Intravascular lymphoma masquerading as septic shock

Abstract Intravascular lymphoma (IVL) is a rare type of extranodal lymphoma that selectively affects small blood vessels. We report a patient who presented with dyspnea and weight loss as well as refractory shock and multiple‐organ dysfunction. The postmortem revealed disseminated involvement of an IVL but no evidence of infection.


| INTRODUCTION
Intravascular lymphoma is a rare extranodal subtype of diffuse large B-cell lymphoma characterized by proliferation of lymphoma cells within the lumina of small blood vessels. 1 The median age at diagnosis is 67 years, and there is no sex predilection. 2,3 The clinical presentation is diverse and often includes symptoms related to organ dysfunction caused by occlusion of blood vessels. We herein describe a patient who presented with refractory shock and multiple-organ dysfunctions that mimicked septic shock. Postmortem examination revealed intravascular large B-cell lymphoma and no evidence of infection.

| CASE REPORT
A previously healthy 64-year-old Japanese man presented to the emergency department with dyspnea on exertion, severe fatigue, decreased appetite, and weight loss for the preceding 2 weeks. One week before his presentation, esophagogastroduodenoscopy and colonoscopy were performed because of investigation of unintentional weight loss. The result revealed advanced rectal carcinoma ( Figure 1). He did not report any chills, night sweats, or fevers, was a current cigarette smoker (44 packyear history of smoking), and reported minimal alcohol use. On examination, the patient appeared distressed, his respiratory rate was 30 breaths/min, oxygen saturation was 99% on oxygen supplementation at 2 L/min via nasal cannula, heart rate was 96 beats/min, blood pressure was 80/57 mm Hg, and body temperature was 35.8°C. He had conjunctival pallor, jaundice, and 4+ pitting edema in lower extremities, but no jugular venous distension, cardiac murmurs, or peripheral adenopathy.
Despite aggressive fluid resuscitation, the patient remained persistently hypotensive and was admitted to the intensive care unit. A diagnosis of septic shock was considered, and the patient was started on vasopressors and empirical broad-spectrum antibiotics. The clinical presentation of pancytopenia, splenomegaly, and severe lactic acidosis, without lymphadenopathy, was consistent with hematologic malignancy, especially intravascular lymphoma. In addition to bone marrow biopsy, a random skin biopsy was performed. While awaiting pathological diagnosis, the patient went into shock and experienced multiple-organ dysfunction syndrome involving the circulatory system, liver, and coagulation system (Table 1). He died 5 days after hospitalization. Later, biopsies from the bone marrow and skin revealed intravascular large B-cell lymphoma ( Figure 3). A postmortem examination was notable for the demonstration of intravascular large B-cell lymphoma with extensive involvement of the bone marrow, lungs, liver, spleen, kidneys, and adrenals ( Figure 4). The rectal carcinoma was confined to invasion of the muscularis propria ( Figure 5), and no lymph node or distant metastasis was detected. No infectious focus was found.

| DISCUSSION
The patient was a 64-year-old man with a 2-week history of dyspnea on exertion and weight loss. Key findings included elevated CRP level, refractory shock, pancytopenia, splenomegaly, and lactic acidosis. Despite treatment for presumed septic shock, rapid progression of multipleorgan dysfunction developed, and the patient died 5 days after hospitalization. Postmortem examination revealed evidence of intravascular large B-cell lymphoma, and no infectious focus.
Intravascular lymphoma (IVL) was first described by Pleger and Tapeiner in 1959 as angioendotheliomatosis proliferans systemisata 4 and was initially thought to be   a neoplasm of endothelial origin, but subsequent immunohistochemical studies confirmed the lymphoid nature of the neoplasm. 5 Almost all reported cases of IVL have been a neoplasm of B cells. 6 IVL characteristically manifests as fever, pronounced fatigue, decreased appetite, and a decline in functional status. 3 The clinical presentation is diverse and appears to differ by country of origin. 7,8 In Western countries, patients present most commonly with symptoms related to involvement of the central nervous system (39%) and skin (40%). Bone marrow (32%), liver (26%), and spleen (26%) involvement are less common. Patients from Asian countries preferentially show bone marrow involvement (75%), hepatomegaly (55%), splenomegaly (67%), and hemophagocytic syndrome (61%). Less commonly involved tissues include the nervous system (27%) and skin (15%). Patients often present with the following laboratory abnormalities 9 : anemia (93%), leukopenia (62%), and thrombocytopenia (51%) as well as elevated of serum LDH (97%), CRP (96%), and ferritin (83%). Patients from Western countries and Asian countries differ in the rates of hypoalbuminemia (18% vs. 84%). The patient's initial presentation was consistent with septic shock, including elevated CRP level, thrombocytopenia, hyperbilirubinemia, renal insufficiency, and refractory shock. 10 Neither microbiology nor autopsy confirmed an infectious source that would account for the clinical picture. Shock is an unusual initial presentation of IVL and has been previously described only in case reports (11-15, Table 2).
Diagnosis of IVL requires a tissue biopsy of an involved organ. Although bone marrow, lymph nodes, peripheral blood, and cerebrospinal fluid are often uninvolved in IVL, 16 the most relevant diagnostic site seems to be the bone marrow in Asian cohorts. 8 Furthermore, random biopsy of apparently normal skin is a valuable, relatively noninvasive, diagnostic tool. 17 The fact that lymphoma cells have been identified from random skin biopsies, not only in European series in which the cutaneous involvement is prevalent, but also in Asian series in which the cutaneous involvement is rare, is remarkable. 18,19 This case shows that IVL can be a cause of refractory shock of unknown origin. The patient underwent a prompt evaluation over a period of days to investigate his pancytopenia and splenomegaly. Unfortunately, the antemortem diagnosis of IVL could not be established. Prior to diagnostic biopsy, corticosteroid treatment complicates the histological interpretation and may delay definitive diagnosis. 20 However, after the biopsy, corticosteroid therapy can be tried and may improve critical illness transiently but dramatically, without a diagnostic problem. 21

| CONCLUSION
In the first 24 h of management of suspected septic shock, the absence of a source of infection is not so uncommon, and the septic focus may be identified later. If no source is found, reassess the differential diagnosis and consider many mimics for sepsis. This case highlights that intravascular lymphoma can be a cause of refractory shock of unknown origin.