Hemophagocytic syndrome as the primary clinical symptom of Hodgkin's disease

It is now well recognized that hemophagocytic syndrome (HPS) is occasionally associated with malignant lymphomas. However, its association with Hodgkin's disease has been only rarely reported. We present here a 72-year-old woman manifesting with HPS as the primary and solitary clinical symptom of Hodgkin's disease. She had been suffering from high-grade fever and anemia for more than a month. Based on the findings in bone marrow aspirates, she was diagnosed as having HPS. In spite of extensive surveys including various cultures, serological tests for collagen disease, abdominal and cardiac sonography, chest computed tomography (CT), and renal biopsy, the origin of the fever was not determined. She was treated with steroid pulse therapy and then referred. Radiological studies revealed only mild hepatosplenomegaly and small lymph node swellings around celiac and common hepatic arteries. Reevaluation of the bone marrow specimen revealed the infiltration of small numbers of CD30-, CD15-, and EBER-1-positive large-sized lymphocytes with bizarre nucleus. Under the diagnosis of Hodgkin's disease, she was treated with combination chemotherapy containing pirarubicin, cyclophosphamide, vincristine, and prednisolone. However, it was not effective and she died of rapidly progressive hepatic failure on the 5th day of the chemotherapy. Autopsy was performed, which showed proliferation of lymphoma cells in para-aortic lymph nodes. We believe that diagnostic survey to rule out the underlying lymphoma should be vigorously performed for patients with hemophagocytic syndrome of unknown origin.     

The acute lupus hemophagocytic syndrome

OBJECTIVE: To characterize an unusual mode of presentation of systemic lupus erythematosus: acute and severe pancytopenia related to reactive hemophagocytosis. DESIGN: Retrospective case series. SETTING: Two general community hospitals in Hong Kong. PATIENTS: Six patients presenting with a reactive hemophagocytic syndrome, identified over a 3.5 year period, diagnosed with systemic lupus erythematosus according to the criteria of the American Rheumatism Association. RESULTS: In addition to severe pancytopenia and marrow hemophagocytosis, other characteristic features were fever, hypocomplementemia, high antinuclear antibody titer, and cutaneous and visceral vasculitis. There was no evidence of an underlying infection. The pancytopenia responded dramatically to treatment with steroids. CONCLUSION: Recognition of the acute lupus hemophagocytic syndrome and distinction from an infection-associated hemophagocytic syndrome is important because it responds well to steroid therapy. The evaluation of patients presenting with a hemophagocytic syndrome should include serologic tests for systemic lupus erythematosus.     

Reactive Hemophagocytic Syndrome in Adults: A Retrospective Analysis of 162 Patients

ObjectivesCurrent knowledge in reactive hemophagocytic syndrome mainly relies on single-center case series including a relatively small number of patients. We aimed to identify a multicenter large cohort of adult patients with reactive hemophagocytic syndrome and to describe relevant clinical and laboratory features, underlying conditions, and outcome.MethodsWe conducted a multicenter study in 3 tertiary care centers in France over a 6-year period. The medical files of 312 patients with suspected hemophagocytic syndrome were retrospectively reviewed. Patients were classified with a positive, negative, or undetermined diagnosis of hemophagocytic syndrome by experts' consensus.ResultsAmong the 312 patients fulfilling our inclusion criteria, 162 were classified with positive hemophagocytic syndrome (male, 67%; median age, 48 [35-62] years). Compared with patients without hemophagocytic syndrome, patients with hemophagocytic syndrome more frequently had an underlying immunodepression (45% vs 33%, P = .03) and exhibited higher temperature, ferritin, triglycerides, aspartate transaminase, bilirubin, lactate dehydrogenase, and C-reactive protein, and lower hemoglobin, leukocytes, platelets, and sodium levels. Only 70% of them had hemophagocytosis features on bone marrow aspiration. Hematologic malignancies, especially non-Hodgkin lymphomas, were the main trigger of hemophagocytic syndrome, accounting for 56% of cases. The early mortality rate (ie, within 1 month after diagnosis) was 20%. Patients with hematologic malignancies-associated hemophagocytic syndrome had a poorer early outcome than those with underlying infection.ConclusionsIn this large, multicenter study, hematologic malignancies are the main disease associated with hemophagocytic syndrome in adults. Early mortality is high, and outcome is influenced by the underlying disease.     

A case of hemophagocytic syndrome with terminal ileal ulcerations]

Reactive hemophagocytic syndrome or hemophagocytic lymphohistiocytosis, is characterized by the proliferation of benign histiocytes showing phagocytosis of blood cells in hematopoietic organs including bone marrow, spleen, or lymph nodes, accompanied by fever, hepatosplenomegaly, hepatic dysfunction, pancytopenia, and hypertriglyceridemia. The pathogenesis of reactive hemophagocytic syndrome is unknown. It is often associated with infection, malignant neoplasm, autoimmune disease, drugs and various immunodeficiencies. The prognosis of this syndrome is poor and the causes of death are hemorrhage, infection, or multiorgan failure. We experienced a case of hemophagocytic syndrome with terminal ileal ulcers, not associated with other causes. Thus, we report this case with a review of literatures.     

Hodgkin's lymphoma as a cause of fever of unknown origin in HIV infection

The risk of Hodgkin's lymphoma is increased in HIV-infected patients. In these patients Hodgkin's lymphoma is an aggressive disease with poor clinical outcome. Complete remission and survival rates are far below that reported in HIV-uninfected population. Since the widespread use of highly active antiretroviral therapy, malignancies are the major cause of mortality in HIV-infected patients. We report a case of a 29-year-old HIV-positive male who presented with fever of unknown origin, pancytopenia, and hemophagocytic syndrome. The diagnosis of Hodgkin's lymphoma with bone marrow involvement was made on bone marrow biopsy, 5 months after the onset of fever. The patient was treated with chemotherapy and achieved a complete remission. Relapse occurred 28 months later and he died 31 months after initial diagnosis. Prolonged fever is frequently observed in HIV-infected patients and could represent a diagnostic challenge. Infectious diseases are the most common causes, however lymphomas are the third most common cause of fever of unknown origin in HIV disease. This case illustrates the difficulties in accurately diagnosing Hodgkin's lymphoma in patients presenting with prolonged, unexplained fever, and emphasizes the use of bone marrow biopsy to confirm Hodgkin's lymphoma, particularly if cytopenia and hemophagocytic syndrome are present.     

Low glycosylated ferritin, a good marker for the diagnosis of hemophagocytic syndrome

OBJECTIVE: A very low percentage of glycosylated ferritin (<20%) has only been reported in association with adult-onset Still's disease (AOSD), a disease classically associated with hemophagocytic syndrome. We undertook this study to determine whether hemophagocytic syndrome outside the context of AOSD is also associated with a very low percentage of glycosylated ferritin. METHODS: From October 2006 to September 2007, the serum level of glycosylated ferritin was determined in all consecutive patients seen in 3 departments and for whom the diagnosis of hemophagocytic syndrome was suspected. The level of glycosylated ferritin in these patients was compared with that in age- and sex-matched controls with a marked inflammatory syndrome not associated with hemophagocytic syndrome. We assessed the value of glycosylated ferritin as a marker for the diagnosis of hemophagocytic syndrome. RESULTS: Forty-two patients were included in the study (14 with confirmed hemophagocytic syndrome, 7 with suspected but unconfirmed hemophagocytic syndrome, and 21 controls). The median level (interquartile range [IQR]) of total serum ferritin was significantly higher in patients with confirmed hemophagocytic syndrome (3,344 microg/liter [2,074-7,334]) than in patients with suspected but unconfirmed hemophagocytic syndrome (555 microg/liter [464-1,420]) (P = 0.02) or in controls (451 microg/liter [126-929]) (P < 0.001). The median (IQR) percentage of glycosylated ferritin was significantly lower in patients with confirmed hemophagocytic syndrome (10% [3-14]) than in patients with suspected but unconfirmed hemophagocytic syndrome (40% [36-47]) (P < 0.001) or in controls (36% [26-49]) (P < 0.001). The diagnostic performance of glycosylated ferritin tended to be higher than that of total serum ferritin for the diagnosis of hemophagocytic syndrome (area under the receiver operating characteristic curve [95% confidence interval] 0.97 [0.92-1.00] versus 0.79 [0.59-1.00]; P = 0.10). CONCLUSION: These results suggest that glycosylated ferritin may be a helpful marker for the diagnosis of hemophagocytic syndrome.     

Macrophage activation syndrome in Still’s disease: analysis of clinical characteristics and survival in paediatric and adult patients

Clinical Rheumatology - Macrophage activation syndrome (MAS) is a reactive form of hemophagocytic lymphohistiocytosis, complicating Still’s disease, both in paediatric and adult patients. In...     

Intravenously administered gamma-globulins in reactive hemaphagocytic syndrome. Multicenter study to assess their importance, by the immunoglobulins group of experts of CEDIT of the AP-HP

Reactive hemophagocytic syndrome is characterized by systemic proliferation and activation of benign hemophagocytic cells of the monocyte-macrophage lineage. Treatment should be directed to the etiology, but successful treatment with high-dose gamma-globulin has been reported, especially in viral-associated hemophagocytic syndrome. We report 17 patients, of which 9 had infection-associated hemophagocytic syndrome, all treated with high-dose gamma-globulin. High-dose gamma-globulins appear to be more effective in infection-associated hemophagocytic syndrome, with a mean dose of 1.6gm/kg for one or two cycles. A multicentric randomized study is required to evaluate high-dose gamma-globulin in the treatment of reactive hemophagocytic syndrome.     

Paraneoplastic cerebellar degeneration preceding the diagnosis of Hodgkin's lymphoma

Paraneoplastic cerebellar degeneration (PCD) can present as a severe and (sub)acute cerebellar syndrome. PCD can accompany different kinds of neoplasms including small cell lung cancer, adenocarcinoma of the breast and ovary, and Hodgkin's lymphoma. A 34-year-old patient is described with acute dysarthria, gait ataxia and diplopia. Despite extensive laboratory and radiological evaluations in this patient with rapidly deteriorating cerebellar syndrome, the diagnosis of a paraneoplastic syndrome was only made after several months, when an anti-Tr antibody was detected in his serum. The search for Hodgkin's disease as concomitant disorder was then started and resulted in stage II B disease. The patient was successively treated with six courses of etoposide, bleomycin, vinblastine and dexamethasone and radiotherapy, which resulted in a complete remission of the Hodgkin's disease. After starting therapy the cerebellar degeneration stabilised. The pathogenesis of neuronal damage in central nervous system paraneoplastic disorders such as the one we describe is not completely understood. Antitumour therapy is assumed to be the important cornerstone in stabilising the neurological condition. Improvement of the cerebellar syndrome in anti-Tr autoantibody paraneoplastic disease is a rare achievement. Early recognition of the concomitant disorders (anti-Tr autoantibody disease and Hodgkin's lymphoma) is of crucial importance.     

Macrophage activation syndrome and reactive hemophagocytic lymphohistiocytosis: the same entities?

PURPOSE OF THE REVIEW: One of the most perplexing features of systemic-onset juvenile rheumatoid arthritis is the association with macrophage activation syndrome, a life-threatening complication caused by excessive activation and proliferation of T cells and macrophages. The main purpose of the review is to summarize current understanding of the relation between macrophage activation syndrome and other clinically similar hemophagocytic disorders. RECENT FINDINGS: Clinically, macrophage activation syndrome has strong similarities with familial and virus-associated reactive hemophagocytic lymphohistiocytosis. The better understood familial hemophagocytic lymphohistiocytosis is a constellation of rare, autosomal recessive immune disorders. The most consistent immunologic abnormalities in patients with familial hemophagocytic lymphohistiocytosis are decreased natural killer and cytotoxic cell functions. In approximately one third of familial hemophagocytic lymphohistiocytosis patients, these immunologic abnormalities are secondary to mutations in the gene encoding perforin, a protein that mediates cytotoxic activity of natural killer and cytotoxic CD8+ T cells. Several recent studies have suggested that profoundly depressed natural killer cell activity and abnormal levels of perforin expression may be a feature of macrophage activation syndrome in systemic-onset juvenile rheumatoid arthritis as well. Although it has been proposed that in both hemophagocytic lymphohistiocytosis and macrophage activation syndrome, natural killer and cytotoxic cell dysfunction may lead to inadequate control of cellular immune responses, the exact nature of such dysregulation and the relation between macrophage activation syndrome and hemophagocytic lymphohistiocytosis still remain to be determined.     

Hemophagocytic syndrome with hemophagocytes in the peripheral blood]

A 79-year-old man developed a high fever, facial erythema, anemia and thrombocytopenia during conservative therapy for ischemic colitis. Peripheral hemophagocytes (PHP) were identified in smear specimens of peripheral blood, and hemophagocytes also showed proliferation in the bone marrow. After treatment with steroid and antibiotics under a diagnosis of bacteria-associated hemophagocytic syndrome, the patient recovered rapidly. Although the prognosis of hemophagocytic syndrome (HPS) depends on the underlying disease, any delay in diagnosis can sometimes result in a poor outcome in cases of infection-associated hemophagocytic syndrome. In the present case, early diagnosis of bacteria-associated hemophagocytic syndrome was made by detection of PHP. The appearance of PHP in virus-associated hemophagocytic syndrome (VAHS) and after administration of macrophage colony stimulating factor has been described. However, the significance and cytological characteristics of PHP have been unknown. In this report, we propose that PHP can be a useful indicator for early diagnosis of HPS, and we report 7 additional cases in which the PHP was detected retrospectively. The cytological characteristics and biological significance of PHP are discussed.     

Hemophagocytic syndrome causing complete bone marrow failure. Report of an extreme case of a reactive histiocytic disorder

The hemophagocytic syndrome is a reactive disorder of the mononuclear phagocytic system. Most of the cases are rare complications of common infectious and neoplastic diseases, although there may be an underlying immune disorder predisposing to this syndrome. We report a case in association with immune thrombocytopenia and hemolytic anemia (Evans' syndrome). The hemophagocytic reaction appeared after a bacterial infection of the urinary tract and presented with abrupt pancytopenia and complete hemopoietic failure. We discuss the possible mechanisms of bone marrow failure related with the hemophagocytic syndrome.     

Ammoniacal silver staining of lymph node cells. II. Reactive follicular hyperplasia and its relationship with Hodgkin's disease

Lymph node biopsy specimens from 150 cases of reactive follicular hyperplasia, 52 cases of Hodgkin's disease and 30 cases of chronic lymphadenitis were studied. Clinical follow-up of cases for a period of two years at least was also considered. Formalin fixed and paraffin embedded tissues were stained with hematoxylin and eosin, and ammoniacal silver. Cytoplasmic accumulations of basic proteins were evidence in 30 out of 150 cases, but only 27 of these cases presented new lymph nodes with histological setting of Hodgkin's disease. The data suggest possible relationship between reactive follicular hyperplasia and Hodgkin's disease. However this relationship is not absolute as documented by two cases that being negative for the ammoniacal silver staining, were later diagnosed as Hodgkin's disease. Different types of atypical cells occurring in lymph nodes of reactive follicular hyperplasia were also studied. The potential use of ammoniacal silver staining in the early diagnosis of Hodgkin's disease is discussed.     

不明原因发热伴脾肿大时脾切除术的临床意义

目的　探讨不明原因发热伴脾肿大时脾切除术病理学检查的临床意义。方法　回顾分析了我院血液内科1996年以来以不明原因发热收住院,除发热、脾肿大外无其他明显阳性体征,且辅助检查也不能做出病因诊断的35例患者的临床资料,所有患者均行剖腹探查加脾切除术,并获得病理学检查结果。结果　35例患者中,非霍奇金淋巴瘤17例(占486%),霍奇金淋巴瘤5例,恶性组织细胞病2例,结缔组织病5例,慢性淤血性脾肿大2例,噬血细胞综合征、脾陈旧性梗死、脾结核和脾血管肉瘤各1例。结论　发热伴脾肿大而不能明确诊断时,应动员患者尽早作诊断性脾切除术并送病理学检查,以免延误诊断和治疗。     

Lack of evidence of circulating retroviral antibodies in patients with classic Hodgkin's disease

Because of the T-cell abnormalities observed in Hodgkin's disease and the growing number of Hodgkin's disease cases observed in association with the acquired immunodeficiency syndrome (AIDS), concern has been expressed that a retrovirus may be the primary cause of Hodgkin's disease. We examined plasma specimens from 17 patients with Hodgkin's disease that were drawn in 1979. Because serum containing antibodies to either human T-lymphotropic virus type I (HTLV-I) or HTLV-II precipitate the major core protein, p24, of HTLV-I, lack of reactivity to HTLV-I p24 in all the specimens demonstrated absence of antibodies to HTLV-I or -II. None of the specimens was reactive to human immunodeficiency virus type 1 (HIV-1) by ELISA. None of the specimens were reactive on Western blot assays for HTLV-I or -II or HIV-1. Lack of evidence of cross-reacting antibodies to prototype strains of those retroviruses in specimens drawn before the AIDS epidemic suggests that classic Hodgkin's disease is not the result of infection with one of the known human lymphocytotropic retroviruses or a closely related agent.     

Nephrotic syndrome in Hodgkin's disease. Evidence for pathogenesis alternative to immune complex deposition.

The nephrotic syndrome has been reported to occur in patients with Hodgkin's disease even in the absence of amyloidosis, tumor infiltration of renal vein thrombosis. Three patients are presented with Hodgkin's disease and the nephrotic syndrome whose renal biopsy specimens studied with light, immunofluorescence and electron microscopy were compatible with "lipoid nephrosis" (minimal change disease). A review of the literature reveals 35 patients with Hodgkin's disease and the nephrotic syndrome. Renal tissue was available for examination in only 27 patients. The majority of patients apparently had glomerular alterations consistent with lipoid nephrosis. The nephrotic syndrome in most of these patients remitted with a variety of methods of therapy (including excision, irradiation, prednisone and cyclophosphamide) and tended to relapse with a recurrence of Hodgkin's disease. In three-fourths of the patients with Hodgkin's disease and the nephrotic syndrome, the Hodgkin's disease was of a mixed cellularity type. The etiology of lipoid nephrosis, although unclear, may be a consequence of altered lymphocyte function. Hodgkin's disease is a malignancy involving T lymphocytes, and the nephrotic syndrome occurring in the course of Hodgkin's disease may be a result of an adverse effect of glomeruli by products of tumor lymphocytes rather than of glomerular deposition of immune complexes.     

Allogeneic bone marrow transplantation for active Epstein-Barr virus-related lymphoproliferative disease and hemophagocytic lymphohistiocytosis in an infant with severe combined immunodeficiency syndrome

A 5-month-old male presented with fever, hepatosplenomegaly, leukocytosis with atypical lymphoblasts, anemia and thrombocytopenia. Severe combined imunodeficiency syndrome (T-, B+, NK+), B lymphoproliferative disease and hemophagocytic lymphohistiocytosis triggered by Epstein-Barr virus (EBV) were diagnosed. As his clinical situation deteriorated rapidly, BMT was performed with unmanipulated marrow stem cells from his EBV-positive HLA-identical sister after conditioning with dexamethasone (1.75 mg/kg/day), cyclophosphamide (114 mg/kg) and etoposide (10 mg/kg), with no immunosuppression given post transplant. Engraftment occurred on day 6 with explosive proliferation of donor CD8(+) T cells. The patient died 3 days later from acute respiratory distress syndrome. Autopsy revealed full donor engraftment and no signs of hemophagocytic lymphohistiocytosis or B lymphoproliferative disease. Thus, transplanted T cells can expand very rapidly within days after BMT and clear EBV lymphoproliferative disease and hemophagocytic lymphohistiocytosis.     

DEVELOPMENT OF HODGKIN'S DISEASE IN THE COURSE OF PRIMARY SJOGREN'S SYNDROME

We report two patients with a definite diagnosis of primarySjögren's syndrome who developed Hodgkin's disease. Clinicaland laboratory features of this transformation comprised prolongedfever, the appearance of lymphadenopathy together with lossof serum autoantibodies and a reduction in serum gammaglobulinlevels. We know of only one well documented case of such anassociation. From these observations, it seems reasonable toinclude Hodgkin's disease in the clinical spectrum of the lymphoproliferativedisorders that may occur in the course of primary Sjögren'ssyndrome. KEY WORDS: Sjögren's syndrome, Hodgkin's disease, Lymphoma, B-cell     

Hodgkin's disease in homosexual men with generalized lymphadenopathy

The authors present 4 cases of Hodgkin's disease developing in homosexual men with persistent, generalized lymphadenopathy. Laboratory abnormalities associated with the acquired immunodeficiency syndrome (AIDS) and the lymphadenopathy syndrome were present in these patients. In 2 patients, diagnosis of lymphadenopathy syndrome preceded the diagnosis of Hodgkin's disease by 2-3 years; in the other 2, the 2 conditions were noted simultaneously. 2 patients had nodular sclerosing Hodgkin's disease, while the other 2 had mixed cellularity disease. All patients presented with clinical stage III or IV Hodgkin's disease. 2 patients in this group have died: 1 of progressive Hodgkin's disease with evidence of atypical myobacterial infection, and 1 with no evidence of Hodgkin's disease but with AIDS-related infections. The lymphadenopathy syndrome has a presentation similar to that of Hodgkin's disease: lymphadenopathy often accompanied by malaise, fever, night sweats, weight loss, and splenomegaly. When a homosexual man presents with painless adenopathy, with or without constitutional symptoms, the potential diagnosis of Hodgkin's disease or other malignancy should be considered in addition to lymphadenopathy syndrome. Evaluation by lymph node biopsy is advisable. The natural history of Hodgkin's disease in patients at risk for AIDS may be altered to a more aggressive form. Unusual features of Hodgkin's disease observed in this group of patients included presentation with stage IV disease, cutaneous Hodgkin's disease, and bone marrow but no splenic involvement. The effects of the treatment modes used for Hodgkin's disease in homosexual patients should be evaluated for their effect on the risk of AIDS.     

Cloak and dagger: the case for adult onset still disease and hemophagocytic lymphohistiocytosis

Adult onset Still’s disease (AOSD) is a rare systemic inflammatory disorder of unknown etiology. Systemic onset juvenile idiopathic arthritis (SoJIA) is the preferred nomenclature of Still’s disease. Strong association with so-called macrophage activation syndrome (MAS) may provide a clue to the understanding of the distinctive pathogenetic features of SoJIA. MAS is a severe, potentially life-threatening complication characterized by the excessive activation of well-differentiated macrophages. It is more appropriately named autoimmune disease associated reactive hemophagocytic lymphohistiocytosis (ReHLH), a subset of a histiocytic disorder: class II histiocytosis hemophagocytic lymphohistiocytosis (HLH). The relation of SoJIA with HLH is still under debate. We propose that MAS, HLH, SoJIA, and AOSD are indeed the same disease, in different clinical presentations that may be classified based on severity and laboratory findings, but with essentially the same physiopathogenesis. We propose that the case described by Hong & Lee (Rheumatol Int 2008) was actually an AOSD-associated MAS/RHS/ReHLH fulminant disease.