Clinical and splenectomy-based treatment outcomes in 40 cases of hepatosplenic T-cell lymphoma: a comprehensive analysis

Hepatosplenic T-cell lymphoma: clinicopathologic, immunophenotypic, and molecular characterization of17 Chinese cases

In February 2007, the Food and Drug Administration (FDA) reported eight cases of hepatosplenic T cell lymphoma (HSTCL) associated with infliximab use in young patients treated for inflammatory bowel disease (IBD) that were received by our Adverse Event Reporting System (AERS) database (1). Although our initial report described cases of HSTCL associated with infliximab use, cases have since been reported with another member of the TNF blocker class as well. This publication serves as an update of cumulative HSTCL cases associated with immunosuppressant use since our previous publication (1). As a class, the FDA-approved TNF blockers currently include the biological agents infliximab, adalimumab, etanercept, and certolizumab. These agents block the biological effects of TNF-α including induction of proinflammatory cytokines as well as leukocyte chemotaxis and activation. From time of marketing in 1998 through June 30, 2008, FDA's AERS database has received a total of 15 cases of HSTCL in patients with IBD treated with TNF blocker therapy: 13 cases were associated with infliximab use and 2 cases were associated with infliximab use followed by adalimumab use; all patients were receiving concomitant immunosuppressants (Table 1). These numbers are cumulative and include the cases reported in our previous publication (the first eight cases in Table 1 [note that cases 4 and 11 also were reported in the literature]) (2,3).TABLE 1: Select clinical and demographic data of AERS cases of alpha/beta and gamma/delta T cell lymphoma associated with infliximab use or infliximab/adalimumab use from marketing in 1998 to June 30, 2008† (n = 15)In addition to patients with IBD, AERS has received 1 case of fatal γδ HSTCL in a 61-year-old female who received adalimumab for 1 year, concomitantly with steroids only, to treat rheumatoid arthritis; she had received approximately 1 year of methotrexate therapy 3 years before the diagnosis of HSTCL. There have been no other cases of HSTCL associated with adalimumab use to treat any indication reported to AERS or published in the scientific literature. There have been no cases of HSTCL associated with infiximab use to treat any condition other than IBD reported to AERS or the scientific literature. As for other TNF-blocking agents (ie, etanercept or certolizumab), no cases of HSTCL for any indication have been reported to AERS or the scientific literature (note that etanercept is not indicated for treatment of IBD and certolizumab was approved by the FDA in April 2008). Smaller numbers of HSTCL cases have been reported in association with other immunomodulating agents (without TNF blockers) used to treat IBD: 7 cases are associated with azathioprine use and 3 cases are associated with mercaptopurine use. Seven cases associated with azathioprine use have been published; many of these reports provided little specific clinical and/or demographic data (4–10). Of the 7 cases, all developed HSTCL (5 reported γδ subtype, 2 did not report a subtype) associated with azathioprine use to treat Crohn disease (CD; n = 4), ulcerative colitis (UC; n = 2), or UC/hepatitis (n = 1) for a duration of 4 to 17 years (mean 7.5 years). Two of these patients were receiving steroids concomitantly; no concomitant immunosuppressants were reported for the other 5 patients. Three patients were male, 1 patient was female, and sex was not specified for 3 patients; the mean age was 22 years (n = 5). Five of the 7 cases were fatal. AERS has received 2 fatal cases of γδ HSTCL in male patients (younger than 18 and 33) using mercaptopurine to treat CD for a duration of 3 to 5 years; an additional case in the literature identified a patient of unknown age and sex who developed HSTCL after using mercaptopurine for an unknown duration to treat CD (little information provided) (11). No AERS or literature cases associated with mesalamine or methotrexate therapy when used alone to treat IBD were identified. As discussed in our previous publication, HSTCL is a rarely occurring tumor (2); to date, there have been fewer than 200 cumulative cases of this lymphoma reported in the literature. In turn, the pediatric IBD population is estimated to be 100,000 children (younger than 18 years of age) affected in the United States; the number of patients with severe IBD would be smaller (12). Because 15 of the fewer than 200 known HSTCL cases are associated with infliximab use (and rarely adalimumab use), it appears that young patients using these products may be at greater risk for developing this lymphoma. It has not been established that infliximab or adalamimub had an exclusive or primary role in the pathogenesis of each reported case of HSTCL. These cases could be causally related to a number of factors (eg, underlying disease, exposure to concomitant immunosuppressant medications). Health care practitioners are encouraged to report cases of HSTCL to FDA (http://www.fda.gov/medwatch).

A rare case of hepatosplenic γδ T-cell lymphoma expressing CD19 with ring chromosome 7 and trisomy 8

Acute <scp>Epstein‐Barr</scp> virus associated haemophagocytosis in an Asian female: What is the diagnosis?

Purpose: Hepatosplenic T-cell lymphoma is a serious and often fatal condition seen in patients with Inflammatory Bowel Disease taking thiopurine therapy. To date, there have been no comparisons of outcomes of IBD-related and non-IBD related HSTCL. Methods: Eight previously unpublished cases of non-IBD HSTCL were seen at Memorial Sloan-Kettering Cancer Center. IRB approval was obtained. In addition, a systematic review of the literature was performed; MEDLINE was searched with the keywords “hepatosplenic” and “lymphoma” and English-language case series with 5 or more patients were included. Data was compared to a recent review of clinical outcomes of IBD-associated HSTCL (Kotlyar 2010, Clin Gastroenterol Hepatol). Demographics analyzed included gender, three age ranges (0-30, 31-50, 51+), clinical response (complete response, partial response, or progressive disease), mortality, and months of overall survival amongst patients who expired. Results were compared using the GraphPad Prism program, with paired two tailed t-tests. Results: Of 295 citations, 4 were selected (Falchook 2009, Ann Oncol; Belhadj 2003, Blood; Wei 2005, World J Gastroenterol; Macon 2001, Am J Surg Pathol). There were 63 non-IBD HSTCL cases identified, and 36 IBD-related HSTCL cases. Significant differences were noted between non-IBD and IBD related HSTCL with regards to the percentage of male patients (62.7% vs. 93.5% of patients respectively, p<0.0017), and ages of patients (median 34 vs. 22.5 years respectively, p<0.02) showing differences. Although not significant (p<0.118), there was a trend of higher overall survival in patients who expired with non-IBD HSTCL (median survival 9.95 months) as compared to those with IBD-related HSTCL (median survival 5 months). There was no difference in mortality between groups (non-IBD HSTCL 80.7% vs. IBD-related HSTCL 84.4%, p<0.669). Conclusion: IBD-associated HSTCL seems to affect more men than women and at a younger age as compared with non-IBD HSTCL; however, the prognosis of patients in both IBD-related and non IBD-related HSTCL seems similar with treatment. Further prospective studies of lymphoma in IBD, and a prospective registry of HSTCL cases may shed more light on this rare but lethal disease.Table: Table. Comparison of outcomes of HSTCLDisclosure: David Kotlyar: NO financial relationship with a commercial interest Robert Hirten: NO financial relationship with a commercial interest Steven Horwitz: YES financial relationship with a commercial interest;Merck & Co: Self: Consulting fee:Consulting;Allos: Self:Consulting fee:Grant/Research Support; Celgene Corporation:Self:Consulting fee:Grant/Research Support;Seattle Genetics:Self:Consulting fee:Consulting;Millenium:Self:Consulting fee:Consulting Wojciech Blonski: NO financial relationship with a commercial interest Gary Lichtenstein: YES financial relationship with a commercial interest;UCB, Inc.: Other financial benefit not in list (use freeform entry below):Grant/Research Support;Abbott Laboratories:Other financial benefit not in list (use freeform entry below):Grant/Research Support;Abbott Laboratories:Other financial benefit not in list (use freeform entry below):Consulting;Bristol-Myers Squibb Co.: Other financial benefit not in list (use freeform entry below):Grant/Research Support;Centocor/Orthobiotech, Inc.:Other financial benefit not in list (use freeform entry below):Consulting;Centocor/Orthobiotech, Inc.:Other financial benefit not in list (use freeform entry below):Grant/Research Support;Elan Pharmaceuticals, Inc.: Other financial benefit not in list (use freeform entry below):Consulting;Ferring Pharmaceuticals Inc: Other financial benefit not in list (use freeform entry below):Consulting;Millennium Research Group:Other financial benefit not in list (use freeform entry below):Consulting;Procter & Gamble Pharmaceuticals: Other financial benefit not in list (use freeform entry below):Grant/Research Support;Procter & Gamble Pharmaceuticals: Other financial benefit not in list (use freeform entry below):Consulting;Procter & Gamble Pharmaceuticals: Other financial benefit not in list (use freeform entry below):Grant/Research Support;Prometheus Laboratories Inc.:Other financial benefit not in list (use freeform entry below):Consulting;Prometheus Laboratories Inc.:Other financial benefit not in list (use freeform entry below):Grant/Research Support;Salix Pharmaceuticals, Inc.:Other financial benefit not in list (use freeform entry below):Grant/Research Support;Salix Pharmaceuticals, Inc.: Other financial benefit not in list (use freeform entry below):Consulting;Salix Pharmaceuticals, Inc.:Other financial benefit not in list (use freeform entry below):Consulting;Warner Chilcotte:Other financial benefit not in list (use freeform entry below):Consulting;Schering-Plough Corp.:Other financial benefit not in list (use freeform entry below):Consulting;Shire Pharmaceuticals Inc.: Other financial benefit not in list (use freeform entry below):Grant/Research Support;Shire Pharmaceuticals Inc.:Other financial benefit not in list (use freeform entry below):Consulting;Wyeth Pharmaceuticals:Other financial benefit not in list (use freeform entry below):Consulting;UCB, Inc.:Other financial benefit not in list (use freeform entry below):Consulting;Warner Chilcotte: Other financial benefit not in list (use freeform entry below):Grant/Research Support;Warner Chilcotte:Other financial benefit not in list (use freeform entry below):Consulting.

Fatal Case of EBV-negative Posttransplant Lymphoproliferative Disorder With Hemophagocytic Lymphohistiocytosis in an Adult Kidney Transplant Recipient.

Modern management of children with haemophagocytic lymphohistiocytosis.

Outcomes in Patients with Enteropathy-Associated T-Cell Lymphoma (EATL) and Hepatosplenic T-Cell Lymphoma (HSTCL): A Population Based Analysis Using the SEER Data

Cutaneous T-Cell Lymphoma

Purpose: Introduction: Hepatosplenic T cell lymphoma (HSTCL) is characterized by cytotoxic T-cells that infiltrate sinuses of the liver, spleen, and bone marrow. Associated with organ transplant and immune-modifying therapy, about 200 cases of HSTCL have been reported. In 2002, several cases of non-Hodgkin's lymphoma in patients receiving anti-TNFα therapy sparked concern that biologic agents may carry a risk of cancer. We report the first case of a patient with CD diagnosed with HSTCL after receiving natalizumab therapy. Case: This is a 52-year-old man with a 35-year history of CD. Initially treated with sulfasalazine, he developed obstructive symptoms in 1983 requiring ileal and colon resections. In 1989, azathioprine and steroid therapy was started. In 1990, mesalamine therapy replaced azathioprine. He remained off steroids until 1999 when his diarrhea returned and he received three infusions of infliximab followed by budesonide. In 2000, he was diagnosed with polycythemia vera. In 2005, he flared and failed a repeat trial of infliximab, but was successfully switched to adalimumab. In 2008 his diarrhea and rectal discomfort recurred and he was changed to natalizumab monotherapy. At that time, he was noted to have splenomegaly and pancytopenia. A bone marrow biopsy again revealed polycythemia vera. There was a mild response of his Crohn's systems to the second natalizumab infusion, but as he was not sufficiently improved, steroids were restarted, and the natalizumab was discontinued. In 2009, while hospitalized for fever, abdominal pain and diarrhea, an abdominal MRI revealed splenic infarcts. A splenectomy was performed and pathology revealed HSTCL. Discussion: The first case of HSTCL associated with 5-aminosalycilates, steroid and azathioprine therapy was described in 2003. Subsequently, several cases of HSTCL have been reported. Despite the elevated risk of lymphoma with immunomodulator and biologic agents, the recent SONIC trial highlights their efficacy in CD. Natalizumab, an anti-alpha 4 integrin antibody, has been linked to ten cases of progressive multifocal leucoencephalopathy. There have to date been no reported cases of HSTCL associated with natalizumab. We report the first case of a patient with CD treated sequentially with infliximab, adalimumab, and natalizumab, as well as long-term steroids and azathioprine, who developed HSTCL. The likely mechanism is decreased immune surveillance and this case raises the possibility of increased oncogenicity in patients receiving multiple immunosuppressive therapies.

Dear Sir, I read with interest a recent article by Antonodimitrakis and colleagues in your journal presenting a case of acquired hemophagocytic lymphohistiocytosis (HLH) in a 60-year-old woman suffering from diabetes mellitus type 2 (1). The reported patient developed a life-threatening HLH associated with a reactivation of an Epstein–Barr virus (EBV) infection and was successfully treated by means of corticosteroids alone. Hemophagocytic lymphohistiocytosis (HLH) is a clinical syndrome of an exaggerated inflammatory reaction triggered by various inherited and/or acquired factors (2). The literature on the topic of HLH in adults is limited; however, acquired (i.e. secondary) forms of HLH (e.g. infection-associated HLH, I-HLH; autoimmune-associated HLH, A-HLH; malignancy-associated HLH, M-HLH) are the most prevalent. Antonodimitrakis et al. wrote in their article that ‘the patient's age showed that a familial form of HLH was unlikely' (1). Familial forms of HLH (FHL) are autosomal recessive disorders related to different mutations in genes encoding proteins required for lymphocyte cytotoxicity (i.e. PRF1, UNC13D, STX11, STXBP2) (2). Although FHL usually arises in infants and the vast majority of HLH cases in adults are acquired, it should be stressed that, albeit rarely, FHL can occur in adulthood, including older individuals (so-called late-onset FHL) (3–5). Therefore, the possibility of late-onset FHL in adults with HLH cannot be univocally excluded before tests of NK/T cell degranulation and activity, as well as genetic testing, have been performed. A retrospective study from Japan revealed that the frequency of different forms of HLH in adults varied depending on the age bracket (6). Among HLH patients aged 15–29 years, I-HLH was the most common (68% of cases). It was caused in equal parts by EBV-HLH (34%) and I-HLH other than EBV-HLH (34%). In this age group, the second most common cause of HLH was A-HLH (22%), followed by M-HLH (10%). In the group of patients aged 30–59 years, M-HLH occurred only slightly less frequently than I-HLH (37% and 47%, respectively), followed by A-HLH (9%) and HLH after hematopoietic stem cell transplantation (7%). In the group of patients aged ≥60 years, however, malignancy was the most frequent cause of HLH (68%), followed by I-HLH (26%) and A-HLH (6%) (6). A recent, retrospective, population-based study from our group showed the annual incidence of M-HLH in adults to be 1:280,000 per year, or 0.36/100,000 individuals per year (7). The results of this study were limited by the small population of the Swedish region of northern Halland but were strengthened by the long observation period of over 14 years. Although M-HLH in East Asia is most often associated with NK/T cell lymphoproliferative malignancies, M-HLH in Europe tends to develop more frequently in the course of the hematological malignancies (6,7). Importantly, it is worth to remember that M-HLH can occur before or during the treatment of known malignancy, or as the first manifestation of an occult malignancy (7,8). Therefore an episode of HLH with unclear etiology in the older individual should always serve as a warning signal for a yet undiagnosed malignancy, leading to further careful cancer diagnostics and follow-up, as was done in the case reported by Antonodimitrakis and colleagues. The patient reported by Antonodimitrakis et al. underwent repeated biopsies, which failed to show hemophagocytosis in affected organs (1). The diagnosis of HLH can be confirmed in some cases by cytological and/or histopathological evaluation of bone-marrow, spleen, liver, lymph nodes, and cerebrospinal fluid (8,9). Cytohistological examination reveals accumulation of lymphocytes and histiocytes (macrophages), sometimes with hemophagocytic activity (Figure 1). Although examination of bone-marrow slides has the highest sensitivity for the detection of HLH, approximately 20% of patients lack features of HLH on their initial bone-marrow examination (9). Hemophagocytic activity is a rather late sign of advanced HLH (7). Therefore, further search for hemophagocytic activity of macrophages is encouraged if hemophagocytosis is not proven at the time of HLH onset (8). If the bone-marrow specimen is not conclusive, serial marrow aspirates over time may be helpful as well as a biopsy obtained from other organs (8). Figure 1. May–Grunwald–Giemsa stain of bone marrow aspirate smear showing four macrophages displaying massive hemophagocytic activity (magnification ×400). All forms of HLH, even when treated in a timely manner, can be fatal. M-HLH has the worst prognosis compared to other forms of HLH (2,6,7). Ishii et al. found that 5-year survival reaches only 12% in patients with M-HLH associated with T/NK cell non-Hodgkin lymphoma (NHL), 48% in patients with M-HLH associated with B cell NHL, 54% in patients with FHL, and 83%–90% in patients with either I-HLH or A-HLH (6). The therapy of any form of HLH should focus on: 1) suppression of the hyperinflammatory status by destruction of activated CD8+ T lymphocytes and macrophages, and 2) treatment of any existing HLH triggers (2,8). In cases of FHL, an additional aim is the correction of the underlying immune defect by allogeneic stem cell transplantation (allo-SCT) (9). Treatment of acquired HLH is not standardized so far and remains highly variable across clinical centers. HLH treatment categories include: 1) proapoptotic chemotherapy with etoposide (50–150 mg/m2/dose i.v.), and 2) immunosuppressive drugs, targeting the hyperactivated macrophages (e.g. etoposide, corticosteroids, intravenous immunoglobulin (IVIG)) and T cells (e.g. corticosteroids, cyclosporine A (CyA)) (2,8). Obviously, if possible, treatment of any existing trigger of HLH is mandatory (8). Antonodimitrakis et al. successfully treated their patient with corticosteroids only (1). It may be a sufficient approach to employ corticosteroids (with or without IVIG) to control hyperinflammation as a frontline therapy in I-HLH and A-HLH (particularly of milder grades) (2). After the improvement of the complete blood count and resolution of coagulopathy, steroids are slowly tapered down to avoid relapses of HLH. Corticosteroid-resistant non-responders may benefit from second-line therapies, such as CyA (2). If there is no response to the aforementioned drugs (corticosteroids, IVIG, CyA), use of the HLH-2004 protocol including etoposide is recommended (2,7,8). Thus, patients with acquired HLH could be started on therapy without etoposide, as long as treatment adjustments are made rapidly in refractory cases. If HLH is driven by EBV infection, monoclonal anti-CD20 antibodies (i.e. rituximab) that deplete B lymphocytes, the predominant type of cells harboring EBV virus, should be used (10). Anecdotal reports have also shown the efficacy of allo-SCT in refractory or recurrent acquired HLH (e.g. EBV-HLH, M-HLH) (11,12). Since HLH can be encountered by various specialists in the medical field, knowledge of this entity and its diagnostic criteria should be familiar to all physicians. Treatment of HLH is difficult, long-lasting, and often associated with a high morbidity and mortality. The article by Antonodimitrakis and colleagues is a valuable voice in the debate over adult HLH.

Hemophagocytic lymphohistiocytosis (HLH) is not one condition but descriptive of a life-threatening, hyper-inflammatory syndrome with multiorgan involvement with a variety of triggers, both genetic and environmental. It is described as primary HLH (familial HLH) and secondary HLH (acquired following malignancy, rheumatologic disorders, primary immune deficiencies or infection alone). Infections commonly precipitate HLH in those with primary HLH, in combination with an underlying disease (malignancy, rheumatologic or primary immune deficiency) or may be the sole trigger.1 Many people with “secondary” HLH may also have potentially pathogenic polymorphisms in an HLH- associated gene.2 Rapid diagnosis of HLH and initiation of appropriate treatment is essential to reduce mortality from this condition. PATHOGENESIS Across the spectrum of HLH, impaired natural killer (NK) and cytotoxic T lymphocytes (CTL) function has been a consistent finding. These cytotoxic deficiencies lead to loss of feedback inhibition on activated macrophages resulting in a “cytokine storm,” causing multiorgan tissue damage. The excessive activated macrophages engulf host blood cells (hemophagocytosis), which may be seen in biopsies from the bone marrow, lymph nodes, liver and spleen.1,3 Around 25% of all HLH presentations are thought to be autosomal recessive primary HLH and these commonly present in early life, although may develop at any age. Genes identified as causing monogenic HLH include: PRF1, UNC13D, STX11, STXBP2. Other genetic causes of HLH include primary immunodeficiency syndromes including Griscelli syndrome (RAB27A), Chediak-Higashi syndrome (LYST), Hermansky-Pudlak 2 (Ap3B1) and X-linked lymphoproliferative disease 1 and 2 (SH2D1A, XIAP).2 Viral infections are a common precipitant in primary HLH, malignancy and in those without known underlying disease. Epstein-Barr virus (EBV) is a well-described trigger and X-linked lymphoproliferative disease is almost exclusively associated with EBV.4,5 Other common viruses found in association with HLH include cytomegalovirus (CMV), parvovirus, herpes simplex virus (HSV) (particularly neonates), varicella-zoster virus (VZV), measles, human herpes virus (HHV)-6, HHV-8, H1N1 influenza virus, parechovirus, parvovirus, Dengue virus and HIV. Bacteria causing HLH are far less common, but Gram-negative bacterial infections, Brucellosis and Mycobacterium tuberculosis associated HLH have been described. HLH has also been described in fungal infections such as Histoplasma capsulatum and in parasitic infections such as Leishmania and malaria.6 Malignancy is a common cause of HLH, especially lymphoid malignancies with acute B-lymphoblastic leukemia being the commonest. Cytokines produced by malignant cells activate CTLs, NK cells and macrophages. HLH also can occur during hematopoietic stem cell transplantation, especially in the early phase.6 Rheumatologic conditions, especially systemic-onset juvenile idiopathic arthritis and less commonly polyarticular juvenile idiopathic arthritis, systemic lupus erythematous and Kawasaki disease can present with HLH at diagnosis, during treatment or any time in response to infection; therapeutic drugs themselves may trigger HLH. In the context of a rheumatologic condition, HLH is referred to as macrophage activating syndrome.6 Any of the primary immune deficiency disorders will increase the risk of HLH as a result of the immune dysregulation. In combined immune deficiencies, viral infections are commonly associated with HLH, especially EBV and CMV, and in chronic granulomatous disease patients, common infectious precipitants were Burkholderia cepacia, Leishmania and fungi. The development of HLH in patients with absence of T and NK cells indicates excess macrophage activation may occur independently of lymphocytes.7 CLINICAL PRESENTATION AND INVESTIGATION OF HLH Regardless of the underlying cause, HLH is a clinical diagnosis with supporting laboratory criteria. Typically, patients are febrile, acutely unwell with multiorgan involvement; therefore, the initial differential diagnosis includes liver disease, encephalitis, malignancy, autoimmune, rheumatologic diseases and general sepsis. A family history of immunodeficiency, consanguinity or autoimmunity may be relevant. Key clinical features identified in the HLH-94 study were hepatosplenomegaly (95%), fever (93%), lymphadenopathy (33%), neurologic symptoms (33%) and rash (31%).8 Other features include bleeding (epistaxis, hematemesis, rectal bleeding, petechiae and purpura), liver dysfunction and respiratory insufficiency. Specific features (such as albinism) may point towards syndromes predisposing to HLH (eg, Chediak-Higashi syndrome, Griscelli syndrome type 2 and Hermansky-Pudlak syndrome type 2). In the neonate, HLH may present with isolated central nervous system disease or fulminant liver failure.6 Figure 1 outlines suggested investigations and management. Early laboratory parameters in a septic child which indicate the development of HLH are a climbing ferritin >500 μg/L (ferritin >10 000 μg/L in children was found to be 90% sensitive and 96% specific for HLH9 however, diagnosis and treatment should not be delayed until ferritin reaches this threshold); evolving cytopenias which are transfusion dependent, (anemia and thrombocytopenia present in over 80% patients on presentation9); and multiple organ involvement (renal, liver, neurologic). High triglycerides and low fibrinogen further support the diagnosis of HLH. A rising C-reactive protein occurs, while erythrocyte sedimentation rate may fall due to reduced fibrinogen from liver consumption.6 Low immunoglobulins or lymphocyte subsets point towards an underlying immunodeficiency although commonly deranged by severe illness.FIGURE 1.: Investigation and management of HLH. CRP indicates C-reactive protein; ESR, erythrocyte sedimentation rate; HLA, human leukocyte antigen; IV, intravenous; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging; PCR, polymerase chain reaction. Full blood count (FBC), Chest radiograph (CXR), haematopoietic stem cell transplant (HSCT).Bone marrow biopsy, where possible, is useful to provide evidence of hemophagocytosis and to look for any underlying malignancy. It should also be sent for microscopy, culture and viral and Leishmania polymerase chain reactions (in endemic areas). Hemophagocytosis is not always visualized in the bone marrow during HLH; it may also be present in lymph nodes, liver and spleen and is not specific for HLH. If lymphadenopathy is present, node biopsy should be taken as lymphoma is frequently the underlying condition. Cerebrospinal fluid shows a pleocytosis in 50% of cases and a high protein. DIAGNOSIS The HLH-2004 protocol uses the presence of 5/8 criteria to diagnose HLH: (1) fever, (2) splenomegaly, (3) bicytopenia, (4) hypertriglyceridemia and or hypofibrinogenemia, (5) hemophagocytosis, (6) low/absent NK cell activity, (7) hyperferritinemia (>500) and (8) high soluble interleukin-2 receptor levels.10 However, probable HLH should be considered and treated well before the presence of 5/8 criteria, as several of the tests are only done in reference laboratories and if treatment is delayed for these results, it may be too late to reverse the process. Other common features aiding diagnosis include liver enzyme derangement and neurologic abnormalities. All cases of HLH should be investigated for primary immunodeficiency syndromes, and underlying genetic causes as clinical presentation cannot distinguish between primary and secondary HLH. Soluble interleukin-2 receptor alpha is a useful marker of disease activity but is not available in most centers. Protein expression studies and genetic panels are helpful in diagnosing primary HLH conditions which will need HSCT for definitive cure. MANAGEMENT Patients with HLH commonly require pediatric intensive care support to maximize chances of survival. Replacement blood products are necessary to maintain hemoglobin, platelet levels and normal coagulation. Induction of amenorrhea is advised in menstruating girls. Whilst supportive therapy is given, the priorities for initial management are identifying and treating the trigger, exclusion of malignancy (as this diagnosis is difficult once immunosuppression has been given) and early immune modulation.11 These patients may deteriorate quickly and should be treated in centers with facilities for bone marrow transplantation and intensive care. Prompt aggressive therapy may be necessary even when infection is present. It may be possible to tailor therapy according to the severity of the condition and the rapidity of response. In some cases, where early intervention produces a rapid response then induction chemotherapy may be avoided or weaned with close monitoring. However, if the condition does not respond to initial management, then early recourse to more aggressive treatment will be necessary; in primary, persistent or recurring HLH, chemotherapy should be continued to HSCT.12 Opportunistic infection during therapy may confound the picture and careful surveillance is necessary particularly where symptoms recur after an apparent initial response. Key markers of response to treatment are resolution of fever, reducing ferritin (although it can be slow to decline and levels fluctuate with blood transfusions), reducing transfusion requirements, improved coagulation parameters and resolving organ dysfunction. Neurologic involvement should be monitored with serial cerebrospinal fluid analysis with each intrathecal therapy and neuroimaging. Weekly monitoring of soluble interleukin-2 receptor alpha or soluble CD163 may be helpful to guide reduction or increase in therapy. Markers of infection should be monitored for response to treatment.12 When induction therapy is being planned, HLA tissue typing should be sent to allow for rescue HSCT without delay if this becomes necessary. The HLH-1994 protocol8 recommends combination chemotherapy [etoposide, ciclosporin A, corticosteroids and intrathecal methotrexate if (central nervous system) involvement] followed by HSCT for persistent, recurring or primary HLH. The HLH-2004 protocol modified this with early cyclosporin, but survival was not significantly improved.10 An alternate regimen using steroids and anti-thymocyte globulin (ATG) was similarly effective.13 Survival is dramatically improved with these protocols compared with survival without treatment with an overall survival at 3 years of 55% (51% in the familial cases) and 3-year probability of survival 3 years after HSCT of 62%.8 Trials comparing a combination of the two main regimes (the Hybrid Immunotherapy trial and the European cooperative pilot study for testing Hydbrid ImmunoTherapy for Hemophagocytic LymphoHistiocytosis (Euro-HIT-HLH) trial) have finished recruiting, and results are awaited. Other studies of alternate or combination approaches have also been initiated with agents such as alemtuzumab, ruxolitinib and anti-interferon gamma monoclonal antibody. Alemtuzumab (monoclonal antibody to CD52 protein expressed on surface of mature T cells and NK cells) may be a useful salvage agent for refractory HLH enabling survival to HSCT.12 CONCLUSIONS HLH is a life-threatening hyperinflammatory condition that needs to be considered early in any patient with fever, multiorgan failure and cytopenias. Infection plays a key role as a trigger but also causes concern for clinicians when delivering the necessary immunosuppression to terminate the cytokine storm. Immunomodulatory treatment should be started if high clinical suspicion, and not wait for specific immunology and genetic testing. Early recourse to chemotherapy and planning for HSCT if HLH is recurrent or refractory to initial treatment. Survival has improved with this treatment, however, mortality remains very high.

Hemophagocytic Syndrome in an Adolescent With Crohn Disease Receiving Azathioprine and Infliximab

Hepatosplenic T-cell lymphoma and inflammatory bowel disease

We report 8 cases of hepatosplenic T-cell lymphoma (HSTCL) involving bone marrow and correlate histologic findings with disease progression. Immunophenotypic analysis demonstrated mature, aberrant gamma/delta T-cell immunophenotypes. Isochromosome 7q was identified in 4 cases; 1 case showed the t(7;14)(q34;q13). Seven of 7 cases tested had monoclonal TCR gamma gene rearrangements. The initial diagnostic bone marrow biopsy specimens were hypercellular with a frequently subtle, predominantly sinusoidal infiltrate of atypical small to medium-sized lymphoid cells. In all cases, aspirate smears at diagnosis and in subsequent specimens contained malignant cells that resembled blasts, some with fine cytoplasmic granules. With progression, the pattern of HSTCL in bone marrow biopsy specimens became increasingly interstitial, and the neoplastic cells became larger. In aspirate smears, the proportion of blasts increased. Seven patients died; 1 was lost to follow-up. Autopsy performed on 1 patient demonstrated malignant cells within vascular channels in all organs sampled, with relatively little tumor formation, resembling intravascular lymphoma at these sites. HSTCL often can be recognized in bone marrow by its unique combination of a sinusoidal pattern in core biopsy specimens and blastic cytology in aspirate smears.