Special Report

Consensus recommendations for the diagnosis and clinical

management of Rosai-Dorfman-Destombes disease
Oussama Abla,1 Eric Jacobsen,2 Jennifer Picarsic,3 Zdenka Krenova,4,5 Ronald Jaffe,6 Jean-Francois Emile,7,8 Benjamin H. Durham,9
Jorge Braier,10 Frédéric Charlotte,11,12 Jean Donadieu,13 Fleur Cohen-Aubart,12,14 Carlos Rodriguez-Galindo,15 Carl Allen,16-18
James A. Whitlock,1 Sheila Weitzman,1 Kenneth L. McClain,16,* Julien Haroche,12,14,* and Eli L. Diamond19,20,*
1
Division of Haematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, Toronto, ON, Canada; 2Dana-Farber Cancer Institute, Boston, MA;
3
Department of Pathology, Children’s Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA; 4Pediatric Oncology Clinic,

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Faculty of Medicine, Masaryk University, Brno, Czech Republic; 5Department of Pathology, University Hospital, Brno, Czech Republic; 6Department of Pathology,
Magee Women’s Hospital of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA; 7Pathology Department, Ambroise Paré Hospital, Assistance
Publique–Hôpitaux de Paris (AP-HP), Boulogne, France; 8Research Unit EA4340, Versailles SQY University, Paris-Saclay University, Boulogne, France; 9Department
of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY; 10Department of Hematology, Oncology, Hospital de Pediatrı́a JP Garrahan, Buenos Aires,
Argentina; 11Department of Pathology, Pitié-Salpêtrière Hospital, AP-HP, Paris, France; 12Department of Internal Medicine, Paris VI University, Université Pierre et
Marie Curie, Sorbonne Universités, Paris, France; 13Department of Haematology, AP-HP, Trousseau Hospital, Paris, France; 14Department of Internal Medicine 2,
French National Centre for Rare Systemic Diseases, Pitié-Salpêtrière Hospital, AP-HP, Paris, France; 15St. Jude Children’s Research Hospital, Memphis, TN;
16
Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX; 17Texas Children’s Cancer Center, Texas Children’s
Hospital, Houston, TX; 18Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX; 19Department of Neurology,
Memorial Sloan Kettering Cancer Center, New York, NY; and 20Department of Neurology, Weill Cornell Medical College, New York, NY

Rosai-Dorfman-Destombes disease (RDD) is a rare non–
Langerhans cell histiocytosis characterized by accumu-
lation of activated histiocytes within affected tissues.
RDD, which now belongs to the R group of the 2016
revised histiocytosis classification, is a widely heteroge-
neous entity with a range of clinical phenotypes occurring
in isolation or in association with autoimmune or malig-
nant diseases. Recent studies have found NRAS, KRAS,
MAP2K1, and ARAF mutations in lesional tissues, raising
the possibility of a clonal origin in some forms of RDD.
More than 1000 reports have been published in the
English literature; however, there is a lack of consensus
regarding approach for the clinical management of RDD.
Although in most cases RDD can be observed or treated
with local therapies, some patients with refractory or
multifocal disease experience morbidity and mortality.
Here we provide the first consensus multidisciplinary
recommendations for the diagnosis and management
of RDD. These recommendations were discussed at the
32nd Histiocyte Society Meeting by an international
group of academic clinicians and pathologists with ex-
pertise in RDD. We include guidelines for clinical, labora-
tory, pathologic, and radiographic evaluation of patients
with RDD together with treatment recommendations
based on clinical experience and review of the literature.
(Blood. 2018;131(26):2877-2890)

Introduction need for an evidence-based approach to the evaluation and

Rosai-Dorfman-Destombes disease (RDD) is a rare non–Langerhans
cell histiocytosis (LCH) first described in 1965 by a French pa-
thologist, Pierre Paul Louis Lucien Destombes, who reported
4 children and young adults with lymphadenopathy and sinus his-
tiocytosis upon histologic analysis.1 Four years later, Juan Rosai and
Ronald Dorfman analyzed 34 cases of the same entity under the
name sinus histiocytosis with massive lymphadenopathy.2 Char-
acteristic lesional histiocytes are S1001, CD681, and CD1a2 and
demonstrate variable frequency of emperipolesis. Historically, RDD
has been considered a self-limited disorder of unknown etiology,
although few patients have poor outcomes.3 Patients with classical
RDD present with bilateral cervical lymphadenopathy, but 43% of
patients with RDD present with extranodal disease.3 RDD is a
heterogeneous entity that can occur as an isolated disorder or in
association with autoimmune, hereditary, and malignant diseases.
Because of the wide clinical spectrum of RDD and the consequent
variety of specialists evaluating and treating such patients, there is a
treatment of this protean condition.
Methods
An English-language search of PubMed was conducted for RDD-
related literature from 1965 until the present. Recommendations
were derived from a review of the literature and extensive
collective clinical experience and deliberation among experts.
A group of pathologists, pediatric and adult oncologists, he-
matologists, and internists, all with extensive (up to 30 years)
experience in the treatment of histiocytic disorders, collaborated
to establish these recommendations. The 4 pathologists in this
group have collectively diagnosed .300 RDD cases. The rec-
ommendations proposed here were discussed and approved
by the Rare Histiocytoses Steering Committee and Working
Group of the Histiocyte Society during its 32nd Annual Meeting
in Dublin, Ireland, on 16 October 2016 by members of the

© 2018 by The American Society of Hematology blood® 28 JUNE 2018 | VOLUME 131, NUMBER 26 2877
 A B A146T
A146V
G12D Q22K K117N
Rosai-Dorfman Disease (RDD)
ARAF

Domain 2

Domain 3

Domain 4
Effective
Domain
Binding

Binding

Binding

Binding

Binding
P-Loop

GTP -

GTP -

GTP -

GTP -
Hypervariable Region

Site
SWI SWII

1
(HVR)
NRAS
KRAS

G13D

MAP2K1

Domain 2

Domain 3

Domain 4
Effective
Domain
Binding

Binding

Binding

Binding

Binding
P-Loop

GTP -

GTP -

GTP -

GTP -
Hypervariable Region

Site
SWI SWII

1
(HVR)

NRAS
Unknown/
KRAS Missense RDD
Unmutated

8D
C

G R
P1 V
3V

24
5

12
1
F5

L1

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Regulatory

Activiation
Negative

Segment
Catalytic
Binding
Nuclear

Binding
P-Loop
Export

Loop
Proline C - Terminal

ERK

ATP

Mg
Catalytic Care Catalytic Care
Rich Domains

MAP2K1

D N217K

Activiation
Segment
G-Loop
CR3

CRD
RBD

CR2
CR1
Kinase Domain

ARAF

Figure 1. Summary of the diverse kinase mutations documented in RDD. (A) Pie chart illustrating the known activating kinase mutations in RDD (N 5 34). (B) Diagrams of
somatic mutations described in KRAS and NRAS. (C) Diagram of somatic mutations uncovered in MAP2K1. (D) Diagram of somatic mutation discovered in ARAF.

North American Consortium for Histiocytosis, a collaborative net-
work of North American physicians studying and treating histiocytic
diseases, and by experts from the Euro-Histio-Net. Subsequently,
the authors refined these recommendations by an iterative and
collaborative process. The absence of large and/or prospective
studies in RDD renders the evidence here largely anecdotal, albeit
synthesized by experts, and therefore, a grading scheme for con-
sensus recommendations has not been proposed.
Epidemiology
RDD is a rare disease with a prevalence of 1:200 000 and an
estimated 100 new cases per year in the United States. 4 It is
more frequently seen in children and young adults (mean age,
20.6 years), although it has been reported up to age 74 years.
RDD is more common in males and in individuals of African de-
scent, with the cutaneous form more common in female Asians.5
Since the publication of the RDD registry (423 cases) by Foucar
et al3 in 1990, .1000 reports describing various aspects of this
disease have been published.
Pathogenesis
The etiology of RDD is not well defined and is likely not uniform
across the spectrum of phenotypes. Historically, clonality studies
suggested that lesional RDD cells were polyclonal, reactive, and
nonneoplastic.6 Studies have associated RDD with viral infec-
tions such as herpes viruses, Epstein-Barr virus, cytomegalovirus,
and HIV,7 although a clear link has not been proven. In light of
the finding of recurrent BRAF-V600E mutations in Erdheim-
Chester disease (ECD), another non-LCH, 23 RDD samples
were analyzed and found to be BRAF-V600E wild type.8 Simi-
larly, Chakraborty et al9 did not identify any somatic alterations
by whole-exome sequencing of 4 RDD cases. However, recent
studies identified NRAS, KRAS, MAP2K1, and ARAF mutations in
patients with features of RDD.10-14 Further research is needed to
investigate the cell of origin of neoplastic forms of RDD, as has
been done in ECD and LCH.15 Figure 1 and Table 1 present the
somatic mutations observed to date in RDD. Below, we outline
several RDD subtypes and their related phenotypes.
Associated diseases
Inherited conditions predisposing to RDD Germ line muta-
tions in SLC29A3 have been reported in patients with familial
RDD. The SLC29A3 disease spectrum includes familial or Fai-
salabad histiocytosis, H syndrome, and pigmented hypertrichotic
dermatosis with insulin-dependent diabetes, all described as
histiocytosis-lymphadenopathy plus syndrome (MIM602782).16
Heterozygous germ line mutations in the FAS gene TNFRSF,
which is responsible for autoimmune lymphoproliferative syn-
drome (ALPS) type I, may be associated with RDD. 17,18 These
patients have more aggressive manifestations of ALPS, male
predominance, and early age at onset, but the RDD-like changes
are usually self-limited.17
Neoplasia-associated RDD Histologic features of RDD have
been observed in patients with Hodgkin and non-Hodgkin
lymphomas, where lymphoma and RDD can either precede or
follow each other or occur in the same lymph node.19 The
disease was also reported after myelodysplastic syndrome20 or
bone marrow transplantation for acute leukemia,21 concurrent
with cutaneous clear-cell sarcoma22 and concurrent with or
following L-group histiocytoses or malignant histiocytoses. 23
Small foci of RDD-like histopathology (ie, histiocytes with

2878 blood® 28 JUNE 2018 | VOLUME 131, NUMBER 26 ABLA et al

Table 1. Summary of kinase mutations discovered in RDD

Gene Genetic alteration Amino acid variant Protein domain Discovery year Reference

ARAF Missense p.N217K CR2 domain 2016 10

MAP2K1 Missense p.F53V N-terminal negative regulatory 2017 13

MAP2K1 Missense p.L115V N-terminal catalytic core of kinase 2017 14

MAP2K1 Missense p.P124R N-terminal catalytic core of kinase 2017 13

MAP2K1 Missense p.G128D N-terminal catalytic core of kinase 2017 13

NRAS Missense p.G13D P-loop and GTP-binding 1 2016 10

KRAS Missense p.G12D P-loop and GTP-binding 1 2016 10

KRAS Missense p.G12R P-loop and GTP-binding 1 2017 101

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KRAS Missense p.Q22K GTP-binding 1 2017 13

KRAS Missense p.K117N GTP-binding 3 2016 11

KRAS Missense p.A146T GTP-binding 4 2017 13

KRAS Missense p.A146V GTP-binding 4 2017 12

emperipolesis) are nonspecific; therefore, .10% of a specimen
should demonstrate RDD morphology to constitute a neoplasia-
associated RDD as a distinct entity rather than a reactive process.
Immune-related RDD RDD coexists with an immunologic dis-
ease in 10% of cases.3 It has been associated with systemic lupus
erythematous, idiopathic juvenile arthritis, autoimmune hemo-
lytic anemia,24 and 1 case of RAS-associated autoimmune leu-
koproliferative disease.25
IgG4-related RDD Some forms of extranodal RDD, such as
those involving the liver, lungs, or colon, have been associated
with an increased number of immunoglobulin G4-positive (IgG41)
plasma cells,26 although other studies have shown a low number of
IgG41 plasma cells and low IgG4/IgG ratios (,40%) as compared
with IgG4-related disease samples.27 No clear evidence suggests
that the 2 disorders share the same pathogenesis; however, the
most recent classification of histiocytoses recommends evaluating
the IgG4/IgG ratio in all patients with RDD.28
Pathology
The diagnostic pathologic features of nodal RDD include the
sinus expansion of large histiocytes, described by Destombes as
possessing ample pale or “watery-clear” cytoplasm with a large
hypochromatic nucleus and prominent nucleolus (Figure 2A-C).
Nodal RDD is often accompanied by numerous plasma cells in
the medullary cords and around the venules, with varying pro-
portions of IgG4/IgG plasma cells. Detailed pathologic review
of RDD is provided elsewhere.29 Consistent features, regardless of
the site, include the cytomorphology of the large pale histiocytes
and their immunophenotype. Emperipolesis, the trafficking of
intact leukocytes through the cytoplasm, is a helpful finding but
is not required for diagnosis, because it can be focal, especially
at extranodal sites, and may be seen focally in other histiocytoses
such as ECD,30 juvenile xanthogranuloma, and malignant his-
tiocytoses. Extranodal lesions are usually associated with more
fibrosis, fewer RDD histiocytes and less emperipolesis. In such
cases, immunostains are needed to highlight the residual RDD
histiocytes in a rich lymphoplasmacytic background with stromal
fibrosis and a variable xanthomatous histiocytic reaction. These
extranodal cases can be difficult to differentiate from ECD and
require clinical correlation. The immunophenotype of the large
RDD histiocytes is characterized by cytoplasmic and nuclear
S100 (Figure 2D) and fascin (Figure 2E) positivity, with CD68 and
variable CD163 and CD14 positivity. The cells are CD1a2/
CD2072 in contrast to LCH. An important aspect of making the
diagnosis of nodal RDD is evaluation for superimposed pa-
thology, either within the node itself or other associated con-
ditions.29 The presence of RDD histology is required, but not
sufficient, for the diagnosis of RDD, which depends on the
appropriate clinical and radiologic context and exclusion of
primary malignant disorders in relation to which RDD histology
may represent a minor (,10%) reactive process. Because the
pathologic features of RDD are variable, compounded by its
heterogeneous clinical manifestations, in many instances the
primary hurdle to establishing an RDD diagnosis is suspecting
the disorder in the first place, particularly for extranodal disease.
The presence of slowly progressive or subacutely clinical symp-
tomatology; biopsy specimens demonstrating ostensibly non-
specific inflammation, including lymphoid aggregates and
plasma cells with a large histiocytic presence; and clinical findings
compatible with those described in “Clinical features” should
raise concern for an RDD diagnosis and, in difficult cases, prompt
clinical and histopathologic evaluation by experts familiar with
the disease.
Clinical features
Classic (nodal) RDD Most patients with RDD present with bi-
lateral, massive, and painless cervical lymphadenopathy (Figure 2F)
with or without intermittent fevers, night sweats, and weight loss.31
Mediastinal, axillary, and inguinal nodes may also be involved, but
retroperitoneal lymphadenopathy is uncommon.32 Prognosis has
been found to correlate with the number of nodal groups involved
by RDD.3

CONSENSUS GUIDELINES FOR RDD blood® 28 JUNE 2018 | VOLUME 131, NUMBER 26 2879
 A B F G

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C D E

Figure 2. Pathologic and clinical features of RDD. (A-E) Representative images of nodal RDD from tissue biopsies (A-B) and fine-needle aspiration (C-E). (A) Mixed RDD/LCH
case with sinus expansion. The large RDD histiocytes display conspicuous emperipolesis with pale cytoplasm, as compared with the intermixed LCH cells with dense eosinophilic
cytoplasm and convoluted nuclei (original magnification [OM] 3400; hematoxylin and eosin [H&E] stain). (B) The RDD histiocytes show pale watery-clear cytoplasm, a central
round nucleus with a conspicuous nucleolus, and emperipolesis (OM 31000; H&E stain). Cell block preparation shows clusters of RDD histiocytes (OM 3400; H&E stain) (C), with
nuclear and cytoplasmic staining for S100 (OM 31000) (D) and fascin (OM 31000) (E); the trafficking intact leukocytes are negative. (F) A child with immunodeficiency and RDD
with massive cervical lymphadenopathy. (G) RDD of the skin showing red nodular lesions. (H) Tongue enlargement resulting from oral RDD.

Extranodal RDD Extranodal involvement has been reported in
43% of RDD cases.3 A brief discussion of extranodal sites af-
fected by RDD follows, with differential diagnoses for each site.
Other histiocytoses such as LCH and ECD should be considered
as alternative or associated diagnoses for all sites. Multisystem
involvement occurs in 19% of cases, and prognosis is correlated
with the number of extranodal systems involved.3
Cutaneous manifestations The skin is involved in 10% of extranodal
RDD cases, and isolated cutaneous disease is rare.31 Lesions are
typically slow growing, painless, nonpruritic nodules, plaques,
or papules with coloration varying from yellow to red to brown
(Figure 2G). Any skin site can be affected. The differential diagnosis
includes acne vulgaris, varicella-zoster virus, sarcoidosis, cutaneous
lymphoma, and metastasis.31
Intracranial, spinal, CNS, and ophthalmic manifestations
Central nervous system (CNS) involvement occurs in ,5% of
cases, with 75% occurring as intracranial and 25% as spinal le-
sions. Neurologic RDD has been reported in .300 cases33 and
usually occurs in older patients and without lymphadenopathy.34
Symptoms include headaches, seizures, gait difficulty, motor or
sensory abnormalities, and cranial nerve deficits, usually evolv-
ing over weeks or months.33 Familial cases are associated with
damage to the auditory nerve pathway and deafness.16,35 The
most common radiographic appearance of intracranial RDD is a
solitary extraaxial, homogeneously enhancing dural mass (Figure
3A) mimicking a meningioma,36,37 although RDD can cause dif-
fuse pachymeningitis. Parenchymal lesions are frequently
infratentorial (brainstem and pons; Figure 3B),38 whereas supra-
tentorial, intraventricular, and multifocal lesions are rare.39,40 Ce-
rebrospinal fluid is often unremarkable although may show
lymphocytic pleocytosis, elevated protein, low glucose, and
emperipolesis.37
Spinal dural or epidural lesions are most common in the cervical
and thoracic regions41 (Figure 3C-D) and present with mye-
lopathy or symptoms of spinal cord compression. Although CNS
RDD can have a rapidly progressive and even fatal course, many
patients will have a favorable outcome after surgical resection
when this is feasible.34
Ophthalmic manifestations occur in 11% of RDD cases,3 mani-
festing as a mass in the orbital soft tissues (Figure 3E), eyelids,
lacrimal glands, conjunctiva, or cornea and as uveitis or com-
pressive optic neuropathy.42
Head and neck manifestations Involvement of the nasal cavity
and paranasal sinuses occurs in 11% of RDD cases3 and is more
common in patients of Asian descent. Symptoms of sinonasal
RDD include nasal obstruction, epistaxis, nasal dorsum de-
formity, facial asymmetry, and aural fullness.43 Oral cavity in-
volvement can present as soft and hard palate nodules, gingival
and oral mucosa swelling, tongue enlargement (Figure 2H), thick-
ened mucosa of the oropharynx, enlarged tonsils, or frequent
tonsillitis.3 Other less frequently involved sites include the salivary
and parotid glands, larynx, pharynx, thymus, and thyroid gland,
which can cause symptoms related to mass effect.44,45

2880 blood® 28 JUNE 2018 | VOLUME 131, NUMBER 26 ABLA et al

Figure 3. Radiographic features of RDD. (A)
Gadolinium-enhanced coronal T1-weighted mag-
netic resonance imaging (MRI) demonstrates a dural- A B
based lesion at the base of the right frontal lobe (blue
arrow). (B) Patchy enhancing lesions in the brain-
stem on gadolinium-enhanced axial T1-weighted
MRI (green arrow). (C) Gadolinium-enhanced axial T1-
weighted MRI demonstrates lesions in the bilateral
cavernous sinuses and Meckel’s cave (red asterisks)
as well as the left orbit (red arrow), with resulting
proptosis. (D) Axial fused [18F]fluorodeoxyglucose
(FDG)–positron emission tomography (PET)/computed
tomography (CT) demonstrates a hypermetabolic
dural-based paraspinal mass with involvement of the
osseous elements of the thoracic spine with forami-
nal extension. (E) Response to 12 weeks of 1 mg/kg per
day of prednisone is demonstrated, with near resolution
of hypermetabolism and regression of the tumor. (F)
Partly T2-weighted bright-blood image shows an oval
mass (black arrow) in the left atrium (LA) arising from the

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central part of the heart at the atrioventricular junction.
LV, left ventricle; RA, right atrium; RV, right ventricle.
C D

Intrathoracic manifestations Intrathoracic RDD is described in
2% of patients, usually with concurrent lymphadenopathy.46
Manifestations include interstitial lung disease, pulmonary nod-
ules, tracheobronchial disease, and pleural effusions with an
obstructive pattern on pulmonary function tests.47 Symptoms
include chronic dry cough, progressive dyspnea, or acute re-
spiratory failure. Pulmonary RDD can mimic primary lung
cancers, interstitial lung disease or organizing pneumonias,
sarcoidosis, granulomatous polyangiitis, rheumatoid arthritis–
related lung disease, and mycobacterial and fungal infections.46
RDD affecting the lower respiratory tract can have an aggres-
sive phenotype, with a mortality rate of almost 45%.3 Cardiac
involvement with RDD is rare, occurring in 0.1% to 0.2% of cases
(Figure 3F).48
Retroperitoneal and genitourinary manifestations The kidneys
are affected in 4% of RDD cases, with a discrete mass or diffuse
infiltration.49,50 Symptoms include hematuria, flank pain, ab-
dominal fullness, renal failure, hypercalcemia, or nephrotic syn-
drome caused by amyloidosis or renal vein thrombosis.51-54
Hydronephrosis and ureteral obstruction can occur.55 The dif-
ferential diagnosis of renal RDD includes ECD, lymphoma, renal
cell carcinoma, tuberculosis, IgG4-related disease, or metastatic
tumor. Patients with renal involvement have a poor prognosis,
with 40% mortality rate.3
Testicular involvement is rare and manifests as a painful testicular
or epididymal mass mimicking tumor or epididymitis.3,56 An-
ecdotally, testicular RDD can also present as diffuse enlargement

CONSENSUS GUIDELINES FOR RDD blood® 28 JUNE 2018 | VOLUME 131, NUMBER 26 2881
Table 2. Baseline clinical evaluation recommendations
for patients with RDD
Recommendation
Medical history
Constitutional: fevers, night sweats, fatigue
HEENT: cervical swelling, double vision, retroorbital pain,
eyelids/lacrimal swelling, nasal obstruction, epistaxis, hyposmia,
oral sores, or pain
Cardiovascular: dyspnea, orthopnea
Pulmonary: dyspnea, cough
GI: abdominal pain, constipation, hematochezia
Renal: hematuria, flank pain
Musculoskeletal: bone pain
Dermatologic: rash, pruritus
Endocrine: polydipsia/polyuria
Neurologic: headaches, seizures, gait difficulty, limb or facial
weakness, sensory changes, hearing impairment, new or focal
back pain
History of: autoimmune disease, ALPS, malignancy, LCH, or another
histiocytic disorder
Family history (pediatric patients): consanguineous parents,
autoimmune disease, Turkish/Pakistani or Middle Eastern
background
Physical examination
HEENT: dysmorphic face and hearing abnormalities (familial RDD),
enlarged cervical nodes, proptosis, lesions of oral mucosa,
enlarged tongue or tonsils
Cardiac: hypertension, irregular pulse, cardiomegaly, murmurs
Thoracic: diminished lung aeration, rales, axillary nodes, breast mass
Skin: nodules, papules, or plaques
Abdominal: flank mass, hepatosplenomegaly, enlarged inguinal nodes
Genital: testicular mass or enlargement
Musculoskeletal: osseous mass
Neurologic: disconjugate gaze, cranial nerve palsies, dysarthria,
ataxic gait, hemiparesis, hyperreflexia
Radiological evaluation
All patients
PET/CT: recommended by some authors for all patients,
including children (judicious use is recommended in this age
group), but no universal consensus was reached
Ultrasound neck/abdomen, chest X-ray or whole-body MRI:
reasonable alternatives
Selected patients based on symptoms or organ involvement
CT sinuses with contrast
MRI orbit/brain with contrast
MRI spine with contrast
High-resolution CT chest
Pulmonary function tests
Thyroid ultrasound
Testicular ultrasound
and hardening of the testes, with or without pain. Adrenal gland
involvement is also possible but rare.57
GI manifestations Gastrointestinal (GI) involvement occurs in
,1% of RDD cases, most commonly in middle-age women with
concurrent lymphadenopathy or other extranodal disease.3
GI RDD can be solitary or segmental and has a predilection for the
ileocecal area, appendix, and distal colon, with most cases being
located beyond the pylorus.58,59 Symptoms include hematochezia,
2882 blood® 28 JUNE 2018 | VOLUME 131, NUMBER 26
Table 2. (continued)
Recommendation
Laboratory evaluation
Complete blood count with differential
Serum immunoglobulins
ALPS panel, ANA, RF, HLA-B27: if autoimmune disease is suspected
Erythrocyte sedimentation rate
Complete metabolic panel, coagulation parameters, uric acid, LDH
Patients with anemia: Coombs test, haptoglobin, reticulocyte count
and blood smear
Targeted-capture, next-generation sequencing of lesional tissue for
mutations in RAF-RAS-MEK-ERK pathway (eg, KRAS, MAP2K1): in
severe or refractory cases
Bone marrow aspirate/biopsy (if cytopenias or abnormal peripheral
blood smear are present)
Lumbar puncture (for brain lesions inaccessible to biopsy); CSF
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pleocytosis with emperipolesis visible upon cytologic
examination is indicative of RDD
Check lesional tissue for PDGFR-a/b and c-kit
Germ line mutations in SLC29A3: if familial RDD is suspected
CSF, cerebrospinal fluid; HEENT, head, eyes, ears, nose, and throat; LDH, lactate
dehydrogenase.
constipation, abdominal pain, abdominal mass, and intestinal
occlusion, although asymptomatic cases have been identified
after colonoscopy or appendectomy.59,60 Almost 20% of the
reported patients in 1 series died as a result of disease.58 Pan-
creatic or hepatic involvement is reported but extremely
rare.3,61,62
Bone manifestations Bone involvement occurs in 5% to 10% of
RDD cases, typically in association with nodal disease.3,63 Bone
pain is common, whereas pathologic fractures are rare.51 Bone
lesions typically occur in the metaphysis or diaphysis, are osteo-
lytic or mixed lytic/sclerotic, and have a narrow zone of transition.
Soft tissue extension can occur. The clinical differential diagnosis
includes chronic osteomyelitis, fibrous dysplasia, lymphoma, and
Ewing sarcoma. Lesions in the femurs and tibia should raise
concern for ECD. The prognosis of bony RDD is generally good.64
Hematologic manifestations Normochromic normocytic anemia
(in 67% of cases), leukocytosis (in 60%, typically neutrophilia),
thrombocytopenia, eosinophilia, hypergammaglobulinemia, and
elevated erythrocyte sedimentation rate are common, although
bone marrow infiltration is rare.17,65
Baseline evaluations
Imaging and laboratory studies The diagnostic and staging
evaluation of patients with newly diagnosed RDD (Table 2)
should include an assessment of disease extent, as well as
evaluation for conditions either known to be associated with
RDD, particularly autoimmune disorders, or known to contain an
RDD-like reactive component secondary to malignancies.
A comprehensive medical history and physical and neurologic
examinations should be performed. In children, a chest X-ray
with neck and abdominal ultrasounds are routinely performed
initially. For older patients, CT of the neck/chest/abdomen and
pelvis is recommended. RDD lesions are known to be FDG-
avid, including extranodal areas,66 and FDG-PET/CT is used by
some investigators for initial staging when possible, similarly to
ABLA et al
patients with ECD.30 Of note, RDD lesions can have appearance
and avidity on FDG-PET similar to those of intermediate- and
high-grade lymphomas, and these should be diagnostic con-
siderations. Rather than skull-to-thigh scanning, full-body PET
including the distal extremities should be performed for com-
prehensive osseous evaluation. However, there is no consensus
among the authors about the benefits of PET/CT in patients
with RDD as compared with anatomic imaging. In children, efforts
must be made to minimize radiation exposure and need for
anesthesia. Whole-body MRI is usually recommended instead
of CT scans, and PET scans should be used judiciously. Patients
with orbital or neurologic symptoms should have a gadolinium-
enhanced MRI of the brain, orbits, or total spine depending on the
localizing symptoms; screening MRI of the brain and spine with
contrast may be appropriate to identify asymptomatic neurologic
involvement. Dedicated organ-specific imaging (ie, MRI of the
heart or abdomen) may be necessary to evaluate structural lesions
identified but poorly characterized by CT or PET.
Laboratory evaluation should include comprehensive meta-
bolic panel, a complete blood count with differential, erythrocyte
sedimentation rate, C-reactive protein, and quantitative immu-
noglobulin levels. Serologies for HIV and hepatitis B and C are
suggested to exclude these as associated diagnoses. Testing
for antinuclear antibodies and rheumatoid factor is suggested,
because screening for associated systemic lupus erythematous
or idiopathic juvenile arthritis and further evaluation for evidence
of autoimmunity should be carried out if other diagnoses are
considered on the basis of medical history and physical examina-
tion. Bone marrow aspirate and biopsy are required only for patients
with unexplained cytopenias or abnormal peripheral blood cells.
Acquisition and analysis of lesional tissue It is important that
sufficient tissue be acquired to establish an RDD diagnosis and
that biopsies be reviewed by a pathologist familiar with RDD.
Flow cytometry and cytogenetic testing may be required to rule
out a lymphoproliferative disorder. Immunohistochemistry for
IgG4 should be performed when pathology samples show an
enriched plasma-cell presence. In the event of severe or re-
fractory disease, lesional tissue should be analyzed to detect
gain-of-function mutations of genes of the MAPK pathway ame-
nable to targeted therapies (including at least KRAS, NRAS, HRAS,
ARAF, BRAF, and MAP2K1).
Treatment
General principles No uniform approach has been delineated
for RDD, and treatment is best tailored to the individual clinical
circumstances. Accordingly, notions of first-line and second-
line treatments are not felt to be applicable to RDD. Below
we summarize therapeutic strategies and their implementation
(Table 3) and propose a management algorithm (Figure 4).
Observation After the diagnosis of RDD is established, obser-
vation is reasonable in many cases, because 20% to 50% of pa-
tients with nodal/cutaneous disease will have spontaneous
remissions.67,68 This strategy is suitable for patients with un-
complicated lymphadenopathy or asymptomatic cutaneous RDD
and potentially for those with asymptomatic disease in other sites.
Surgery Surgery for RDD is usually limited to biopsy, but
resection can be curative for unifocal disease, and debulking
may be warranted for upper airway obstruction, spinal cord
CONSENSUS GUIDELINES FOR RDD
compression, or large lesions causing end-organ compromise.
Long-term remissions with resection alone have been reported
in isolated intracranial disease.69 The most effective treatment
of cutaneous RDD is surgical excision.31 Endoscopic resection of
sinonasal RDD can achieve symptomatic control and restoration
of function.43 In cases of multifocal disease, surgical resection of
single foci should be reserved for bulky disease with neurologic
or end-organ dysfunction.
Corticosteroids Steroids are usually helpful in reducing nodal
size and symptoms, although responses have been variable. The
optimal corticosteroid (prednisone or dexamethasone) dose
and duration are not clearly defined. Prednisone (40-70 mg per
day) has produced complete or partial responses in cases of
orbital, CNS, bone, and autoimmune hemolytic anemia–associated
disease.70,71 Compared with other immune diseases (eg, sar-
coidosis), therapeutic prednisone doses are usually higher
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(.0.5 mg/kg per day). Similarly, dexamethasone (8-20 mg per day)
was effective in cases of CNS RDD and hilar lymphadenopathy.72,73
One viable approach is to treat to the best observed response,
followed by slow taper. An anecdotal response to intralesional
steroids has been reported in an adult with orbital RDD and optic
nerve compression.74 Nevertheless, other reports of orbital,
tracheal, renal, or soft tissue RDD have shown a failure to re-
spond to steroids.75,76 Furthermore, relapses of RDD lesions can
sometimes occur after a short period of interruption. Anecdot-
ally, the experience of the authors is that patients with extranodal
disease do not generally demonstrate a durable response to
steroids alone.
Sirolimus Mammalian target of rapamycin is a critical pathway
for the control of proliferation and cytokine production from
immune cells and has been found to be dysregulated in RDD.77
Sirolimus and prednisone induced objective responses and dis-
ease stabilization in 80% of patients with ECD in 1 report,78 and
sirolimus was found to be beneficial in a child with resistant RDD
and recurrent autoimmune cytopenias.77 The use of this agent for
ALPS- or autoimmune-associated RDD requires further study.
Chemotherapy Treatment of RDD with chemotherapeutic
agents has shown mixed results. Although chemotherapy is
generally reserved for refractory or relapsed cases, sometimes
it is used as initial therapy in disseminated or life-threatening
disease. Anthracyclines and alkylating agents have little effi-
cacy, whereas vinca alkaloids have shown variable responses.67
Low-dose MTX and 6-MP administered in combination were ef-
fective in few patients.67,79 Sustainable remissions after regimens
containing vinblastine/MTX/6-MP and 6-thioguanine,80 vinblas-
tine/prednisone/MTX/6-MP,81 or vinorelbine/MTX82 have been
reported. Single-agent 6-MP was effective in halting disease in an
adult with orbital and intracranial RDD.83 Furthermore, long-term
remission of intracranial RDD has been reported after postsurgical
maintenance with CHOP (cyclophosphamide, doxorubicin, vin-
cristine, and prednisone)–like regimens.84 A patient with multiply-
relapsed nodal RDD responded to cytarabine/prednisone/
vincristine followed by MTX/6-MP maintenance.85 Successful
treatment of refractory cutaneous RDD was reported with single-
agent vincristine86 and low-dose MTX.87 In addition, azathioprine
and interferon-a induced long-term remissions in patients with
RDD.88,89 However, interferon-a in combination with chemotherapy
failed to induce any response in another report.67 Therefore, these
agents could be considered for steroid-refractory disease or early
blood® 28 JUNE 2018 | VOLUME 131, NUMBER 26 2883
 2884
Table 3. Treatment strategies for patients with RDD

Treatment Dose/schedule Indication Supportive evidence Comments

Observation NA Uncomplicated adenopathy Case series of 80 patients showed 50% Can consider observation for
spontaneous remission67 near-complete resection of unifocal
Asymptomatic cutaneous RDD lesions with minimal residual
Postoperatively for resected unifocal disease after surgery
disease

Corticosteroids Prednisone: 40-70 mg or 1 mg/kg per Symptomatic nodal or cutaneous disease Several case reports and case series with Responses, when favorable, are
d followed by taper prednisone showing responses in unpredictable in their durability
orbital, CNS, and bone RDD and

blood® 28 JUNE 2018 | VOLUME 131, NUMBER 26

AHA-associated disease69,70
Dexamethasone: 8-20 mg per d followed Nonresectable or multifocal extranodal Dexamethasone was effective in CNS Optimal duration of treatment is not
by taper disease requiring systemic treatment and nodal RDD in case reports71,72 known because early relapse can occur

Case report of intralesional steroids in One reasonable approach is to treat to

orbital RDD74 optimal response followed by slow taper

No response to steroids in other case After successful steroid treatment:

reports of orbital, tracheal, renal, or soft consider second-line agents to
tissue RDD75,76 maintain response

Surgical resection NA Unifocal extranodal disease Case series with long-term remission Local recurrences can occur,31,43 for
after resection of isolated cutaneous which case systemic treatment should
Symptomatic cranial, spinal, sinus, or and intracranial disease31,69 be considered
airway disease

Sirolimus 2.5 mg/m2 per d for 18 mo, then taper off Prolonged CR in RDD with autoimmune Reasonable first choice in
over 6 mo cytopenia77 ALPS-associated RDD

Radiotherapy 30-50 Gy, lymphoma-like schedule102 Refractory or symptomatic disease not
amenable to resection, recurrent after
resection, or with a contraindication to
systemic therapy
Palliative benefit in case reports,
including refractory soft tissue and
orbital RDD with visual compromise97
and for mass effect causing airway
obstruction67,103
No established fractionation schedule
Can also be considered as adjuvant
treatment after resection of cranial or
spinal lesions with residual but not
bulky disease

AHA, autoimmune hemolytic anemia; CR, complete response; 6-MP, 6-mercaptopurine; MTX, methotrexate; NA, not applicable; PD, progressive disease; PR, partial response.

ABLA et al
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 Table 3. (continued)

Treatment Dose/schedule Indication Supportive evidence Comments

Chemotherapy
Cladribine 5 mg/m2 per d for 5 d, every 28 d for up to Severe, disseminated, or refractory 11 patients reported: 7 with CR, 1 with Can cause myelosuppression with
6 cycles disease PR, and 3 with PD13,51,90-92 associated infections

CNS involvement
MTX or 6-MP/MTX 20 mg/m2 per wk of MTX, alone or with Multifocal, skin, or CNS RDD PR or CR in refractory cases79-85 Reasonable as maintenance therapy

CONSENSUS GUIDELINES FOR RDD

6-MP (50 mg/m2 per d) or steroids after surgery or steroids
Optimal duration unknown
Vinca alkaloids Standard doses; vinblastine usually Vincristine effective in 1 report of Variable responses
combined with prednisone skin RDD86
Several reports showing prolonged CR Optimal duration unknown
when combined with other agents81-83

Immunomodulatory
Thalidomide 50-300 mg per d; variable duration Refractory cutaneous RDD Recent review: several reports with Notable toxicities include skin rash
prolonged CR94 and neuropathy

Variable responses Optimal dose and duration unknown

Lenalidomide Not known Refractory disease Sustained CR in an adult with multiply Myelosuppressive but less neuropathy
relapsed RDD95 and skin rash than thalidomide
Rituximab 500 mg/m2 per dose every 1 or 2 wk for For refractory nodal and immune- Efficacy described in single case reports96 Mechanism of efficacy is not
2-6 cycles related RDD understood
- alone or with chemotherapy There are reports of refractoriness and
relapses,85,97 and therefore, reports of
success are interpreted with caution
Imatinib mesylate 400-600 mg per d for 7 mo Refractory/relapsed RDD Anecdotal activity in 1 adult with Variable responses
refractory RDD98

1 case of skin RDD was refractory99 May work only in PDGFRa/b1 cases

Clinical trial
(experimental)
Cobimetinib Per trial guidelines Refractory RDD Substantial regression of abdominal Several case reports of successful
(NCT02649972) masses in a single patient with KRAS treatment of ECD with cobimetinib10,100
p.G12R–mutated RDD101
Clofarabine 25 mg/m2 per d for 5 d, every 28 d for Severe, disseminated, or refractory 3 patients: 2 with CR, 1 had PR93 Myelosuppressive and expensive
(NCT02425904) 6 cycles disease

CNS involvement Prospective studies ongoing to

determine optimal dosing, long-term
efficacy, and toxicity

blood® 28 JUNE 2018 | VOLUME 131, NUMBER 26

AHA, autoimmune hemolytic anemia; CR, complete response; 6-MP, 6-mercaptopurine; MTX, methotrexate; NA, not applicable; PD, progressive disease; PR, partial response.

2885
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 Rosai-Dorfman Disease
Severe or refractory disease

Nodal/Cutaneous Extranodal
Consider enrollment in clinical trials at all stages

Asymptomatic

Consider targeted
Symptomatic capture next-
generation sequencing
for MAPK pathway
mutations (eg KRAS,
Biopsy/Resection Systemic therapy for Resection/debulking of MAP2K1)
of Single-Site unresectable or sites causing neurologic
disease* multifocal disease or end-organ dysfunction

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Observation/
Surveillance
Can consider
Progression
re-challenge
Relapse

Consider targeted
Next rational therapy (MEK inhibitor)
Systemic if driver mutation
Therapy identified

*Asymptomatic sites often can be observed following biopsy while symptomatic lesions can be resected

Figure 4. A proposed management algorithm for patients with RDD.

recurrence after interruption of steroids or when steroids are The efficacy of rituximab has been described, especially in
contraindicated. autoimmune-related RDD cases,96 although refractoriness87 and
recurrences97 have also been described.
Nucleoside analogs cladribine and clofarabine have induced
responses in RDD.51,90-93 They impair the function of monocytes Targeted therapies Imatinib mesylate, a tyrosine kinase in-
through inhibition of interleukin-6 (IL-6), IL-1b, and tumor ne- hibitor, showed some activity in 1 patient with refractory RDD.
crosis factor a (TNF-a) production. Cladribine (2.1-5 mg/m2 per Lesional histiocytes were positive for the imatinib target proteins
day for 5 days every 28 days for 6 months) induced prolonged PDGFRB and KIT by immunohistochemistry, but no concurrent
remissions in cases of recurrent or refractory systemic RDD,51,90-92 mutation was found.98 In another case, cutaneous RDD was
and clofarabine (25 mg/m2 per day for 5 days every 28 days for refractory to imatinib.99
6 months) was effective as salvage therapy in a series of pa-
tients with refractory or relapsed RDD.93 These agents should be Unlike ECD and LCH, BRAF-V600E mutations have not been ob-
served in RDD8-14; thus, the use of BRAF inhibitors is not relevant.
considered in severe or refractory cases when the potential benefit
MEK inhibition has shown preliminary activity in BRAF–wild-type
justifies their myelosuppressive toxicity. A multicenter prospective
ECD100 and in an adult with KRAS-mutated RDD.101 A phase 2 trial
study (registered at www.clinicaltrials.gov as #NCT02425904) is
of cobimetinib for patients with BRAF–wild-type histiocytoses, in-
being conducted by the North American Consortium for Histio-
cluding RDD, is ongoing (registered at www.clinicaltrials.gov as
cytosis to study the efficacy and safety of clofarabine salvage in
#NCT02649972), with promising early results.102 The robust activity
patients with histiocytoses, including RDD.
of targeted therapies in other histiocytoses raises interest in their
potential for RDD, especially in cases with demonstrated somatic
Immunomodulatory therapy TNF-a inhibitors thalidomide and
mutations; however, currently, the broad applicability of tumor
lenalidomide have shown promising results in RDD because
sequencing and targeted treatments has not yet been established.
the identification of high levels of TNF-a and IL-6 provides a
rational basis for their effectiveness. A recent review showed that Radiotherapy Radiotherapy has modest efficacy in RDD, al-
low-dose thalidomide (100 mg per day) was effective in re- though it can be beneficial in refractory soft tissue and orbital
fractory cutaneous RDD.94 However, responses to thalidomide bone disease with visual compromise97 or resistant airway ob-
have not been universal, and optimal dosing and duration of this struction or to palliate local symptoms.67,103 Radiotherapy has
drug remain unknown. Lenalidomide recently showed an excel- also been implemented in patients whose symptoms persist or
lent response in an adult with multiply-refractory nodal and bone recur after resection of isolated disease and in those who are not
RDD and may be more tolerable than thalidomide (fewer skin suitable candidates for surgery and/or when other treatments
rashes and less neuropathy), although more myelosuppressive.95 are contraindicated.33,64 No standard doses of radiotherapy have

2886 blood® 28 JUNE 2018 | VOLUME 131, NUMBER 26 ABLA et al

been established, but doses between 30 and 50 Gy have been
employed.103
Treatment course, disease surveillance,
and prognosis
The optimal duration of steroids or other systemic therapies for
RDD is not known. Six to 12 months of systemic therapy followed
by observation, assuming tolerance and a favorable response to
treatment, is a reasonable approach. When initiating treatment,
a first response assessment should be carried out within 4 months;
if disease stabilizes or is in remission, interval of surveillance can
be extended to 6 to 12 months.
Data are insufficient to characterize the prognosis of RDD in
great detail. Outcomes are usually favorable, particularly for
cases of nodal and cutaneous disease, which are often self-
limited. Other patients experience an unpredictable clinical
of cooccurring disorders. Many cases of RDD can be managed
with observation alone, whereas other patients require a variety
of immunomodulatory and antineoplastic agents. The roles of
tumor sequencing and targeted therapies, such as MEK inhib-
itors, are promising and require further study. The ongoing In-
ternational Registry for the Rare Histiocytic Disorders (registered
at www.clinicaltrials.gov as #NCT02285582) aims to better un-
derstand the clinicopathologic features, treatment strategies,
and outcomes of patients with RDD and other rare histiocytic
disorders.
Acknowledgments
This work was supported by a National Institutes of Health, National
Cancer Institute Core Grant (P30 CA008748) awarded to Memorial Sloan
Kettering Cancer Center. B.H.D. is supported by the American Society of
Hematology Senior Research Training Award for Fellows and the New

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course, with alternating periods of remission and reactivation
that may last years. In the largest series, conducted by Foucar
et al3 in 1990, 17 (7%) of 238 patients died as a result of direct
complications of their disease, infections, or amyloidosis.3 In a
review by Pulsoni et al67 in 2002, 10 (12%) of 80 patients died as a
result of RDD.67 Patients with multifocal and extranodal RDD,
particularly those with kidney, liver, or lower respiratory tract
disease, seem to have an unfavorable prognosis. Thus, intensive
systemic chemotherapy, targeted therapies, and investigational
agents may be justified in this context. Further elucidation of the
role of these therapies in refractory RDD may mitigate the poor
prognosis of some of these cases.
York State Council on Graduate Medical Education Empire Clinical
Research Investigator Program Fellowship from Memorial Sloan Ket-
tering Cancer Center. E.L.D. is supported by the Frame Fund generously
donated to Memorial Sloan Kettering Cancer Center. J.A.W. is supported
in part by the Women’s Auxiliary Millennium Chair in Haematology/
Oncology at The Hospital for Sick Children.
Authorship
Contribution: The paper was written by O.A., E.L.D., E.J., K.L.M., J.H.,
and J.P.; all authors participated in editing the manuscript and providing
expert recommendations; histopathologic images were provided by J.P.;
genome sequencing image and table were provided by B.H.D.; clinical
images were provided by O.A. and J.H.; and radiographic images were
provided by E.L.D. and O.A.

Conflict-of-interest disclosure: The authors declare no competing fi-

Conclusions
RDD is a rare and heterogeneous disorder presenting many
diagnostic and therapeutic challenges. The recent biologic and
molecular advances in other histiocytoses such as LCH and ECD
have not been matched in RDD; therefore, there is urgent need
to continue investigating the mutational landscape of RDD and
its therapeutic relevance. Multidisciplinary collaboration is often
vital to the evaluation and management of patients with RDD,
and systematic investigation of novel therapies for RDD is needed.
Comprehensive RDD evaluation involves careful medical his-
tory, physical examination, imaging studies, and laboratory
evaluations to determine the extent of disease and presence
nancial interests.
Correspondence: Oussama Abla, Division of Hematology/Oncology,
The Hospital for Sick Children, University of Toronto, 555 University
Ave, Toronto, ON M5G1X8, Canada; e-mail: oussama.abla@sickkids.ca.
Footnotes
Submitted 15 March 2018; accepted 27 April 2018. Prepublished online
as Blood First Edition paper, 2 May 2018; DOI 10.1182/blood-2018-03-
839753.
*K.L.M., J.H., and E.L.D. contributed equally to the paper.

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