Dendritic Histiocytoses: An Update
The meaning of the term "histiocyte" has changed over time. First used to describe a "fixed tissue
macrophage", thought to arise directly in the tissues, the term histiocyte has now come to be used as a
global term to encompass the monocyte-macrophage and dendritic accessory cell lines. Likewise, the term
"histiocytosis" has different meanings: Dorland's Medical Dictionary 27th Edition defines it
as "the abnormal appearance of histiocytes (macrophages) in the blood"- surely not most people's current
concept of the condition! Whereas earlier usage referred to the accumulation of macrophage histiocytes
at various body sites, the distinction between metabolic disease, infectious diseases and immune disorder
was less clear than it is today. The "Contemporary Classification of Histiocytic Disorders"  lists
localized histiocytomas and disseminated histiocytoses of dendritic cells or macrophages with varied
biological potential, from benign to malignant.
The dendritic cell histiocytoses appear to represent accumulations of myeloid dendritic cells at
various points along their life cycle as depicted in the Figure. The juvenile xanthogranuloma family
(JXG) has the phenotypic and morphologic characteristics of the interstitial dermal dendritic cell.
Langerhans' cell histiocytosis, (LCH) represents an immature, Langerhans'-type dendritic cell with
limited capacity to mature . There are lesions with the phenotype of maturing, non-Langerhans'
myeloid dendritic cells (non-LCH) and examples of mature interdigitating dendritic cell lesions, IDC.
There are "benign" and sarcomatous examples of each.
Histiocytoses and Dendritic Cell Biology
There appear to be lymphoid and myeloid precursors of dendritic cell subtypes . This review
concerns itself with the myeloid dendritic cell subset, and the lymphoid dendritic cells (plasmacytoid DC
or plasmacytoid monocyte/interferon-producing cells PM/IPC) will not be further considered. There are
circulating precursors of DC subsets, most in the monocyte pool and these cells can develop into
macrophages or DC
driven by inflammatory or infectious stimuli. Starting with a CD34+ progenitor,
cultured hematopoietic cells can be driven by GM-CSF and TNFα to CD1a+ Langerhans' cell precursors
or to CD14+ cells that will express on further maturation CD68 and FXIIIa, the phenotype of
interstitial/dermal type dendritic cell. These interstitial/dermal dendrocytes also express mannose
receptor CD206, DC-SIGN, CD209 and CD13 but not CD1a or Langerin CD207 . It should be noted that
there is some plasticity in the system, and that the distinction between macrophages and dendritic cells
is not absolute. CD14+ monocytes can be driven towards the dendritic cell phenotype by GM-CSF/IL-4,
TNFα, TGFβ, IFNα, IL-15 among others and towards macrophage phenotype by M-CSF, IFNγ
or IL-6 among others. But cells with a dendritic cell phenotype can still be converted to a macrophage
phenotype by M-CSF or by IL-10
. Akagawa et al  demonstrated that terminal differentiation of
dendritic cells by TNFα abrogates this potential to convert dendritic cells to macrophages (or
osteoclast-like multinucleated giant cells) by down-regulating the M-CSF receptor, cfms.
The myeloid dendritic cells migrate continuously through peripheral tissues, skin, mucosa and numerous
organs contributing to self-tolerance and immune surveillance . Immature dendritic cells can
capture antigen through an extensive endowment of cytokine and Toll-like receptors and respond rapidly to
inflammatory (endogenous) or infectious (exogenous) stimuli. Stimulation of the dendritic cells leads to
their "maturation", the ability to present their antigen in an MHC-restricted manner to a variety of cell
types, T lymphocytes, B lymphocytes, NK or NKT cells to induce immune or tolerizing effects .
This maturation sequence is accompanied by phenotypic changes, the acquisition of maturation markers such
as CD80, CD83, CD86, upregulation of surface HLA-II and maturation of chemokine receptors. Morphologic
changes accompany migration to central lymphoid sites where the cells adopt an extensive dendritic
network in the paracortex (as interdigitating dendritic cells) and proliferation may also occur to a
The Biological Spectrum of Dendritic Cell Lesions
Langerhans' Cell Histiocytosis
Langerhans' cell histiocytosis (Langerhans' cell tumor, ) can have a wide range of biological
manifestations, being localized, multifocal or visceral/disseminated. The Langerhans' Cell Histiocytosis
International studies have identified a number of risk factors for high stage, poor prognosis disease.
These are young age, under 2 years, and organ involvement of one or more of the following – bone marrow,
spleen or liver. Lung involvement also confers high risk, but only as part of multisystem disease.
Non-response to initial treatment is also a predictor of poor outcome . Non-cranial vault lesions of
the skull (facial or temporal bones) with intracranial extension predict high risk of CNS disease.
At present, there are no validated histopathologic features that will prospectively identify high-risk
disease other than the morphologic criteria for Langerhans' cell sarcoma. Geissmann et al  have
suggested that loss of E-cadherin from LCH cells was a marker for systemic disease and that evidence of
LCH cell maturation in the skin (CD14-CD86+) was indicative of benign or self-involuting disease.
Neither has been prospectively validated.
Investigation into the local control of LCH cells has yielded ambiguous results. Egeler et al 
have shown high expression of CD40 on these cells with concomitant CD40L on infiltrating T cells,
suggesting in situ increase in pro-inflammatory signals including those for cell proliferation and
apoptosis. Annels et al  have demonstrated the presence of the immature dendritic cell chemokine
CCR6 on LCH cells, but not CCR7, the mature dendritic cell marker, indicating arrested development. The
cognate ligand CCL20/MIP-2 alpha was also demonstrated on LCH cells. Fleming et al  however, found
both CCR6 and CCR7 to be aberrantly co- expressed on lesional cells, more characteristic of a disordered
Petersen et al  demonstrated that both FAS and FAS-L were present on some LCH cells, but that
TUNEL-reactive apoptotic cells were sparse. Schouten et al  have shown that the p53-p21 and p16-Rb
pathways are activated in LCH, and that BCL-2 and p53 are overexpressed and may account for the limited
apoptosis despite the fact that cell proliferation (Ki-67) is often prodigious. Despite these
perturbations in proliferation vs. apoptosis, all forms of Langerhans' cell histiocytosis are
There is evidence that LCH cells follow the usual migratory pathways, entering lymph node sinuses from
afferent lymphatics and thence to the nodal paracortex where they undergo some maturation but not to
mature interdigitating dendritic cells. The LCH cells lose their CD1a/Langerin and upregulate the
surface expression of HLA-DR (abstract).
Langerhans' Cell Sarcoma 
Dendritic Cell-related Histiocytic Sarcoma of Langerhans' Cell Phenotype 
Langerhans' cell sarcoma, by contrast (with LCH) is cytologically "malignant". Nuclear pleomorphism
and atypical mitoses are present. The disorder most commonly presents in the skin of adults, associated
with tumoral disease, distant metastases and poor outcome. The cells are often more spindled than LCH,
but have the Langerhans' cell phenotype of CD1a/Langerin/Birbeck granules. Some are S100-negative. Only
an exceptionally rare lesion transformed from a pre-existing LCH .
Juvenile Xanthogranuloma (family)
The juvenile xanthogranuloma family of disorders shares a common phenotype (CD163+, CD68+, Factor
XIIIa+, fascin +, CD14+, CD1a-, S100-) and includes local skin and soft tissue lesions (JXG, deep JXG,
benign cephalic histiocytosis), visceral/mucosal lesions (xanthoma disseminatum) and bone/lung lesions
(Erdheim-Chester disease) (Jaffe unpublished). The cell of origin appears to be a myeloid dendritic
cell described as the interstitial/dermal dendritic cells, but the monocyte/macrophage markers, CD14 and
CD163 are also strongly expressed (see Figure). A suggestion that JXG is derived from the plasmacytoid
monocyte  has not been confirmed, as the lesions are CD123- (plasmacytoid monocytes are CD123+). The
biology is not unlike that of LCH - lesions usually involute but rarely become more systemic with worse
outcome and the two are not predictable on the basis of their histopathology . Juvenile
xanthogranulomas, like LCH, can be prominently cellular and mitotic, but not cytologically atypical
. An interesting association is the one that links JXG with neurofibromatosis and juvenile chronic
myeloid leukemia. Zvulonov et al  have demonstrated a 20x higher risk for JCML when the patient has
NF-1. The association of an eruptive "histiocytosis" in association with acute monocytic leukemia is
another reminder of this phenomenon in which a skin lesion is a more "mature" representation of an
underlying marrow disorder .
Histiocytic Sarcoma, JXG-type
(Dendritic Cell-related Histiocytic Sarcoma, Dermal/Interstitial Cell Phenotype }
There are rare examples of adult sarcomas that have the microscopic appearance of atypical,
cytologically malignant histiocytic lesions and that share the JXG phenotype, CD14+, CD163+, CD68+,
Factor XIIIa+, fascin+, CD1a-, S100-
Non-Langerhans' Cell Dendritic Cell Lesions
There is a small group of dermal and soft-tissue lesions that resemble LCH on morphological grounds,
but are CD1a-/Langerin- and lack Birbeck granules (when these have been sought). Other features of
dendritic cell affiliation, ultrastructural appearance, CD68+, HLA-DR+, S100+, fascin+ are invariably
present to varying degree, hence "non-Langerhans' dendritic cell-related histiocytomas or sarcomas".
Most of the characterized lesions have the phenotype of the maturing "semi-mature" myeloid dendritic cell
An index case presented at 6 years of age with classical LCH in the clavicle. Six years later, there
was a local recurrence that looked similar, but now lacked CD1a, Langerin and Birbeck granules, but had
S100+, high fascin expression, high surface expression of HLA-DR (intracytoplasmic in the original) and
was CD68+. These non-Langerhans' dendritic cell lesions appear to have predilection for the covering of
the nervous system, being seen in the cranium or spinal canal, as well as at soft-tissue sites, and the
clinical behavior is unlike that of LCH. The lesions are usually unifocal with high rate of local
recurrence and only very rare visceral involvement .
Lesions that phenotypically and morphologically resemble dendritic cell proliferations of the LCH-type
but lack Birbeck granules have been called "Indeterminate cell" lesions . Sampling error is an
important issue in this diagnosis that rests on the absence of an ultrastructural finding. Better
phenotyping will place these lesions more firmly in the spectrum of dendritic cell lesions as illustrated
in the Figure.
Interdigitating Dendritic Cell Tumor/Sarcoma 
As can be seen from the Figure, lesions of this kind have the morphologic and phenotypic features of
the mature interdigitating paracortical dendritic cell. The IDC cells are Vimentin+, S100+, fascin-high,
CD68+ in some, LCA-, CD1a low to absent, Langerin-, Factor XIIIa-. Ultrastructure generally reveals
interdigitating dendritic cell features-with complex cellular junctions but without the desmosomes seen
in follicular dendritic cells.
Interdigitating cell sarcomas are generally spindle cell or oval cell lesions with a cytoplasm-rich
"histiocytic" appearance and cytologic pleomorphism
Fibroblastic Reticulum Cells and Cytokeratin-Positive Interstitial Reticulum
Cells of lymph nodes
There is no evidence that these unusual cells are related to the dendritic accessory cells, though
they may present a differential diagnostic challenge
particularly because of the variable
staining for S100, factor XIIIa, or CD68.
Dendritic Cell Lesions and Macrophages
Inter-relationships between dendritic cells and macrophages are complex. That they can be modulated
between one and the other phenotype has already been described, but the cytokines and other molecules
that regulate their behavior are commonly produced by one or the other. Dendritic cells and macrophages
can also respond in their own manner to stimuli produced by cells such as regulatory T cells. The
macrophage activation syndrome is a systemic manifestation of generalized macrophage reactivity to
stimuli such as TNFα or IFNγ often in association with NK or T cell dysfunction. Macrophage
activation of varying severity can be seen in association dendritic cell lesions, most commonly the
multifocal forms of LCH or JXG .
Some of the manifestations of macrophage activation lead to diagnostic confusion in children with
dendritic cell disorders. In LCH, macrophage activation can cause hepatomegaly and hypoalbuminemia, both
of which may be transient and do not lead to the severe, long-term effects of true LCH involvement of the
liver. The diagnosis of lymph node and splenic involvement with LCH can be confounded by the
simultaneous presence of a macrophage activation syndrome. Bone marrow can be substantially altered by
macrophage activation, most notably by the increased number and activity of the macrophages with
hemophagocytosis, stromal edema and, in the most severe form, marrow suppression with pancytopenia .
It is likely that some of the mortality in children with multisystem LCH is due to an associated
hemophagocytic syndrome. Interestingly, treatment of a child with etanercept, a TNFα inhibitory
agent, not only abrogated features that could be ascribed to a hemophagocytic syndrome, but also led to
signs of healing in the LCH bone lesions .
Diagnosis of LCH involvement in the marrow is unequivocal when there are clusters of oval CD1a+ LCH
cells. Macrophage activation can obscure LCH involvement and that is compounded by marrow changes after
systemic treatment that leads to an increase in the number of marrow macrophages. It is not known
whether LCH cells can "mature" in the marrow in the same manner as they do in lymph nodes, losing
CD1a-positivity in the process, and hence our ability to recognize them.
Insights into normal dendritic cell biology have given us some tentative thoughts on the place of the
histiocytoses in this scheme. A spectrum of clinical behavior from benign, though unpredictable, to
frank sarcoma is noted for cells at various points of dendritic cell development. At present the debate
continues as to whether the histiocytoses, like LCH, are truly neoplastic or reflect deranged local
The Marjorie Harmer Pediatric Pathology Endowment of the Children's Hospital of Pittsburgh supports
work on the hIstiocytic disorders of childhood.
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