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Rosai-Dorfman Disease

Updated May 2024

Simeon Lauer, MD

Establishing the diagnosis

Etiology

    • Synonym = sinus histiocytosis with massive lymphadenopathy (Arch Pathol 1969; 87:63).
    • Many etiologic agents have been postulated including varicella-zoster and cytomegalovirus
    • Parvovirus (J Clin Pathol 2006; 59:1320) and its B19 capsid proteins VP1/VP2 have been identified as a possible etiologic agent (J Hematol Oncol 2008; 1:1).
    • Postulated to be a hyperstimulation of humoral immunity.
      • Patients have high levels of anti-infectious antibodies including:
        • anti-streptolysin
        • anti-Epstein–Barr virus
        • anti-human herpesvirus 6
        • anti-syphilis
        • polyclonal gammopathy.
    • Direct microbial invasion has been suggested – but cultures negative
      • Salmonella
      • Klebsiella
      • Brucella
    • Autoimmune dysfunction or aberrant response to unspecified antigen

Epidemiology

    • Typically a disease of the young but can occur at any age
      • Average age at onset is 20 years old.
    • No racial predilection.
    • Slight male predominance.
    • Sporadic Rosai-Dorfman can be subclassified as nodal, extranodal, neoplasia-associated and autoimmune-associated (Bruce-Brand, 2020)
    • Rosai Dorfman can rarely be familial (Bruce-Brand, 2020)
    • Some Rosai Dorfman cases are clonal, with a variety of different mutations (Bruce-Brand, 2020)

History

    • Ocular involvement typically presents as lid swelling.
    • Proptosis, may be bilateral.
    • Lacrimal gland enlargement.
    • Originally described in association with massive bilateral cervical lymphadenopathy
      • Extranodal disease may be isolated, even if multifocal, without lymphadenopathy.
    • Malaise symptoms
      • Fever
      • Fatigue
      • Night sweats

Clinical features including less common presentation patterns

    • Extranodal disease in the ocular adnexa, and at may other extranodal sites, often presents without lymphadenopathy (J Craniofacial Surgery 2010; 21:1733).
    • Extranodal disease has a predilection for the head and neck region.
    • Among 97 patients who presented with bilateral lacrimal gland enlargement, three had Rosai Dorfman disease (Ophthalmology 2014; PAP).
    • May mimic an optic nerve tumor (J Ped Ophthalmol Strab 2003; 40:172).
    • May exhibit optic neuropathy (J Neuro-Oncol 2003; 61:137).
    • May produce uveitis (Chang Gung Med J 2002; 25:621).
    • May also present as an eyelid lesion, intraocular or epibulbar mass, corneal infiltrate (Tan, 2016).
    • Ocular involvement appears to be associated with more systemic disease, as opposed to orbital involvement, which is more likely to be limited (Choi, 2018).

Testing and evaluation for establishing the diagnosis

    • Hypergammaglobulinemia.
    • CT and MRI shows soft tissue mass without bony destruction.
    • May involve lid and/or orbit.
    • Hilar and mediastinal adenopathy may be prominent in patients with systemic adenopathy, mimicking sarcoidosis (Hematol Am Soc Hematol Educ Progr 2004; 1:283).  
    • Biopsy is preferred over fine needle aspiration, when practical.
      • Polymorphous cell population with plasma cells, lymphocytes, large histiocytes and neutrophils.
      • Histiocytes have abundant foamy cytoplasm with vesicular nuclei and few, small inconspicuous nucleoli.
      • Characteristic finding in histiocytes is emperipolesis, where plasma cells, lymphocytes and/or neutrophils are engulfed by the histiocytes.   
    • Rubbery and firm with surrounding fibrosis.
    • Fine needle aspiration and cytopathologic diagnosis possible (J Cytol 2011; 28:131).
    • Describe appropriate testing and evaluation to determine staging or level of fundamental impairment

Risk factors

  • Age is not a risk factor for presentation
    • May be a risk factor for prognosis
    • Deaths reported in pediatric population

List the differential diagnosis

  • Langerhans cell histiocytosis – rod shaped Birbeck granules are not seen.
  • Malignant histiocytosis
  • Plasma cell granuloma
  • Idiopathic orbital inflammation – some IgG4 plasma cells may be evident in the orbit of Rosai Dorfman disease (Orbit 2013; 32:315).
    • S-100 positive macrophages favor Rosai Dorfman disease.

Patient management: treatment and follow-up

Natural history including common variants in disease evolution

    • Observation is preferred for clinically stable patients (Am J Hematol 2002; 69:67).
      • Spontaneous regression is typical

Medical therapy options

    • Systemic corticosteroids may be effective (Eur J Cancer Care 2007; 16:286).
    • Uniquely, resistance to prednisone and response to dexamethasome has been reported (Ped Blood Canc 2005; 44:92)
    • Intralesional triamcinolone injection may be effective
    • Low dose methotrexate may be effective (JAMA Dermatol 2014; 150:787).
      • Starting dose can be 15 mg once weekly
      • Tapered to 5 mg once weekly over 3-4 months
    • Cyclosporine may also target T-lymphocytes
    • Rituximab to concurrently target B-lymphocytes (Am J Hematol 2007; 82:1121.

Radiation therapy options

    • Low dose radiotherapy may be used as adjuvant therapy to reduce systemic toxicity of medical therapy.
    • In a review of 80 published cases, 9 were treated with radiotherapy and 3 complete remissions were obtained (Am J Hematol 2002; 69:67).

Surgery options

    • Complete excision (Indian J Ophthalmol 2008; 56:507) or debulking is preferred (Ophth Plas Recon Surg 2006; 22:163)

Other management considerations

    • Referral to oncologist is appropriate because of association with lymphoma (Internal Med 2004; 43:741).
      • Bone marrow biopsy may show malignant lymphoma, despite biopsy evidence of Rosai-Dorfman elsewhere.

Patient management: follow-up and secondary treatment

  • Typically has a protracted course
  • Overall indolent disease but deaths have been reported
  • Mortality rate with systemic disease approaches 7%
  • Variable pattern of response to treatment
  • Spontaneous regression common

Disease-related complications

  • Malignancies including Hodgkin’s lymphoma, non-Hodgkin’s lymphoma and multiple myeloma have developed in patients who presented with Rosai Dorfman (Human Pathology 1995; 26:1378).
    • Unclear if this represents malignant transformation.
    • Vigilant follow-up is critical.
  • Autoimmune hemolytic anemia can complicate Rosai Dorfman disease.
    • Etiology is unknown.
    • Prognosis is generally good (Br J Dermatol 2001; 145:323).

References and additional resources

  • Beckingsale P, Sullivan T, Whitehead K: A case of Rosai-Dorfman disease involving the lacrimal gland in an elderly patient. Orbit 2002; 21:169.
  • Bruce-Brand C, Schneider JW, Schubert P. Rosai-Dorfman disease: an overview. J Clin Pathol. 2020 Nov;73(11):697-705. doi: 10.1136/jclinpath-2020-206733. Epub 2020 Jun 26. PMID: 32591351. 
  • Choi MB, Salomão DR, Smith WM, Pulido JS, Garrity JA. Ophthalmic Findings of Rosai-Dorfman Disease. Am J Ophthalmol. 2018 Apr;188:164-172. doi: 10.1016/j.ajo.2018.01.037. Epub 2018 Feb 9. PMID: 29428455.
  • Foucar E, Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: an analysis of 14 deaths occurring in a patient registry. Cancer 1984; 54:1834.
  • Foucar E, Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): review of the entity. Semin Diagn Pathol 1990; 7:19.
  • Kala C, Agarwal A, Kala S. Extranodal manifestation of Rosai–Dorfman disease with bilateral ocular involvement. J Cytol 2011; 28:131.
  • Khan R, Moriarity P, Kennedy S: Rosai Dorfman disease or sinus histiocytosis with massive lymphadenopathy of the orbit. Br J Ophthalmol 2003; 87:1054.
  • Kidd DP, Revesz T, Miller NR: Rosai-Dorfman disease presenting with widespread intracranial and spinal cord involvement. Am J Ophthalmol 2007; 143:544.
  • Lee-Wing M, Oryschak A, Attariwala G, Ashenhurst M: Rosai-Dorfman disease presenting as bilateral lacrimal gland enlargement. Am J Ophthalmol 2001; 131:677.
  • Maia DM, Dorfman RF. Focal changes of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) associated with nodular lymphocyte predominant Hodgkin’s disease. Human Pathology 1995; 26:1378.
  • McClain KL, Natkunam Y, Swerdlow SH. Atypical cellular disorders. Hematol Am Soc Hematol Educ Progr 2004; 1:283.
  • McClellan SF, Ainbinder DJ: Orbital Rosai-Dorfman disease. Orbit 2013; 32:341.
  • Mohadjer Y, Holds JB, Rootman J, et al. The spectrum of orbital Rosai-Dorfman disease. Ophth Plas Recon Surg 2006; 22:163.
  • Mudhar HS, Duke R: A case of orbital Rosai-Dorfman disease with IgG4 positive plasma cells. Orbit 2013; 32:315.
  • Pulsoni A, Anghel G, Falcucci P, et al. Treatment of sinus histiocytosis with massive lymphadenopathy (Rosai- Dorfman disease): report of a case and literature review. Am J Hematol 2002; 69:67.
  • Quintyn JC, Ranty ML, Courville P, et al: Orbital sinus histiocytosis (Rosai Dorfman disease): a lacrimal gland involvement. Ophthalmologica 2002; 216:277.
  • Rosai J, Dorfman RF: Sinus histiocytosis with massive lymphadenopathy. Arch Pathol 1969; 87:63.
  • Rosai J, Dorfman RF: Sinus histiocytosis with massive lymphadenopathy: a pseudolymphomatous benign tumor. Cancer 1972; 30:1174.
  • Sun NZ, Galvin J, Cooper KD: Cutaneous Rosai-Dorfman disease successfully treated with low-dose methotrexate. JAMA Dermatol 2014; 150:787.
  • Tan JJ, Narang S, Purewal B, Langer PD, Blaydon S, Schwarcz RM, McCormick SA, Kim JY, Walrath JD, Burt BO, Shinder R. Extranodal Rosai-Dorfman Disease of the Orbit: Clinical Features of 8 Cases. Ophthalmic Plast Reconstr Surg. 2016 Nov/Dec;32(6):458-461. doi: 10.1097/IOP.0000000000000589. PMID: 26561955.
  • Tang SX, Lim RP, Al-Dahmash S, et al: Bilateral lacrimal gland disease: Clinical features of 97 cases. Ophthalmology 2014; PAP.
  • Vemuganti GK, Naik MN, Honavar SG. Rosai-Dorfman disease of the orbit. J Hematol Oncol 2008; 1:1.