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C H A P T E R 52

HISTIOCYTIC DISORDERS

Michael B. Jordan and Alexandra Hult Filipovich

The histiocytic disorders comprise a broad grouping of hematologic to all of the varied manifestations of this protean disorder. It is now
and immunologic diseases united by the observation that monocyte/ well recognized that LCH can present at any time in life from the
macrophages or dendritic cells appear to be prominently involved neonatal period to old age. LCH lesions may spontaneously regress
in disease pathophysiology. The term histiocyte refers to phagocytic or repeatedly “reactivate”, contributing to long-term disabilities such
cells, historically identified on tissue sections but now more precisely as DI or a neurodegenerative disease. Life-threatening forms of LCH,
defined as cells of the monocyte/macrophage lineage (Fig. 52.1). The previously referred to as Letterer–Siwe disease, typically present in
ontogeny of these cells continues to be actively studied and debated, infancy and clearly require intensive therapy and sometimes salvage
and their role(s) in pathogenesis is an active area of investigation. The treatment such as allogeneic bone marrow transplantation (BMT) to
characteristic cells seen in various histiocytic lesions can, in general, cure the children.
be differentiated by a variety of functional and phenotypic markers.
The modern classification of the histiocytoses mirrors this biology
(Table 52.1). Although malignant disorders involving monocyte/ Epidemiology
macrophages or dendritic cells were originally included in this clas-
sification, this chapter focuses solely on nonmalignant disorders in The incidence of LCH has been estimated to be between 5 and 15 cases
this category. per million children, per year. The incidence of LCH in adults is believed
Of the dendritic cell-related histiocytoses, the most clinically to be lower than in children but is likely underestimated because of a
common and prominent one is Langerhans cell histiocytosis (LCH). lack of recognition of LCH in adult medicine. Notably, LCH does not
This chapter also briefly discusses other dendritic cell-related appear to have significant geographic or ethnic predilections. Although
histiocytic disorders, including juvenile xanthogranuloma (JXG); families with multiple cases of LCH have been reported, these kindreds
Erdheim–Chester disease (ECD); and sinus histiocytosis with massive are extremely rare. One notable clinical or epidemiologic association
lymphadenopathy (SHML), also referred to as Rosai-Dorfman disease reported thus far involves an unexplained coincidence of both LCH
(RDD). and leukemia (of various subtypes) in rare patients.
The prominent monocyte/macrophage-related histiocytic dis-
order, hemophagocytic lymphohistiocytosis (HLH), is discussed in
detail later in this chapter. In HLH, activated macrophages, activated Pathobiology
T cells, and defective natural killer (NK) cells are the dysfunctional
interactive partners. The understanding of the pathobiology of LCH is currently undergo-
Table 52.1 lists a currently accepted classification of histiocytic ing significant evolution, driven by new insights into both normal
disorders. These disorders are a diverse grouping, ranging from and disease-associated Langerhans cells. Over the years, LCH has been
benign skin lesions to rapidly life-threatening systemic disorders. classified as a neoplasm, a reactive disorder, or an aberrant immune
Tables 52.2 and 52.3 list clinical features and commonly used response. LCH cells are pathologic in that they bear heterogeneous
pathologic markers or features that may be used to help distinguish characteristics not normally identified in healthy Langerhans cells
some of these disorders. The clinical diversity of histiocytic disorders that are typically resident in the skin. The granulomatous lesions
is underscored by recent discoveries related to their pathogenesis. of LCH, which can be found in nearly any organ, represent an
Studies dating to the late 1990s have demonstrated that HLH (at accumulation of normal inflammatory cells, including eosinophils,
least in its familial form) is a unique immune-regulatory disorder. lymphocytes (especially T cells), and macrophages, in addition to
LCH is another disorder, historically considered to be nonmalignant. the LCH cells. The clinically benign behavior of most cases, includ-
However, demonstrations of clonality as well as genetic abnormalities ing spontaneous remissions and lack of aggressive disease evolution
of B-Raf now demonstrate that LCH is a benign neoplasm despite with recurrences, as well as the benign histopathologic appearance of
its variable clinical phenotype. The pathogeneses of less common lesions, have suggested a nonmalignant etiology. The failure of many
dendritic cell- and macrophage-related histiocytic disorders are still laboratories to culture pathologic Langerhans cells has reinforced
unknown. this impression. Thus, LCH has been hypothesized to be a reactive
or immunologic disorder by many. On the other hand, lesional
Langerhans cells have been demonstrated by several investigators
LANGERHANS CELL HISTIOCYTOSIS to be clonal. This observation, combined with the clinical utility of
antineoplastic drugs, has bolstered the opinion that LCH may be a
LCH is the most common of the histiocytoses. The central cell of neoplastic disorder.
LCH, the Langerhans dendritic cell, was first described in 1868 Several reports in the last 5 years of highly prevalent B-Raf muta-
by 21-year-old Paul Langerhans. Between 1893 and 1920, Hand, tions in lesional Langerhans cells have again shifted thinking and
Schüller, and Christian described the various nonfatal presentations strongly support a neoplastic etiology. The mutation in question
of LCH, which include bony lesions, skin rash, and diabetes insipidus (BRAF V600E) is well described in both malignant melanomas and
(DI). Letterer and Siwe (1924 and 1933, respectively) added to the in benign nevi, among other neoplasms. This mutation leads to
list of clinical presentations by describing cases with liver and spleen activation of the extracellular signal-related kinase (ERK) pathway.
involvement in infants and toddlers. These disorders were later grouped More recently, additional mutations associated with the ERK
under the term histiocytosis X (denoting the uncertainty about disease pathway activation have been described in LCH patients. Along
pathogenesis) by Lichtenstein. It was eventually theorized by Nezelof with these disease-specific findings, understanding of the biology
(1973) that histiocytosis X is caused by a proliferation of pathologic of normal Langerhans cells has advanced. Cutaneous Langerhans
Langerhans cells. At present, the term LCH has been adopted to refer dendritic cells have been shown to arise from in situ precursors,

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