eMedicine Specialties > Pediatrics: General Medicine > Oncology

Lymphohistiocytosis (Hemophagocytic Lymphohistiocytosis)

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School

Updated: Aug 21, 2009

Introduction

Background

Hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal disease of normal but overactive histiocytes and lymphocytes that commonly appears in infancy, although it has been seen in all age groups. Fever, hepatosplenomegaly, pancytopenia, lymphadenopathy, and rash often comprise the initial presentation. Cutaneous involvement occurs in as many as 65% of patients.¹ Varied skin manifestations of hemophagocytic lymphohistiocytosis are noted, including erythroderma, generalized purpuric macules and papules, and morbilliform eruptions. Detection of cutaneous involvement can assist in the initial diagnosis of hemophagocytic lymphohistiocytosis and potentially signify recurrences.

Primary hemophagocytic lymphohistiocytosis (ie, familial erythrophagocytic lymphohistiocytosis [FEL]), an inherited form of hemophagocytic lymphohistiocytosis syndrome, is a heterogeneous autosomal recessive disorder found to be more prevalent with parental consanguinity. Secondary hemophagocytic lymphohistiocytosis (ie, acquired hemophagocytic lymphohistiocytosis) occurs after strong immunologic activation, such as that which can occur with systemic infection, immunodeficiency, or underlying malignancy. Both forms are characterized by the overwhelming activation of normal T lymphocytes and macrophages, invariably leading to clinical and hematologic alterations and death in the absence of treatment.² The clinical picture, differential diagnosis, workup, and treatment options are discussed.

Pathophysiology

The pathological hallmark of this disease is the aggressive proliferation of activated macrophages and histiocytes, which phagocytose other cells, namely RBCs, WBCs, and platelets, leading to the clinical symptoms. The uncontrolled growth is nonmalignant and does not appear clonal in contrast to the lineage of cells in Langerhans cells histiocytosis (histiocytosis X). The spleen, lymph nodes, bone marrow, liver, skin, and membranes that surround the brain and spinal cord are preferential sites of involvement.³

Over the past 2 decades, the underlying pathophysiology of hemophagocytic lymphohistiocytosis has been characterized, although the processes are not entirely understood. A current accepted theory involves an inappropriate immune reaction caused by proliferating and activated T cells associated with macrophage activation and inadequate apoptosis of immunogenic cells.⁴ Although the precise mechanism remains unclear, many research teams propose convincing pictures for the role of perforin and natural killer (NK) cells in the hemophagocytic lymphohistiocytosis subtypes.^5,6,7

Perforin or pore-forming protein (PFP), gene map location 10q22, is one of the major cytolytic proteins of granules contained in cytotoxic cells.⁸  When activated by a challenge, NK cells release granules that contain perforin and granzymes, which form pores in the target cell membrane and cause osmotic lysis and protein degradation, respectively. Additionally, the endocytotic and exocytotic mechanisms may also be affected.⁹ Patients with perforin deficiency may have impaired defenses against intracellular pathogens and cancers, as has been demonstrated in animal models.

Although the mechanism is yet to be determined, decreased NK cell activity results in increased T-cell activation and expansion, with resulting production of large quantities of cytokines, including interferon gamma (IFNg), tumor necrosis factor-a (TNF–a), and granulocyte-macrophage colony-stimulating factor (GM-CSF). This causes sustained macrophage activation and tissue infiltration as well as production of interleukin-1 (IL–1) and interleukin-6 (IL-6). The resulting inflammatory reaction causes extensive damage and the associated symptoms.¹⁰

Frequency

International

Incidence is reported to be 1.2 cases per million persons per year. However, unpublished observations estimate that the figures have slightly increased over time because of improved detection.¹¹ This amounts to 1 case per every 50,000 births.¹²

Perforin mutations account for approximately 20% of cases of FEL, with a somewhat higher prevalence (30%) in children of Turkish descent. Chromosome arm 9q mutations account for approximately 10% of familial cases; the remainder of FEL cases are caused by mutations in as yet unidentified genes.¹³

Mortality/Morbidity

Familial hemophagocytic lymphohistiocytosis is uniformly fatal if not treated; the median survival time reported in various studies is 2-6 months after diagnosis. The historical series collected by the International Hemophagocytic Lymphohistiocytosis Registry reports a less than 10% probability that the patient survives for 3 years.¹⁴ Even with treatment, only 21-26% can be expected to survive 5 years. Remission is always temporary, as the disease inevitably returns. Bone marrow transplant is the only hope for cure. One study found that 50% of deaths from FEL were due to invasive fungal infections, which are probably underdiagnosed.¹² The outcomes of secondary hemophagocytic lymphohistiocytosis vary.

Race

Hemophagocytic lymphohistiocytosis has not been epidemiologically shown to have a predilection for persons of any race. A sample of European countries, including Sweden, England, and Italy, has reported similar statistical incidences as mentioned above.¹⁰

Sex

The disease has an equal distribution among males and females.

Age

The age of onset is usually in people younger than 1 year for the familial form but can be later for the secondary sporadic form, usually after age 6 years.⁴ Although the familial form of the disease frequently affects infants from birth to age 18 months, familial forms have been reported in individuals as old as 8 years, and adult onset has been reported. At this point, no criteria for age have been established, and an upper age limit does not exist.¹²

Clinical

History

The diagnostic criteria set forth by the Histiocyte Society for inclusion in the International Registry for Hemophagocytic Lymphohistiocytosis (HLH) is as follows.¹⁵ All 5 criteria must be met to establish a diagnosis of hemophagocytic lymphohistiocytosis:

• Fever - Seven or more days of a temperature as high as 38.5°C (101.3°F)
• Splenomegaly - A palpable spleen greater than 3 cm below the costal margin
• Cytopenia - Counts below the specified range in at least 2 of the following cell lineages:
  • Absolute neutrophils less than 1000/µL
  • Platelets less than 100,000/µL
  • Hemoglobin less than 9.0 g/dL
• Hypofibrinogenemia or hypertriglyceridemia - (1) Fibrinogen less than 1.5 g/L or levels greater than 3 standard deviations below the age adjusted reference range value or (2) fasting triglycerides greater than 2 mmol/L or levels greater than 3 standard deviations above the age-adjusted reference range value
• Hemophagocytosis - Must have tissue demonstration from lymph node, spleen, or bone marrow without evidence of malignancy
• Rash - Skin findings in more than half of patients;¹ scaly and waxy lesions; rashes on the scalp and behind the ear
• Other - Swollen or hemorrhagic gums that can result in tooth loss; feeding problems (especially prominent in infants); abdominal pain, vomiting, diarrhea, and weight loss

Physical

• Clinical findings, including evidence of infection due to decreased immunity and white cell killing defects, easy bruisability, and pallor, are related to pancytopenia secondary to bone marrow infiltration or splenic sequestration.
• Evidence of a coagulopathy with an increased activated partial thromboplastin time (aPTT) is present.
• Jaundice is often present due to hyperbilirubinemia.
• As many as 65% of patients have a nonspecific rash that is often vaguely termed maculopapular although it has also been described as ranging from erythroderma to generalized purpuric macules and papules to morbilliform eruptions.¹
• One Swedish study described nearly 75% of patients having some form of CNS involvement, with half showing neurologic symptoms including seizures, ataxia, hemiplegia, mental status changes, or simply irritability.¹⁶
• Because of the predilection of the disease for certain tissues, lymphadenopathy is commonly found on physical examination.
• Other common constitutional findings such as malaise, anorexia with or without weight loss, and failure to thrive can occur.¹⁵
• The skin can be involved in various ways; this is clinically best characterized as erythroderma, generalized purpuric macules and papules, or morbilliform eruptions.

Causes

• See Pathophysiology.

Differential Diagnoses

Other Problems to Be Considered

Primary versus secondary hemophagocytic lymphohistiocytosis (HLH) 
Langerhans cell histiocytosis
Rosai-Dorfman disease
Solitary histiocytoma with macrophage phenotype
Leukemias
Lymphomas
Sarcomas
X-linked lymphoproliferative syndrome
Chediak-Higashi syndrome
Griscelli syndrome
DiGeorge syndrome
Metabolic disorders
Seborrheic dermatitis
Juvenile xanthogranuloma
Acquired immunodeficiency syndrome (AIDS)
Macrophage activation syndrome
Tuberculosis¹⁷

Workup

Laboratory Studies

• Because natural killer (NK) cell function or activity is decreased in as many as 90% of patients with hemophagocytic lymphohistiocytosis (HLH), it is one of the most useful laboratory tests. NK cell number is usually not diagnostic.
• In addition to pancytopenia, hypofibrinogenemia, and hypertriglyceridemias, as previously mentioned, other laboratory abnormalities have been linked to hemophagocytic lymphohistiocytosis. Ferritin has been observed as a marker for hemophagocytic lymphohistiocytosis, with the serum levels paralleling the course of the disease.¹⁸ Liver damage has also been reported as evidenced by hyperbilirubinemia, hypoalbuminemia, and elevated findings on liver function tests including aspartate aminotransferase (AST) and alanine aminotransferase (ALT).¹⁹
• The presence of a PRF1 gene mutation can be determined based on flow cytometry by staining perforin contained in lymphocytes.

Imaging Studies

• No specific imaging patterns are diagnostic of hemophagocytic lymphohistiocytosis.
• CT or ultrasonography findings may include ascites, gallbladder wall thickening, increased periportal echogenicity, lymphadenopathy, and pleural effusion.
• MRI may show CNS involvement, but the diagnosis is clinical and molecular, as is discussed below.²⁰

Other Tests

In October 2002, Arico et al proposed an approach to the diagnostic workup of a patient with suspected hemophagocytic lymphohistiocytosis.³

• A detailed clinical history should be obtained to exclude other associated conditions, such as metabolic disorders or the DiGeorge syndrome. However, if the diagnostic hemophagocytic lymphohistiocytosis criteria are fulfilled, and the findings for associated conditions are negative, initial testing involves perforin expression by NK cells using flow cytometry.
• Patients lacking perforin expression should be analyzed for the PRF1 gene mutation.
• NK cell activity should also be determined to aid in differentiating between the hemophagocytic lymphohistiocytosis subtypes.
• Normal activity is suggestive of the reactive form of hemophagocytic lymphohistiocytosis rather than the familial type.
• DNA samples and fresh cells are suggested to be stored in case of need for future use in familial cases for which no genetic defect can be identified.

Procedures

• A skin biopsy can be performed for histological examination.
• Lymph node biopsy, bone marrow biopsy, or liver biopsy may demonstrate the characteristic hemophagocytosis.
  
  

  

  A lymph node biopsy is performed. Note that a marking pen has been used to outline the node before removal and that a silk suture has been used to provide traction to assist the removal.

  
  

Histologic Findings

• A skin biopsy can assist in distinguishing this disorder from other systemic and potentially neoplastic diseases, such as Langerhans cell histiocytosis, myofibrosis, extramedullary hematopoiesis, and leukemia cutis.¹ However, skin biopsy findings are usually not diagnostic and only rarely show hemophagocytosis.
• Because hemophagocytosis must be demonstrated in the bone marrow, spleen, or lymph nodes, appropriate specimens should be collected for documentation.¹⁵  RBCs are affected more often than the white cells or platelets.
• Findings in up to two thirds of initial bone marrow aspirates may be nondiagnostic; thus, a negative examination finding may not rule out hemophagocytic lymphohistiocytosis.
• An additional bone marrow finding includes dyserythropoiesis, which has been observed in the absence of hemophagocytic histiocytes.
• Additional studies, including lymph node biopsy, should be performed, and treatment should not be delayed if all other criteria have been met.²¹
• Although problematic in a patient with a coagulopathy, a liver biopsy demonstrating a picture similar to chronic persistent hepatitis can support the diagnosis, as can the presence of mononuclear cells in the cerebrospinal fluid (CSF).

Treatment

Medical Care

• A pediatric hematology-oncology specialist is best equipped to manage hemophagocytic lymphohistiocytosis (HLH), which is a rare and potentially life-threatening disease.
• The newest protocol, HLH-2004, opened on January 1, 2004, and is based on the Histiocyte Society's original HLH-94 protocol, which had previously opened on January 1, 1995, with some minor modifications. The full HLH-2004 protocol is available by contacting the Histiocytosis Association of America. It represents a consolidation of the various approaches to treatment, with the goals being to first achieve clinical stability and then to cure with bone marrow transplantation (BMT). Antimycotic prophylaxis is used during the initial doses of dexamethasone. Sulfamethoxazole and trimethoprim (ie, cotrimoxazole) is continuously administered as prophylaxis for Pneumocystis carinii because of immune suppression. More details are discussed below.²²
• One group found that intravenous immunoglobulin (IVIG) was effective in suppressing symptoms when administered within hours of disease onset. Serum ferritin was used as a marker for macrophage activation, and treatment was administered accordingly.²³ Patients may be classified into high-risk and low-risk groups, with only the high-risk groups receiving the etoposide (ie, VP-16) regimens. Patients who are at low risk may be treated as effectively with only cyclosporine, corticosteroids, or IVIG.¹⁸ More studies, including randomized control trials, are needed.
• People with hemophagocytic lymphohistiocytosis may be at increased risk of developing posterior reversible encephalopathy syndrome.²⁴ CNS involvement of hemophagocytic lymphohistiocytosis may trigger this syndrome and other neurotoxic side effects experienced during therapy.

Surgical Care

• BMT is performed when a suitable donor can be found and the patient is stable.
• A more recent study has found favorable long-term disease control in patients who received a reduced-intensity conditioned regimen instead of the conventional stem cell transplant.²⁵
• If the patient is experiencing life-threatening respiratory difficulty or uncontrolled hypersplenism, splenectomy is an option.

Consultations

• Consultation with a gastroenterologist may be helpful, especially if a transcutaneous liver biopsy is necessary.
• If the primary form of hemophagocytic lymphohistiocytosis is suspected, a genetic counselor may be helpful. In addition to analyzing inheritance patterns and determining risk, they can provide supportive counseling to the patient and family.

Medication

Initial therapy in patients with hemophagocytic lymphohistiocytosis (HLH) consists of etoposide and dexamethasone for 8 weeks in varying doses as described below. In the HLH-2004 protocol, cyclosporine is added in the beginning. Intrathecal methotrexate is used only with persistently abnormal CSF or progressive neurologic symptoms. Resolved nonfamilial hemophagocytic lymphohistiocytosis does not require continuation of the therapy regimen unless disease reactivation occurs after completion of the initial therapy or unless patients are undergoing bone marrow transplantation (BMT). For the remaining children with persistent nonfamilial disease or familial disease, continuation therapy with etoposide IV infusions, dexamethasone pulses, and cyclosporine PO is instituted at week 9 from the start of initial treatment.²² Hemophagocytic lymphohistiocytosis associated with malignancies demands prompt therapy directed at the neoplasm.

Antineoplastic agents

These agents interfere with cell reproduction. Some agents are cell cycle specific, whereas others (eg, alkylating agents, anthracyclines, cisplatin) are not phase specific. Cellular apoptosis (ie, programmed cell death) is also a potential mechanism of many antineoplastic agents.

Etoposide (Toposar, VePesid)

Also called VP-16. Inhibits topoisomerase II and results in DNA strand breakage causing cell proliferation to arrest in late S or early G2 portion of the cell cycle.

Dosing

Adult

Pediatric

Induction (weeks 1-8): 150 mg/m² IV 2 times/wk for 2 wk, then qwk for remaining 6 wk
Continuation (initiate at week 9): 150 mg/m² IV infusion q2wk (alternate with dexamethasone)

Interactions

May prolong the effects of warfarin and increase the clearance of methotrexate; cyclosporine and etoposide have additive effects in the cytotoxicity of tumor cells

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Bleeding and severe myelosuppression may occur; mucositis, hypotension, liver toxicity, and diarrhea can also be seen

Methotrexate (Trexall)

Antimetabolite that inhibits dihydrofolate reductase, thereby hindering DNA synthesis and cell reproduction in malignant cells. Satisfactory response observed 3-6 wk following administration.
Adjust dose gradually to attain satisfactory response.

Dosing

Adult

Pediatric

PO/IM: 7.5-30 mg/m² PO/IM q1-2wk
IV: 10-12,000 mg/m² IV bolus or continuous IV infusion over 6-42 h; may repeat up to 4 doses (ie, at weeks 3, 4, 5, 6)
IT:
<1 year: 6 mg/dose IT
1-2 years: 8 mg/dose IT
2-3 years: 10 mg/dose IT
>3 years: 12 mg/dose IT
May administer up to 4 doses IT if progressive neurologic symptoms exist or abnormal CSF has not improved

Interactions

PO aminoglycosides may decrease absorption and blood levels of concurrent PO methotrexate (MTX); charcoal lowers MTX levels; coadministration with etretinate may increase hepatotoxicity of MTX; folic acid or its derivatives contained in some vitamins may decrease response to MTX
Probenecid, NSAIDs, salicylates, procarbazine, and sulfonamides, including TMP-SMZ, can increase MTX plasma levels; may decrease phenytoin plasma levels; may increase plasma levels of thiopurines

Contraindications

Documented hypersensitivity; alcoholism; hepatic insufficiency; documented immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia); renal insufficiency

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Monitor CBC counts monthly and liver and renal function q1-3mo during therapy (monitor more frequently during initial dosing, dose adjustments, or risk of elevated MTX levels [eg, dehydration]); MTX has toxic effects on hematologic, renal, GI, pulmonary, and neurologic systems; discontinue if significant drop in blood counts occur; fatal reactions reported when administered concurrently with NSAIDs; mucositis is known toxicity

Corticosteroids

These agents elicit anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.

Dexamethasone (Decadron, Hexadrol)

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reducing capillary permeability. Postulated mechanisms of action of corticosteroids in tumors include reduction in vascular permeability, cytoxic effects on tumors, and inhibition of tumor formation.

Dosing

Adult

Pediatric

Induction (weeks 1-8): 10 mg/m²/d PO for 2 wk, then 5 mg/m²/d for 2 wk, 2.5 mg/m²/d for 2 wk, then 1.25 mg/m²/d for 1 wk, continue tapering and discontinue during week 8
Continuation (initiate at week 9): Pulses of 10 mg/m²/d PO for 3 d q2wk (alternate with etoposide)

Interactions

Effects decrease with coadministration of barbiturates, phenytoin, and rifampin; dexamethasone decreases effect of salicylates and vaccines used for immunization

Contraindications

Documented hypersensitivity; active bacterial or fungal infection

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Increases risk of multiple complications, including severe infections; monitor adrenal insufficiency when tapering drug; abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, pancreatitis, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections are possible complications of glucocorticoid use

Immunosuppressant agents

These agents may be used in combination with corticosteroids and immune globulin in patients at low risk.

Cyclosporine (Sandimmune, Neoral)

Cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft versus host disease for various organs.
In children and adults, base dosing on ideal body weight.

Dosing

Adult

Pediatric

Initiate after dexamethasone 8-wk induction regimen completed
Initial dose: 6 mg/kg/d PO divided bid
Continuation therapy: Adjust PO dose to maintain target trough levels of 200 mcg/L

Interactions

Carbamazepine, phenytoin, isoniazid, rifampin, and phenobarbital may decrease concentrations; azithromycin, itraconazole, nicardipine, ketoconazole, fluconazole, erythromycin, verapamil, grapefruit juice, diltiazem, aminoglycosides, acyclovir, amphotericin B, and clarithromycin may increase toxicity; acute renal failure, rhabdomyolysis, myositis, and myalgias increase when taken concurrently with lovastatin; methylprednisolone and cyclosporine mutually inhibit one another, resulting in increased plasma levels of each drug

Contraindications

Documented hypersensitivity; uncontrolled hypertension or malignancies; concomitant administration with PUVA or UVB radiation in psoriasis (may increase risk of cancer)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Evaluate renal and liver functions often by measuring BUN, serum creatinine, serum bilirubin, and liver enzymes; may increase risk of infection and lymphoma; reserve IV use only for those who cannot take PO

Immune globulins

Immune globulin is a purified preparation of gamma globulin. It is derived from large pools of human plasma and is comprised of 4 subclasses of antibodies, approximating the distribution of human serum.

Immune globulin, intravenous (Carimune NF, Gamumex, Gammagard)

Neutralizes circulating myelin antibodies through anti-idiotypic antibodies. Down-regulates proinflammatory cytokines, including INF-g. Blocks Fc receptors on macrophages. Suppresses inducer T and B cells and augments suppressor T cells. Blocks complement cascade. Promotes remyelination. May increase CSF IgG (10%).

Dosing

Adult

Pediatric

400 mg/kg/d IV for 5 d; alternatively, 1 g/kg/d IV for 2 d

Interactions

Globulin preparation may interfere with immune response to live virus vaccine (MMR) and reduce efficacy (do not administer within 3 mo of vaccine)

Contraindications

Documented hypersensitivity; IgA deficiency

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Check serum IgA before administering IVIG (use an IgA-depleted product, eg, Gammagard S/D); infusions may increase serum viscosity and thromboembolic events; infusions may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-30 d postinfusion)
Increases risk of renal tubular necrosis in elderly patients and in patients with diabetes mellitus, volume depletion, and preexisting kidney disease; laboratory result changes associated with infusions include elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increase in ESR for 2-3 wk, and apparent hyponatremia

Follow-up

Further Outpatient Care

• Supportive care is needed to ensure that the patient with hemophagocytic lymphohistiocytosis (HLH) remains stable until a bone marrow donor can be found. This includes transfusions of RBCs, platelets, and fresh frozen plasma, as well as nutritional support in addition to the treatment protocol.²²
• Patients should be continually monitored for evidence of infection because of their immunosuppressed state. Be aware of the possibility of underlying malignancy.
• Biopsies and diagnostic cytogenetics may be needed in addition to selective radiographic imaging.¹²

Complications

• Complications of individual drugs in the regimen were outlined above (see Medication).
• Complications due to a subsequent transplant are numerous and include both acute and chronic graft versus host disease, acute inflammatory events, respiratory distress syndrome, and exacerbation of neurologic symptoms.²⁶

Prognosis

• Although the prognosis varies between studies and with different approaches to treatment, the disease is invariably fatal if not treated. The median survival rate has been reported to be 2-6 months without treatment, but survival time has dramatically improved with the advent of the HLH-94 protocol already discussed.
• A study of 122 patients from the International Registry for hemophagocytic lymphohistiocytosis found that the overall estimated 5-year survival rate was 21%, with 66% of patients who received bone marrow transplantation (BMT) surviving 5 years versus only 10.1% of patients treated with chemotherapy alone.¹⁴ More recent studies have shown that the HLH-94 protocol resulted in an overall survival rate of 55%. Success or failure of an allogeneic BMT is the most important long-term prognostic factor. Unfortunately, many cases are diagnosed late in the course of the disease, after irreversible damage has occurred.
• Although patients with hemophagocytic lymphohistiocytosis are at high risk for death early in their disease course, steroids, intravenous immunoglobulin (IVIG), or both may be sufficient as first-line therapy for selected patients.²⁷

Patient Education

• All physicians who treat young patients must be aware of life-threatening diseases such as hemophagocytic lymphohistiocytosis.
• Pediatricians, dermatologists, and neurologists should especially take note because the presenting symptoms of hemophagocytic lymphohistiocytosis are likely to bring the patient into their offices.
• Any suspicion warrants a referral to a pediatric hematologic-oncologist who is equipped with the necessary tools to make a rapid diagnosis.

Miscellaneous

Medicolegal Pitfalls

• Be aware of this disease, both in its typical onset and when it occurs later in life with the initial presentation of CNS symptoms or underlying malignancy rather than the typical triad of a fever, hepatosplenomegaly, and pancytopenia.
• Cases of hemophagocytic lymphohistiocytosis (HLH) erroneously labeled as child abuse have been reported in the literature.²⁸
• Failure to make the diagnosis of hemophagocytic lymphohistiocytosis may result in adverse consequences.

Special Concerns

• Although rare, the disease onset can occur later in life with the initial presentation of CNS symptoms or underlying malignancy rather than the typical triad of a fever, hepatosplenomegaly, and pancytopenia.
• Physicians should be aware of this atypical presentation and consider hemophagocytic lymphohistiocytosis in their differentials.²⁰

Multimedia

Media file 1: A lymph node biopsy is performed. Note that a marking pen has been used to outline the node before removal and that a silk suture has been used to provide traction to assist the removal.

References

1. Morrell DS, Pepping MA, Scott JP, et al. Cutaneous manifestations of hemophagocytic lymphohistiocytosis. Arch Dermatol. Sep 2002;138(9):1208-12. [Medline].

2. Feldmann J, Le Deist F, Ouachee-Chardin M, et al. Functional consequences of perforin gene mutations in 22 patients with familial haemophagocytic lymphohistiocytosis. Br J Haematol. Jun 2002;117(4):965-72. [Medline].

3. Arico M, Allen M, Brusa S, et al. Haemophagocytic lymphohistiocytosis: proposal of a diagnostic algorithm based on perforin expression. Br J Haematol. Oct 2002;119(1):180-8. [Medline].

4. Imashuku S, Ueda I, Teramura T, et al. Occurrence of haemophagocytic lymphohistiocytosis at less than 1 year of age: analysis of 96 patients. Eur J Pediatr. May 2005;164(5):315-9. [Medline].

5. Risma KA, Frayer RW, Filipovich AH, Sumegi J. Aberrant maturation of mutant perforin underlies the clinical diversity of hemophagocytic lymphohistiocytosis. J Clin Invest. Jan 2006;116(1):182-92. [Medline]. [Full Text].

6. Katano H, Cohen JI. Perforin and lymphohistiocytic proliferative disorders. Br J Haematol. Mar 2005;128(6):739-50. [Medline].

7. Rieux-Laucat F, Le Deist F, De Saint Basile G. Autoimmune lymphoproliferative syndrome and perforin. N Engl J Med. Jan 20 2005;352(3):306-7; author reply 306-7. [Medline].

8. Menasche G, Feldmann J, Fischer A, de Saint Basile G. Primary hemophagocytic syndromes point to a direct link between lymphocyte cytotoxicity and homeostasis. Immunol Rev. Feb 2005;203:165-79. [Medline].

9. zur Stadt U, Schmidt S, Kasper B, et al. Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. Hum Mol Genet. Mar 15 2005;14(6):827-34. [Medline]. [Full Text].

10. Arico M, Danesino C, Pende D, Moretta L. Pathogenesis of haemophagocytic lymphohistiocytosis. Br J Haematol. Sep 2001;114(4):761-9. [Medline].

11. Malloy CA, Polinski C, Alkan S, et al. Hemophagocytic lymphohistiocytosis presenting with nonimmune hydrops fetalis. J Perinatol. Jul 2004;24(7):458-60. [Medline].

12. Sung L, King SM, Carcao M, et al. Adverse outcomes in primary hemophagocytic lymphohistiocytosis. J Pediatr Hematol Oncol. Oct 2002;24(7):550-4. [Medline].

13. Ericson KG, Fadeel B, Andersson M, et al. Sequence analysis of the granulysin and granzyme B genes in familial hemophagocytic lymphohistiocytosis. Hum Genet. Jan 2003;112(1):98-9. [Medline].

14. Arico M, Janka G, Fischer A, et al. Hemophagocytic lymphohistiocytosis. Report of 122 children from the International Registry. FHL Study Group of the Histiocyte Society. Leukemia. Feb 1996;10(2):197-203. [Medline].

15. [Guideline] Henter JI, Elinder G, Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol. Feb 1991;18(1):29-33. [Medline].

16. Henter JI, Elinder G, Soder O, Ost A. Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr Scand. Apr 1991;80(4):428-35. [Medline].

17. Su NW, Chen CK, Chen GS, Hsieh RK, Chang MC. A case of tuberculosis-induced hemophagocytic lymphohistiocytosis in a patient under hemodialysis. Int J Hematol. Apr 2009;89(3):298-301. [Medline].

18. Imashuku S, Teramura T, Morimoto A, Hibi S. Recent developments in the management of haemophagocytic lymphohistiocytosis. Expert Opin Pharmacother. Sep 2001;2(9):1437-48. [Medline].

19. Hafsteinsdottir S, Jonmundsson GK, Kristinsson Jr, et al. Findings in familial haemophagocytic lymphohistiocytosis prior to symptomatic presentation. Acta Paediatr. 2002;91(8):974-7. [Medline].

20. Clementi R, Emmi L, Maccario R, et al. Adult onset and atypical presentation of hemophagocytic lymphohistiocytosis in siblings carrying PRF1 mutations. Blood. Sep 15 2002;100(6):2266-7. [Medline].

21. Macheta M, Will AM, Houghton JB, Wynn RF. Prominent dyserythropoiesis in four cases of haemophagocytic lymphohistiocytosis. J Clin Pathol. Dec 2001;54(12):961-3. [Medline].

22. Henter JI, Samuelsson-Horne A, Arico M, et al. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood. Oct 1 2002;100(7):2367-73. [Medline].

23. Emmenegger U, Spaeth PJ, Neftel KA. Intravenous immunoglobulin for hemophagocytic lymphohistiocytosis?. J Clin Oncol. Jan 15 2002;20(2):599-601. [Medline].

24. Thompson PA, Allen CE, Horton T, Jones JY, Vinks AA, McClain KL. Severe neurologic side effects in patients being treated for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. May 2009;52(5):621-5. [Medline].

25. Cooper N, Rao K, Gilmour K, et al. Stem cell transplantation with reduced-intensity conditioning for hemophagocytic lymphohistiocytosis. Blood. Feb 1 2006;107(3):1233-6. [Medline].

26. Filipovich AH. Life-threatening hemophagocytic syndromes: current outcomes with hematopoietic stem cell transplantation. Pediatr Transplant. Dec 2005;9 Suppl 7:87-91. [Medline].

27. Gupta AA, Tyrrell P, Valani R, Benseler S, Abdelhaleem M, Weitzman S. Experience with hemophagocytic lymphohistiocytosis/macrophage activation syndrome at a single institution. J Pediatr Hematol Oncol. Feb 2009;31(2):81-4. [Medline].

28. Rooms L, Fitzgerald N, McClain KL. Hemophagocytic lymphohistiocytosis masquerading as child abuse: presentation of three cases and review of central nervous system findings in hemophagocytic lymphohistiocytosis. Pediatrics. May 2003;111(5 Pt 1):e636-40. [Medline].

29. Chen RL, Lin KH, Lin DT, et al. Immunomodulation treatment for childhood virus-associated haemophagocytic lymphohistiocytosis. Br J Haematol. Feb 1995;89(2):282-90. [Medline].

30. Goransdotter Ericson K, Fadeel B, Nilsson-Ardnor S, et al. Spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis. Am J Hum Genet. Mar 2001;68(3):590-7. [Medline].

31. Pradalier A, Teillet F, Molitor JL, Drappier JC. [Macrophage activation syndrome, hemophagocytic syndrome]. Pathol Biol (Paris). Sep 2004;52(7):407-14. [Medline].

32. Schmidt MH, Sung L, Shuckett BM. Hemophagocytic lymphohistiocytosis in children: abdominal US findings within 1 week of presentation. Radiology. Mar 2004;230(3):685-9. [Medline]. [Full Text].

Keywords

lymphohistiocytosis, hemophagocytic lymphohistiocytosis, HLH, familial hemophagocytic lymphohistiocytosis, FHL, familial erythrophagocytic lymphohistiocytosis, FEL, primary hemophagocytic lymphohistiocytosis, primary HLH, secondary hemophagocytic lymphohistiocytosis, secondary HLH, acquired hemophagocytic lymphohistiocytosis, acquired HLH, infection-associated hemophagocytic syndrome, IAHS, reactive HLH, hepatosplenomegaly, pancytopenia, lymphadenopathy, ascites, gallbladder wall thickening, treatment, diagnosis

Contributor Information and Disclosures

Author

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

Medical Editor

Kathleen M Sakamoto, MD, PhD, Professor and Chief, Division of Hematology-Oncology, Vice-Chair of Research, Mattel Children's Hospital at UCLA; Department of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA and California Nanosystems Institute and Molecular Biology, UCLA
Kathleen M Sakamoto, MD, PhD is a member of the following medical societies: American Society of Hematology, American Society of Pediatric Hematology/Oncology, New York Academy of Sciences, Society for Pediatric Research, and Western Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Steven K Bergstrom, MD, Assistant to the Chairman, Department of Pediatrics, Division of Hematology-Oncology, Kaiser Permanente Medical Center of Oakland
Steven K Bergstrom, MD is a member of the following medical societies: Alpha Omega Alpha, American Society of Clinical Oncology, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, and International Society for Experimental Hematology
Disclosure: Nothing to disclose.

CME Editor

Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida; Clinical Professor, Department of Pediatrics, University of North Carolina; Adjunct Professor, Department of Pediatrics, Duke University
Samuel Gross, MD is a member of the following medical societies: American Association for Cancer Research, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, American Society of Hematology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Chief Editor

Max J Coppes, MD, PhD, MBA, Senior Vice President, Children's National Medical Center (Center for Cancer and Blood Disorders); Director, Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center; Professor of Medicine, Oncology, and Pediatrics, Georgetown University
Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American Association for Cancer Research, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors Nicole L Lacz, MD, and Franklin Desposito, MD, to the original writing and development of this article.

© 1994- by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)