Updates on histiocytic disorders

Pediatr Blood Cancer 2014;61:1329–1335
MEETING REPORT
Updates on Histiocytic Disorders
Sarah R. Vaiselbuh,
MD,
1 y
* Yenan T. Bryceson, PhD, MS,2z Carl E. Allen,
and Oussama Abla, MD4§
Histiocytic disorders are rare entities that are becoming more
recognized as our understanding of the molecular pathogenesis lead
to novel diagnostic tests and targeted drug development. A
symposium held at the American Society of Pediatric Hematology/
Oncology (ASPHO) 2013 Annual Meeting discussed new insights
into histiocytic disorders. This review highlights the symposium
presentations, divided into three sections encompassing Langerhans
cell histiocytosis (LCH), hemophagocytic lymphohistiocytosis (HLH)
Key words:
James A. Whitlock,
MD,
4,5§
and Rosai Dorfman disease (RDD) including subsections on
pathogenesis, clinical diagnostic criteria and novel insights into
treatment. Details of other histiocytic disorders as well as the
standard treatment guidelines have been published elsewhere and
are beyond the scope of this discussion [Haupt et al. (2013). Pediatr
Blood Cancer 60:175–184; Henter et al. (2007). Pediatr Blood
Cancer 2014;61:1329–1335. # 2014 Wiley Periodicals, Inc.
hemophagocytic lymphohistiocytosis; Langerhans cell histiocytosis; Rosai Dorfman disease; targeted therapies
INTRODUCTION
Histiocytoses describe a diverse group of proliferative disorders
involving dentritic cells and macrophages. They include a spectrum
of diseases including a reactive inflammatory accumulation of cells,
pathologic immune activation, or neoplastic clonal proliferation.
Advanced molecular technologies are resulting in new breakthroughs in understanding the pathophysiology of histiocytic
disorders that are changing the field. The purpose of this update
report is to aid in understanding the subtle differences in
pathogenesis of three most common histiocytic disorders—
Langerhans cell histiocytosis (LCH), hemophagocytic lymphohistiocytosis (HLH), and Rosai Dorfman disease (RDD) and how new
insights lead to the hope for novel therapeutics (Table I).
LANGERHANS CELL HISTIOCYTOSIS (LCH)
Pathogenesis
“Langerhans” in LCH refers to Dr. Paul Langerhans (1847–
1888) who first described normal epidermal dendritic cells (DCs)
that later were recognized as having some similarity to LCH-lesion
DCs, though he initially thought those cells were neuronal cells due
to their notable dentritic processes. However, despite epidermal
DCs having phenotypic features of cutaneous Langerhans cells
(LCs), data comparing transcriptomes of purified epidermal LCs to
CD207þ cells in LCH lesions found relatively distinct gene
expression profiles, with the LCH CD207þ cells having increased
expression of genes associated with immature myeloid precursors [1]. Studies of mouse and human DCs also suggest that
langerin/CD207 expression is not limited to epidermal LCs, but
occurs in many lineages at different anatomic sites [2–4].
Therefore, it is possible that LCH may have an origin distinct
from the epidermal LC.
The pathogenesis of LCH remains unresolved. Clonality of LCH
was described many years ago [5,6]. Although a key feature of a
neoplasm is its clonal derivation from a single cell, clonality does
not necessarily mean malignancy. Willman et al. [7] defined the
clonal cells in LCH as CD1aþ dentritic cells. Advances in DNA
sequencing technology enabled sensitive screening of CD1aþ cells
purified from LCH lesions, and it was discovered that BRAF-V600E
point mutations were present in the majority of LCH lesions with a
C
3#
MD, PhD,
2014 Wiley Periodicals, Inc.
DOI 10.1002/pbc.25017
Published online 9 March 2014 in Wiley Online Library
(wileyonlinelibrary.com).
frequency ranging from 38% to 57% [8–12]. A novel somatic
mutation in BRAF and germline variants of (T599A) BRAF have
also been described in patients with LCH, though the significance of
these observations remains to be defined [10–12]. The frequency of
the somatic BRAF-V600E mutation implies functional significance
in LCH pathogenesis, but no clinical correlations with BRAF
genotype have been established. BRAF is an intermediate kinase in
the RAS-RAF-MEK-ERK pathway that transduces extracellular
signals to the nucleus. Phosphorylation of BRAF induces activation
of downstream extracellular signal-regulated kinase (ERK) [8]. The
V600E mutation renders BRAF constitutively active, impacting
several cell functions including cell proliferation and migration.
BRAF activation is insufficient to fully transform cells, as BRAFV600E has been identified in not only malignancies, including
melanoma, papillary thyroid carcinoma, and gliomas, but also in
skin nevi and colon polyps [13–15].
Malignant transformation versus immune dysregulation has
been a major focus of LCH research for the past 40 years, with
supporting data for both mechanisms. While molecular mechanisms are being further explored, many studies have investigated
inflammation within the LCH lesion. In addition to the pathologic
LCs, LCH lesions are characterized by an inflammatory infiltrate
typically including macrophages, eosinophils and lymphocytes
1
Children’s Cancer Center, Staten Island University Hospital, Staten
Island, New York; 2Center for Infectious Medicine, Karolinska
Institute, Stockholm, Sweden; 3Department of Pediatrics, Baylor
College of Medicine, Texas Children’s Cancer Center, Houston, Texas;
4
Garron Family Cancer Center, The Hospital for Sick Children,
Ontario, Toronto, Canada; 5Department of Hematology/Oncology, The
Hospital for Sick Children, Ontario, Toronto, Canada
†
Director, Children’s Cancer Center.
‡
Assistant Professor.
#
Professor of Pediatrics, Division Head, Director.
§
Associate Professor.
Correspondence to: Sarah R. Vaiselbuh, Department of Pediatrics,
Staten Island University Hospital, 256C Mason Ave., Staten Island, NY
10305. E-mail: [email protected]
Received 3 September 2013; Accepted 10 February 2014
1330
Vaiselbuh et al.
TABLE I. Classification of Three Most Common Histiocytic Disorders
Histiocytic disorder
Cell type
Reported mutations
Langerhans cell histiocytosis (LCH)
Dentritic cells
Yes (50–57%)
BRAF-V600E
Hemophagocytic lymphohistiocytosis (HLH)
Macrophages
CD8þ T-lymphocytes
Natural killer-cells
Rosai Dorfman disease (RDD)
Macrophages
PRF1
UNC13D
STX11
STXBP2
No
with enrichment of regulatory CD4þCD25þT cells [16]. The
lesion-LCs express high levels of T-cell stimulatory molecules as
well as pro-inflammatory cytokines. In addition to the intralesional
cytokine storm, increased serum levels of pro-inflammatory cytokines and chemokines are documented in active LCH [1,16–18].
Pathogenesis that defines disease subclasses of LCH needs further
elucidation. A specific role for lL17A and its receptor in LCH
pathogenesis has been reported, though IL17A expression by LCH
lesion DCs remains to be validated [19,20].
Diagnosis
LCH, the most common histiocytic disorder in humans, is
estimated to occur in approximately five children per million, but
may arise de novo in adults [21]. No screening tests are available
and the diagnosis is often delayed. While the range of presentations
can make LCH a challenging disease to diagnose, tissue biopsy
is diagnostic with pathologic CD207þ and/or CD1aþ DCs in a
background of inflammatory cells. Clinically, symptoms of LCH
depend on the organs involved. Pulmonary LCH might present with
dyspnea and cough, or chest pain, and shortness of breath in the case
of pneumothorax. Bone lesions may lead to bone pain, abnormal
swelling, or pathological fracture. Skin LCH can occur as a
dermatitis rash with vesicles and bullae (more in infancy). Often
there is a past history of unresolved seborrheic eczema and oozing
of the external ear canal. Pituitary involvement with onset of
diabetes insipidus will cause increased thirst and polyuria. Fatigue,
weight loss and low-grade fevers are signs of the general
inflammatory condition that often occurs with LCH. The clinical
course of LCH is highly variable from self-healing without therapy
to potentially lethal multi-system disease [22].
Clinical stratification for LCH is based on the extent of organ
systems involved, localization and organ dysfunction: single system
LCH (SS-LCH) with one organ/system involved (uni- or multifocal) and multisystem LCH (MS-LCH) with two or more organs/
systems involved, with or without involvement of “Risk Organs.”
Risk organs in LCH include liver, spleen, and bone marrow. The
lung has been considered for many decades a risk organ, but clinical
data do not support a prognostic implication. Isolated pulmonary
LCH can be seen in children but more often in adults, in strong
correlation with smoking. LCH is also classified based on the site of
initial presentation. Vertebral lesions with intraspinal growth or
craniofacial lesions are classified as “special site” lesions and
Pediatr Blood Cancer DOI 10.1002/pbc
Molecular markers
CD207þþ
CD1aþþ
S100þþ
CD163þþþ
S100þ/
CD1a
CD14þ, HLA-DRþ
CD68þþ, CD163þ
S100þ, fascinþ
CD1a
CD207
warrant systemic treatment even as single lesions. Neurodegenerative LCH seems to be a separate entity with a clinical presentation of
symptoms of dysarthria, ataxia, and cognitive defects resembling
multiple sclerosis.
Treatment
Due to incomplete understanding of the pathogenesis of LCH,
treatment has relied on empiric strategies. Outcomes have improved
over the past decades despite few changes in the treatment
backbone, possibly due to improved supportive care. In the most
recent Histiocyte Society trial, LCH-III, patients with “Low-Risk”
LCH had nearly 100% overall survival, while patients with “HighRisk” LCH had 84% 5-year overall survival [23]. Other important
factors are the repetition of induction phase of therapy for all
patients who did not achieve a very good response after the first
6 weeks of induction, and an early move to salvage therapy for poor
responders who have a very high mortality otherwise. In all patients
with LCH, optimizing therapy remains a challenge since
approximately one-half of all patients with MS-LCH still have
refractory/recurrent disease when treated with vinblastine/prednisone-based strategies [23,24], in contrast to single system disease,
which has a lower reactivation rate. Disease- and treatment-related
long-term effects are also problematic, and are more common in
patients with disease recurrence. While modifications in dose,
duration and timing of chemotherapy along with improved
supportive care may continue to achieve incremental improvements
in outcomes for patients with LCH, an optimized therapeutic
approach requires understanding of disease pathogenesis.
Novel Therapeutics in LCH
BRAF targeted therapy has changed the treatment paradigm in
refractory melanoma [25]. Two class I BRAF-inhibitors, vemurafenib and dabrafenib, are orally available and now FDA-approved
for use in advanced BRAF-V600Eþ-melanoma [26,27]. In a phase 3
randomized clinical trial comparing vemurafenib with dacarbazine
in patients with BRAF-V600þ-metastatic melanoma, vemurafenib
produced improved rates of overall and progression-free survival [28]. Non-specific side effects were reported, but the most
worrisome is the development cutanous toxicities like squamous
cell carcinoma in up to 30% of patients, usual well-differentiated
and easily resectable, but also de novo malignant melanoma, rare
but serious [29].
Histiocytic Disorders Review
The clinical potential of BRAF inhibition in patients with LCH
was revealed when two patients with Erdheim Chester disease
(ECD) and biopsy proven BRAF-V600Eþ-LCH lesions (one in
skin, one in lymphnode) showed significant response to vemurafenib after 1 month [30]. Although these data are promising,
validation is necessary with well-designed clinical multicenter
studies. A multicenter Phase I/IIa pediatric trial for patients with
BRAF-V600þ-gliomas, LCH and papillary thyroid carcinoma is
currently open for recruitment in Europe, US and Canada
(clinicaltrials.gov NCT01677741) (Table II). At the Histiocyte
Society meeting 2013, data were presented of a single-arm open
label trial to evaluate the efficacy and safety of afuresertib, an oral
pan-AKT inhibitor in adult and adolescents with relapsed/refractory
LCH. Although 29% patients were reported as better at the 3 and/or
6 months disease assessment, afuresertib did not meet goals for
disease responses of this study.
Progressive MS-LCH (non-risk organ) has been successfully
treated with 2-chlorodeoxyadenosine (2CdA or cladribine) monotherapy [31]. A nucleoside analogue like cladribine is often
recommended as frontline therapy in adult LCH [32]. Adult LCH
with bone lesions only might benefit from cytarabine (Ara-C)
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monotherapy [33]. Progressive MS-LCH with bone marrow
involvement can be brought into remission with reduced intensity
bone marrow transplantation [22]. Alternatively, good responses
in refractory LCH have been obtained by salvage therapy of
clofarabine [34,35]. In addition, the combination of 2CdA and
Ara-C, although very immunosuppressive, shows promise as a
salvage approach in patients with refractory LCH [32] (Table II).
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS
(HLH)
Pathogenesis
The histiological signature of HLH is accumulation of
histiocytes in tissues, such as activated macrophages that engulf
erythrocytes (hemophagocytosis) and activated cytotoxic Tlymphocytes (hence lymphohistiocytosis). Different forms of
HLH can be distinguished [36] (Table III). Primary (familial)
HLH, a familial form of this hyperimmune state, with persistent
fever, cytopenias, hepatosplenomegaly, and hemophagocytosis
as cardinal symptoms, was first described by Farquhar and
TABLE II. Newer Therapeutic Options in Histiocytic Disorders
Histiocytic disorder
Langerhans cell histiocytosis (LCH)
Hemophagocytic lymphohistiocytosis (HLH)
Rosai Dorfman disease (RDD)
Name
Clinical
Vemurafenib
Cladribine
Clofarabine
Cytarabine
HLH-94 protocol
Reduced intensity conditioning
ATGþetoposide/dexa (hybrid immunotherapy)
Rituximab
Alemtuzumab
Tocilizumab (anti-IFN monoclonal antibody)
Imatinib
Cladribine
Clofarabine
Rituximab
Azathiopine
Evaluation in process (NCT01677741)
Salvage therapy
Salvage therapy
Salvage therapy
Standard of care
HSCT
Evaluation in process (NCT01104025)
EBV-associated HLH
Refractory disease
Evaluation in process (NCT02007239)
Validation needed
Refractory disease
Refractory disease
Validation needed
Validation needed
TABLE III. Genes Associated With Primary HLH
Protein
Required for
lymphocyte
cytotoxicity
Required for
lymphocyte
degranulation
Partial
albinism
Gene
Syndrome
Inheritance
PRF1
FHL2
AR
Perforin
Yes
No
No
UNC13D
STX11
STXBP2
RAB27A
LYST
SH2D1A
FHL3
FHL4
FHL5
GS2
CHS1
XLP1
AR
AR
AR
AR
AR
XL
Munc13-4
Syntaxin-11
Munc18-2
RAB27A
LYST
SAP
Yes
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes
No
No
No
No
Yes
Yes
No
XIAP
XLP2
XL
XIAP
No
No
No
Diagnostic cellular assay
Intracellular perforin expression in cytotoxic
lymphocyte subsetsa
Degranulation by cytotoxic lymphocyte subsets
Degranulation by cytotoxic lymphocyte subsets
Degranulation by cytotoxic lymphocyte subsets
Degranulation by cytotoxic lymphocyte subsets
Degranulation by cytotoxic lymphocyte subsets
Intracellular SAP expression in T cells
or NK cellsa
Intracellular XIAP expression in lymphocytesa
FHL, familial hemophagocytic lymphohistiocytosis; GS, Griscelli syndrome; CHS, Chediak–Higashi syndrome; XLP, X-linked lymphoproliferative disease; AR, autosomal recessive; XL, X-linked. aCellular assays may fail to diagnose disease caused by coding mutations that impair protein
function without affecting protein expression.
Pediatr Blood Cancer DOI 10.1002/pbc
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Vaiselbuh et al.
Claireaux [36–38]. Primary HLH, in which genetic mutations in
HLH-associated genes are identified, usually has an early onset
triggered by infection. Primary HLH may also be diagnosed in adult
patients [39]. Secondary (acquired) HLH often presents later in life.
In the absence of a genetic cause or familial inheritance, secondary
HLH occurs in response to viral infections or autoimmunity,
leishmaniasis, malignancies (particularly lymphoma), as well as
metabolic disorders and acquired immunodeficiencies. Macrophage activation syndrome (MAS) is a potentially fatal complication of rheumatic diseases that bears close resemblance to HLH
[40].
Many cases of primary HLH are now known to be caused by
defects in target cell killing by cytotoxic lymphocytes (CTL). The
major subsets of CTL in peripheral blood are CD8þ T-cells and
natural killer (NK) cells. CTL can eliminate virus-infected and
transformed cells through direct release of cytotoxic granules that
contain perforin and granzymes capable of inducing targeted cell
death [41]. CTL also contribute to immune homeostasis through
killing autologous, activated immune cells, thereby limiting the
magnitude of immune responses. Mutations in the genes encoding
perforin as well as other proteins required for cytotoxic granule
trafficking and release have been associated with HLH. Upon
immunological challenge, an inability of CTL to clear pathogens
and control immune responses can result in a massive immune
activation with excessive production of proinflammatory cytokines
and influx of responding activated macrophages, manifesting as
systemic inflammation with the classic immunopathology of HLH.
Thus, current HLH research, focused on how defects of CTL are
related to human diseases, has defined HLH as an immunodeficiency disorder [42].
Diagnosis
HLH is characterized by a sepsis-like systemic inflammation.
The presence of five out of eight established diagnostic criteria,
confirms the diagnosis of HLH (fever, splenomegaly, cytopenias
(2 cell lineages), hypertriglyceridemia/hypofibrinogenemia, hemophagocytosis, low or absent NK activity, high ferritin (>500 mg/
ml) and sCD25 > 2,400 U/ml) [43]. Altered consciousness might
indicate central nervous system involvement [44]. Organ-infiltrating macrophages (CD163þþþ/S100þ/, Cd1a) involved in
hemophagocytosis as well as organ-infiltrating CD8þ T-cell
expansions are often present. Of note, hemophagocytosis typically
manifests late in the course of the disease. Thus, a failure to detect
hemophagocytosis does not negate a diagnosis of HLH. Hypercytokinemia, with high systemic levels of IL-6, IFN-g, and TNF, is
also a hallmark of HLH [45]. Upon clinical diagnosis of HLH, it is
imperative that patients are rapidly evaluated for the possibility of
primary HLH, as this may determine the need for performing
hematopoietic stem cell transplantation (HSCT). Two complimentary approaches, genetic, and cellular, can be taken to confirm a
diagnosis of primary HLH. Loss-of-function mutations in several
genes have been associated with HLH (Table III). Autosomal
recessive mutations in PRF1, encoding perforin, are linked to
familial HLH type 2 (FHL2) [46]. Milder missense mutations in
PRF1 may not cause HLH, but are associated with hematologic
malignancies later in life. Autosomal recessive mutations in
UNC13D, STX11, and STXBP2 are associated with FHL3, FHL4,
and FHL5, respectively [42]. These genes encode the Munc13-4,
syntaxin-11, and Munc18-2 proteins, which regulate critical steps
Pediatr Blood Cancer DOI 10.1002/pbc
in lytic perforin/granzym granule exocytosis pathway. Mutations in
other genes, some of which cause also partial albinism, are also
associated with HLH. Because genetic approaches typically are
limited to sequencing of the coding regions and splice-sites of HLH
associated genes, mutations in non-coding regulatory sequences or
genetic aberrations such as inversions or deletions may not be
detected [47]. Importantly, cellular assays can provide rapid results
to the clinician and can uncover defects missed by conventional
genetic analysis. Assays measuring 51Cr-release by K562 target
cells sensitive to NK cell-mediated lysis have represented the gold
standard for assessment of CTL function and still constitute one
component of the clinical diagnostic criteria for HLH. However,
this assay cannot distinguish between an absence of NK cells or a
defect in NK cell function and thus does not discriminate between
primary and secondary forms of HLH. More recently, sensitive flow
cytometric assays for assessment of NK cell intracellular perforin
content as well as surface expression of CD107a in response to
K562 target cells, the latter representing a measure of NK cell
degranulation, have demonstrated efficacy for identification of
patients with primary HLH [48]. In a prospective study by a panEuropean consortium, assessment of NK cell degranulation
provided 96% sensitivity and 88% specificity for a primary
degranulation disorder in the perforin/granzyme pathway [48].
Elevated granzyme B in CTL and NK cells also represent a general
signature of immune activation, and is elevated in HLH [49].
Improved diagnostic early screening tests are under development. A
modified assay that provides robust quantification of cytotoxic Tcell degranulation may complement existing assays of NK-cell
degranulation and further improve functional diagnostics [50].
Combining cellular phenotypical and functional assessments with
genetic analyses of patients with HLH promises to provide a better
view of how genetic mutations or variations perturb cellular
function and predispose to disease. Future studies may uncover
additional genes associated with HLH and provide greater
understanding of cases hitherto defined as patients with secondary
HLH.
Treatment
The basis of HLH therapy is intensive immunosuppression
(including corticosteroids, etoposide, cyclosporin, intravenous
immunoglobulin, and infliximab) and standard treatment guidelines
are available in excellent reviews [51]. The HLH 94 and HLH 2004
protocols represent consensus protocols developed by the Histiocyte Society and have helped in formalizing a more standard
approach for treatment of HLH [43,52]. Still, therapy is
complicated by high treatment-related morbidity and early disease
recurrence. Because the risks and benefits of the addition of
cyclosporine to induction is not yet established (HLH 2004), the
HLH-94 study should be considered standard of care for all patients
not enrolled in clinical trials [52]. In HLH-94, cyclosporine was
introduced at the beginning of continuation therapy, while in HLH2004 cyclosporine administration began during induction therapy in
an effort to improve remission rates. In primary HLH the 8-week
induction is used as a bridge to allogeneic hematopoietic stem cell
transplant (HSCT), the only curative treatment available. Transplant-related morbidity in HLH has been reduced significantly with
reduced intensity conditioning for HSCT [53]. Antithymocyte
globulin (ATG) based immunotherapy of familial HLH, in
combination with corticosteroids, cyclosporine A, and intrathecal
Histiocytic Disorders Review
injections of methotrexate, is effective as a first treatment with a
73% rapid and complete response in a single center study. When
HSCT was performed early after complete or partial response
induction with ATG in primary HLH, it led to a high rate of cure in
the same study [54]. Hybrid immunotherapy, combining ATG,
dexamethasone, and etoposide is currently in clinical trial
(clinicaltrials.gov NCT01104025) (Table II).
Newer Therapeutic Options in HLH
In regards to new therapeutic options, when combined with
conventional HLH therapies, the anti-CD20 monoclonal antibody,
rituximab, improves symptoms, reduces viral load, and diminishes
inflammation in patients with EBV-induced HLH if the EBV is
proliferating within the B-cell [55]. However, rituximab is of no
value in cases with EBV-associated HLH where EBV proliferates in
T-cells instead of B-lymphocytes, as shown in Japan [56].
Furthermore, a case report remission in primary HLH was achieved
by treatment with the anti-CD52 monoclonal antibody, alemtuzumab, as a bridge to HSCT [57,58]. Alemtuzumab appears to be an
effective salvage agent for refractory HLH with 64% partial
response rate in a single institution study, leading to survival to
undergo HSCT [53,58]. However, commentaries suggested that
alemtuzumab therapy may aid development of HLH in certain
settings, possibly through elimination of CTL that usually
contribute to the maintenance of immune homeostasis [59].
Thus, the efficacy of anti-CD52 monoclonal antibody therapy is
not clear. Finally, anti-IFN-g monoclonal antibody therapy has
demonstrated efficacy in mouse models of HLH and a clinical trial
is currently under way (NCT01818492) [60].
ROSAI DORFMAN DISEASE (RDD)
Pathogenesis
The non-Langerhans cell (non-LCH) histiocytoses are a group
of disorders defined by the accumulation of histiocytes that do not
meet the phenotypic criteria for the diagnosis of LCs [61]. Systemic
non-LCH include juvenile xanthogramuloma (JXG), ECD, and
RDD. The non-LCH are thought to arise from either a DC or a
macrophage cell line, and can be divided clinically into three major
groups—those that primarily affect the skin such as the JXG family
and reticulohistiocytoma, those that affect the skin but have a major
systemic component such as xanthoma disseminatum and multicentric reticulohistiocytosis, and those that predominantly involve
systemic sites, although skin may also be affected, such as systemic
JXG, ECD, and sinus histiocytosis with massive lymphadenopathy
or RDD.
Initially described by Rosai & Dorfman in 1969, RDD is a nonneoplastic, polyclonal, and self-limited non-LCH. RDD cells are
CD14þ, HLA-DRþ, CD68þþ, CD163þ, S100þ, and fascinþ
macrophages, and they are typically negative for CD1a and
langerin [62]. Histologically, RDD lymph nodes show massive
sinus infiltration of large histiocytes mixed with lymphocytes and
plasma cells. The presence of emperipolesis, or the engulfment of
intact erythrocytes, lymphocytes and plasma cells by S100þ
histiocytes, in the appropriate clinical setting is considered
diagnostic but not unique of RDD [63]. RDD lesions have a
moderate expression of IL-6, which could be related to the
associated polyclonal plasmacytosis and hypergammaglobulinemia. Furthermore, the lesions tend to express strongly IL-1b and
Pediatr Blood Cancer DOI 10.1002/pbc
1333
TNF-a. Systemic symptoms in RDD may be related to enhanced
production of these cytokines [64]. A cytokine-mediated migration
of monocytes could be involved in histiocytes accumulation
and activation. This functional activation can be triggered by
hematological malignancies or autoimmune diseases. Indeed, RDD
has been reported following bone marrow transplant for precursorB acute lymphoblastic leukemia [65], and concurrently or after
Hodgkin and non-Hodgkin lymphoma [66]. Similarly, an increased
incidence of autoimmune hemolytic anemia, systemic lupus
erythematosus and juvenile idiopathic arthritis has been documented with RDD [67,68]. Histopathological features of RDD were
recently identified in the lymph nodes of 18/44 (41%) patients with
autoimmune lymphoproliferative syndrome (ALPS) type Ia, with
TNFRSF6 heterozygous germline mutations affecting the gene
encoding Fas, that might classify some of the RDD as an
autoimmune disorder [69]. Patients with ALPS type Ia and RDD
tend to have more severe manifestations of ALPS, present at an
earlier age and are more often males. However, the RDD changes
tend to be mainly nodal and self-limited in these cases and only in
a small number of patients contribute significantly to the clinical
manifestations of ALPS. The transformation of RDD to a
histiocytic sarcoma has been reported in a child with ALPS type
Ia [70]. Given the central role of defective Fas signaling in ALPS,
histiocytes could be another lineage at risk for neoplastic
transformation secondary to an apoptotic block.
Diagnosis
The most common presentation of RDD is bilateral painless
massive cervical lymphadenopathy associated with fever, night
sweats, fatigue, and weight loss. Mediastinal, inguinal, and
retroperitoneal nodes may also be involved. Extranodal involvement by RDD has been documented in 43% of cases with the most
frequent sites being skin, soft tissue, upper respiratory tract,
multifocal bone, eye, and retro-orbital tissue [71]. Other reported
sites include urogenital tract, breast, gastrointestinal tract, liver,
pancreas, and lungs. Head and neck involvement has been reported
in 22% of cases, most commonly the nasal cavity followed by the
parotid gland [72]. Intracranial RDD usually occurs without
extracranial lymphadenopathy, and most intracranial lesions are
attached to the dura with only few extending into the parenchyma.
Central nervous system disease can present clinically and
radiologically as meningioma, but the presence of emperipolesis
in the spinal fluid is usually diagnostic of Rosai–Dorfman
disease [73,74]. RDD cases presenting with kidney, thyroid,
isolated mediastinal, and unifocal skeletal involvement have also
been reported [75–78]. Laboratory abnormalities are non-specific
with elevated sediment rate and leucocytosis, high ferritin,
hypergammaglobulinemia, and autoimmune hemolytic anemia.
Treatment
Since results with chemotherapy for RDD have not been
encouraging, the use of chemotherapy is restricted to patients with
life-threatening disease or multiple relapses. Successful targeted
therapy with platelet-derived growth factor-receptor b (PDGFRB)inhibitors such as imatinib in a recent case report, might suggest a
role for PDGFRB and KIT in the pathogenesis of RDD [79]. Newer
cytotoxic agents such as cladribine (2-chlorodeoxyadenosine) and
clofarabine, have been found to be effective in recurrent, refractory
1334
Vaiselbuh et al.
or severe cases of RDD [80]. Furthermore, the efficacy of the antiCD20 monoclonal antibody rituximab has been described in one
case [81]. Refractory cerebral disease has been successfully treated
with azathioprine in one patient [82] (Table II). The clinical course
of RDD can be unpredictable with episodes of remission and
exacerbation that may last for many years. The outcome is generally
good and the disease is usually self-limited, however, approximately 5–11% of patients die from disease. Patients with combined
immunologic abnormalities have a less favorable outcome and
higher fatality rate. In summary, due to the rarity of RDD and other
non-LCH disorders, prospective treatment studies can be a
challenge to conduct. Biology studies for RDD are urgently
warranted, and will be essential for discovering more effective
targeted therapies.
CONCLUSIONS
New breakthroughs in understanding the pathophysiology of
histiocytic disorders are changing the field and giving hope for
newer therapeutic approaches. Consortium clinical trials with
targeted therapies should help to advance the management of these
unique histiocytic disorders.
ACKNOWLEDGMENTS
This work was supported in part by the Women’s Auxiliary
Millennium Chair in Haematology/Oncology (J.W.).
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