary to an underlying malignancy, typically a primary hematologic neoplasm. TLS is an oncologic emergency characterized by metabolic derangements such as hyperkalemia, hyperphosphatemia, hypocalcemia, and hyperuricemia, and clinical complications such as renal failure, cardiac arrhythmia, and new-onset seizure.1 It most often occurs in the setting of large tumor burden, specifically when rapidly dividing, chemosensitive cancer cells are treated with cytoreductive therapy.2 Laboratory TLS: ≥ 2 of the following laboratory abnormalities occurring simultaneously within 24-h period 3 days prior to and up to 7 days after initiation of cytoreductive therapy Clinical TLS: laboratory TLS in addition to ≥1 of: Our patient met the first 3 criteria of spontaneous TLS. A urine uric acid level was not obtained at the time and urinary uric acid excretion could not be calculated. She was treated with normal saline (100 mL/h) and allopurinol. Serum protein electrophoresis and free light chains were normal. A peripheral smear revealed abnormal lymphocytes. A flow cytometry panel demonstrated a CD19, CD20, CD5-positive, CD10-partial, and kappa immunoglobulin light chain restricted B-cell population representing approximately 2% of the total analyzed events. CT of the chest, abdomen, and pelvis with IV contrast did not reveal lymphadenopathy or splenomegaly. A repeat creatinine was 1.57 mg/dL, and rasburicase was started. The patient subsequently developed persistent hypotension refractory to parenteral fluid resuscitation and was transferred to the ICU for vasopressor support. Our clinical suspicion for spontaneous TLS secondary to lymphoma was extremely high considering her worsening renal function, hyperuricemia, B symptoms, markedly elevated LDH, and abnormal peripheral smear and flow cytometry results. However, TLS typically does not occur without significant tumor burden and her CT did not reveal a malignant focus. We therefore turned our attention to the bone marrow. A healthy adult has approximately 1.4 kg of bone marrow that could “hide” tumor burden significant enough to cause spontaneous TLS, and an abundant amount could also exist in the intravascular space.2 There have been multiple case reports of spontaneous TLS in patients with multiple myeloma (MM), as well as bone marrow infiltrating acute lymphoblastic leukemia (ALL).5 Although our patient had a negative monoclonal gammopathy screen and peripheral smear without evidence of ALL, we needed to rule out malignant infiltration of the bone marrow. A bone marrow biopsy revealed large atypical cells arranged in a snake-like intravascular distribution with co-expression of CD20, CD5, and BCL6 by immunohistochemistry, and partial CD10 by flow cytometry, strongly supporting a diagnosis of intravascular large B-cell non-Hodgkin lymphoma (NHL) (IVLBCL) (Figure 1). There were no hemophagocytic histiocytes on bone marrow exam. Cytogenetic analysis revealed a complex karyotype with several numeric and structural abnormalities including t(3;14)(q27;q32), which corresponds to immunoglobulin heavy chain (IGH)-BCL6 gene fusion, and is the most common translocation involving BCL6 in NHL.6 There was no evidence of IGH-BCL2 gene fusion or MYC (8q24) rearrangement (Figure 2). A PET-CT scan revealed diffusely increased bone marrow fluorodeoxyglucose (FDG) uptake (standardized uptake value [SUV] max 4.95) throughout the axial and proximal appendicular skeleton as well as increased splenic FDG uptake (SUVmax 4.77) (Figure 3). The skull base, calvarium and a single, 1.5 cm common iliac lymph node also displayed increased FDG activity (SUVmax 6.6). Subsequently, three random skin punch biopsies showed evidence of IVLBCL with a similar phenotype noted in the bone marrow. Serum ferritin and serum fibrinogen were mildly elevated at 507 μg/L and 600 mg/dL, respectively. The 4th edition of the World Health Organization (WHO) classification defines IVLBCL as a rare and aggressive subtype of extranodal diffuse large B-cell lymphoma (DLBCL) that grows selectively within the lumen of blood vessels.7 Immunophenotypically, IVLBCL cells are mature peripheral B cells that express B-cell markers (i.e., CD20, CD79a, PAX5) in almost all cases, and demonstrate variable expression of CD10 (13–22%), BCL-6 (22–26%), and the T-cell marker CD5 (22–38%).8 Notably, CD5 is co-expressed with BCL-6 in ~20% of IVLBCL.8 There is significant immunophenotypic overlap between IVLBCL and DLBCL-not otherwise specified (DLBCL-NOS) as the latter also typically express pan-B cell makers, although CD5 expression is much rarer (~5%).8 While DLBCL-NOS may demonstrate intravascular involvement, it is associated with considerable extravascular proliferation whereas IVLBCL, by definition, may only minimally invade the extravascular space.9 Although largely considered a disseminated disease at diagnosis, IVLBCL is rarely detected in peripheral blood smears (5–10% of cases).10 The genetic landscape in IVLBCL is highly heterogeneous without hallmark mutations. A case series of 12 patients with IVLBCL included five cases with normal karyotype and the other seven cases were highly complex with an average of 13 aberrations.11 The study also reported no significant difference in survival between complex and normal karyotype. Similar to our patient, all seven cases had abnormalities in chromosome 6 (which have also been reported in other studies), and structural abnormalities at 6q13 were seen in 57%.8, 11 However, in contrast to our patient, all seven had aberrations in chromosome 8 and 71% had abnormalities at 19q13.11 A retrospective study of 17 patients from Thailand with IVLBCL reported that six patients (35%) had C-MYC/BCL2 double-hit lymphoma which was associated with poorer survival (14 vs 1.8 persons per 100 persons per month, p = .042).12 Three distinct patterns of clinical presentations of IVLBCL have been described (i.e., classic, cutaneous, and hemophagocytic) and are summarized in Table 1. Cutaneous IVLBCL affects females almost exclusively and is characterized by skin lesions without other organ involvement and systemic symptoms (~30%).8 Both hemophagocytic and classic IVLBCL can involve the bone marrow. Our patient met at least 3 of 8 criteria for hemophagocytic lymphohistiocytosis (HLH) (CD25 and NK cell activity were not obtained), but in the absence of hemophagocytic histiocytes on bone marrow exam or bicytopenia, and only mildly elevated ferritin, HLH was unlikely. Western countries Median age 70 years No sex predilection Western countries Median age 59 years Female predominance Heterogenous presentation Nonspecific B symptoms in >50% Cutaneous lesions in 40% Central nervous system (CNS), bone marrow, lung, endocrine (pituitary, thyroid, adrenal glands) Associated with benign nonhematologic epithelial, soft tissue, and vascular neoplasms in 15% Single or multiple skin lesions without other organ involvement Systemic symptoms in 30% Bone marrow involvement, hepatosplenomegaly, thrombocytopenia Hemophagocytic lymphohistiocytosis Multiorgan failure Clinical and lab criteria (at least 2 of 3): Anemia or thrombocytopenia Hepatomegaly or splenomegaly Absence of overt lymphadenopathy Histopathologic criteria (all 3 required): Erythrocyte-hemophagocytosis Immunophenotypical evidence of large B cell lymphoma Intravascular proliferation and/or sinusoidal involvement of lymphoma MRI showed diffuse bone marrow involvement in the skull and upper cervical spine, as well as multiple hyperintense foci throughout the periventricular white matter, right thalamus, and right putamen without associated enhancement or abnormally restricted diffusion. These changes were felt to be nonspecific, but have also been described in the presence of intracranial IVLBCL (Figure 4). Cerebrospinal fluid (CSF) analysis did not reveal malignant cells but did reveal increased CSF protein 64 mg/dL (RR l0-35 mg/dL). There are no pathognomonic neuroradiological signs in IVLBCL and findings may be variable and change over time.13 Mass lesions (rarely seen) are typically iso-dense on T1-weighted images. Brain MRI more commonly reveals hyperintense T2-weighted signals and the differential diagnosis includes primary CNS lymphoma, toxoplasmosis, glioblastoma multiforme, abscess, metastasis, and vasculitis. Nonspecific white matter lesions and infarct-like lesions may also be seen.13 Importantly, CSF analysis frequently shows increased protein but cytology rarely shows malignant cells, which makes confirmation of CNS involvement difficult without a brain biopsy, as was the case in our patient.8 A retrospective study of 109 patients with IVLBCL reported that patients without CNS involvement at diagnosis (n = 82) had a 25% risk of CNS recurrence at 3 years and this risk was higher in patients with skin involvement at diagnosis (HR 5.27; p = .007).14 2-year survival after CNS recurrence was 12%. Comparatively, there was a 25% risk of CNS recurrence at 1 year in patients with CNS disease at diagnosis (n = 27).14 Addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) did not significantly affect the risk of CNS recurrence (p = .52).14 Consistent with this, a separate study of 34 patients with IVLBCL treated with R-CHOP found that at median follow-up of 2 years, 6 patients had relapsed and all had CNS involvement (1/6 had CNS disease at diagnosis).15 CNS treatment or prophylaxis therefore constitutes an important part of the management of IVLBCL. IV fluids, allopurinol, and rasburicase were continued and R-CHOP and intrathecal methotrexate were started, with a plan for six cycles. Her serum uric acid levels normalized (5.7 mg/dL), AKI resolved (serum creatinine 0.72 mg/dL), and LDH significantly decreased (500 U/L). Her hypercalcemia had also resolved (corrected calcium 9.6 mg/dL) suggesting that hypercalcemia could have been in the setting of her lymphoma. Given the overall improvement in functional status, she received high-dose intravenous methotrexate (3.5 g/m2 on day 14 of even cycles) with R-CHOP from her second cycle onwards. This case highlights that diagnosis of IVLBCL can be challenging and should be considered in patients presenting with fever of unknown origin, neurological symptoms and signs, and laboratory abnormalities suggestive of spontaneous TLS. Importantly, spontaneous TLS may be associated with normal serum phosphorus and calcium, and the Cairo-Bishop criteria may lead to under-recognition of this entity. TLS is most effectively managed by vigilant laboratory and clinical monitoring and early initiation of prophylaxis in patients at risk. Our approach is similar to previously established guidelines and Figure 5 summarizes the workup and management of both TLS and spontaneous TLS.17 Spontaneous TLS has been reported in patients with isolated bone marrow disease (e.g., MM and ALL).5 A negative whole-body CT scan does not rule out IVLBCL and PET-CT or nuclear MRI should be obtained if there is a high index of suspicion. A definitive diagnosis requires histopathologic confirmation of large atypical B-cells within blood vessels in the absence of significant extravascular disease. Random cutaneous/subcutaneous tissue biopsy (even in the absence of skin lesions) may be a useful and minimally-invasive way to facilitate early diagnosis.18 For a more targeted approach, PET-CT may be helpful in choosing the most FDG-avid lesions to biopsy. Interestingly, our patient's lipid panel over the past 2 years showed a precipitous decrease in serum high-density lipoprotein cholesterol (HDL-C) and increase in serum triglycerides, which have been reported in patients with NHL.19 The chronic inflammation milieu of lymphomagenesis is thought to suppress HDL-C.20 Our patient's presentation was most consistent with classic IVLBCL. Approximately 25% of patients present with only systemic symptoms (most commonly fever of unknown origin), while > 50% of patients have addition to organ-related manifestations.8 Fatigue is present in over 30%, and 40% have skin lesions. Endocrine insufficiency or pulmonary involvement may also occur.8 About a third of the patients present with highly heterogeneous neurological symptoms.8 Importantly, ~15% of patients have associated benign nonhematologic tumors of epithelial, soft tissue, or vascular origin and IVLBCL cells are frequently (if not exclusively) found within the vessels supplying these tumors.8 A meta-analysis of 704 intravascular lymphoma (IVL) cases, of which 651 (88%) were B-cell lymphoma, reported age < 70 years (p = .0073), absence of CNS involvement at diagnosis (p = .0014), LDH <700 (p = .0112), and rituximab therapy (p < .0001) as favorable prognostic factors.22 Prior to the use of rituximab, CHOP was the standard of care for IVLBCL and prognosis was most favorable in patients with the cutaneous variant (3-year OS: 56 ± 16%) followed by the classic variant (3-year OS: 22% ± 10%), and the hemophagocytic variant (median survival 2–8 months).8 The introduction of R-CHOP for CD20+ IVLBCL led to an 88% complete remission rate, 91% overall response rate, and 81% 3-year OS.8 Data on autologous stem cell transplantation (ASCT) is limited. In the pre-rituximab era, out of nine patients who received ASCT and were followed for at least 3 years, five were alive and in complete remission (CR) at 3 years, while four had died (3-year OS: 55.6%).22 On the other hand, out of 14 patients who had received both rituximab and ASCT and were followed for at least 3 years, 11 were alive and in CR, while 3 had died (3-year OS: 78.6%).22 It is difficult to draw conclusions from ASCT data due to the small sample size and the issue of selection bias as ASCT tends to only be tolerated in younger fitter patients. Unfortunately, there is also a paucity of data on the optimal treatment or prophylactic regimen for CNS IVLBCL, making it difficult to determine whether intrathecal or high-dose methotrexate is more effective for CNS prophylaxis. A recent retrospective study of 585 patients with newly diagnosed DLBCL at high-risk for CNS relapse reported no significant difference in 5-year risk (5.6% vs 5.2%) of CNS relapse in patients who received high-dose (n = 42; 7%) versus intrathecal methotrexate (n = 253; 43%).23 The benefit of intrathecal delivery is reduced systemic toxicity due to the small volume of distribution of the CSF and this tends to be better tolerated by elderly and frail patients. The PRIMEUR-IVL single-arm study looked at R-CHOP in combination with prophylactic high-dose methotrexate and intrathecal chemotherapy in 38 Japanese patients with IVLBCL who did not have CNS disease at diagnosis and reported a 2-year progression-free survival (PFS) of 76%.24 Although there was no comparator arm, an earlier study by the same group showed reported a 2-year PFS of 53% after R-CHOP alone, supporting the addition of CNS-oriented prophylaxis.25 One caveat is the heterogeneity in patient characteristics between the two trials (e.g., 21% of patients in PRIMEUR-IVL had the prognostically-poor hemophagocytic variant versus 60% in the comparator trial). In summary, we report the case of a patient with spontaneous tumor lysis syndrome who was diagnosed with IVLBCL. Prompt recognition of this entity is paramount since appropriate management can improve renal parameters and the use of R-CHOP along with CNS prophylaxis using methotrexate can lead to durable response in these patients. Research funding has been provided to the institution from Pharmacyclics, Janssen, AstraZeneca, TG Therapeutics, Merck, AbbVie, and Ascentage Pharma for clinical studies in which Sameer A. Parikh is a principal investigator. Sameer A. Parikh has received honoraria for participation in consulting activities/advisory board meetings for Pharmacyclics, AstraZeneca, Genentech, GlaxoSmithKline, Adaptive Biotechnologies, and AbbVie (no personal compensation); and from Aptitude Health, Curio Science, and MedEd on the Go (with personal compensation). The other authors have nothing to disclose and there are no conflicts of interest to report. Informed consent was obtained from patient. Data sharing is not applicable to this article as no new data were created or analyzed in this study.