FAMILIAL HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS: Primary Hemophagocytic Lymphohistiocytosis

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The term histiocytosis identifies a group of disorders that have in common the proliferation and accumulation of macrophages and dendritic cells. In 1987 the Writing Group of the Histiocyte Society recommended a division into three classes: Langerhans cell histiocytosis (LCH) (class I); non–Langerhans cell histiocytosis (class II), which is the focus of this and the following articles; and malignant histiocytic disorders (class III).84 A minor revision of this classification has recently been proposed, and the three major groups are now termed (1) dendritic cell–related disorders (of which LCH is by far the most common), (2) macrophage-related disorders, and (3) malignant disorders.22

Hemophagocytic lymphohistiocytosis (HLH) includes most of the patients with macrophage-related disorders (previously class II histiocytoses). It includes two different conditions that may be difficult to distinguish from each other38, 45: (1) primary HLH: familial hemophagocytic lymphohistiocytosis (FHL, FHLH, or FEL)—this is an autosomal recessive disorder29 and at onset the family history is often negative (sporadic cases). The onset as well as bouts of the disease may be triggered by infections3, 40; and (2) secondary HLH: infection-associated hemophagocytic syndrome (IAHS or VAHS) and malignancy-associated hemophagocytic syndrome (MAHS).

A lymphohistiocytic proliferation with hemophagocytosis may develop also as a result of and secondary to strong immunologic activation, such as a severe infection. The condition has been described in immunocompromised hosts in association with viral infections. Although the term virus-associated hemophagocytic syndrome (VAHS) is frequently used,72 bacteria and parasites may induce secondary HLH as well. The syndrome may also develop subsequent to other types of immunologic stress and activation, such as in association with malignancies (malignancy-associated hemophagocytic syndrome, MAHS).45

The major aims of this and the following article are to describe clinical and laboratory features of these disorders and to provide diagnostic and therapeutic guidelines. A brief overview of their biology, immunology, and pathophysiology is also presented. The present article concentrates on primary HLH (FHL), which by far is most commonly seen in infancy and childhood. It is followed by an article (see Janka et al, p. 435) on secondary HLH (IAHS and MAHS), which can affect all ages. A presentation of sinus histiocytosis with massive lymphadenopathy (SHML) is also included, although this disease may not be included in the class II histiocytoses in the future.

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Incidence and Epidemiology

In a retrospective Swedish study, the incidence of primary HLH in children was estimated to be 0.12 per 100,000 children per year.43 Similar figures were later found in a British study (M. Layton, London, personal communication). These figures must be considered as the minimal incidence, and most probably there are still patients who are not diagnosed. The male-to-female ratio is 1:1.4, 43, 51

The disease has been reported from all continents and many ethnic groups.3, 33 Because FHL is an

SINUS HISTIOCYTOSIS WITH MASSIVE LYMPHADENOPATHY (SHML; ROSAI-DORFMAN DISEASE)

About 25 years after the first description by Rosai and Dorfman, this condition, usually characterized by a persistent, massive enlargement of the cervical lymph nodes and an inflammatory syndrome, remains intriguing.73, 74 Although affected patients may range from infants to elderly, the mean age is about 20 years. There is a mild predominance of males, and only very few familial cases have been reported.27 Fewer than 10% of patients present with other than bilateral cervical lymphadenomegaly,

ACKNOWLEDGMENT

We are indebted to Dr Marion Schneider for her valuable contribution to the immunologic investigations and Dr Marco Paulli for his assistance on SHML.

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    Address reprint requests to Jan-Inge Henter, MD, PhD, Pediatric Hematology and Oncology, Karolinska Hospital, S-171 76 Stockholm, Sweden

    This research is supported by grants from the Children's Cancer Foundation of Sweden and the Medical Research Council of Sweden.

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    Copyright © 1998 W. B. Saunders Company. Published by Elsevier Inc. All rights reserved.