Clinical characteristics of B-cell lymphoma-associated hemophagocytic syndrome (B-LAHS): comparison of CD5+ with CD5- B-LAHS

OBJECTIVE: B-cell lymphoma-associated hemophagocytic syndrome (B-LAHS) has been increasingly reported in Asia and is regarded as a variant of intravascular lymphomatosis (IVL). Recently CD5 was reported to be expressed in some cases of diffuse large cell lymphoma and IVL. We therefore examined the expression of CD5 on lymphoma cells in B-LAHS and compared the clinical and laboratory data between CD5+ and CD5- B-LAHS. METHODS: The expression of CD5 on lymphoma cells was examined using flow cytometry and immunohistochemical analysis of paraffin sections. The clinical records were reviewed to characterize clinical features. PATIENTS: Twelve patients with B-LAHS; ten men and two women, age ranging from 41 to 82 years (median, 63.5 years) were included in this study. RESULTS: B-LAHS is characterized by fever and hepatosplenomegaly without lymphadenopathy at the initial presentation. Histological examination showed hemophagocytosis and infiltration of lymphoma cells in the bone marrow, and in some cases intravascular proliferation of lymphoid cells characteristic of IVL. All patients showed increased levels of lactate dehydrogenase, C-reactive protein, ferritin and soluble interleukin-2 receptor. In eight of the twelve patients, lymphoma cells were positive for CD5. But no differences were observed in the clinical or laboratory findings between CD5+ B-LAHS and CD5- B-LAHS. CONCLUSION: No clinical differences were observed between CD5+ B-LAHS and CD5- B-LAHS. Further studies are required to elucidate the differences in pathogenesis between these two subgroups of B-LAHS.     

Malignant histiocytosis-like B-cell lymphoma, a distinct pathologic variant of intravascular lymphomatosis: a report of five cases and review of the literature

Malignant histiocytosis (MH)-like B-cell lymphoma (BCL) is a neoplastic proliferation of large B cells clinically characterized by fever, hepatosplenomegaly, haemophagocytosis and abnormal laboratory data, without lymphadenopathy or skin lesions. Interestingly, most cases have been reported in Asian patients, and it is unclear whether MH-like BCL is biologically distinct from conventional large B-cell lymphomas. We report five Japanese patients with MH-like BCL. Biopsied specimens of bone marrow, liver and/or spleen showed infiltration of neoplastic B cells accompanied by haemophagocytosing histiocytes. Lymphoma cells were positive for CD19, CD20 and HLA-DR surface antigens, and negative for CD5 and CD10. In four cases elevated serum levels of interleukin (IL)-6 and the soluble IL-2 receptor isoform were noted, but not IL-1β, IL-2 or tumour necrosis factor-α. Autopsies of two cases were pathologically diagnosed as intravascular lymphomatosis (IVL). Based on these observations, the current and nine previous cases reported as MH-like BCL in Japan were re-evaluated. They appear to form a peculiar variant of IVL, characterized by bone marrow involvement at presentation, haemophagocytic syndrome, and a rapidly aggressive clinical course, but rarely neurological complications or skin lesions. This variant may merit separate consideration because of the problems posed in the initial diagnosis and therapeutic approaches.     

Clinical course of 8 patients with intravascular large B-cell lymphoma diagnosed while alive

We retrospectively evaluated the diagnosis and clinical courses of 8 patients with intravascular large B-cell lymphoma (IVL) diagnosed while they were alive. The median age was 67 years old (range 54 to 82). Most complaints at diagnosis were fever or dyspnea. All patients were in clinical stage IV with B symptoms and 4 patients showed performance status 4. The diagnosis of IVL was confirmed by biopsy specimens from the bone marrow in 4, lung in 2, muscle, adrenal gland, and lymph node in 1 case, respectively. Initial bone marrow involvement was found in 6 patients. Chemotherapy was performed in 7 patients. Rituximab was added to chemotherapy in 5 patients. Though 5 patients are alive at the median follow up of 12.3 months, only 1 patient is in remission. Four of 5 patients treated with Rituximab relapsed. In suspicious cases, it is important to bear IVL in mind and examine bone marrow biopsies for an early diagnosis. In addition, it is suggested that Rituximab may play only a temporary role in the treatment of IVL.     

Intravascular T-cell lymphoma with bowel involvement: case report and literature review

Intravascular lymphoma (IVL) is a rare form of non-Hodgkin lymphoma characterized by massive proliferation of large, neoplastic cells in small- and medium-sized blood vessels. Most cases of IVL are of B-cell immunophenotype; fewer than 15 cases of T-cell IVL have been reported. A 23-year-old male presented with acute abdominal pain, fever, and tender lower abdomen. Pathology at laparotomy revealed infiltration of colonic vessels with large lymphoid cells compatible with IVL. We reviewed all cases of IVL diagnosed at the Queen Elizabeth II Health Sciences Centre in Halifax, Nova Scotia, from August 1992 to August 2002. A literature review was also performed. Five additional cases of IVL were identified at this institution during a 10-year period. Three patients presented with neurological symptoms, and two with abdominal pain. In 4 of 5 cases, patients died of lymphoma within 3 months of presentation; one patient experienced a 10-month remission. While visceral involvement with IVL is common at autopsy, IVL presenting as an acute abdomen in an immunocompetent patient has not previously been described. Among the 15 cases of T-cell IVL reported in the literature, only two occurred in people under age 30. Given the rarity of T-cell IVL, it is remarkable that three cases of T-cell IVL have been diagnosed at our institution during a 10-year period.     

A clinicopathological study of 13 cases of intravascular lymphoma: experience in a single institution over a 9-yr period

Intravascular lymphoma (IVL) is a rare type of extranodal lymphoma in which the lymphoma cells proliferate exclusively in lumina of small vessels. Here, we report a clinicopathological study of 13 cases IVL diagnosed at our institution between March 1999 and July 2007, and evaluated the clinical characteristics, usefulness of random skin biopsy and response to chemotherapy containing rituximab. Three of 13 patients were diagnosed at autopsy. The most common clinical features were unexplained fever, neurological deterioration, respiratory failure, and poor performance status. Thrombocytopenia, high serum lactate dehydrogenase and soluble interleukin2 receptor levels were the most common laboratory abnormalities. Adrenal tumor was detected in four cases and pituitary involvement was seen in all three autopsied cases and in two surviving patient by brain magnetic resonance imaging. Bone marrow invasion was seen in all 13 cases by bone marrow smear, and it was subtle in trephine biopsy. Immunohistochemical analyses revealed that CD5 was positive in one-third of the cases. Most of the cases were positive for MUM1/IRF, Bcl-2 and negative for CD10 and BCL-6 indicating the postgerminal center cell origin of this peculiar type of lymphoma. On random skin biopsy, the most recent seven patients were diagnosed promptly and chemotherapy containing rituximab was successfully administered. Patients with IVL exhibit the characteristic clinical and immunophenotypic features cited above and the use of random skin biopsy facilitates prompt diagnosis. Early commencement of chemotherapy containing rituximab appears promising for this peculiar lymphoma. As the recent seven patients were diagnosed by random skin biopsy over the past 13 months, the incidence of IVL is thought to be much higher than generally accepted.     

Intravascular lymphoma in a patient with systemic lupus erythematosus: a case report

Intravascular lymphoma IVL is a rare and aggressive disorder characterized by proliferation of large lymphoid cells (most commonly B-cells) within the lumen of small vessels of nearly every organ. Obliteration of vessels leads to the different clinical signs, being cutaneous lesions and neurological signs the most frequent presentations, whereas lymph node and reticuloendothelial system involvement is typically absent. No association with SLE has been described up to the present. We report a case of IVL in a patient with systemic lupus erythematosus (SLE) involving skin, central nervous system (CNS) and bone marrow.     

Intravascular lymphomatosis diagnosed by bone marrow biopsy

Intravascular lymphomatosis (IVL) is a rare malignancy characterized by neoplastic proliferation of lymphoid cells within the lumina of small vessels. We report a case of IVL in a 69-year-old woman, who presented with pancytopenia and elevation of the serum LDH level. There was no skin eruption or neurological abnormalities. Clusters of abnormal lymphoid cells were barely evident in a peripheral blood smear. Laboratory examinations revealed high levels of LDH (2,602 IU/l) and sIL-2R (5,640 U/ml). Bone marrow aspiration revealed a normal cellular marrow with mild hemophagocytosis, but no tumor cells were detected. After admission, respiratory failure due to multiple pulmonary embolisms progressed, and continuous infusion of heparin had no apparent effect. Bone marrow vessels filled with lymphoma cells were observed in a biopsy specimen, thus establishing a diagnosis of IVL. Chemotherapy with the CHOP regimen was immediately instituted. The respiratory failure was dramatically improved, resulting in disappearance of the abnormal lymphoid cells from the bone marrow. After eight courses of CHOP, low-dose etoposide therapy was administered, and no symptoms of relapse were noticed. The diagnosis of IVL is difficult because it does not form masses of tumor cells. Bone marrow biopsy may be helpful for early diagnosis of IVL if the disease is suspected and searched for.     

Random skin biopsy and bone marrow biopsy for diagnosis of intravascular large B cell lymphoma

Intravascular lymphoma (IVL) is a rare type of extranodal lymphoma in which the lymphoma cells proliferate exclusively in the lumina of small vessels. The diagnosis of IVL requires histological confirmation. Although random skin biopsy from healthy-appearing skin in patients with suspected IVL appeared to be useful, the sensitivity of this method for the diagnosis of IVL remains unknown. We performed a random skin biopsy from 12 consecutive cases of IVL diagnosed at our institution over the past 4 years and evaluate its relevance of clinical and laboratory characteristics, presence or absence of skin lesions, and bone marrow involvement. All 12 patients were diagnosed antemortem by either random skin biopsy or bone marrow biopsy and treated with rituximab-containing chemotherapy. Random skin biopsy was performed in all 12 patients, and the results were positive in ten patients (83.3%). Erythematous skin lesions were seen in 3 of 12 patients, but biopsy was positive for lymphoma lesion in two patients. Bone marrow invasion was seen in 11 of the 12 patients (91.6%) by bone marrow smear and/or flow cytometric analysis, but was detected in only half of the patients by trephine biopsy. We concluded that random skin biopsy from normal-appearing skin is highly sensitive in the diagnosis of IVL comparable to bone marrow trephine biopsy. It should be performed irrespective of the presence or absence of skin lesions in patients who were suspicious of IVL.     

Usefulness of FDG-PET to diagnose intravascular lymphomatosis presenting as fever of unknown origin

Intravascular lymphomatosis (IVL) is a rare systemic disease characterized by proliferation of lymphoid cells within the lumina of small arteries, veins, and capillaries. Diagnosis requires skin, liver, lung, bone marrow, renal, meningeal, or brain vessel biopsy but is often made only when the illness has progressed or post mortem because early involvement of organs was not evident. We report a case of IVL presenting as fever of unknown origin (FUO). In this case, gallium scintigraphy and computed tomography (CT) showed no evidence of malignancy, whereas (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) showed increased FDG uptake in the sternum, left and right vertebra, humerus, femur, and especially ilium. The diagnosis was made on iliac bone marrow biopsy examination. FDG-PET was useful for the detection of spread of disease in a patient with IVL suffering from FUO.     

An Asian variant of intravascular large B-cell lymphoma: clinical, pathological and cytogenetic approaches to diffuse large B-cell lymphoma associated with haemophagocytic syndrome

Diffuse large B-cell lymphoma with haemophagocytic syndrome (BCL-HS) has been reported mainly in Asia and is regarded as a distinct variant of intravascular lymphoma (IVL). However, it is unclear whether all cases of BCL-HS fall within the framework of IVL and available clinical information is limited. We analysed 25 cases with BCL-HS, including 11 autopsied cases (median, 66 years; male-female ratio, 1.1:1). The patients presented with fever, anaemia, thrombocytopenia, hepatosplenomegaly, haemophagocytosis, bone marrow invasion, respiratory disturbance and disseminated intravascular coagulopathy, but usually lacked lymphadenopathy, mass formation, neurological abnormalities and skin lesions. The clinical course was aggressive with a median survival of 7 months. The morphological findings were uniform: large lymphoid cells infiltrated vessels and/or sinusoids of the liver, marrow, lung, kidney and other organs. They were positive for CD19, CD20, CD79a and HLA-DR, but negative for CD10, CD23 and CD30. CD5 was positive in five out of 17 cases. Our critical review indicates that BCL-HS is the equivalent of the Asian variant of IVL.     

Asian variant of CD5+ intravascular large B-cell lymphoma with splenic infarction

A 57-year-old man was admitted with fever and epigastralgia, and presented with splenomegaly and pancytopenia. A CT scan revealed splenic infarctions. There were no lymphadenopathies, skin lesions, or neurological abnormalities. A splenectomy was performed. Bone marrow involvement with hemophagocytosis was noted. The diagnosis of Asian variant of intravascular diffuse large B-cell lymphoma was based on intravascular and sinusoidal distribution of large CD5+ B cells. The patient died of the disease 11 months after onset. To our knowledge, this is the first report of AIVL that presented with splenic infarction. This distinct lymphoma should be included in the differential diagnosis of splenic infarction.     

Bilateral adrenal enlargement with an unexpected diagnosis

A 78-year-old man, previously treated for prostate and colorectal cancer, was admitted to the hospital because of persistent fever. He was found to have bilateral large adrenal masses and adrenal insufficiency. Primary large B-cell lymphoma was proven by aspiration biopsy of the left adrenal gland. On presentation, no evidence of lymphoma outside the adrenal glands was found. The patient died before treatment could be initiated. The autopsy report is discussed briefly. Primary adrenal lymphoma is a rare entity and should be considered in a patient with bilateral adrenal masses without nodular involvement.     

Intravascular lymphoma associated with hemophagocytic syndrome: a rare but aggressive clinical entity

We report a 55-year-old male with a diagnosis of intravascular lymphoma and hemophagocytosis. He initially presented with hemolytic anemia and splenomegaly and was successfully treated with oral steroids. His clinical course was later complicated by fever, cytopenias, hypoalbuminemia, disseminated intravascular coagulation, gastrointestinal bleeding and acute tubular necrosis. Results of an extensive investigation for fever of unknown origin were negative. Although the patient was treated aggressively with antimicrobials, transfusion support and dialysis, he expired 3 weeks after hospitalization. Post-mortem analysis revealed large CD30- and CD45-positive lymphoma cells in an intravascular distribution in most of the organs studied. Histopathology of the spleen and bone marrow was significant for fulminant hemophagocytosis.     

Intravascular lymphoma: clinical presentation, natural history, management and prognostic factors in a series of 38 cases, with special emphasis on the 'cutaneous variant'

Despite its recognition as a distinct, extremely rare entity, no large studies of intravascular lymphoma (IVL) have been reported. The clinico-pathological characteristics of 38 human immunodeficiency virus-negative patients with IVL diagnosed in Western countries were reviewed to better delineate clinical presentation, clinical variants, natural history and optimal therapy. The IVL is an aggressive and usually disseminated disease (Ann Arbor stage IV in 68% of cases) that predominantly affects elderly patients (median age 70 years, range: 34-90; male:female ratio 0.9), resulting in poor Eastern Cooperative Oncology Group Performance Status (ECOG-PS >1 in 61%), B symptoms (55%), anaemia (63%) and high serum lactate dehydrogenase level (86%). The brain and skin are the most common sites of disease. In contrast to previous reports, hepatosplenic involvement (26%) and bone marrow infiltration (32%) were found to be common features in IVL, while nodal disease was confirmed as rare (11% of cases). Patients with disease limited to the skin ('cutaneous variant'; 26% of cases) were invariably females with a normal platelet count, and exhibited a significantly better outcome than the remaining patients, which deserves further investigation. Overall survival was usually poor; however, the early use of intensive therapies could improve outcome in young patients with unfavourable features. ECOG-PS >1, 'cutaneous variant', stage I and chemotherapy use were independently associated with improved survival.     

Subcutaneous panniculitis-like T-cell lymphoma presenting with hemophagocytic lymphohistiocytosis and skin lesions with characteristic high-resolution ultrasonographic findings

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is an unusual type of skin lymphoma, characterized by subcutaneous soft tissue infiltration with pleomorphic T-cells and benign macrophages that mimic panniculitis. Hemophagocytic lymphohistiocytosis is a rare but potentially fatal disorder which is thought to result from uncontrolled activation and proliferation of T-cells and excessive activation of macrophages. Hemophagocytic lymphohistiocytosis have been reported as the presenting feature in 37% of SPTCL patients. High-resolution ultrasonographic appearance of SPTCL with a characteristic finding has been described in only one patient. We report a 28-year-old woman with hemophagocytic lymphohistiocytosis presented with nonremitting fever, thrombocytopenia, hypofibrinogenemia, hyperferritinemia, increased serum levels of soluble interleukin (IL)-2 receptors and hemophagocytosis in bone marrow examination. Markedly elevated level of serum IL-18 was also demonstrated in our patient. The fever subsided and the ferritin level declined to normal after treatment with oral steroid and etoposide. No evidence of hemophagocytosis was revealed in a follow-up bone marrow examination. However, nonremitting high fever and panniculitis-like skin lesions over her back, arm, lower abdominal wall, and bilateral pretibial regions developed 1 month later. A high-resolution ultrasonography revealed thickening of the subcutaneous fat layer with homogeneous hyperechogenicity pattern and poor-defined margin over the skin lesions. An ultrasound-guided excision biopsy of the nodular lesion over left upper arm was performed and the histopathology showed neoplastic cells with hyperchromatic nucleoli, which extended from deep dermis to subcutaneous fat. The immunochemical stain showed a T-cell lineage of tumor cells. SPTCL was diagnosed and the skin lesions subsided gradually after treatment with anthracycline-based combination chemotherapy.     

Intravascular malignant lymphoma (angiotrophic large-cell lymphoma)

Intravascular lymphoma (IVL) is characterized by proliferation of large malignant lymphoid cells within the lumen of small vessels. Sites usually affected include the central nervous system and skin although involvement of multiple organ symptoms have been described. IVL is very rare and aggressive type of lymphoma. Based on review of the literature we present clinicopathological, immunohistochemical and molecular features of the IVL. The etiological possibilities are discussed.     

B-cell lymphoma-associated hemophagocytic syndrome: clinicopathological characteristics

Seven patients with peripheral B-cell lymphoma associated with hemophagocytic syndrome are reported. In all cases, the histologic subtype was diffuse large B-cell lymphoma. Hemophagocytic features were noted in the bone marrow with lymphomatous infiltration. Hemophagocytic syndrome occurred with presentation of the lymphoma and was characterized by high fever, cytopenias, and elevated levels of lactate dehydrogenase, ferritin, C-reactive protein, and cytokines [interferon γ, macrophage colony-stimulating factor, soluble interleukin (sIL)-2R, and IL-6] without evidence of infection. The phenotypes of lymphomas were suspected CD19⁺, CD20⁺, S-Ig⁺, CD10⁻, and co-expression of CD5 in some cases. Flow cytometric analysis showed a low CD4/CD8 ratio in peripheral blood and bone marrow. We suggest that the pathogenesis of hemophagocytic syndrome is hypercytokinemia induced by a proliferation of reactive CD8⁺ T cells. Previous reports of B-cell lymphoma with hemophagocytic syndrome demonstrated similar clinical manifestations and poor prognoses. The invasion patterns of these diffuse large B-cell lymphomas with hemophagocytosis may be classified into three groups: microscopic lymph-node involvement type, gross lymph-node involvement type, and splenic lymphoma type. Although hemophagocytic syndromes have been reported to be associated with T-cell lymphomas, our results indicate an association with diffuse large B-cell lymphoma. Received: 16 July 1999 / Accepted: 13 December 1999     

Intravascular large B-cell lymphoma or intravascular lymphomatosis: report of a case diagnosed by testicle biopsy

Intravascular large B-cell lymphoma or intravascular lymphomatosis (IVL) is an extremely rare form of non-Hodgkin's lymphoma. The most common clinical sign is fever of unknown origin (FUO). Histologically, there is proliferation of malignant lymphoid cells within vascular lumina. Cytologically, the cells have features similar to those found in classical large cell lymphoma. Examination of pulmonary artery blood showed the presence of this abnormal population in our patient; to the best of our knowledge there are only four other. reports of detection of circulating tumor cells in IVL. The outcome is very poor. The diagnosis is most frequently made after biopsy of skin or brain but is often established post mortem. We present what is--to our knowledge--the first reported case of IVL diagnosed after biopsy of a testicle. In the event of FUO and suspicion of a malignancy, IVL--although very rare--should be one of the differential diagnoses.     

Intravascular proliferating anaplastic lymphoma kinasepositive anaplastic large-cell lymphoma

An 82-year-old Japanese man visited our emergency unit complaining of dyspnea. Laboratory data showed 15% atypical lymphocytes in peripheral blood which expressed the T-cell phenotype. Chest/abdominal computed tomography depicted hepatosplenomegaly and swelling of systemic lymph nodes. The patient died of advanced respiratory failure 5 d after the first occurrence of his dyspnea. At autopsy, the pathological features revealed a diffuse infiltration of large atypical lymphocytes to systemic organs including the spleen and lung. In immunohistochemical staining, these cells expressed CD30, TIA-1, anaplastic lymphoma kinase(ALK), CD5 and CD3. An advanced surface molecule analysis revealed a lack of CD54(intercellular cell adhesion molecule-1) and CD56(neural cell adhesion molecule). We observed the proliferation and infiltration of these lymphoma cells specifically at the intravascular lesions similar to intravascular lymphoma(IVL). T-cell IVL is not established as an independent clinical entity in the World Health Organization classification, and our patient's ALK-positive T-IVL in lung appears to be the first reported case.     

Anaplastic large cell Ki-1 lymphoma involving bone marrow: marrow findings and association with reactive hemophagocytosis.

This report describes the bone marrow findings in four patients whose marrow was involved by anaplastic large-cell Ki-1 lymphoma, an uncommon event in this type of lymphoma. In the marrow aspirate smears, the involvement was subtle, and was in the form of isolated large cells with irregular nuclear configuration, coarse chromatin, prominent nucleoli, and basophilic cytoplasm which might be vacuolated. One case showed paradoxically massive involvement in the trephine biopsy taken from the same site as the marrow aspirate. Reactive histiocytic proliferation with hemophagocytosis was also present. Since marrow aspirate or biopsy may be the first pathologic specimen examined in patients having anaplastic large-cell Ki-1 lymphoma, it is important to be able to recognize the small population of neoplastic cells, which should lead to prompt treatment or further investigations as deemed necessary.