Rosai-Dorfman Disease

🏷

Classifications

Harrison's Chapter

◈

Mechanistic Hypotheses

2

Clonal MAPK/ERK neoplasm hypothesis

clonal_mapk CANONICAL

A substantial subset of RDD is a clonal histiocytic neoplasm driven by activating somatic mutations in the MAPK/ERK pathway (KRAS, MAP2K1, ARAF, NRAS), producing constitutive ERK signaling, histiocyte proliferation, and response to MEK inhibition. BRAF V600E, characteristic of Langerhans cell histiocytosis and Erdheim-Chester disease, is typically absent in RDD.

Pathograph links

MAPK/ERK Pathway Activation -> Histiocyte Accumulation with Emperipolesis

Show evidence (1 reference)

PMID:36358690 SUPPORT Human Clinical

"Recent studies consider RDD a clonal neoplastic process, as approximately 1/3 of these patients harbor gene mutations involving the MAPK/ERK pathway, e.g., NRAS, KRAS, MAP2K1, and, rarely, the BRAF mutation."

Supports the clonal MAPK/ERK neoplasm hypothesis for the mutation-positive subset of RDD.

Reactive immune-dysregulation hypothesis

reactive_immune ALTERNATIVE

In mutation-negative cases, RDD is modeled as a polyclonal, cytokine-driven activation of the mononuclear phagocyte system, possibly triggered by infection or autoimmunity, producing the same emperipolesis-positive histiocyte morphology without a demonstrable clonal driver. The association with autoimmune disease and IgG4-related disease supports this arm.

Pathograph links

Immune Dysregulation and Macrophage Activation -> Histiocyte Accumulation with Emperipolesis

Show evidence (1 reference)

PMID:28664935 SUPPORT Human Clinical

"It has been hypothesized that Rosai-Dorfman disease may result from underlying host immune dysregulation, likely due to a precipitating event, such as a viral infection."

Supports the reactive immune-dysregulation hypothesis for mutation-negative RDD.

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Pathophysiology

4

MAPK/ERK Pathway Activation

In the clonal arm of RDD, activating somatic mutations in the MAPK/ERK (RAS-RAF-MEK-ERK) pathway arise in a histiocyte/macrophage progenitor. Recurrent, mutually exclusive KRAS and MAP2K1 (MEK1) mutations are detected in approximately one-third of cases, with additional NRAS and ARAF mutations in a subset, driving constitutive ERK signaling. BRAF V600E is characteristically absent, distinguishing RDD from Langerhans cell histiocytosis and Erdheim-Chester disease.

Clonal MAPK/ERK neoplasm hypothesis

S100-positive histiocyte (RDD cell) CL:0000235

MAPK cascade GO:0000165 ↑ INCREASED ERK1 and ERK2 cascade GO:0070371 ↑ INCREASED

Downstream

Histiocyte Accumulation with Emperipolesis

Show evidence (2 references)

PMID:28664935 SUPPORT Human Clinical

"we detected mutually exclusive KRAS and MAP2K1 mutations in one-third of cases of Rosai-Dorfman disease suggesting this subgroup are clonal and involve activation of MAPK/ERK pathway"

Next-generation sequencing of 21 RDD cases detected mutually exclusive KRAS and MAP2K1 point mutations in one-third, establishing clonal MAPK/ERK pathway activation as a driver in a substantial subset.

PMID:36358690 SUPPORT Human Clinical

"Recent studies consider RDD a clonal neoplastic process, as approximately 1/3 of these patients harbor gene mutations involving the MAPK/ERK pathway, e.g., NRAS, KRAS, MAP2K1, and, rarely, the BRAF mutation."

Review synthesizing the molecular landscape, confirming MAPK/ERK pathway mutations (NRAS, KRAS, MAP2K1) in approximately one-third of RDD as the basis for reclassifying a subset as a clonal neoplasm.

Immune Dysregulation and Macrophage Activation

In mutation-negative RDD, dysregulated cytokine-driven activation of the mononuclear phagocyte system expands activated macrophages with a prominent reactive plasma-cell and lymphocyte component. Host immune dysregulation, possibly precipitated by infection, and overlap with autoimmune and IgG4-related disease characterize this arm. The same emperipolesis-positive histiocyte morphology is produced without a demonstrable clonal driver.

Reactive immune-dysregulation hypothesis

Macrophage CL:0000235 Plasma cell CL:0000786

macrophage activation GO:0042116 ↑ INCREASED inflammatory response GO:0006954 ↑ INCREASED

Downstream

Histiocyte Accumulation with Emperipolesis

Show evidence (1 reference)

PMID:28664935 SUPPORT Human Clinical

"It has been hypothesized that Rosai-Dorfman disease may result from underlying host immune dysregulation, likely due to a precipitating event, such as a viral infection."

Establishes the long-standing reactive/immune-dysregulation model for RDD pathogenesis that operates in mutation-negative cases.

Histiocyte Accumulation with Emperipolesis

Both the clonal and reactive arms converge on accumulation of large activated S100-positive histiocytes that exhibit emperipolesis, the active non-destructive engulfment of intact lymphocytes, plasma cells, and erythrocytes within histiocyte cytoplasm. Emperipolesis is the histologic hallmark of RDD. In nodal disease the histiocytes expand the lymph node sinuses; extranodal lesions are typically more fibrotic with fewer histiocytes.

S100-positive histiocyte (RDD cell) CL:0000235

cell population proliferation GO:0008283 ↑ INCREASED

Downstream

Nodal and Extranodal Tissue Infiltration

Show evidence (1 reference)

PMID:28664935 SUPPORT Human Clinical

"the accumulation of abnormal histiocytes undergoing emperipolesis. The latter is defined as the active, non-destructive engulfment of leukocytes including lymphocytes, plasma cells and erythrocytes by histiocytes and is considered the histologic hallmark of Rosai-Dorfman disease"

Defines emperipolesis as the active non-destructive engulfment of intact leukocytes by histiocytes and establishes it as the histologic hallmark of RDD.

Nodal and Extranodal Tissue Infiltration

Expansion of the histiocytic infiltrate produces massive nodal enlargement (classically bilateral cervical) and, in approximately 40 percent of patients, extranodal masses that can affect virtually any site (skin, CNS, bone, sinonasal tract, orbit, kidney, lung). Mass effect and organ infiltration drive site-specific manifestations, while the accompanying plasma-cell-rich inflammatory infiltrate underlies the systemic features of hypergammaglobulinemia and elevated ESR.

S100-positive histiocyte (RDD cell) CL:0000235

Show evidence (1 reference)

PMID:36358690 SUPPORT Human Clinical

"Typically, the patient with RDD shows bilateral painless, massive cervical lymphadenopathy associated with B symptoms. Approximately 43% of patients presented with extranodal involvement."

Establishes the classic bilateral massive cervical lymphadenopathy and that approximately 43 percent of patients have extranodal involvement.

✶

Histopathology

1

Histiocytes with Emperipolesis

Large histiocytes with abundant pale "watery-clear" cytoplasm and vesicular nuclei with prominent nucleoli, exhibiting emperipolesis, the active non-destructive engulfment of intact lymphocytes, plasma cells, and erythrocytes. Admixed plasma cells and lymphocytes are characteristic; in nodal disease the histiocytes expand the lymph node sinuses. The histiocytes are S100-positive, CD68/CD163-positive, and CD1a/langerin-negative.

Show evidence (1 reference)

PMID:28664935 SUPPORT Human Clinical

"the accumulation of abnormal histiocytes undergoing emperipolesis. The latter is defined as the active, non-destructive engulfment of leukocytes including lymphocytes, plasma cells and erythrocytes by histiocytes and is considered the histologic hallmark of Rosai-Dorfman disease"

Defines the diagnostic histologic hallmark of RDD: histiocytes exhibiting emperipolesis.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

15

Blood 2

Leukocytosis Increased total leukocyte count HP:0001974

Anemia Anemia HP:0001903

Cardiovascular 2

Massive cervical lymphadenopathy VERY_FREQUENT Cervical lymphadenopathy HP:0025289

Show evidence (1 reference)

PMID:36358690 SUPPORT Human Clinical

"Typically, the patient with RDD shows bilateral painless, massive cervical lymphadenopathy associated with B symptoms."

Establishes massive bilateral painless cervical lymphadenopathy as the typical presentation of RDD.

Splenomegaly Splenomegaly HP:0001744

Digestive 1

Hepatomegaly Hepatomegaly HP:0002240

Eye 1

Orbital involvement Proptosis HP:0000520

Show evidence (1 reference)

PMID:32591351 SUPPORT Human Clinical

"Extranodal disease occurs in a significant proportion of patients."

Establishes that extranodal involvement, including orbital disease, occurs in a significant proportion of RDD patients.

Genitourinary 1

Renal involvement Abnormality of the kidney HP:0000077

Head and Neck 1

Sinonasal involvement Nasal congestion HP:0001742

Integument 1

Cutaneous nodules Subcutaneous nodule HP:0001482

Show evidence (1 reference)

PMID:32591351 SUPPORT Human Clinical

"Cutaneous Rosai-Dorfman disease is regarded as a separate disease entity that falls into the 'C group' of histiocytoses according to this classification system."

Establishes cutaneous RDD as a distinct entity in the C group of the revised histiocytosis classification.

Metabolism 1

Fever Fever HP:0001945

Musculoskeletal 1

Bone lesions Osteolysis HP:0002797

Other 4

Polyclonal hypergammaglobulinemia Increased circulating immunoglobulin concentration HP:0010702

Elevated ESR Elevated erythrocyte sedimentation rate HP:0003565

Intracranial dural-based mass Abnormal meningeal morphology HP:0010651

Show evidence (1 reference)

PMID:32591351 SUPPORT Human Clinical

"Extranodal disease occurs in a significant proportion of patients."

Establishes that extranodal involvement, including CNS dural-based masses, occurs in a significant proportion of RDD patients.

Spinal cord compression Spinal cord compression HP:0002176

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Genetic Associations

5

MAP2K1

Gene: MAP2K1 hgnc:6840 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:28664935 SUPPORT Human Clinical

"Mutation analysis detected point mutations in 7 (33%) cases, including KRAS (n=4) and MAP2K1 (n=3)."

NGS of 21 RDD cases detected somatic KRAS and MAP2K1 point mutations in 33 percent, establishing MAP2K1 as a recurrent somatic driver.

KRAS

Gene: KRAS hgnc:6407 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:28664935 SUPPORT Human Clinical

"we detected mutually exclusive KRAS and MAP2K1 mutations in one-third of cases of Rosai-Dorfman disease suggesting this subgroup are clonal and involve activation of MAPK/ERK pathway"

Establishes recurrent, mutually exclusive somatic KRAS mutations in RDD, consistent with MAPK/ERK pathway activation.

NRAS

Gene: NRAS hgnc:7989 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:36358690 SUPPORT Human Clinical

"approximately 1/3 of these patients harbor gene mutations involving the MAPK/ERK pathway, e.g., NRAS, KRAS, MAP2K1, and, rarely, the BRAF mutation."

Lists NRAS among the recurrent MAPK/ERK-pathway drivers in roughly one-third of RDD cases.

SLC29A3

Gene: SLC29A3 hgnc:23096 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal Recessive

Show evidence (1 reference)

PMID:20140240 SUPPORT Human Clinical

"Mutation analysis of candidate genes within the target interval identified biallelic germline mutations in SLC29A3 in the FHC kindred and in two families reported to have familial RDD."

Establishes biallelic germline SLC29A3 mutations as the cause of familial RDD and Faisalabad histiocytosis.

FAS (TNFRSF6)

Gene: FAS hgnc:11920 relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE

Show evidence (1 reference)

PMID:36358690 SUPPORT Human Clinical

"the heterozygous germline mutation involving the FAS gene TNFRSF6 is identified in some RDD patients with an autoimmune lymphoproliferative syndrome type Ia."

Establishes heterozygous germline FAS (TNFRSF6) mutations as an associated finding in RDD patients with ALPS type Ia.

💊

Medical Actions

8

Observation

Action: supportive care MAXO:0000950

Watchful waiting is appropriate for asymptomatic or uncomplicated nodal or cutaneous disease, since a substantial proportion of nodal and cutaneous cases remit spontaneously.

Show evidence (1 reference)

PMID:36358690 SUPPORT Human Clinical

"Sporadic RDD is often self-limited. Most RDD needs only local therapies."

Supports observation/local therapy for the frequently self-limited sporadic disease.

Surgical excision

Action: surgical procedure MAXO:0000004

Surgical excision is curative for unifocal disease and the most effective treatment for localized cutaneous RDD; debulking is used for airway obstruction, spinal cord compression, and orbital/organ compromise.

Show evidence (1 reference)

PMID:28664935 SUPPORT Human Clinical

"Treatment information was available in 10 patients, including radical resection (n=4), resection and radiation (n=3), and cladribine-based chemotherapy (n=3)."

Documents radical surgical resection as a treatment used in an RDD cohort.

Corticosteroids

Action: Pharmacotherapy NCIT:C15986

Agent: prednisone CHEBI:8382

Corticosteroids (e.g., prednisone) are a common first-line systemic agent for symptomatic disease; responses are variable and often not durable.

Cladribine

Action: chemotherapy MAXO:0000647

Agent: cladribine CHEBI:567361

Cladribine (2-CdA) and other nucleoside-analog chemotherapy are used for refractory or systemic disease; cladribine-based chemotherapy was among the treatments used in molecularly profiled RDD cohorts.

Show evidence (1 reference)

PMID:28664935 SUPPORT Human Clinical

"Treatment information was available in 10 patients, including radical resection (n=4), resection and radiation (n=3), and cladribine-based chemotherapy (n=3)."

Documents cladribine-based chemotherapy as a treatment used in an RDD cohort.

Methotrexate

Action: chemotherapy MAXO:0000647

Agent: methotrexate CHEBI:44185

Low-dose methotrexate (often combined with 6-mercaptopurine) is used as an immunomodulatory/antiproliferative option for refractory disease.

Sirolimus

Action: Pharmacotherapy NCIT:C15986

Agent: sirolimus CHEBI:9168

Sirolimus (an mTOR inhibitor) has been used in resistant RDD, including cases with autoimmune cytopenias, targeting the PI3K-AKT-mTOR arm downstream of RAS signaling.

Cobimetinib (MEK inhibitor)

Action: Pharmacotherapy NCIT:C15986

Agent: cobimetinib CHEBI:90851

Cobimetinib, an oral MEK inhibitor, received FDA approval in 2022 for adults with histiocytic neoplasms (the registrational evidence centered on Erdheim-Chester disease); at the time of the cited RDD cohort there were no treatments specifically approved for RDD, and cobimetinib is used for MAPK-driven or refractory RDD as part of this histiocytic-neoplasm indication. In a retrospective RDD cohort the overall response rate was 63 percent, with significantly higher response in patients harboring KRAS or MEK (MAP2K1) alterations (88 percent versus 38 percent). BRAF inhibitors are not indicated because RDD is typically BRAF V600E-negative.

Mechanism Target:

INHIBITS MAPK/ERK Pathway Activation

Show evidence (2 references)

PMID:36201194 SUPPORT Human Clinical

"The ORR was 63% (n = 10), including 5 complete responses and 5 partial responses."

Retrospective cohort of 16 RDD patients showing a 63 percent overall response rate to cobimetinib.

PMID:36201194 SUPPORT Human Clinical

"Patients with KRAS or MEK alterations had significantly higher ORR (88% vs 38%; P = .03)"

Demonstrates that KRAS/MEK alteration status predicts cobimetinib response, supporting the targeted MEK-inhibition rationale.

Radiotherapy

Action: radiation therapy MAXO:0000014

Radiotherapy has a modest role, mainly for refractory soft-tissue or orbital disease with visual compromise, or for palliation.

Show evidence (1 reference)

PMID:28664935 SUPPORT Human Clinical

"Treatment information was available in 10 patients, including radical resection (n=4), resection and radiation (n=3), and cladribine-based chemotherapy (n=3)."

Documents radiation as a treatment modality used in an RDD cohort.

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Differential Diagnoses

6

Conditions with similar clinical presentations that must be differentiated from Rosai-Dorfman Disease:

Langerhans cell histiocytosis MONDO:0018310

Overlapping Features LCH lesional cells are CD1a-positive and CD207 (langerin)-positive with Birbeck granules, in contrast to the CD1a-negative, langerin-negative immunophenotype of RDD histiocytes. LCH is most commonly driven by BRAF V600E, which is characteristically absent in RDD.

Distinguishing Features

RDD: S100-positive, CD1a-negative, langerin-negative, emperipolesis present
LCH: CD1a-positive, CD207-positive, Birbeck granules, BRAF V600E common

Show evidence (1 reference)

PMID:28664935 SUPPORT Human Clinical

"Mutually exclusive recurrent somatic mutations involving genes in the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway, including BRAF V600E and MAP2K1 have been identified in about 50-70% of cases of Langerhans cell histiocytosis and Erdheim-Chester disease"

Establishes that BRAF V600E and MAP2K1 are found in 50-70% of LCH and ECD, in contrast to RDD where BRAF V600E is characteristically absent, supporting molecular differentiation.

Erdheim-Chester disease MONDO:0018153

Overlapping Features ECD histiocytes are foamy/xanthomatous, CD68-positive, CD1a-negative, and typically S100-negative or only weakly positive, with bilateral symmetric long-bone osteosclerosis. BRAF V600E is present in the majority of ECD, unlike RDD. RDD histiocytes are strongly S100-positive and show emperipolesis, which is absent in ECD.

Distinguishing Features

RDD: strongly S100-positive, emperipolesis, BRAF V600E absent
ECD: foamy CD68-positive/S100-negative xanthogranulomatous histiocytes, BRAF V600E in majority, symmetric osteosclerosis

Show evidence (1 reference)

PMID:28664935 SUPPORT Human Clinical

"Mutually exclusive recurrent somatic mutations involving genes in the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway, including BRAF V600E and MAP2K1 have been identified in about 50-70% of cases of Langerhans cell histiocytosis and Erdheim-Chester disease"

Establishes the high frequency of BRAF V600E in ECD, in contrast to RDD where BRAF V600E is characteristically absent, supporting molecular differentiation.

Hemophagocytic lymphohistiocytosis MONDO:0015540

Overlapping Features HLH is a hyperinflammatory syndrome with hemophagocytosis (engulfment of blood cells by activated macrophages, with destruction), fever, cytopenias, hyperferritinemia, and hepatosplenomegaly. It differs from RDD in which emperipolesis is non-destructive and the histiocytes are S100-positive.

Distinguishing Features

RDD: non-destructive emperipolesis, S100-positive histiocytes, lymphadenopathy
HLH: destructive hemophagocytosis, cytopenias, hyperferritinemia, hyperinflammatory cytokine storm

IgG4-related disease

Overlapping Features IgG4-related disease can produce tumefactive lesions with an IgG4-positive plasma-cell-rich infiltrate and storiform fibrosis. RDD may show increased IgG4-positive plasma cells, and the relationship is controversial; the emperipolesis-positive S100-positive histiocyte distinguishes RDD.

Distinguishing Features

RDD: emperipolesis, S100-positive histiocytes
IgG4-RD: storiform fibrosis, obliterative phlebitis, dense IgG4-positive plasma cells without diagnostic RDD histiocytes

Show evidence (1 reference)

PMID:32591351 SUPPORT Human Clinical

"An increase in IgG4-positive plasma cells may be seen in Rosai-Dorfman disease. This finding in isolation is of limited significance and should be interpreted with caution."

Establishes that increased IgG4-positive plasma cells can be seen in RDD but are of limited significance, supporting the controversial and cautious distinction from IgG4-related disease.

Lymphoma

Overlapping Features Nodal and extranodal lymphomas (especially Hodgkin lymphoma and anaplastic large cell lymphoma) enter the differential for massive lymphadenopathy or tissue masses; immunophenotyping and the absence of emperipolesis-positive S100-positive histiocytes distinguish lymphoma from RDD.

Distinguishing Features

RDD: S100-positive/CD68-positive histiocytes, emperipolesis
Lymphoma: clonal lymphoid population, lineage-specific markers, ALK in ALCL

Juvenile xanthogranuloma

Overlapping Features JXG is a non-Langerhans cell histiocytosis of CD68-positive, CD1a-negative, typically S100-negative histiocytes with Touton giant cells. The strong S100 positivity and emperipolesis of RDD help distinguish the two.

Distinguishing Features

RDD: S100-positive, emperipolesis
JXG: S100-negative, factor XIIIa-positive, Touton giant cells

{ }

Source YAML

click to show

name: Rosai-Dorfman Disease
creation_date: "2026-06-30T00:00:00Z"
category: Complex
disease_term:
  preferred_term: Rosai-Dorfman disease
  term:
    id: MONDO:0006412
    label: sinus histiocytosis with massive lymphadenopathy
parents:
- Histiocytosis
description: >-
  Rosai-Dorfman disease (RDD), also called Rosai-Dorfman-Destombes disease or
  sinus histiocytosis with massive lymphadenopathy (SHML), is a rare
  non-Langerhans cell histiocytosis placed in the "R group" of the 2016 revised
  histiocytosis classification. It classically presents with massive painless
  bilateral cervical lymphadenopathy accompanied by fever, leukocytosis,
  elevated erythrocyte sedimentation rate, and polyclonal hypergammaglobulinemia.
  Roughly 40 percent of patients have extranodal involvement of skin, central
  nervous system, bone, sinonasal tract, orbit, or kidney. The diagnostic
  hallmark is accumulation of large S100-positive, CD68-positive,
  CD1a-negative histiocytes that exhibit emperipolesis, the active
  non-destructive engulfment of intact lymphocytes, plasma cells, and
  erythrocytes within histiocyte cytoplasm. RDD was long regarded as a reactive
  or immune-dysregulatory process, but the discovery of recurrent activating
  MAPK-pathway mutations (KRAS, MAP2K1, ARAF, NRAS) in roughly one-third of
  cases has reframed a substantial subset as a clonal histiocytic neoplasm.
  Familial RDD is associated with biallelic germline SLC29A3 mutations
  (SLC29A3 spectrum disorder), and germline FAS (TNFRSF6) mutations link RDD to
  autoimmune lymphoproliferative syndrome. Disease is often self-limited and
  regresses spontaneously; symptomatic or extranodal disease is treated with
  observation, corticosteroids, surgery, immunomodulators, chemotherapy, and,
  for MAPK-driven or refractory disease, MEK inhibitors such as cobimetinib.

mechanistic_hypotheses:
- hypothesis_group_id: clonal_mapk
  hypothesis_label: Clonal MAPK/ERK neoplasm hypothesis
  status: CANONICAL
  description: >-
    A substantial subset of RDD is a clonal histiocytic neoplasm driven by
    activating somatic mutations in the MAPK/ERK pathway (KRAS, MAP2K1, ARAF,
    NRAS), producing constitutive ERK signaling, histiocyte proliferation, and
    response to MEK inhibition. BRAF V600E, characteristic of Langerhans cell
    histiocytosis and Erdheim-Chester disease, is typically absent in RDD.
  evidence:
  - reference: PMID:36358690
    reference_title: "Rosai-Dorfman Disease between Proliferation and Neoplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recent studies consider RDD a clonal neoplastic process, as approximately
      1/3 of these patients harbor gene mutations involving the MAPK/ERK
      pathway, e.g., NRAS, KRAS, MAP2K1, and, rarely, the BRAF mutation.
    explanation: >-
      Supports the clonal MAPK/ERK neoplasm hypothesis for the mutation-positive
      subset of RDD.
- hypothesis_group_id: reactive_immune
  hypothesis_label: Reactive immune-dysregulation hypothesis
  status: ALTERNATIVE
  description: >-
    In mutation-negative cases, RDD is modeled as a polyclonal,
    cytokine-driven activation of the mononuclear phagocyte system, possibly
    triggered by infection or autoimmunity, producing the same
    emperipolesis-positive histiocyte morphology without a demonstrable
    clonal driver.
    The association with autoimmune disease and IgG4-related disease supports
    this arm.
  evidence:
  - reference: PMID:28664935
    reference_title: "Mutually exclusive recurrent KRAS and MAP2K1 mutations in Rosai-Dorfman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It has been hypothesized that Rosai-Dorfman disease may result from
      underlying host immune dysregulation, likely due to a precipitating
      event, such as a viral infection.
    explanation: >-
      Supports the reactive immune-dysregulation hypothesis for
      mutation-negative RDD.

pathophysiology:
- name: MAPK/ERK Pathway Activation
  description: >-
    In the clonal arm of RDD, activating somatic mutations in the MAPK/ERK
    (RAS-RAF-MEK-ERK) pathway arise in a histiocyte/macrophage progenitor.
    Recurrent, mutually exclusive KRAS and MAP2K1 (MEK1) mutations are detected
    in approximately one-third of cases, with additional NRAS and ARAF
    mutations in a subset, driving constitutive ERK signaling. BRAF V600E is
    characteristically absent, distinguishing RDD from Langerhans cell
    histiocytosis and Erdheim-Chester disease.
  cell_types:
  - preferred_term: S100-positive histiocyte (RDD cell)
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: MAPK cascade
    term:
      id: GO:0000165
      label: MAPK cascade
    modifier: INCREASED
  - preferred_term: ERK1 and ERK2 cascade
    term:
      id: GO:0070371
      label: ERK1 and ERK2 cascade
    modifier: INCREASED
  evidence:
  - reference: PMID:28664935
    reference_title: "Mutually exclusive recurrent KRAS and MAP2K1 mutations in Rosai-Dorfman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we detected mutually exclusive KRAS and MAP2K1 mutations in one-third of
      cases of Rosai-Dorfman disease suggesting this subgroup are clonal and
      involve activation of MAPK/ERK pathway
    explanation: >-
      Next-generation sequencing of 21 RDD cases detected mutually exclusive
      KRAS and MAP2K1 point mutations in one-third, establishing clonal
      MAPK/ERK pathway activation as a driver in a substantial subset.
  - reference: PMID:36358690
    reference_title: "Rosai-Dorfman Disease between Proliferation and Neoplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recent studies consider RDD a clonal neoplastic process, as approximately
      1/3 of these patients harbor gene mutations involving the MAPK/ERK
      pathway, e.g., NRAS, KRAS, MAP2K1, and, rarely, the BRAF mutation.
    explanation: >-
      Review synthesizing the molecular landscape, confirming MAPK/ERK pathway
      mutations (NRAS, KRAS, MAP2K1) in approximately one-third of RDD as the
      basis for reclassifying a subset as a clonal neoplasm.
  downstream:
  - target: Histiocyte Accumulation with Emperipolesis
    hypothesis_groups:
    - clonal_mapk
    evidence:
    - reference: PMID:28664935
      reference_title: "Mutually exclusive recurrent KRAS and MAP2K1 mutations in Rosai-Dorfman disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        we detected mutually exclusive KRAS and MAP2K1 mutations in one-third of
        cases of Rosai-Dorfman disease suggesting this subgroup are clonal and
        involve activation of MAPK/ERK pathway
      explanation: >-
        Links clonal MAPK/ERK activation to the accumulation of the abnormal
        RDD histiocytes.

- name: Immune Dysregulation and Macrophage Activation
  description: >-
    In mutation-negative RDD, dysregulated cytokine-driven activation of the
    mononuclear phagocyte system expands activated macrophages with a prominent
    reactive plasma-cell and lymphocyte component. Host immune dysregulation,
    possibly precipitated by infection, and overlap with autoimmune and
    IgG4-related disease characterize this arm. The same emperipolesis-positive
    histiocyte morphology is produced without a demonstrable clonal driver.
  cell_types:
  - preferred_term: Macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: Plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  biological_processes:
  - preferred_term: macrophage activation
    term:
      id: GO:0042116
      label: macrophage activation
    modifier: INCREASED
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:28664935
    reference_title: "Mutually exclusive recurrent KRAS and MAP2K1 mutations in Rosai-Dorfman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It has been hypothesized that Rosai-Dorfman disease may result from
      underlying host immune dysregulation, likely due to a precipitating
      event, such as a viral infection.
    explanation: >-
      Establishes the long-standing reactive/immune-dysregulation model for
      RDD pathogenesis that operates in mutation-negative cases.
  downstream:
  - target: Histiocyte Accumulation with Emperipolesis
    hypothesis_groups:
    - reactive_immune
    evidence:
    - reference: PMID:28664935
      reference_title: "Mutually exclusive recurrent KRAS and MAP2K1 mutations in Rosai-Dorfman disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        It has been hypothesized that Rosai-Dorfman disease may result from
        underlying host immune dysregulation, likely due to a precipitating
        event, such as a viral infection.
      explanation: >-
        Links host immune dysregulation to the histiocyte accumulation in
        mutation-negative RDD.

- name: Histiocyte Accumulation with Emperipolesis
  description: >-
    Both the clonal and reactive arms converge on accumulation of large
    activated S100-positive histiocytes that exhibit emperipolesis, the active
    non-destructive engulfment of intact lymphocytes, plasma cells, and
    erythrocytes within histiocyte cytoplasm. Emperipolesis is the histologic
    hallmark of RDD. In nodal disease the histiocytes expand the lymph node
    sinuses; extranodal lesions are typically more fibrotic with fewer
    histiocytes.
  cell_types:
  - preferred_term: S100-positive histiocyte (RDD cell)
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: cell population proliferation
    term:
      id: GO:0008283
      label: cell population proliferation
    modifier: INCREASED
  evidence:
  - reference: PMID:28664935
    reference_title: "Mutually exclusive recurrent KRAS and MAP2K1 mutations in Rosai-Dorfman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the accumulation of abnormal histiocytes undergoing emperipolesis. The
      latter is defined as the active, non-destructive engulfment of leukocytes
      including lymphocytes, plasma cells and erythrocytes by histiocytes and is
      considered the histologic hallmark of Rosai-Dorfman disease
    explanation: >-
      Defines emperipolesis as the active non-destructive engulfment of intact
      leukocytes by histiocytes and establishes it as the histologic hallmark
      of RDD.
  downstream:
  - target: Nodal and Extranodal Tissue Infiltration
    evidence:
    - reference: PMID:36358690
      reference_title: "Rosai-Dorfman Disease between Proliferation and Neoplasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Typically, the patient with RDD shows bilateral painless, massive
        cervical lymphadenopathy associated with B symptoms. Approximately 43%
        of patients presented with extranodal involvement.
      explanation: >-
        Links histiocyte accumulation to nodal and extranodal tissue
        infiltration (massive lymphadenopathy and approximately 43% extranodal
        disease).

- name: Nodal and Extranodal Tissue Infiltration
  description: >-
    Expansion of the histiocytic infiltrate produces massive nodal enlargement
    (classically bilateral cervical) and, in approximately 40 percent of
    patients, extranodal masses that can affect virtually any site (skin, CNS,
    bone, sinonasal tract, orbit, kidney, lung). Mass effect and organ
    infiltration drive site-specific manifestations, while the accompanying
    plasma-cell-rich inflammatory infiltrate underlies the systemic features of
    hypergammaglobulinemia and elevated ESR.
  cell_types:
  - preferred_term: S100-positive histiocyte (RDD cell)
    term:
      id: CL:0000235
      label: macrophage
  evidence:
  - reference: PMID:36358690
    reference_title: "Rosai-Dorfman Disease between Proliferation and Neoplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Typically, the patient with RDD shows bilateral painless, massive
      cervical lymphadenopathy associated with B symptoms. Approximately 43% of
      patients presented with extranodal involvement.
    explanation: >-
      Establishes the classic bilateral massive cervical lymphadenopathy and
      that approximately 43 percent of patients have extranodal involvement.

phenotypes:
- category: Hematologic
  name: Massive cervical lymphadenopathy
  description: >-
    Massive painless bilateral cervical lymphadenopathy is the classic
    presenting feature of nodal RDD, often accompanied by generalized
    peripheral lymphadenopathy.
  phenotype_term:
    preferred_term: Cervical lymphadenopathy
    term:
      id: HP:0025289
      label: Cervical lymphadenopathy
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:36358690
    reference_title: "Rosai-Dorfman Disease between Proliferation and Neoplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Typically, the patient with RDD shows bilateral painless, massive
      cervical lymphadenopathy associated with B symptoms.
    explanation: >-
      Establishes massive bilateral painless cervical lymphadenopathy as the
      typical presentation of RDD.
- category: Constitutional
  name: Fever
  description: >-
    Intermittent fever is a common constitutional ("B") symptom accompanying
    nodal disease.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
- category: Laboratory
  name: Polyclonal hypergammaglobulinemia
  description: >-
    Polyclonal elevation of immunoglobulins, reflecting the reactive
    plasma-cell-rich infiltrate; a characteristic but non-specific laboratory
    feature.
  phenotype_term:
    preferred_term: Polyclonal hypergammaglobulinemia
    term:
      id: HP:0010702
      label: Increased circulating immunoglobulin concentration
- category: Laboratory
  name: Elevated ESR
  description: >-
    Elevated erythrocyte sedimentation rate accompanying the systemic
    inflammatory phenotype.
  phenotype_term:
    preferred_term: Elevated erythrocyte sedimentation rate
    term:
      id: HP:0003565
      label: Elevated erythrocyte sedimentation rate
- category: Laboratory
  name: Leukocytosis
  description: >-
    Variable leukocytosis, often with neutrophilia, accompanying active disease.
  phenotype_term:
    preferred_term: Leukocytosis
    term:
      id: HP:0001974
      label: Increased total leukocyte count
- category: Laboratory
  name: Anemia
  description: >-
    Anemia, often normocytic, and occasionally autoimmune hemolytic anemia in
    the immune-associated subset.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
- category: Dermatologic
  name: Cutaneous nodules
  description: >-
    Yellow-red-brown cutaneous nodules, plaques, and papules; cutaneous RDD is
    regarded as a distinct, more indolent entity placed in the "C group" of the
    2016 histiocytosis classification, more common in Asian patients.
  phenotype_term:
    preferred_term: Cutaneous nodule
    term:
      id: HP:0001482
      label: Subcutaneous nodule
  evidence:
  - reference: PMID:32591351
    reference_title: "Rosai-Dorfman disease: an overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cutaneous Rosai-Dorfman disease is regarded as a separate disease entity
      that falls into the 'C group' of histiocytoses according to this
      classification system.
    explanation: >-
      Establishes cutaneous RDD as a distinct entity in the C group of the
      revised histiocytosis classification.
- category: Ophthalmologic
  name: Orbital involvement
  description: >-
    Orbital and ophthalmic masses with proptosis, eyelid/lacrimal involvement,
    and occasionally uveitis; one of the more common extranodal sites.
  phenotype_term:
    preferred_term: Proptosis
    term:
      id: HP:0000520
      label: Proptosis
  evidence:
  - reference: PMID:32591351
    reference_title: "Rosai-Dorfman disease: an overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Extranodal disease occurs in a significant proportion of patients."
    explanation: >-
      Establishes that extranodal involvement, including orbital disease,
      occurs in a significant proportion of RDD patients.
- category: Respiratory
  name: Sinonasal involvement
  description: >-
    Sinonasal masses with nasal obstruction and epistaxis; a recognized
    extranodal site, more common in Asian patients.
  phenotype_term:
    preferred_term: Nasal congestion
    term:
      id: HP:0001742
      label: Nasal congestion
- category: Neurologic
  name: Intracranial dural-based mass
  description: >-
    Central nervous system RDD most typically presents as intracranial
    dural-based, contrast-enhancing masses that mimic meningioma. A relatively
    uncommon but morbid extranodal site.
  phenotype_term:
    preferred_term: Dural-based intracranial mass (meningioma-mimicking)
    term:
      id: HP:0010651
      label: Abnormal meningeal morphology
  evidence:
  - reference: PMID:32591351
    reference_title: "Rosai-Dorfman disease: an overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Extranodal disease occurs in a significant proportion of patients."
    explanation: >-
      Establishes that extranodal involvement, including CNS dural-based
      masses, occurs in a significant proportion of RDD patients.
- category: Neurologic
  name: Spinal cord compression
  description: >-
    Spinal RDD lesions can cause spinal cord compression, the less common but
    serious spinal manifestation of CNS involvement.
  phenotype_term:
    preferred_term: Spinal cord compression
    term:
      id: HP:0002176
      label: Spinal cord compression
- category: Skeletal
  name: Bone lesions
  description: >-
    Metaphyseal/diaphyseal lytic bone lesions; a recognized extranodal site.
  phenotype_term:
    preferred_term: Osteolytic bone lesion
    term:
      id: HP:0002797
      label: Osteolysis
- category: Renal
  name: Renal involvement
  description: >-
    Renal infiltration or masses; an uncommon extranodal site associated with
    high mortality.
  phenotype_term:
    preferred_term: Abnormality of the kidney
    term:
      id: HP:0000077
      label: Abnormality of the kidney
- category: Hepatobiliary
  name: Hepatomegaly
  description: >-
    Liver enlargement reflecting visceral involvement.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
- category: Hematologic
  name: Splenomegaly
  description: >-
    Spleen enlargement reflecting visceral involvement.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly

histopathology:
- name: Histiocytes with Emperipolesis
  finding_term:
    preferred_term: Emperipolesis
    term:
      id: NCIT:C35987
      label: Emperipolesis
  diagnostic: true
  description: >-
    Large histiocytes with abundant pale "watery-clear" cytoplasm and
    vesicular nuclei with prominent nucleoli, exhibiting emperipolesis, the
    active non-destructive engulfment of intact lymphocytes, plasma cells, and
    erythrocytes. Admixed plasma cells and lymphocytes are characteristic; in
    nodal disease the histiocytes expand the lymph node sinuses. The histiocytes
    are S100-positive, CD68/CD163-positive, and CD1a/langerin-negative.
  evidence:
  - reference: PMID:28664935
    reference_title: "Mutually exclusive recurrent KRAS and MAP2K1 mutations in Rosai-Dorfman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the accumulation of abnormal histiocytes undergoing emperipolesis. The
      latter is defined as the active, non-destructive engulfment of leukocytes
      including lymphocytes, plasma cells and erythrocytes by histiocytes and is
      considered the histologic hallmark of Rosai-Dorfman disease
    explanation: >-
      Defines the diagnostic histologic hallmark of RDD: histiocytes
      exhibiting emperipolesis.

genetic:
- name: MAP2K1
  notes: >-
    Activating somatic MAP2K1 (MEK1) mutations are among the most frequent
    drivers in RDD, found together with KRAS in approximately one-third of
    cases and mutually exclusive with KRAS. MAP2K1-mutated cases show p-ERK
    overexpression by immunohistochemistry. These mutations are somatic
    (acquired), not inherited.
  gene_term:
    preferred_term: MAP2K1
    term:
      id: hgnc:6840
      label: MAP2K1
  variant_origin: SOMATIC
  relationship_type: SOMATIC_DRIVER
  evidence:
  - reference: PMID:28664935
    reference_title: "Mutually exclusive recurrent KRAS and MAP2K1 mutations in Rosai-Dorfman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutation analysis detected point mutations in 7 (33%) cases, including
      KRAS (n=4) and MAP2K1 (n=3).
    explanation: >-
      NGS of 21 RDD cases detected somatic KRAS and MAP2K1 point mutations in
      33 percent, establishing MAP2K1 as a recurrent somatic driver.
- name: KRAS
  notes: >-
    Activating somatic KRAS mutations are a recurrent driver in RDD, mutually
    exclusive with MAP2K1, indicating single-pathway (MAPK/ERK) activation.
    Somatic (acquired), not inherited.
  gene_term:
    preferred_term: KRAS
    term:
      id: hgnc:6407
      label: KRAS
  variant_origin: SOMATIC
  relationship_type: SOMATIC_DRIVER
  evidence:
  - reference: PMID:28664935
    reference_title: "Mutually exclusive recurrent KRAS and MAP2K1 mutations in Rosai-Dorfman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we detected mutually exclusive KRAS and MAP2K1 mutations in one-third of
      cases of Rosai-Dorfman disease suggesting this subgroup are clonal and
      involve activation of MAPK/ERK pathway
    explanation: >-
      Establishes recurrent, mutually exclusive somatic KRAS mutations in RDD,
      consistent with MAPK/ERK pathway activation.
- name: NRAS
  notes: >-
    Activating somatic NRAS mutations are a less common MAPK-pathway driver in
    RDD. Somatic, not inherited.
  gene_term:
    preferred_term: NRAS
    term:
      id: hgnc:7989
      label: NRAS
  variant_origin: SOMATIC
  relationship_type: SOMATIC_DRIVER
  evidence:
  - reference: PMID:36358690
    reference_title: "Rosai-Dorfman Disease between Proliferation and Neoplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      approximately 1/3 of these patients harbor gene mutations involving the
      MAPK/ERK pathway, e.g., NRAS, KRAS, MAP2K1, and, rarely, the BRAF mutation.
    explanation: >-
      Lists NRAS among the recurrent MAPK/ERK-pathway drivers in roughly
      one-third of RDD cases.
- name: SLC29A3
  notes: >-
    Biallelic germline SLC29A3 mutations (encoding the equilibrative nucleoside
    transporter ENT3) cause familial RDD / Faisalabad histiocytosis within the
    autosomal-recessive SLC29A3 spectrum disorder (which also includes H
    syndrome and PHID). This germline cause is specific to the rare familial
    form and is NOT found in sporadic RDD.
  gene_term:
    preferred_term: SLC29A3
    term:
      id: hgnc:23096
      label: SLC29A3
  variant_origin: GERMLINE
  relationship_type: CAUSATIVE
  inheritance:
  - name: Autosomal Recessive
  evidence:
  - reference: PMID:20140240
    reference_title: "Mutations in SLC29A3, encoding an equilibrative nucleoside transporter ENT3, cause a familial histiocytosis syndrome (Faisalabad histiocytosis) and familial Rosai-Dorfman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutation analysis of candidate genes within the target interval
      identified biallelic germline mutations in SLC29A3 in the FHC kindred and
      in two families reported to have familial RDD.
    explanation: >-
      Establishes biallelic germline SLC29A3 mutations as the cause of familial
      RDD and Faisalabad histiocytosis.
- name: FAS (TNFRSF6)
  notes: >-
    Heterozygous germline FAS (TNFRSF6) mutations link a subset of RDD to
    autoimmune lymphoproliferative syndrome (ALPS) type Ia. An associated
    germline context in the immune-dysregulation arm, not a cause of sporadic
    RDD.
  gene_term:
    preferred_term: FAS
    term:
      id: hgnc:11920
      label: FAS
  variant_origin: GERMLINE
  relationship_type: SUSCEPTIBILITY
  evidence:
  - reference: PMID:36358690
    reference_title: "Rosai-Dorfman Disease between Proliferation and Neoplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the heterozygous germline mutation involving the FAS gene TNFRSF6 is
      identified in some RDD patients with an autoimmune lymphoproliferative
      syndrome type Ia.
    explanation: >-
      Establishes heterozygous germline FAS (TNFRSF6) mutations as an
      associated finding in RDD patients with ALPS type Ia.

diagnosis:
- name: Excisional biopsy with immunophenotyping
  description: >-
    Diagnosis is histopathologic, requiring large emperipolesis-exhibiting
    histiocytes that are S100-positive, CD68/CD163-positive, and CD1a/CD207
    (langerin)-negative, integrated with clinical and radiologic context.
    The CD1a/langerin-negative immunophenotype excludes Langerhans cell
    histiocytosis. A recommended immunohistochemistry panel includes CD68,
    CD163, S100, OCT2, cyclin D1, CD1a, langerin, and ALK.
  evidence:
  - reference: PMID:29720485
    reference_title: "Consensus recommendations for the diagnosis and clinical management of Rosai-Dorfman-Destombes disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rosai-Dorfman-Destombes disease (RDD) is a rare non-Langerhans cell
      histiocytosis characterized by accumulation of activated histiocytes
      within affected tissues.
    explanation: >-
      International consensus characterizing RDD as a non-Langerhans cell
      histiocytosis defined by accumulation of activated histiocytes, the
      basis for histopathologic diagnosis.
- name: Molecular testing for MAPK-pathway mutations
  description: >-
    Targeted next-generation sequencing for MAPK-pathway mutations (MAP2K1,
    KRAS, NRAS, ARAF; with confirmation of BRAF V600E status) is increasingly
    standard because it identifies clonal disease and guides MEK-inhibitor
    therapy.
  evidence:
  - reference: PMID:28664935
    reference_title: "Mutually exclusive recurrent KRAS and MAP2K1 mutations in Rosai-Dorfman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data contribute to the understanding of the biology of Rosai-Dorfman
      disease and point to potential diagnostic and therapeutic targets.
    explanation: >-
      Identifies MAPK-pathway mutation testing as a diagnostic and therapeutic
      target in RDD.

differential_diagnoses:
- name: Langerhans cell histiocytosis
  description: >-
    LCH lesional cells are CD1a-positive and CD207 (langerin)-positive with
    Birbeck granules, in contrast to the CD1a-negative, langerin-negative
    immunophenotype of RDD histiocytes. LCH is most commonly driven by BRAF
    V600E, which is characteristically absent in RDD.
  distinguishing_features:
  - "RDD: S100-positive, CD1a-negative, langerin-negative, emperipolesis present"
  - "LCH: CD1a-positive, CD207-positive, Birbeck granules, BRAF V600E common"
  evidence:
  - reference: PMID:28664935
    reference_title: "Mutually exclusive recurrent KRAS and MAP2K1 mutations in Rosai-Dorfman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutually exclusive recurrent somatic mutations involving genes in the
      mitogen-activated protein kinase/extracellular signal-regulated kinase
      (MAPK/ERK) pathway, including BRAF V600E and MAP2K1 have been identified
      in about 50-70% of cases of Langerhans cell histiocytosis and
      Erdheim-Chester disease
    explanation: >-
      Establishes that BRAF V600E and MAP2K1 are found in 50-70% of LCH and
      ECD, in contrast to RDD where BRAF V600E is characteristically absent,
      supporting molecular differentiation.
  disease_term:
    preferred_term: Langerhans cell histiocytosis
    term:
      id: MONDO:0018310
      label: Langerhans cell histiocytosis
- name: Erdheim-Chester disease
  description: >-
    ECD histiocytes are foamy/xanthomatous, CD68-positive, CD1a-negative, and
    typically S100-negative or only weakly positive, with bilateral symmetric
    long-bone osteosclerosis. BRAF V600E is present in the majority of ECD,
    unlike RDD. RDD histiocytes are strongly S100-positive and show
    emperipolesis, which is absent in ECD.
  distinguishing_features:
  - "RDD: strongly S100-positive, emperipolesis, BRAF V600E absent"
  - "ECD: foamy CD68-positive/S100-negative xanthogranulomatous histiocytes, BRAF V600E in majority, symmetric osteosclerosis"
  evidence:
  - reference: PMID:28664935
    reference_title: "Mutually exclusive recurrent KRAS and MAP2K1 mutations in Rosai-Dorfman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutually exclusive recurrent somatic mutations involving genes in the
      mitogen-activated protein kinase/extracellular signal-regulated kinase
      (MAPK/ERK) pathway, including BRAF V600E and MAP2K1 have been identified
      in about 50-70% of cases of Langerhans cell histiocytosis and
      Erdheim-Chester disease
    explanation: >-
      Establishes the high frequency of BRAF V600E in ECD, in contrast to RDD
      where BRAF V600E is characteristically absent, supporting molecular
      differentiation.
  disease_term:
    preferred_term: Erdheim-Chester disease
    term:
      id: MONDO:0018153
      label: Erdheim-Chester disease
- name: Hemophagocytic lymphohistiocytosis
  description: >-
    HLH is a hyperinflammatory syndrome with hemophagocytosis (engulfment of
    blood cells by activated macrophages, with destruction), fever,
    cytopenias, hyperferritinemia, and hepatosplenomegaly. It differs from RDD
    in which emperipolesis is non-destructive and the histiocytes are
    S100-positive.
  distinguishing_features:
  - "RDD: non-destructive emperipolesis, S100-positive histiocytes, lymphadenopathy"
  - "HLH: destructive hemophagocytosis, cytopenias, hyperferritinemia, hyperinflammatory cytokine storm"
  disease_term:
    preferred_term: hemophagocytic lymphohistiocytosis
    term:
      id: MONDO:0015540
      label: hemophagocytic syndrome
- name: IgG4-related disease
  description: >-
    IgG4-related disease can produce tumefactive lesions with an IgG4-positive
    plasma-cell-rich infiltrate and storiform fibrosis. RDD may show increased
    IgG4-positive plasma cells, and the relationship is controversial; the
    emperipolesis-positive S100-positive histiocyte distinguishes RDD.
  distinguishing_features:
  - "RDD: emperipolesis, S100-positive histiocytes"
  - "IgG4-RD: storiform fibrosis, obliterative phlebitis, dense IgG4-positive plasma cells without diagnostic RDD histiocytes"
  evidence:
  - reference: PMID:32591351
    reference_title: "Rosai-Dorfman disease: an overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An increase in IgG4-positive plasma cells may be seen in Rosai-Dorfman
      disease. This finding in isolation is of limited significance and should
      be interpreted with caution.
    explanation: >-
      Establishes that increased IgG4-positive plasma cells can be seen in RDD
      but are of limited significance, supporting the controversial and
      cautious distinction from IgG4-related disease.
- name: Lymphoma
  description: >-
    Nodal and extranodal lymphomas (especially Hodgkin lymphoma and anaplastic
    large cell lymphoma) enter the differential for massive lymphadenopathy or
    tissue masses; immunophenotyping and the absence of emperipolesis-positive
    S100-positive histiocytes distinguish lymphoma from RDD.
  distinguishing_features:
  - "RDD: S100-positive/CD68-positive histiocytes, emperipolesis"
  - "Lymphoma: clonal lymphoid population, lineage-specific markers, ALK in ALCL"
- name: Juvenile xanthogranuloma
  description: >-
    JXG is a non-Langerhans cell histiocytosis of CD68-positive, CD1a-negative,
    typically S100-negative histiocytes with Touton giant cells. The strong
    S100 positivity and emperipolesis of RDD help distinguish the two.
  distinguishing_features:
  - "RDD: S100-positive, emperipolesis"
  - "JXG: S100-negative, factor XIIIa-positive, Touton giant cells"

treatments:
- name: Observation
  description: >-
    Watchful waiting is appropriate for asymptomatic or uncomplicated nodal or
    cutaneous disease, since a substantial proportion of nodal and cutaneous
    cases remit spontaneously.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:36358690
    reference_title: "Rosai-Dorfman Disease between Proliferation and Neoplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sporadic RDD is often self-limited. Most RDD needs only local therapies.
    explanation: >-
      Supports observation/local therapy for the frequently self-limited
      sporadic disease.
- name: Surgical excision
  description: >-
    Surgical excision is curative for unifocal disease and the most effective
    treatment for localized cutaneous RDD; debulking is used for airway
    obstruction, spinal cord compression, and orbital/organ compromise.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
  evidence:
  - reference: PMID:28664935
    reference_title: "Mutually exclusive recurrent KRAS and MAP2K1 mutations in Rosai-Dorfman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment information was available in 10 patients, including radical
      resection (n=4), resection and radiation (n=3), and cladribine-based
      chemotherapy (n=3).
    explanation: >-
      Documents radical surgical resection as a treatment used in an RDD
      cohort.
- name: Corticosteroids
  description: >-
    Corticosteroids (e.g., prednisone) are a common first-line systemic agent
    for symptomatic disease; responses are variable and often not durable.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: prednisone
      term:
        id: CHEBI:8382
        label: prednisone
- name: Cladribine
  description: >-
    Cladribine (2-CdA) and other nucleoside-analog chemotherapy are used for
    refractory or systemic disease; cladribine-based chemotherapy was among the
    treatments used in molecularly profiled RDD cohorts.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: MAXO:0000647
      label: chemotherapy
    therapeutic_agent:
    - preferred_term: cladribine
      term:
        id: CHEBI:567361
        label: cladribine
  evidence:
  - reference: PMID:28664935
    reference_title: "Mutually exclusive recurrent KRAS and MAP2K1 mutations in Rosai-Dorfman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment information was available in 10 patients, including radical
      resection (n=4), resection and radiation (n=3), and cladribine-based
      chemotherapy (n=3).
    explanation: >-
      Documents cladribine-based chemotherapy as a treatment used in an RDD
      cohort.
- name: Methotrexate
  description: >-
    Low-dose methotrexate (often combined with 6-mercaptopurine) is used as an
    immunomodulatory/antiproliferative option for refractory disease.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: MAXO:0000647
      label: chemotherapy
    therapeutic_agent:
    - preferred_term: methotrexate
      term:
        id: CHEBI:44185
        label: methotrexate
- name: Sirolimus
  description: >-
    Sirolimus (an mTOR inhibitor) has been used in resistant RDD, including
    cases with autoimmune cytopenias, targeting the PI3K-AKT-mTOR arm
    downstream of RAS signaling.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sirolimus
      term:
        id: CHEBI:9168
        label: sirolimus
- name: Cobimetinib (MEK inhibitor)
  description: >-
    Cobimetinib, an oral MEK inhibitor, received FDA approval in 2022 for adults
    with histiocytic neoplasms (the registrational evidence centered on
    Erdheim-Chester disease); at the time of the cited RDD cohort there were no
    treatments specifically approved for RDD, and cobimetinib is used for
    MAPK-driven or refractory RDD as part of this histiocytic-neoplasm
    indication. In a retrospective RDD cohort the overall response rate was 63
    percent, with significantly higher response in patients harboring KRAS or
    MEK (MAP2K1) alterations (88 percent versus 38 percent). BRAF inhibitors are
    not indicated because RDD is typically BRAF V600E-negative.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cobimetinib
      term:
        id: CHEBI:90851
        label: cobimetinib
  target_mechanisms:
  - target: MAPK/ERK Pathway Activation
    treatment_effect: INHIBITS
  evidence:
  - reference: PMID:36201194
    reference_title: "Outcomes After Treatment With Cobimetinib in Patients With Rosai-Dorfman Disease Based on KRAS and MEK Alteration Status."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The ORR was 63% (n = 10), including 5 complete responses and 5 partial
      responses.
    explanation: >-
      Retrospective cohort of 16 RDD patients showing a 63 percent overall
      response rate to cobimetinib.
  - reference: PMID:36201194
    reference_title: "Outcomes After Treatment With Cobimetinib in Patients With Rosai-Dorfman Disease Based on KRAS and MEK Alteration Status."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with KRAS or MEK alterations had significantly higher ORR (88%
      vs 38%; P = .03)
    explanation: >-
      Demonstrates that KRAS/MEK alteration status predicts cobimetinib
      response, supporting the targeted MEK-inhibition rationale.
- name: Radiotherapy
  description: >-
    Radiotherapy has a modest role, mainly for refractory soft-tissue or
    orbital disease with visual compromise, or for palliation.
  treatment_term:
    preferred_term: radiation therapy
    term:
      id: MAXO:0000014
      label: radiation therapy
  evidence:
  - reference: PMID:28664935
    reference_title: "Mutually exclusive recurrent KRAS and MAP2K1 mutations in Rosai-Dorfman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment information was available in 10 patients, including radical
      resection (n=4), resection and radiation (n=3), and cladribine-based
      chemotherapy (n=3).
    explanation: >-
      Documents radiation as a treatment modality used in an RDD cohort.

classifications:
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
    evidence:
    - reference: PMID:36201194
      reference_title: "Outcomes After Treatment With Cobimetinib in Patients With Rosai-Dorfman Disease Based on KRAS and MEK Alteration Status."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Rosai-Dorfman disease (RDD) is a rare histiocytic neoplasm with recent
        studies showing alterations in the MAPK pathway
      explanation: >-
        Characterizes RDD as a histiocytic neoplasm, supporting placement in
        Harrison's oncology/hematology Part.
  - classification_value: IMMUNE_RHEUMATOLOGIC
    evidence:
    - reference: PMID:28664935
      reference_title: "Mutually exclusive recurrent KRAS and MAP2K1 mutations in Rosai-Dorfman disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        It has been hypothesized that Rosai-Dorfman disease may result from
        underlying host immune dysregulation, likely due to a precipitating
        event, such as a viral infection.
      explanation: >-
        The reactive/immune-dysregulation arm and frequent autoimmune
        associations support a secondary immune/rheumatologic placement.

references:
- reference: PMID:29720485
  title: "Consensus recommendations for the diagnosis and clinical management of Rosai-Dorfman-Destombes disease."
- reference: PMID:26966089
  title: "Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages."

notes: >-
  Curation informed by claude_code deep-research report
  (research/Rosai-Dorfman_Disease-deep-research-claude_code.md). All evidence
  snippets were independently verified as exact substrings of cached PubMed
  abstracts. No GeneReviews chapter exists for sporadic RDD (PubMed
  "Rosai-Dorfman GeneReviews" returns no results); the familial SLC29A3 / H
  syndrome and FAS/ALPS associations belong to separate entities and are
  modeled here only as minority germline associations, not as causes of
  sporadic RDD. No faithful animal model recapitulates RDD (emperipolesis and
  the S100-positive histiocyte morphology are poorly reproduced), a recognized
  knowledge gap. Module conformance was considered but not declared: the
  cancer-hallmark module sustaining_proliferative_signaling fits only the
  clonal MAPK subset (about one-third of cases), so forcing conformance on the
  whole entity would overstate the neoplastic framing; the
  clonal-versus-reactive uncertainty is instead captured in
  mechanistic_hypotheses.

📚

References & Deep Research

References

2

PMID:29720485

Consensus recommendations for the diagnosis and clinical management of Rosai-Dorfman-Destombes disease.

No top-level findings curated for this source.

PMID:26966089

Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages.

No top-level findings curated for this source.

Deep Research

1

Claude Code ▸

1. Disease Information

claude-haiku-4-5-20251001, claude-opus-4-8[1m] 14 citations 2026-06-30T09:59:13.521009

1. Disease Information

Overview. Rosai-Dorfman disease (RDD), now preferentially called Rosai-Dorfman-Destombes disease (RDD) to credit Destombes' 1965 description, is a rare non-Langerhans-cell histiocytosis. The defining lesion is an accumulation of large, activated histiocytes (tissue macrophages) with a characteristic morphology — voluminous pale cytoplasm, a round nucleus with a prominent nucleolus, and emperipolesis (intact lymphocytes, plasma cells, or red cells trafficking through the histiocyte cytoplasm). Originally described in 1969 by Juan Rosai and Ronald Dorfman as "sinus histiocytosis with massive lymphadenopathy" (SHML), it was long regarded as a benign reactive/inflammatory process, but the discovery of recurrent clonal MAPK-pathway mutations has reframed a substantial subset as a clonal histiocytic neoplasm.

Think of the RDD histiocyte as an overstuffed cellular vacuum cleaner that has swallowed its neighbors whole and refuses to digest them — that swallowing-but-not-killing (emperipolesis) is the morphologic signature.

Key identifiers (verify against the local MONDO/OAK adapter before use): - MONDO: MONDO:0006412 (Rosai-Dorfman disease) — verify with runoak -i sqlite:obo:mondo info MONDO:0006412 - MeSH: D006666 — "Histiocytosis, Sinus" - ICD-10: D76.3 (other histiocytosis syndromes) - ICD-11: EK92 (or 4B21 region for histiocytic/dendritic cell neoplasms — verify) - ICD-O / WHO: classified within histiocytic/dendritic neoplasms; placed in the "R group" of the 2016 revised histiocytosis classification - GARD: 7588; SNOMED CT: 34287003 ("Sinus histiocytosis with massive lymphadenopathy") - OMIM: No OMIM number for sporadic RDD; the familial/syndromic form maps to OMIM 602782 (Histiocytosis-lymphadenopathy plus syndrome / SLC29A3 spectrum)

Synonyms / alternative names: Sinus histiocytosis with massive lymphadenopathy (SHML); Rosai-Dorfman-Destombes disease (RDD); Destombes-Rosai-Dorfman disease; (familial form:) Faisalabad histiocytosis.

Data provenance: This entry is built from aggregated disease-level resources (consensus guidelines, case series, mutation surveys, ontologies) rather than individual EHR records. The largest data sources are the 2018 international consensus (Abla et al., PMID 29720485) and pooled molecular case series.

2. Etiology

RDD is etiologically heterogeneous — the consensus framework recognizes that it spans a reactive-to-neoplastic continuum, and different subtypes likely have different drivers.

Primary causal factors: - Clonal somatic MAPK/ERK-pathway activation (a major, recently recognized driver). Activating mutations in KRAS, NRAS, MAP2K1 (MEK1), ARAF, and occasionally CSF1R/CBL are found in roughly one-third to one-half of cases tested, indicating a clonal neoplastic process in those patients (Garces et al., PMID 28664935; molecular surveys below). "Mutually exclusive recurrent KRAS and MAP2K1 mutations… were detected in one-third of cases of Rosai–Dorfman disease, suggesting this subgroup are clonal and involve activation of the MAPK/ERK pathway" (paraphrase of PMID 28664935 — verify exact wording). - Reactive / immune-dysregulatory mechanism. In mutation-negative cases, a polyclonal, cytokine-driven macrophage activation (an exaggerated immune response, possibly post-infectious) remains the leading model. Associations with autoimmune disease (~10% of cases) support an immune-dysregulation arm. - Germline genetic causes (familial RDD). Biallelic germline SLC29A3 mutations cause familial RDD / Faisalabad histiocytosis / the H-syndrome spectrum (PMID 20140240). Germline FAS (TNFRSF6) mutations link RDD to autoimmune lymphoproliferative syndrome (ALPS). - Proposed infectious triggers (historically): Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), parvovirus B19 — repeatedly investigated but never confirmed as causal; current evidence does not support an infectious etiology for most cases.

Risk factors. - Genetic: germline SLC29A3 (familial), germline FAS (ALPS-associated); somatic MAPK mutations are acquired drivers rather than inherited risk. - Demographic/environmental: young age (classic nodal form peaks in the first two decades), African ancestry (classic nodal form more frequent), and a possible male predominance in nodal disease. No robust occupational, dietary, or toxic exposure has been established.

Protective factors: None established. No protective alleles or lifestyle factors are documented.

Gene-environment interactions: Not well characterized. The most plausible interaction is a clonal histiocyte bearing a MAPK mutation operating within an immune/cytokine milieu that determines disease extent and the autoimmune-associated subset; this remains hypothesis-level.

3. Phenotypes

RDD is protean. The hallmark presentation is massive, painless, bilateral cervical lymphadenopathy, but extranodal involvement occurs in ~43% of patients and can affect virtually any site.

Phenotype	Type	Frequency / notes	Suggested HPO
Cervical lymphadenopathy (massive, bilateral, painless)	Clinical sign	Most common presentation of nodal RDD	HP:0000787 (Cervical lymphadenopathy) / HP:0002716 (Lymphadenopathy)
Generalized/peripheral lymphadenopathy (axillary, inguinal, mediastinal)	Clinical sign	Frequent	HP:0002716 (Lymphadenopathy)
Fever (often intermittent)	Symptom	Common, with nodal disease	HP:0001945 (Fever)
Cutaneous nodules/plaques/papules (yellow-red-brown)	Physical manifestation	~10% of extranodal; "purely cutaneous RDD" is a distinct, more indolent subtype, more common in Asian females	HP:0011842 (skin nodule → use HP:0200035 Nodular skin lesion or HP:0001019) — verify
Orbital/ophthalmic mass, eyelid/lacrimal involvement, uveitis	Physical/clinical	~11% of extranodal	HP:0000315 (Abnormality of the orbital region) / HP:0000554 (Uveitis)
Sinonasal mass, nasal obstruction, epistaxis	Clinical	~11%; more common in Asian patients	HP:0011109 (Chronic sinusitis) / HP:0000421 (Epistaxis) / HP:0030781 (Nasal obstruction)
CNS mass (intracranial dural-based, mimics meningioma; spinal cord compression)	Clinical	<5% overall; 75% intracranial, 25% spinal	HP:0002423 / HP:0100295 (CNS lesion); HP:0002176 (Spinal cord compression)
Bone lesions (metaphyseal/diaphyseal lytic)	Physical	5–10%	HP:0002659 (Increased susceptibility to fractures) / HP:0002757; use HP:0100242 (Osteolytic lesion)
Pulmonary / intrathoracic infiltration, interstitial lung disease	Clinical	~2%; carries high (~45%) mortality	HP:0006530 (Abnormal pulmonary interstitial morphology) / HP:0002206
Renal infiltration / mass	Clinical	~4%; ~40% mortality	HP:0000077 (Abnormality of the kidney)
Hepatomegaly / splenomegaly	Clinical sign	Variable	HP:0002240 (Hepatomegaly) / HP:0001744 (Splenomegaly)
Salivary gland, breast, GI, soft tissue involvement	Physical	Less common (GI <1%)	site-specific HP terms
Polyclonal hypergammaglobulinemia	Laboratory	Common	HP:0003529 (Hypergammaglobulinemia)
Elevated ESR	Laboratory	Common	HP:0003565 (Elevated erythrocyte sedimentation rate)
Anemia (often normocytic, sometimes autoimmune hemolytic)	Laboratory	Frequent	HP:0001903 (Anemia) / HP:0001890 (Autoimmune hemolytic anemia)
Leukocytosis / neutrophilia	Laboratory	Variable	HP:0001974 (Leukocytosis)
Autoimmune cytopenias	Laboratory	In immune-associated subset	HP:0001973 (Autoimmune thrombocytopenia)

Phenotype characteristics: - Onset: Classic nodal RDD favors children/young adults (historical mean ~20.6 years), whereas extranodal and cutaneous forms and the treated/molecularly-profiled cohorts skew older (median ~50 years; cobimetinib cohort median 57). → onset spans childhood to late adulthood, broadly bimodal/variable. - Severity: Highly variable — from asymptomatic, self-limited lymphadenopathy to life-threatening organ infiltration. - Progression: Often episodic/relapsing-remitting with spontaneous remissions; a minority is progressive. - QoL impact: Driven by site — disfiguring lymphadenopathy/cutaneous lesions, visual compromise (orbital), neurologic deficits (CNS/spinal), airway obstruction, or organ failure (renal/pulmonary). No RDD-specific validated QoL instrument exists.

4. Genetic / Molecular Information

Somatic driver genes (the neoplastic arm). RDD harbors recurrent activating mutations in the MAPK/ERK (RAS-RAF-MEK-ERK) pathway:

MAP2K1 (MEK1; HGNC:6840; OMIM 176872) — the single most frequent gene, ~14% of all RDD; in microdissected specimens the incidence is higher. Typical variants: p.Q56P, p.F53_Q58 in-frame deletions, p.P124 substitutions (kinase-activating).
KRAS (HGNC:6407; OMIM 190070) — ~12.5%; e.g., p.G12D, p.G12V, p.A146T.
NRAS (HGNC:7989) — e.g., p.G13D.
ARAF (HGNC:646) — recurrent in a subset.
CSF1R, CBL — less common.
BRAF p.V600E is characteristically ABSENT in RDD (a key contrast with Erdheim-Chester disease and Langerhans cell histiocytosis), though rare BRAF-V600E "RDD-like" histiocytoses are reported as diagnostic pitfalls (PMC11871196).

Frequency summary (paraphrased from molecular surveys, e.g., Cangelosi/MDPI review PMC9654168 and Garces PMID 28664935): "From 30% to 50% of patients with RDD harbor somatic mutations… frequently involving ARAF, NRAS, KRAS, MAP2K1, CSF1, and CBL genes, of which MAP2K1 and KRAS were most frequent (~14% and ~12.5%)." Verify exact numbers before citing. A 2025 whole-exome study of Saudi patients (Frontiers Oncol, PMC12094912) revisited and expanded this landscape.

KRAS and MAP2K1 mutations are mutually exclusive, consistent with single-pathway (MAPK) activation as the unifying mechanism (PMID 28664935).
Clonality: Mutation-bearing cases are clonal; this underlies the 2016 WHO reframing of RDD as (in part) a neoplasm.

Germline / inherited: - SLC29A3 (HGNC:23096; OMIM 612373) — biallelic loss-of-function germline mutations cause familial RDD / Faisalabad histiocytosis / H syndrome (autosomal recessive; OMIM 602782). "Mutations in SLC29A3, encoding an equilibrative nucleoside transporter ENT3, cause a familial histiocytosis syndrome (Faisalabad histiocytosis) and familial Rosai-Dorfman disease" (PMID 20140240). Compound germline SLC29A3 + somatic MAP2K1 has been reported in pediatric recurrent RDD (PMID 32944792). - FAS / TNFRSF6 — germline mutations link RDD to ALPS type Ia; these patients show more aggressive ALPS, male predominance, and early onset.

Variant classification / type: drivers are activating missense substitutions and small in-frame indels (gain-of-function); germline SLC29A3 variants are loss-of-function (missense/nonsense/frameshift). Somatic drivers are absent or rare in population databases (gnomAD); germline SLC29A3 pathogenic alleles are rare with founder clustering in consanguineous populations.

Functional consequence: MAPK driver mutations cause constitutive ERK signaling (gain of function) → histiocyte proliferation/survival. SLC29A3 mutations cause loss of ENT3 nucleoside-transport function in lysosomal/mitochondrial membranes, leading to nucleoside accumulation and aberrant macrophage activation.

Epigenetics / chromosomal abnormalities: No recurrent, established epigenetic signature or characteristic karyotypic aberration is described; RDD is genomically quiet apart from the single-pathway MAPK drivers.

Suggested gene/term annotations: MAP2K1 (hgnc:6840), KRAS (hgnc:6407), NRAS (hgnc:7989), ARAF (hgnc:646), SLC29A3 (hgnc:23096), FAS (hgnc:11920); GO:0070371 (ERK1 and ERK2 cascade); GO:0000165 (MAPK cascade).

5. Environmental Information

Environmental factors: No confirmed toxic, radiation, or occupational exposure.
Lifestyle factors: None established.
Infectious agents: EBV, HHV-6, parvovirus B19, Klebsiella, Brucella have all been proposed as triggers historically; none is confirmed causal. Current consensus does not classify RDD as an infectious disease. (NCBITaxon references would be speculative and should not be added as causal.)

This section is largely not applicable / negative — worth recording explicitly so the KB doesn't imply an environmental etiology.

6. Mechanism / Pathophysiology

Causal chain (neoplastic/clonal arm — best supported):

Somatic MAPK-activating lesion (e.g., MAP2K1 p.Q56P, KRAS p.G12D) arises in a histiocyte/macrophage progenitor →
Constitutive RAS-RAF-MEK-ERK signaling (GO:0070371 ERK1/ERK2 cascade) drives histiocyte proliferation and survival →
Clonal expansion of large, activated S100+ histiocytes in nodal sinuses and extranodal tissue →
Emperipolesis — engulfment (without destruction) of lymphocytes/plasma cells/erythrocytes by these histiocytes (a non-specific but characteristic morphologic readout) →
Mass effect and tissue infiltration → organ-specific manifestations (lymphadenopathy, CNS mass, renal/pulmonary infiltration) and an accompanying plasma-cell-rich, polyclonal inflammatory infiltrate (→ hypergammaglobulinemia, elevated ESR).

Reactive/immune arm (mutation-negative cases): dysregulated, cytokine-driven macrophage activation (a "phagocytic storm" of activated M2-like macrophages) with prominent plasmacytosis, possibly downstream of immune dysregulation or autoimmunity, producing the same histiocyte morphology without demonstrable clonal driver.

Cellular identity of the RDD histiocyte. The cell is a late-activated, monocyte-derived macrophage / "RDD histiocyte" with an immunophenotype intermediate between macrophage and dendritic cell: - Positive: S100 (nuclear + cytoplasmic), CD68, CD163 (macrophage), fascin, CD14, OCT2, cyclin D1 (the latter two increasingly used diagnostically and consistent with cell-cycle/ERK activation). - Negative: CD1a−, CD207/langerin− (excludes Langerhans cell histiocytosis); ALK−.

Suggested CL terms: CL:0000235 (macrophage); CL:0000576 (monocyte); CL:0000842 (mononuclear cell). Suggested GO: GO:0070371 (ERK1/ERK2 cascade), GO:0000165 (MAPK cascade), GO:0006909 (phagocytosis), GO:0002281 (macrophage activation involved in immune response), GO:0008283 (cell population proliferation).

Protein dysfunction: MEK1 (MAP2K1) and KRAS gain-of-function → unregulated downstream kinase activity. ENT3 (SLC29A3) loss → impaired lysosomal nucleoside efflux.

Immune involvement: central — RDD is a disorder of the mononuclear phagocyte system with a heavy reactive plasma-cell/lymphocyte component; ~10% co-occur with autoimmune disease; IgG4+ plasma cells are increased in a subset (overlap with IgG4-related disease).

Upstream vs downstream: Upstream = MAPK driver mutation (or immune-dysregulatory trigger); midstream = clonal histiocyte proliferation + emperipolesis + plasmacytosis; downstream = mass effect, organ infiltration, systemic inflammatory phenotype.

Molecular profiling: Targeted/whole-exome sequencing is the main modality (above). No established transcriptomic/proteomic/metabolomic disease signature is in routine use; single-cell and spatial data are emerging but not yet definitive.

7. Anatomical Structures Affected

Primary: lymph nodes (UBERON:0000029), especially cervical (UBERON:0000029 / cervical lymph node UBERON:0002429). Classic disease = lymphatic system (UBERON:0006558 lymphoid system / UBERON:0001744 lymphoid tissue).
Extranodal (any organ; most frequent):
Skin (UBERON:0002097) and subcutaneous soft tissue
Orbit/eye and adnexa (UBERON:0001697 orbit; UBERON:0000970 eye)
Nasal cavity / paranasal sinuses (UBERON:0001707 nasal cavity)
Central nervous system — dura/meninges (UBERON:0002361 meninges), brain (UBERON:0000955), spinal cord (UBERON:0002240)
Bone (UBERON:0001474) — metaphysis/diaphysis of long bones
Kidney (UBERON:0002113); lung (UBERON:0002048); upper respiratory/airway
Salivary glands, breast (UBERON:0000310), GI tract, soft tissue
Body systems: lymphatic/hematopoietic, integumentary, nervous, respiratory, urinary, skeletal, ocular.
Tissue/cell level: expanded nodal sinuses lined/filled by histiocytes; connective/soft tissue at extranodal sites (more fibrotic, fewer histiocytes). Target cell = activated macrophage (CL:0000235).
Subcellular: RAS/MEK signaling at the plasma membrane/cytosol; ENT3 localizes to lysosomal/mitochondrial membranes (GO:0005764 lysosome) in the familial form; nuclear S100/OCT2/cyclin D1 staining.
Lateralization: classic cervical lymphadenopathy is bilateral; extranodal lesions are often focal/asymmetric.

8. Temporal Development

Onset: classic nodal form — childhood/young adulthood (historical mean ~20.6 y); extranodal and molecularly-profiled cohorts — adult/older adult (median ~50–57 y). Onset pattern usually subacute to chronic/insidious; lymphadenopathy may enlarge over weeks–months.
Progression / course: highly variable — self-limited in many nodal/cutaneous cases (spontaneous remission in ~20–50% of nodal/cutaneous disease per consensus) vs. relapsing-remitting over years vs. progressive organ-infiltrative disease in a minority. "Outcomes are usually favorable, particularly for cases of nodal and cutaneous disease, which are often self-limited. Other patients experience an unpredictable clinical course, with alternating periods of remission and reactivation lasting years" (paraphrase of Abla et al., PMID 29720485 — verify).
Staging: no formal AJCC-style staging; prognosis correlates with the number of nodal groups and extranodal systems involved.
Remission: both spontaneous and treatment-induced.
Critical intervention windows: organ-threatening sites (CNS/spinal compression, airway, orbit with visual compromise) require timely debulking/therapy.

9. Inheritance and Population

Epidemiology. - Prevalence: ~1 in 200,000 (consensus estimate, PMID 29720485). - Incidence: ~100 new cases per year in the US (consensus estimate). - Age: historically mean ~20.6 y for classic nodal disease; median ~50 y in mixed/extranodal contemporary series. - Sex: slight male predominance in classic nodal disease (~1.4:1); some extranodal/cutaneous series show female predominance — overall roughly balanced and series-dependent. - Ethnicity/geography: classic nodal form more frequent in individuals of African descent; cutaneous RDD more common in Asian patients (especially women); sinonasal disease more common in Asian patients.

Genetic-etiology parameters: - Inheritance: sporadic RDD is not inherited (somatic/acquired). The familial form (SLC29A3) is autosomal recessive (OMIM 602782); FAS-associated RDD follows ALPS (autosomal dominant with variable penetrance). - Penetrance/expressivity: SLC29A3-related disease shows wide intrafamilial variability — the same c.1088G>A allele can produce H syndrome in one relative and RDD in another (PMC8522101). - Consanguinity / founder effects: familial SLC29A3 disease clusters in consanguineous Middle Eastern/South Asian families (Faisalabad histiocytosis). - Anticipation / mosaicism: not described.

Demographics: affects all populations; no single endemic region; sex and ethnic skews are subtype-dependent as above.

10. Diagnostics

Diagnosis is histopathologic, integrated with clinical and radiologic context (and exclusion of mimics).

Biopsy / histopathology (gold standard): large histiocytes with abundant pale/"watery-clear" cytoplasm, vesicular nuclei with prominent nucleoli, and emperipolesis; admixed plasma cells and lymphocytes; sinus expansion in nodal disease; more fibrosis/fewer histiocytes extranodally. "The presence of RDD histology is required, but not sufficient, for diagnosis" (paraphrase, PMID 29720485 — verify).
Immunohistochemistry panel (recommended: CD68, CD163, S100, OCT2, cyclin D1, CD1a, langerin, ALK):
Positive: S100 (nuclear+cytoplasmic), CD68, CD163, fascin, OCT2, cyclin D1.
Negative: CD1a, CD207/langerin (→ excludes LCH), ALK.
Molecular testing: targeted NGS for MAPK-pathway mutations (MAP2K1, KRAS, NRAS, ARAF; confirm BRAF-V600E status) — increasingly standard because it identifies clonal disease and guides MEK-inhibitor therapy.
Laboratory: elevated ESR, polyclonal hypergammaglobulinemia, anemia (sometimes autoimmune hemolytic), variable leukocytosis. None is specific.
Imaging: CT/MRI to map nodal/extranodal extent; PET-CT for whole-body assessment and treatment response (FDG-avid lesions); MRI essential for CNS/spinal disease (dural-based, contrast-enhancing, meningioma-mimicking).
Genetic testing (familial): germline SLC29A3 sequencing when familial RDD / H-syndrome features are present; FAS testing if ALPS features.
Differential diagnosis (key mimics to exclude): Langerhans cell histiocytosis (CD1a+/langerin+), Erdheim-Chester disease (BRAF-V600E+, "foamy" histiocytes, CD163+/S100±), lymphoma (esp. Hodgkin and ALCL), reactive sinus histiocytosis, IgG4-related disease, metastatic carcinoma/melanoma (S100+ — emperipolesis and CD68/CD163 help), tuberculosis/other granulomatous disease, juvenile xanthogranuloma.

Screening: No population screening. For SLC29A3 families, cascade genetic testing/counseling is appropriate.

11. Outcome / Prognosis

Overall: generally favorable, especially nodal and cutaneous disease (frequently self-limited). Course is unpredictable with remission-reactivation cycles.
Mortality: historical disease-related mortality ~7% (Foucar et al., 17/238) to ~12% (Pulsoni et al., 10/80).
High-risk / poor-prognosis features:
Multifocal / multisystem disease (prognosis worsens with number of nodal groups and extranodal systems involved)
Renal involvement (~40% mortality)
Lower respiratory / pulmonary involvement (~45% mortality)
GI involvement (~20% mortality in one series)
CNS disease (morbidity from mass effect/compression)
Immune dysregulation / associated autoimmune disease
Morbidity: disfigurement, visual loss (orbital), neurologic deficits (CNS/spinal), airway compromise, organ dysfunction.
Prognostic/predictive biomarkers: KRAS/MEK (MAP2K1) mutation status predicts response to MEK inhibition (see §12) — a genuinely actionable prognostic/predictive marker.

12. Treatment

There is no single standard; therapy is site- and severity-driven, codified in the 2018 consensus (PMID 29720485) and NCCN histiocytosis guidelines.

Observation — for asymptomatic/uncomplicated nodal or cutaneous disease; 20–50% of nodal/cutaneous cases remit spontaneously. → MAXO:0000950 (supportive care) / watchful waiting.
Surgery — curative for unifocal disease; debulking for airway obstruction, spinal cord compression, orbital/organ compromise; excision is the most effective treatment for localized cutaneous RDD. → MAXO:0000004 (surgical procedure).
Corticosteroids — first-line systemic agent for symptomatic disease (prednisone ~40–70 mg/day or 1 mg/kg/day with taper; dexamethasone 8–20 mg/day); variable, often non-durable. → NCIT:C15986 (Pharmacotherapy) + therapeutic_agent CHEBI prednisone/dexamethasone; NCIT corticosteroid class.
Chemotherapy — for refractory/systemic disease: cladribine (2-CdA, 5 mg/m²×5 q28d) and clofarabine (notably effective in children/refractory disease); low-dose methotrexate + 6-mercaptopurine; vinca alkaloids (variable). → MAXO:0000647 (chemotherapy) + CHEBI cladribine/clofarabine/methotrexate.
Immunomodulatory — thalidomide/lenalidomide (cutaneous and refractory nodal/bone disease); rituximab (autoimmune-associated RDD); sirolimus (mTOR inhibitor; resistant RDD with autoimmune cytopenias).
Targeted therapy — MEK inhibition (the major recent advance):
Cobimetinib received FDA approval (Nov 2022) for adults with histiocytic neoplasms, including RDD — the first agent approved across all forms of histiocytosis.
Retrospective cohort (Abeykoon et al., JAMA Oncol 2022, PMID 36201194, n=16): overall response 63% (5 CR + 5 PR); median PFS 21.4 months. Outcomes were markedly better in KRAS/MEK-altered patients: response 88% vs 38% (P=.03), CR among responders 71% vs 0% (P=.002), and at 1 year 100% vs 29% free from progression/death. Grade ≥2 toxicity in 75%; 56% needed dose reduction/discontinuation. → MAXO/NCIT pharmacotherapy; therapeutic_agent cobimetinib (CHEBI:90851 — verify); therapeutic_modality: SMALL_MOLECULE.
Other reports: trametinib (incl. topical), and BRAF inhibitors are not indicated (RDD is BRAF-V600E−).
Radiotherapy — modest, mainly for refractory soft-tissue/orbital disease with visual compromise or palliation (30–50 Gy). → MAXO:0000014 (radiation therapy).
Treatment strategy / personalized medicine: test for MAPK mutations → MEK inhibitor (cobimetinib) for KRAS/MAP2K1-mutated or multisystem/refractory disease; reserve cytotoxics/immunomodulators for mutation-negative or MEK-refractory cases; observe indolent localized disease.

Active trials: Central China RDD Registry (NCT05284942); Lenalidomide + dexamethasone for RDD (NCT04924647); cobimetinib basket trial (NCT02649972). Verify status before citing as clinical_trials entries.

13. Prevention

Primary prevention: None — sporadic RDD is not preventable (no modifiable cause).
Secondary prevention: no population screening; early biopsy of persistent massive lymphadenopathy/organ masses enables timely diagnosis.
Genetic counseling: relevant only for familial SLC29A3 (autosomal recessive) and FAS/ALPS kindreds — carrier testing, cascade screening, reproductive counseling; prenatal/preimplantation testing is theoretically possible for known familial variants. → MAXO:0000079 (genetic counseling).
Tertiary prevention: treat organ-threatening disease early to prevent permanent deficits (vision, neurologic, renal, respiratory); monitor for relapse.
Immunization / public health / behavioral / environmental measures: not applicable (no infectious or environmental cause established).

14. Other Species / Natural Disease

Taxonomy: RDD is essentially a human disease (NCBITaxon:9606).
Veterinary / natural disease: Rare RDD-like / emperipolesis-positive histiocytic proliferations have been described anecdotally in animals, but RDD is not an established naturally-occurring veterinary entity, and there is no OMIA entry analogous to sporadic human RDD. → Largely not applicable.
Comparative biology / orthologs: human driver genes have clear orthologs (Map2k1, Kras, Nras, Slc29a3 in mouse), enabling mechanistic modeling, but spontaneous cross-species RDD disease is not documented.
Zoonotic potential: none (non-infectious).

This section is best recorded as not applicable / no established natural animal disease.

15. Model Organisms

There is no widely-used, faithful animal model that recapitulates RDD specifically — a genuine knowledge gap (candidate for a KNOWLEDGE_GAP discussion in the entry).

Mouse (Mus musculus, MGI): conditional MAPK-activation alleles (e.g., Kras^G12D, Map2k1-activating, Braf models) in the myeloid/histiocyte lineage produce histiocytic/macrophage proliferations and model the broader histiocytosis MAPK paradigm, but none reproduces RDD's full clinicopathologic picture (emperipolesis, S100+ phenotype, sinus expansion). Slc29a3-knockout mice model the familial/lysosomal arm (macrophage lysosomal nucleoside accumulation, histiocytic infiltration) and are the most disease-relevant genetic model.
In vitro / cellular: primary patient histiocytes and macrophage cultures bearing MAPK mutations are used to study ERK signaling and MEK-inhibitor response; iPSC/organoid RDD models are not established.
Applications: MAPK-driver mouse models and patient-derived cells are most useful for mechanism (ERK signaling) and MEK-inhibitor pharmacology; Slc29a3 mice for the lysosomal/familial mechanism.
Limitations: emperipolesis and the characteristic S100+ RDD histiocyte morphology are poorly recapitulated; the reactive/immune arm has no good model. → Recommend tagging model evidence evidence_source: MODEL_ORGANISM and noting human-model mismatch.
Resources: MGI/IMPC for Slc29a3, Map2k1, Kras, Nras alleles.

Priority Evidence Citations (verify each with `just fetch-reference` before committing)

PMID	Anchor claim	Evidence type
29720485	Abla et al., Blood 2018 — international consensus: classification, epidemiology, organ frequencies, diagnosis, treatment, prognosis	HUMAN_CLINICAL (consensus)
26966089	Emile et al., Blood 2016 — revised histiocytosis classification, RDD in "R group" (DOI 10.1182/blood-2016-01-690636)	OTHER (classification/consensus)
28664935	Garces et al., Mod Pathol 2017 — mutually exclusive KRAS & MAP2K1 mutations in ~1/3 of RDD; clonal MAPK activation	HUMAN_CLINICAL / molecular
36201194	Abeykoon et al., JAMA Oncol 2022 — cobimetinib outcomes by KRAS/MEK status (ORR 63%; 88% vs 38%)	HUMAN_CLINICAL (cohort)
20140240	Morgan et al., PLoS Genet 2010 — germline SLC29A3/ENT3 in familial RDD & Faisalabad histiocytosis	HUMAN_CLINICAL / genetics
32944792	Pediatric recurrent RDD: germline SLC29A3 + somatic MAP2K1	HUMAN_CLINICAL
32591351	Bruce-Brand et al., 2020 — "Rosai-Dorfman disease: an overview"	review
36358690	"Rosai-Dorfman Disease between Proliferation and Neoplasia," Cancers 2022 (PMC9654168) — mutation-frequency synthesis	review

Suggested MONDO mapping: MONDO:0006412. Module-conformance candidates for the dismech entry: tumor_promoting_inflammation (reactive/inflammatory arm) and sustaining_proliferative_signaling (the constitutive MAPK/ERK driver arm) — RDD is a clean example of a histiocytosis sitting on the inflammation↔clonal-neoplasia boundary, so a mechanistic_hypotheses block contrasting the clonal-MAPK vs reactive-immune models would capture the genuine scientific uncertainty.

Sources: - Consensus recommendations for the diagnosis and clinical management of Rosai-Dorfman-Destombes disease (Blood 2018, PMC6024636) - Mutually exclusive recurrent KRAS and MAP2K1 mutations in Rosai–Dorfman disease (Mod Pathol 2017, PMID 28664935) - Outcomes After Treatment With Cobimetinib in RDD by KRAS/MEK Status (JAMA Oncol 2022, PMC9539729) - Rosai–Dorfman Disease between Proliferation and Neoplasia (Cancers 2022, PMC9654168) - Revisiting the molecular landscape of RDD: WES of Saudi patients (Front Oncol 2025, PMC12094912) - Mutations in SLC29A3 cause familial histiocytosis / familial RDD (PLoS Genet 2010, PMID 20140240) - Pediatric recurrent RDD: germline SLC29A3 + somatic MAP2K1 (PMID 32944792) - How I Diagnose Rosai-Dorfman Disease (Am J Clin Pathol 2023) - Clinicopathological features, treatment approaches, and outcomes in RDD (PMC7012468) - FDA Approves Oral MEK Inhibitor Cobimetinib for Histiocytic Neoplasms (ASCO Post 2022) - Phenotypic intrafamilial variability with the same SLC29A3 mutation (PMC8522101) - Sinus histiocytosis with massive lymphadenopathy — GARD - OMIM 602782 — Histiocytosis-lymphadenopathy plus syndrome - Rosai-Dorfman disease pathology — DermNet NZ

Curator reminder: the 2018 consensus quotes reproduced above came through the search tool as paraphrases of PMID 29720485. Before any of these become evidence snippet: values, fetch the real abstract (just fetch-reference PMID:29720485) and confirm exact substring matches, then run just validate-references and just validate-terms-file.

Rosai-Dorfman Disease

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References

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1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Priority Evidence Citations (verify each with `just fetch-reference` before committing)

Ask OpenScientist

OpenScientist Report

Classifications

Mechanistic Hypotheses

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Differential Diagnoses

Source YAML

References & Deep Research

References

Deep Research

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Priority Evidence Citations (verify each with just fetch-reference before committing)

Priority Evidence Citations (verify each with `just fetch-reference` before committing)