Lymph nodes & spleen, nonlymphoma

Lymph nodes-inflammatory / reactive disorders

Rosai-Dorfman disease (RDD)

Authors: Aishwarya Ravindran, M.B.B.S., Karen L. Rech, M.D.

Editorial Board Member: Elizabeth Courville, M.D.

Deputy Editor-in-Chief: Genevieve M. Crane, M.D., Ph.D.

Topic Completed: 6 August 2021

Minor changes: 6 August 2021

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Table of Contents

Cite this page: Ravindran A, Rech KL. Rosai-Dorfman disease (RDD). PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphnodessinushistiocytosiswithmassivelymph.html. Accessed January 18th, 2022.

Definition / general

Rare, non-Langerhans cell histiocytosis with heterogeneous clinical features
Described in 1960s as a self limiting condition involving the lymph nodes (Arch Pathol 1969;87:63)
Extranodal involvement in approximately 40% of cases; may be limited or disseminated disease (Blood 2018;131:2877)
May be familial or associated with neoplasia or immune disease (Blood 2016;127:2672)

Essential features

Clinical features depend on the site(s) involved and disease associations
Classic (nodal) Rosai-Dorfman disease (RDD) and cutaneous RDD often self limited and benign
Disseminated RDD may have an aggressive clinical course necessitating systemic therapies (Haematologica 2020;105:348, Blood 2018;131:2877)
Approximately 33% of cases harbor clonal mitogen activated protein kinase / extracellular signal regulated kinase (MAPK / ERK) pathway alterations (Mod Pathol 2017;30:1367, Haematologica 2020;105:e5)

Terminology

Initially described by Destombes as adenitis with lipid excess (Bull Soc Pathol Exot Filiales 1965;58:1169)
Rosai and Dorfman described as sinus histiocytosis with massive lymphadenopathy (Arch Pathol 1969;87:63)
Classified in the R group (nodal and extranodal disease) and the C group (cutaneous disease only) under the revised classification of histiocytic disorders (Blood 2016;127:2672)

ICD coding

ICD-10: D76.3 - Rosai-Dorfman disease

Epidemiology

Mean age at diagnosis: 50 years (range 2 - 79) (Haematologica 2020;105:348)
F:M = 1.5:1

Sites

Lymph node involvement common (30 - 50%) (Am J Surg Pathol 2021;45:35, Blood 2018;131:2877)
Skin is the most common extranodal site (50%)
Other extranodal sites include bone, upper respiratory tract (sinus), central nervous system including dura and parenchymal lesions, orbit, retroperitoneum (Mayo Clin Proc 2019;94:2054)

Etiology

Pathogenesis unclear and likely multifactorial
Association with immune disease suggests that immune dysregulation may play a role in pathogenesis
Subset harbor MAPK / ERK pathway alterations, suggesting a pathogenesis similar to Langerhans cell histiocytosis and Erdheim-Chester disease (Mod Pathol 2017;30:1367, Cancer Discov 2016;6:154)

Clinical features

Heterogeneous clinical course, depending on the site of involvement
Associated conditions include autoimmune disorders (systemic lupus erythematosus, idiopathic juvenile arthritis, autoimmune hemolytic anemia), neoplasia such as lymphomas and myeloid neoplasms and IgG4 related RDD characterized by increased IgG4 positive plasma cells (Blood 2018;131:2877, Haematologica 2020;105:348)
Classic (nodal) RDD presents as enlarged lymph nodes, most commonly involving bilateral cervical nodes in young males
Extranodal RDD manifests with diverse clinical presentations (Blood 2018;131:2877)
- Cutaneous lesions present as slow growing, painless nodules, papules or plaques
- Neurologic involvement may present with headache, seizures, motor / sensory abnormalities and gait disturbances
- Orbital involvement may present with exophthalmos or visual disturbance
- Sinus involvement may display nasal congestion or obstruction
- Pulmonary RDD can present with dry cough, dyspnea and may mimic primary lung cancer, interstitial lung disease and other inflammatory / infectious conditions
- Retroperitoneal involvement may present as diffuse infiltration and less commonly a discrete mass with or without hydronephrosis and ureteral obstruction
Multisystem involvement in approximately 20% cases and prognosis related to the number of extranodal sites
Rosai-Dorfman disease may be a component of mixed histiocytosis with Langerhans cell histiocytosis or Erdheim-Chester disease (Mod Pathol 2010;23:1616, Haematologica 2020;105:e5)

Diagnosis

Comprehensive evaluation, including clinical history, physical examination and imaging studies in conjunction with morphologic features
RDD may be associated with other histiocytic neoplasms, including Langerhans cell histiocytosis and Erdheim-Chester disease, which should be confirmed by biopsy in the setting of atypical clinical manifestations (Mod Pathol 2010;23:1616, Haematologica 2020;105:e5)

Radiology description

Nodal involvement on PET CT harboring RDD shows increased central intake with a photopenic halo (Mayo Clin Proc 2019;94:2054)
Extranodal involvement may show the following findings:
- CNS involvement often presents as hyperattenuating meningeal based mass showing contrast enhancement on CT (Asian J Neurosurg 2010;5:19)
  - Skeletal RDD lesions are usually lytic and centered in medullary space (Mayo Clin Proc 2019;94:2054)
  - Pulmonary involvement may present as cystic change, interstitial lung disease, nodules, focal pulmonary infiltrate or airway disease
  - Sinus involvement may present with maxillary wall thickening
  - Retroperitoneum involvement may present as renal hilar masses, subcapsular hypodense infiltration or renal cortical hypodense nodules

Radiology images

Images hosted on other servers:

Imaging findings in RDD

Prognostic factors

Optimal duration of treatment with systemic therapy is individualized, depending on the extent of involvement
Usually favorable outcomes in cases with nodal and cutaneous involvement
Subset may demonstrate aggressive clinical course usually associated with multifocal involvement (Haematologica 2020;105:348)

Case reports

10 year old boy with polyuria and polydipsia (Front Med (Lausanne) 2020;7:613756)
12 year old boy with dyspnea and left sided chest pain presented with interatrial septal mass (J Radiol Case Rep 2012;6:1)
29 year old woman with arthralgias in the hands and knees and lytic lesions of the left distal radius (Curr Rheumatol Rep 2017;19:29)
41 year old man with paravertebral mass (J Int Med Res 2017;45:875)
53 year old man with diminished vision of right eye associated with a palpable mass (J Microsc Ultrastruct 2019;7:50)
57 year old woman with progressive vision loss (Head Neck Pathol 2016;10:414)

Treatment

Management varies, depending on the site of involvement and the presence / absence of symptoms (Blood 2018;131:2877)
Nodal / cutaneous involvement usually self limited and requires only observation
Surgical resection may be considered in symptomatic cases with single site of involvement
Multifocal and refractory cases may require systemic therapy (first line therapy with cladribine, cytarabine, methotrexate or prednisone)
Targeted therapy with MEK inhibitors is under investigation in those with MAPK / ERK pathway alterations (Haematologica 2020;105:348)

Microscopic (histologic) description

Characterized by the accumulation of histiocytes with enlarged, round to oval hypochromatic nuclei and abundant eosinophilic cytoplasm, often containing engulfed intact inflammatory cells known as emperipolesis (Am J Surg Pathol 2021;45:35)
Lesional histiocytes usually associated with fibrosis and prominent inflammatory infiltrate comprised of plasma cells and lymphocytes
Occasional neutrophilic infiltrates are present
Nodal involvement is characterized by distended sinuses with lesional histiocytes
Rosai-Dorfman disease is rarely detected as an incidental finding concomitantly with lymphoma in the same biopsy specimen (Mod Pathol 2019;32:16)

Microscopic (histologic) images

Contributed by Aishwarya Ravindran, M.B.B.S. and Karen L. Rech, M.D.

Excisional biopsy of
subcutaneous mass

CD163

S100

OCT2

Cyclin D1

Positive stains

Monocyte / macrophage markers: CD68, CD163, OCT2
S100, cyclin D1 / BCL1
Reference: Am J Surg Pathol 2021;45:35

Negative stains

Molecular / cytogenetics description

Approximately 33% of cases harbor mutually exclusive recurrent KRAS and MAP2K1 mutations (Mod Pathol 2017;30:1367)
Germline mutations in SLC29A3 gene may be present in familial cases of RDD (Blood 2016;127:2672)

Sample pathology report

Lymph node, right axillary, excisional biopsy:
Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy) (see comment)
- Comment: Histologic examination shows distended lymph node sinuses containing a prominent population of histiocytes characterized by large, round nuclei and voluminous cytoplasm showing emperipolesis with engulfment of lymphocytes. The lymphoplasmacytic infiltrate within the lymph node parenchyma is cytologically unremarkable. Immunohistochemistry shows that the atypical histiocytes within the lymph node sinuses are positive for CD68, CD163 with coexpression of S100, OCT2 and cyclin D1. They are negative for BRAF V600E by immunohistochemistry. There is no increase in the number of IgG4 positive plasma cells or an abnormal IgG4/IgG ratio. CD3 and CD20 reveal an appropriate mixture of T cells and B cells, respectively. Kappa and lambda immunoglobulin light chains reveal polytypic plasma cells. CD1a and langerin are negative.

Differential diagnosis

Sinus histiocytosis:
- Reactive process characterized by prominent sinuses in lymph nodes containing normal histiocytes
- Immunostains for S100, cyclin D1 and OCT2 are negative
Langerhans cell histiocytosis:
- Langerhans cells are characterized by their irregular, grooved, folded or indented nuclei with fine chromatin, inconspicuous nucleoli and abundant pale eosinophilic cytoplasm
- Positive for CD1a and langerin
Erdheim-Chester disease:
- Bland appearing histiocytes characterized by abundant foamy (xanthomatous) cytoplasm with surrounding fibrosis (Mod Pathol 2018;31:581)
- Touton giant cells are frequently present
- Positive for CD68, CD163, factor XIIIa and negative for OCT2 expression by immunohistochemistry (Am J Surg Pathol 2021;45:35)
- Clinical, radiologic and morphologic correlation required (Mayo Clin Proc 2019;94:2054)
Juvenile xanthogranuloma:
- Usually in infants and young children
- Histologically and phenotypically similar to Erdheim-Chester disease
Low grade B cell lymphoma:
- Lymphoplasmacytic infiltrate with monotypic expression of immunoglobulin light chains
- Absence of S100, OCT2 positive histiocytes

Board review style question #1

A 47 year old woman presented with multiple skin nodules on bilateral arms that were gradually increasing in size over 6 months. Based on the morphology, which of the following is the most likely diagnosis?

Follicular dendritic cell sarcoma
Juvenile xanthogranuloma
Langerhans cell histiocytosis
Reactive process
Rosai-Dorfman disease

Board review style answer #1

E. Rosai-Dorfman disease

Comment Here

Reference: Rosai-Dorfman disease (RDD)

Board review style question #2

Lesional cells in sinus histiocytosis with massive lymphadenopathy show positive expression of which of the following immunostains?

AE1 / AE3, CAM5.2, CK34βE12
CD117, DOG1, muscle specific actin
Cyclin D1, S100 and OCT2
Desmin, MyoD1, myogenin
SMA, p63, p40

Board review style answer #2

C. Cyclin D1, S100 and OCT2 (Am J Surg Pathol 2021;45:35)

Comment Here

Reference: Rosai-Dorfman disease (RDD)