eMedicine Specialties > Pediatrics: General Medicine > Oncology

Lymphohistiocytosis (Hemophagocytic Lymphohistiocytosis)

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
Contributor Information and Disclosures

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.

• Search for CME/CE on This Topic »