Rosai Dorfman disease

Rosai-Dorfman disease (RDD) also called Rosai-Dorfman-Destombes disease or sinus histiocytosis with massive lymphadenopathy (SHML), is a rare benign non-Langerhans cell histiocytosis which is characterized by over-production and accumulation of a specific type of white blood cell called histiocyte in the lymph nodes of your body (lymphadenopathy), most often those in your neck (cervical lymphadenopathy) ¹⁾, ²⁾, ³⁾, ⁴⁾, ⁵⁾, ⁶⁾, ⁷⁾, ⁸⁾, ⁹⁾, ¹⁰⁾, ¹¹⁾, ¹²⁾. Other lymph node groups may also be involved and in some cases, abnormal accumulation of histiocytes may occur in other areas of your body (extranodal disease is present in approximately 43% of cases) usually occurring in the skin, nasal cavity, paranasal sinus, upper respiratory tract, salivary gland, head, and neck, central nervous system (CNS), soft tissues, bone, kidneys, testis, digestive system, eyelid, orbit, and salivary gland is present with or without lymphadenopathy ¹³⁾, ¹⁴⁾, ¹⁵⁾, ¹⁶⁾, ¹⁷⁾. These areas include your skin, central nervous system (brain and spinal cord), kidney and digestive tract. Histiocytes are large phagocytic cells (macrophages) that normally play a role in responding to infection and injury. A phagocytic cell is any “scavenger cell” that engulfs and destroys invading microorganisms or cellular debris. Histiocytes normally function to destroy foreign substances and protect the body from infection. In Rosai-Dorfman disease, the overproduction and accumulation of histiocytes (histiocytosis) in the channels (sinuses) that allow for the passage of lymph (sinus histiocytosis) and less commonly the interfollicular area of the lymph nodes are infiltrated with distinctive histiocytes with round or oval vesicular nuclei with well-defined, delicate nuclear membranes and a single prominent nucleolus ¹⁸⁾, ¹⁹⁾, ²⁰⁾.

Symptoms of Rosai-Dorfman disease is more frequently seen in children or young adults, but most often affects young adults under the age of 20 with peak incidence in the second or third decade (mean age, 20.6 years), although it has been reported up to age 74 years ²¹⁾, ²²⁾. Rosai-Dorfman disease is more common in males and people of African descent, with the cutaneous form more common in female Asians ²³⁾, ²⁴⁾, ²⁵⁾. Some studies suggest that Rosai-Dorfman disease affects males more often than females. Skin Rosai-Dorfman disease occurs more often in females in their 20s or 30s.

The symptoms and physical findings associated with Rosai-Dorfman disease vary depending upon the specific areas of the body that are affected. In most Rosai-Dorfman disease cases, individuals exhibit painless swelling or enlargement of affected lymph nodes (lymphadenopathy), most often those of the neck (cervical lymphadenopathy). Many individuals with Rosai-Dorfman disease do not develop any additional symptoms of the disorder (asymptomatic). In some Rosai-Dorfman disease cases, affected individual may experience nonspecific symptoms that are common to many different conditions including fever, paleness of the skin (pallor), unintended weight loss, a general feeling of ill health (malaise) and a chronically runny nose (rhinitis). In extremely rare cases, affected individuals may experience abnormal enlargement of the liver and/or spleen (hepatosplenomegaly).

Rosai-Dorfman disease is a rare disease with a prevalence of 1 per 200,000 and an estimated 100 new cases diagnosed per year in the United States ²⁶⁾, ²⁷⁾. More than 1000 cases have been reported in the medical literature since the disorder’s first described by the French pathologist Destombes in 1965 ²⁸⁾, then recognized as a distinct clinicopathological entity by Juan Rosai and Ronald F. Dorfman in 1969 ²⁹⁾. In 1969 and 1972 Rosai and Dorfman described a total of 34 cases of patients with painless, bilateral, massive cervical lymphadenopathy, fever, and distinctive abnormalities in laboratory tests: normochromic anaemia, leukocytosis with neutrophilia, increased erythrocyte sedimentation rate (ESR), and often hypergammaglobulinaemia. Subsequently, it was established as being a distinct clinical entity ³⁰⁾, ³¹⁾.

The cause of Rosai-Dorfman disease remains unknown, although altered immune responses and infectious agents may play a role ³²⁾, ³³⁾. Recent studies showed that approximately 1/3 of Rosai-Dorfman disease these patients harbor gene mutations involving the MAPK/ERK pathway, e.g., NRAS, KRAS, MAP2K1, and, rarely, BRAF, indicating a neoplastic process rather than a reactive disorder ³⁴⁾. Genetic predisposition or hereditary forms of Rosai-Dorfman disease has been hypothesized, as cases have been described in twins or family members, which supports this hypothesis ³⁵⁾. Germline mutations in SLC29A3 at 10q23, which is associated with histiocytosis-lymphadenopathy plus syndrome (H syndrome), Faisalabad histiocytosis, and pigmented hypertrichotic dermatosis with insulin-dependent diabetes, have been found in cases of familial Rosai-Dorfman disease ³⁶⁾. Another germline mutation (TNFRSF) that is found in autoimmune lymphoproliferative syndrome (ALPS) type 1 is also found in Rosai-Dorfman disease ³⁷⁾. The emergence of novel molecular data indicates that Rosai-Dorfman disease is a neoplastic process. Rosai-Dorfman disease was recently listed in the 5th Edition of the World Health Organization (WHO) Classification of Myeloid and Histiocytic/Dendritic Neoplasms ³⁸⁾.

The diagnosis of Rosai-Dorfman disease may be confirmed by a thorough clinical evaluation, a detailed patient history and a variety of specialized tests, such as surgical removal and microscopic examination of affected tissue (biopsy). Histopathological examination remains the mainstay of diagnosis – lymph nodes have massive sinusoidal dilation, containing histiocytes positive for S-100 and CD68, and negative for CD1a. The hallmark of Rosai-Dorman disease is lymphophagocytosis or emperipolesis, wherein the viable lymphocytes are located in well-defined cytoplasmic vacuoles of intact histiocytes. Emperipolesis is derived from the Greek (em – inside; peri – around; polemai – wander about) and it is an uncommon biological process, in which a cell penetrates another living cell ³⁹⁾. Unlike in phagocytosis where the engulfed cell is killed by lysosomal enzymes of the macrophage, the cell exists as viable cell within another in emperipolesis and can exit at any time without any structural or functional abnormalities for either of them ⁴⁰⁾. Plasma cells, neutrophils and red blood cells may also occupy this unique intracytoplasmic niche. The involved histiocytes are activated macrophages with features of phagocytic cells as well as immune accessory cells and thus express S-100 protein, HAM 56, α1 antitrypisn, α1 chymotrypsin, lysozyme, Mac 387, Ki-1 (CD 30, Ber-H2), but are negative for CD1a (leu 6) ⁴¹⁾. Rosai-Dorfman disease involving extranodal sites shows similar morphologic features to its nodal counterpart with more fibrosis and fewer histiocytes with emperipolesis ⁴²⁾. The presence of benign histiocytes with emperipolesis, absence of cellular atypia, immunohistochemical profile, and associated clinical features distinguish Rosai-Dorfman disease from other simulating disorders. In laboratory tests the most common abnormalities are increased erythrocyte sedimentation rate (ESR), leukocytosis with neutrophilia, normocytic anemia, and hypergammaglobulinemia ⁴³⁾.

Because Rosai-Dorfman disease is so rare, no large research studies have been performed, and there is no established, widely accepted treatment.

In many cases, the symptoms of Rosai-Dorfman disease may disappear without treatment (spontaneous remission) within in months or a few years. The “watch and wait” approach is used without treatment is preferred for individuals with Rosai-Dorfman disease whenever possible ⁴⁴⁾. In many cases, no therapy will be necessary.

In some cases, various treatment options may become necessary. In these cases, the treatment of Rosai-Dorfman disease is directed toward the specific symptoms that are apparent in each individual. Several different treatment options have been used to treat individuals with Rosai-Dorfman disease including surgical removal of histiocytic lesions. In more serious cases, additional treatment options have included therapy with certain drugs including steroids (e.g., prednisone), alfa-interferon, and a regimen of certain anticancer drugs (chemotherapy). In some cases, affected individuals have shown improvement of symptoms with these treatments. In other cases, drug therapies have been ineffective.

Other treatment is symptomatic and supportive.

Figure 1. Rosai Dorfman disease with enlarged lymph node in the neck (cervical lymphadenopathy)

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Figure 2. Rosai dorfman disease of the orbit

Footnote: Bilateral upper eyelid and preseptal orbital mass in a 16-year-old female with complete mechanical ptosis.

[Source ⁴⁶⁾ ]

Figure 3. Cutaneous Rosai Dorfman disease

Footnote: A 68-year-old Caucasian woman presented to the dermatology department with multiple erythematous nodules localized on the right thigh that had been slowly progressing for 9 months. The lesions were slightly tender on palpation, but no other general symptoms were reported. (A) Multiple violaceous nodules disseminated on the right thigh before the treatment and (B) after 55 weeks on 15 mg methotrexate subcutaneously once weekly with additional 10 mg of prednisone once daily for 12 weeks.

[Source ⁴⁷⁾ ]

Figure 4. Cutaneous Rosai-Dorfman disease

Footnote: A 46-year-old male reported appearance of asymptomatic widespread skin lesions 4 months ago. The lesions grew rapidly on the trunk and left thigh and later spread to involve other extremities and face within a span of 2 months. The patient had no related medical history and was otherwise healthy. The patient reported no systemic symptoms such as fever, malaise or weight loss. There was no organomegaly or lymph node enlargement. Cutaneous examination revealed innumerable generalized papules mainly affecting the face and limbs. The lesions were yellowish to orange papules with confluence forming non infiltrated plaques mainly on the thighs, cheeks, temples and peri-auricular area. There was no mucosal or nail involvement.

[Source ⁴⁸⁾ ]

Figure 5. Rosai-Dorfman disease in the brain

Footnotes: A 33-years-old man was suffering from fainting, frontal headache, ataxia and dizziness with no sensory or motor defect. MRI showed infiltrating mass adjacent to lateral ventricle with effacement of anatomical sign of the left parietal region. (A) Left periventricular mass that occupy temporal white matter and extend to adjacent gray matter. Left frontal horn was collapsed and left temporal horn was dilated. (B) There is enhancing mass that shows subfalcine hernia to right side. No definite lesion was found at the dura. Laboratory tests were unremarkable.

[Source ⁴⁹⁾ ]

Figure 6. Rosai-Dorfman disease pathology outlines

Footnotes: Pathologic and clinical features of Rosai-Dorfman disease. (A-E) Images of Rosai-Dorfman nodal disease and lymph node tissue biopsies (A-B) and fine-needle aspiration (C-E). (A) Mixed Rosai-Dorfman disease/Langerhans cell histiocytosis (LCH) case with sinus expansion. The large Rosai-Dorfman disease histiocytes display conspicuous emperipolesis with pale cytoplasm, as compared with the intermixed LCH cells with dense eosinophilic cytoplasm and convoluted nuclei (magnification ×400; hematoxylin and eosin [H&E] stain). (B) The Rosai-Dorfman disease histiocytes show pale watery-clear cytoplasm, a central round nucleus with a conspicuous nucleolus, and emperipolesis (magnification ×1000; H&E stain). (C) Cell block preparation shows clusters of Rosai-Dorfman disease histiocytes (magnification ×400; H&E stain), (D) with nuclear and cytoplasmic staining for S100 (magnification ×1000) and (E) fascin (magnification ×1000); the trafficking intact leukocytes are negative. (F) A child with immunodeficiency and Rosai-Dorfman disease with massive cervical lymphadenopathy. (G) Rosai-Dorfman disease of the skin showing red nodular lesions. (H) Tongue enlargement resulting from oral Rosai-Dorfman disease.

[Source ⁵⁰⁾ ]

What is histiocytosis?

Histiocytosis is a general name for a group of disorders or “syndromes” that involve an abnormal increase in the number of specialized white blood cells that are called histiocytes ⁵¹⁾. The term histiocyte refers to a bone marrow derived progenitor cell that differentiates, depending on the cytokine and growth factor milieu, into a dendritic antigen presenting cell (Langerhans cell, dermal dendrocyte) or a phagocytic cell (tissue macrophage) ⁵²⁾.

Recently, new knowledge about this family of diseases has led experts to develop a new classification. Five categories have been proposed ⁵³⁾, ⁵⁴⁾:

• L group — includes Langerhans cell histiocytosis (LCH), Erdheim-Chester disease, Indeterminate-cell histiocytosis and mixed Langerhans cell histiocytosis/Erdheim-Chester disease
• C group — includes non-Langerhans cell histiocytosis that involves the skin
  • Cutaneous non-Langerhans cell histiocytosis
    • Xanthomatous granuloma (XG) family: juvenile xanthogranuloma, adult xanthogranuloma, solitary reticulohistiocytoma, benign cephalic histiocytosis, generalized eruptive histiocytosis, progressive nodular histiocytosis
    • Non-Xanthomatous granuloma (non-XG) family: Cutaneous Rosai-Dorfman disease, necrobiotic xanthogranuloma, other
  • Cutaneous non-Langerhans cell histiocytosis with a major systemic component
    • Xanthomatous granuloma (XG) family: xanthoma disseminatum
    • Non-Xanthomatous granuloma (non-XG) family: multicentric reticulohistiocytosis
• M group — includes Primary malignant histiocytoses and Secondary malignant histiocytoses
• R group — includes Rosai-Dorfman disease
  • Familial Rosai-Dorfman disease
  • Sporadic Rosai-Dorfman disease
    • Classical Rosai-Dorfman disease
    • Extranodal Rosai-Dorfman disease
    • Rosai-Dorfman disease with neoplasia or immune disease
    • Unclassified
• H Group — includes hemophagocytic lymphohistiocytosis
  • Primary hemophagocytic lymphohistiocytosis : Monogenic inherited conditions leading to hemophagocytic lymphohistiocytosis
  • Secondary hemophagocytic lymphohistiocytosis (non-Mendelian hemophagocytic lymphohistiocytosis)
  • Hemophagocytic lymphohistiocytosis of unknown/uncertain origin.

Rosai-Dorfman disease types

Under the R group of non-Langerhans cell histiocytosis, Rosai-Dorfman disease can be further classified into five subgroups: classical (nodal), familial, extranodal, neoplasia associated, and immune disease-associated Rosai-Dorfman disease ⁵⁵⁾.

• Familial Rosai-Dorfman disease
• Sporadic Rosai-Dorfman disease
  • Classical (nodal) Rosai-Dorfman disease
    • The classical (nodal) Rosai-Dorfman disease subgroup includes IgG4 lymphoproliferative disorder or those without IgG4 syndrome.
  • Extranodal Rosai-Dorfman disease
    • Bone Rosai-Dorfman disease,
    • Central nervous system (CNS) Rosai-Dorfman disease with or without IgG4 syndrome,
    • Single-organ: The single-organ Rosai-Dorfman disease does not include lymph nodes or central nervous system (CNS) Rosai-Dorfman disease and is further divided into two subtypes: with or without IgG4 syndrome.
    • Disseminated Rosai-Dorfman disease
  • Rosai-Dorfman disease with neoplasia or immune disease
  • Unclassified
• Of note, cutaneous Rosai-Dorfman disease has been reclassified to be included in the C group under the Non-Xanthomatous granuloma (non-XG) family ⁵⁶⁾.

Familial Rosai-Dorfman disease

Germ line mutations in SLC29A3 have been reported in patients with familial Rosai-Dorfman disease ⁵⁷⁾, ⁵⁸⁾. Two mutations have been reported to date: p.G427S and p.G437R ⁵⁹⁾. The spectrum of diseases associated with a mutation in the SLC29A3 gene mainly include the following three diseases:

1. Familial or Faisalabad histiocytosis: Children present with sensorineural deafness and joint contractures. It is autosomal recessive disorder ⁶⁰⁾, ⁶¹⁾. Histologically, it resembles Rosai-Dorfman disease; therefore, obtaining a clinical history along with a genetic consultation is an important step;
2. H syndrome: Children present with hypogonadism, indurated, hyperpigmented, hypertrichotic skin plaques, hepatomegaly, cardiac abnormalities, and hearing loss ⁶²⁾, ⁶³⁾. Skin lesions share histologic features with Rosai-Dorfman disease;
3. Pigmented hypertrichotic dermatosis with insulin-dependent diabetes syndrome: Children present with insulin-dependent diabetes mellitus and pigmented hypertrichosis ⁶⁴⁾.

All these diseases are described as histiocytosis-lymphadenopathy plus syndrome. A recent study confirmed that, despite sharing a missense mutation c.1088 G > A [p.Arg363Gln] of the SLC29A3 gene, the clinical phenotype of the intrafamilial SLC29A3 disorders could be heterogeneous ⁶⁵⁾.

Another cause of familial Rosai-Dorfman disease is heterozygous germline mutations in the FAS and TNFRSF genes, which also cause autoimmune lymphoproliferative syndrome (ALPS) type 1 ⁶⁶⁾, ⁶⁷⁾. Patients with autoimmune lymphoproliferative syndrome (ALPS) tend to have a male predominance, more aggressive disease behavior, and an earlier age of disease onset, but the Rosai-Dorfman disease-like changes are usually self-limited ⁶⁸⁾.

Sporadic Rosai-Dorfman disease

Neoplasia-associated Rosai-Dorfman disease

Histologic features of Rosai-Dorfman disease have been observed in patients with Hodgkin lymphoma and non-Hodgkin lymphoma (NHL), where lymphoma and Rosai-Dorfman disease can either precede or follow each other or occur in the same lymph node ⁶⁹⁾. Rosai-Dorfman disease was also reported after myelodysplastic syndrome ⁷⁰⁾ or bone marrow transplantation for acute leukemia ⁷¹⁾, concurrent with cutaneous clear-cell sarcoma ⁷²⁾ and concurrent with or following L-group histiocytoses or malignant histiocytoses ⁷³⁾. Small foci of Rosai-Dorfman disease-like histopathology (ie, histiocytes with emperipolesis) are nonspecific; therefore, >10% of a specimen should demonstrate Rosai-Dorfman disease morphology to constitute a neoplasia-associated Rosai-Dorfman disease as a distinct entity rather than a reactive process ⁷⁴⁾.

Immune-related Rosai-Dorfman disease

Rosai-Dorfman disease coexists with an immunologic disease in 10% of cases ⁷⁵⁾. Rosai-Dorfman disease has been associated with systemic lupus erythematous (SLE), idiopathic juvenile arthritis, autoimmune hemolytic anemia ⁷⁶⁾ and 1 case of RAS-associated autoimmune leukoproliferative disease, which is caused by gain-of-function mutations in the RAS-family (NRAS and KRAS) ⁷⁷⁾.

IgG4-related Rosai-Dorfman disease

Some forms of extranodal Rosai-Dorfman disease, such as those involving the liver, lungs, or colon, have been associated with an increased number of immunoglobulin G4-positive (IgG4+) plasma cells ⁷⁸⁾, although other studies have shown a low number of IgG4+ plasma cells and low IgG4/IgG ratios (<40%) as compared with IgG4-related disease samples ⁷⁹⁾. No clear evidence suggests that the 2 disorders share the same pathogenesis; however, the most recent classification of histiocytoses recommends evaluating the IgG4/IgG ratio in all patients with Rosai-Dorfman disease ⁸⁰⁾.

Rosai-Dorfman disease cause

The exact cause of Rosai-Dorfman disease is unknown (idiopathic), but it does not seem to be of neoplastic nature ⁸¹⁾. Over the years there have been many theories attempting to explain Rosai-Dorfman disease’s pathogenesis, but each of them has led to conflicting results. Researchers have suggested Rosai-Dorfman disease may be caused by an infectious agent, immunodeficiency, or autoimmunity. Studies have associated Rosai-Dorfman-Destombes disease with viral infections such as human herpesvirus 6 (HHV-6), human herpesvirus-8 (HHV-8), parvovirus B19, Epstein-Barr virus (EBV), cytomegalovirus (CMV), HIV, varicella zoster virus (also known as human herpesvirus 3), Brucella, and Klebsiella infection ⁸²⁾, ⁸³⁾, ⁸⁴⁾, ⁸⁵⁾, ⁸⁶⁾, although a clear link has not been proven ⁸⁷⁾. In some cases, the human herpesvirus 6 (HHV-6) antigen has been identified in the pathological histiocytes, while Epstein-Barr virus (EBV) and parvovirus B19 have been present in lymphocytes, which may eventually be phagocytosed by histiocytes ⁸⁸⁾. In one of the articles, it was observed that primarily infected lymphocytes induce a secondary histiocytic reaction that eventually causes the characteristic microscopic image of Rosai-Dorfman disease ⁸⁹⁾.

Other potential causes may be broadly-defined immunological disorders (e.g. immunodeficiency, autoimmune diseases). In view of the fact that some patients have hypergammaglobulinemia, scientists have been looking for a relationship between Rosai-Dorfman disease and IgG4-related diseases, but detailed analyses have put this theory into question ⁹⁰⁾, ⁹¹⁾, ⁹²⁾.

One of the more recent studies considers the coexistence of Langerhans cell histiocytosis and Rosai-Dorfman disease ⁹³⁾, ⁹⁴⁾, ⁹⁵⁾. Although under the World Health Organization (WHO) classification Langerhans cell histiocytosis and Rosai-Dorfman disease are separate, it has been emphasized that both diseases share the same bone marrow precursor cell, which later undergoes further differentiation ⁹⁶⁾. Common features of histiocytes in these two disorders are, i.a., positive reaction to S-100 staining, and expression of cathepsin D and E ⁹⁷⁾. There are reports of patients treated for Langerhans cell histiocytosis, in whom after chemotherapy Rosai-Dorfman disease is revealed. This may be caused by immunological abnormalities connected with one disease, eventually leading to the disclosure of another one, or, alternatively, exposure to systemic chemotherapy causes disturbed differentiation in cells. In one of the reported cases, the authors observed histiocytes with immunohistochemical phenotype typical for Langerhans cell histiocytosis (S100+, CD1a+, presence of Birbeck granules), which underwent changes during chemotherapy (S100+, CD1a+, no Birbeck granules), finally presenting a profile typical for Rosai-Dorfman disease (S100+, CD1a–) ⁹⁸⁾, ⁹⁹⁾. There are also patients diagnosed with Rosai-Dorfman disease during or after treatment for leukemia, Hodgkin lymphoma, and non-Hodgkin lymphoma ¹⁰⁰⁾, ¹⁰¹⁾.

In light of the finding of recurrent BRAF-V600E mutations in Erdheim-Chester disease (ECD), twenty three Rosai-Dorfman-Destombes disease samples were analyzed and found to be BRAF-V600E wild type ¹⁰²⁾. Similarly, Chakraborty et al ¹⁰³⁾ did not identify any somatic alterations by whole-exome sequencing of 4 Rosai-Dorfman-Destombes disease cases. However, recent studies have found NRAS, KRAS, MAP2K1, and ARAF mutations in Rosai-Dorfman disease tissues (see Figure 7), raising the possibility of a clonal origin in some forms of Rosai Dorfman disease ¹⁰⁴⁾. Characteristic lesional histiocytes are positive for S100, CD68, and negative for CD1a. Further research is needed to investigate the cell of origin of neoplastic forms of Rosai-Dorfman-Destombes disease ¹⁰⁵⁾.

Scientists are also looking for genetic disorders that could be responsible for Rosai-Dorfman disease development. The literature refers to, i.a., SLC29A3 mutations and familial Rosai-Dorfman disease ¹⁰⁶⁾, ¹⁰⁷⁾, ¹⁰⁸⁾.

Table 1. Summary of kinase mutations discovered in Rosai-Dorfman disease

Gene	Genetic alteration	Amino acid variant	Protein domain
ARAF	Missense	p.N217K	CR2 domain
MAP2K1	Missense	p.F53V	N-terminal negative regulatory
MAP2K1	Missense	p.L115V	N-terminal catalytic core of kinase
MAP2K1	Missense	p.P124R	N-terminal catalytic core of kinase
MAP2K1	Missense	p.G128D	N-terminal catalytic core of kinase
NRAS	Missense	p.G13D	P-loop and GTP-binding 1
KRAS	Missense	p.G12D	P-loop and GTP-binding 1
KRAS	Missense	p.G12R	P-loop and GTP-binding 1
KRAS	Missense	p.Q22K	GTP-binding 1
KRAS	Missense	p.K117N	GTP-binding 3
KRAS	Missense	p.A146T	GTP-binding 4
KRAS	Missense	p.A146V	GTP-binding 4

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Figure 7. Rosai-Dorfman disease kinase mutations

Footnotes: (A) Pie chart illustrating the known activating kinase mutations in Rosai-Dorfman disease (N = 34). (B) Diagrams of somatic mutations described in KRAS and NRAS. (C) Diagram of somatic mutations uncovered in MAP2K1. (D) Diagram of somatic mutation discovered in ARAF.

[Source ¹¹⁰⁾ ]

Rosai-Dorfman disease pathology outlines

The diagnostic pathologic features of nodal Rosai-Dorfman disease include the sinus expansion of large histiocytes, described by Destombes as possessing ample pale or “watery-clear” cytoplasm with a large hypochromatic nucleus and prominent nucleolus ¹¹¹⁾. Nodal Rosai-Dorfman disease is often accompanied by numerous plasma cells in the medullary cords and around the venules, with varying proportions of IgG4/IgG plasma cells ¹¹²⁾, ¹¹³⁾. Consistent features, regardless of the site, include the cytomorphology of the large pale histiocytes and their immunophenotype. Emperipolesis, the trafficking of intact leukocytes through the cytoplasm, is a helpful finding but is not required for diagnosis, because it can be focal, especially at extranodal sites, and may be seen focally in other histiocytoses such as Erdheim-Chester disease ¹¹⁴⁾, juvenile xanthogranuloma, and malignant histiocytoses. Extranodal lesions are usually associated with more fibrosis, fewer Rosai-Dorfman disease histiocytes and less emperipolesis ¹¹⁵⁾. In such cases, immunostains are needed to highlight the residual Rosai-Dorfman disease histiocytes in a rich lymphoplasmacytic background with stromal fibrosis and a variable xanthomatous histiocytic reaction ¹¹⁶⁾. These extranodal cases can be difficult to differentiate from Erdheim-Chester disease and require clinical correlation.

The immunophenotype of the large Rosai-Dorfman disease histiocytes is characterized by cytoplasmic and nuclear S100 (Figure 6D) and fascin (Figure 6E) positivity, with CD68 and variable CD163 and CD14 positivity. The cells are CD1a negative/CD207 negative in contrast to Langerhans cell histiocytosis (LCH). An important aspect of making the diagnosis of nodal Rosai-Dorfman disease is evaluation for superimposed pathology, either within the node itself or other associated conditions ¹¹⁷⁾. The presence of Rosai-Dorfman disease histology is required, but not sufficient, for the diagnosis of Rosai-Dorfman disease, which depends on the appropriate clinical and radiologic context and exclusion of primary malignant disorders in relation to which Rosai-Dorfman disease histology may represent a minor (<10%) reactive process.

Because the pathologic features of Rosai-Dorfman disease are variable, compounded by its heterogeneous clinical manifestations, in many instances the primary hurdle to establishing an Rosai-Dorfman disease diagnosis is suspecting the disorder in the first place, particularly for extranodal disease ¹¹⁸⁾. The presence of slowly progressive or subacutely clinical symptomatology; biopsy specimens demonstrating ostensibly nonspecific inflammation, including lymphoid aggregates and plasma cells with a large histiocytic presence; and clinical findings compatible with those described in “clinical features” should raise concern for an Rosai-Dorfman disease diagnosis and, in difficult cases, prompt clinical and histopathologic evaluation by experts familiar with the disease.

Clinical features

Classic (nodal) Rosai-Dorfman disease

Most patients with Rosai-Dorfman disease present with bilateral, massive, and painless cervical lymphadenopathy (Figure 6F) with or without intermittent fevers, night sweats, and weight loss ¹¹⁹⁾. Mediastinal, armpit, and inguinal lymph nodes may also be involved, but retroperitoneal lymphadenopathy is uncommon ¹²⁰⁾. Classic (nodal) Rosai-Dorfman disease prognosis has been found to correlate with the number of nodal groups involved by Rosai-Dorfman disease ¹²¹⁾.

Extranodal Rosai-Dorfman disease

Extranodal involvement has been reported in 43% of Rosai-Dorfman disease cases ¹²²⁾. Extranodal Rosai-Dorfman disease usually occurring in the skin, nasal cavity, paranasal sinus, upper respiratory tract, salivary gland, head, and neck, central nervous system (CNS), soft tissues, bone, kidneys, testis, digestive system, eyelid, orbit, and salivary gland is present with or without lymphadenopathy ¹²³⁾, ¹²⁴⁾, ¹²⁵⁾, ¹²⁶⁾, ¹²⁷⁾. Multisystem involvement occurs in 19% of cases, and prognosis is correlated with the number of extranodal systems involved ¹²⁸⁾.

Cutaneous Rosai-Dorfman disease

Cutaneous Rosai-Dorfman disease was established as a separated clinical entity, in which only skin is involved – patients do not present lymphadenopathy. The skin is involved in 10% of extranodal Rosai-Dorfman disease cases, and isolated cutaneous disease is rare ¹²⁹⁾. Cutaneous Rosai-Dorfman disease usually affects individuals around the age of 50 years, predominantly women, especially from the Caucasian population. Lesions are typically slow growing, painless, nonpruritic nodules, plaques, or papules with coloration varying from yellow to red to brown (Figure 3 and 4). Any skin site can be affected. The differential diagnosis includes acne vulgaris, varicella-zoster virus, sarcoidosis, cutaneous lymphoma, and metastasis ¹³⁰⁾. Cutaneous Rosai-Dorfman disease is associated with an excellent prognosis ¹³¹⁾, ¹³²⁾, ¹³³⁾.

Central nervous system Rosai-Dorfman disease

Central nervous system (CNS) involvement occurs in <5% of Rosai-Dorfman disease cases, with 75% occurring as intracranial and 25% as spinal lesions. Neurologic Rosai-Dorfman disease has been reported in >300 cases ¹³⁴⁾ and usually occurs in older patients and without lymphadenopathy ¹³⁵⁾. Symptoms include headaches, seizures, gait difficulty, motor or sensory abnormalities, and cranial nerve deficits, usually evolving over weeks or months ¹³⁶⁾. Familial cases are associated with damage to the auditory nerve pathway and deafness ¹³⁷⁾, ¹³⁸⁾. The most common radiographic appearance of intracranial Rosai-Dorfman disease is a solitary extraaxial, homogeneously enhancing dural mass mimicking a meningioma ¹³⁹⁾, ¹⁴⁰⁾, although Rosai-Dorfman disease can cause diffuse pachymeningitis. Parenchymal lesions are frequently infratentorial (brainstem and pons) ¹⁴¹⁾, whereas supratentorial, intraventricular, and multifocal lesions are rare ¹⁴²⁾, ¹⁴³⁾. Cerebrospinal fluid (CSF) is often unremarkable although may show lymphocytic pleocytosis, elevated protein, low glucose, and emperipolesis ¹⁴⁴⁾.

Spinal dural or epidural lesions are most common in the cervical and thoracic regions ¹⁴⁵⁾ and present with myelopathy or symptoms of spinal cord compression. Although central nervous system (CNS) Rosai-Dorfman disease can have a rapidly progressive and even fatal course, many patients will have a favorable outcome after surgical resection when this is feasible ¹⁴⁶⁾.

Ophthalmic Rosai-Dorfman disease

Ophthalmic manifestations occur in 11% of Rosai-Dorfman disease cases ¹⁴⁷⁾, manifesting as a mass in the orbital soft tissues (Figure 2), eyelids, lacrimal glands, conjunctiva, or cornea and as uveitis or compressive optic neuropathy ¹⁴⁸⁾.

Head and neck Rosai-Dorfman disease

Involvement of the nasal cavity and paranasal sinuses occurs in 11% of Rosai-Dorfman disease cases ¹⁴⁹⁾ and is more common in patients of Asian descent. Symptoms of sinonasal Rosai-Dorfman disease include nasal obstruction, epistaxis, nasal dorsum deformity, facial asymmetry, and aural fullness ¹⁵⁰⁾. Oral cavity involvement can present as soft and hard palate nodules, gingival and oral mucosa swelling, tongue enlargement (Figure 6H), thickened mucosa of the oropharynx, enlarged tonsils, or frequent tonsillitis ¹⁵¹⁾. Other less frequently involved sites include the salivary and parotid glands, larynx, pharynx, thymus, and thyroid gland, which can cause symptoms related to mass effect ¹⁵²⁾, ¹⁵³⁾.

Intrathoracic Rosai-Dorfman disease

Intrathoracic Rosai-Dorfman disease is described in 2% of patients, usually with concurrent lymphadenopathy ¹⁵⁴⁾. Manifestations include interstitial lung disease, pulmonary nodules, tracheobronchial disease, and pleural effusions with an obstructive pattern on pulmonary function tests ¹⁵⁵⁾. Symptoms include chronic dry cough, progressive dyspnea, or acute respiratory failure. Pulmonary Rosai-Dorfman disease can mimic primary lung cancers, interstitial lung disease or organizing pneumonias, sarcoidosis, granulomatous polyangiitis, rheumatoid arthritis–related lung disease, and mycobacterial and fungal infections ¹⁵⁶⁾. Rosai-Dorfman disease affecting the lower respiratory tract can have an aggressive phenotype, with a mortality rate of almost 45% ¹⁵⁷⁾. Cardiac involvement with Rosai-Dorfman disease is rare, occurring in 0.1% to 0.2% of cases ¹⁵⁸⁾.

Retroperitoneal and genitourinary Rosai-Dorfman disease

The kidneys are affected in 4% of Rosai-Dorfman disease cases, with a discrete mass or diffuse infiltration ¹⁵⁹⁾, ¹⁶⁰⁾. Symptoms include blood in urine (hematuria), flank pain, abdominal fullness, renal failure, hypercalcemia, or nephrotic syndrome caused by amyloidosis or renal vein thrombosis ¹⁶¹⁾, ¹⁶²⁾, ¹⁶³⁾, ¹⁶⁴⁾. Hydronephrosis and ureteral obstruction can occur ¹⁶⁵⁾. Patients with renal involvement have a poor prognosis, with 40% mortality rate ¹⁶⁶⁾.

Testicular involvement is rare and manifests as a painful testicular or epididymal mass mimicking tumor or epididymitis ¹⁶⁷⁾, ¹⁶⁸⁾. Anecdotally, testicular Rosai-Dorfman disease can also present as diffuse enlargement and hardening of the testes, with or without pain.

Adrenal gland involvement is also possible but rare ¹⁶⁹⁾.

Gastrointestinal Rosai-Dorfman disease

Gastrointestinal (GI) involvement occurs in less than 1% of Rosai-Dorfman disease cases, most commonly in middle-age women with concurrent lymphadenopathy or other extranodal disease ¹⁷⁰⁾. Gastrointestinal Rosai-Dorfman disease can be solitary or segmental and has a predilection for the ileocecal area, appendix, and distal colon, with most cases being located beyond the pylorus ¹⁷¹⁾, ¹⁷²⁾. Symptoms include passage of fresh blood per anus (hematochezia), constipation, abdominal pain, abdominal mass, and intestinal occlusion, although asymptomatic cases have been identified after colonoscopy or appendectomy ¹⁷³⁾, ¹⁷⁴⁾. Almost 20% of the reported patients in 1 series died as a result of disease ¹⁷⁵⁾. Pancreas or liver involvement is reported but is extremely rare ¹⁷⁶⁾, ¹⁷⁷⁾, ¹⁷⁸⁾.

Bone Rosai-Dorfman disease

Bone involvement occurs in 5% to 10% of Rosai-Dorfman disease cases, typically in association with nodal disease ¹⁷⁹⁾. Bone pain is common, whereas pathologic fractures are rare ¹⁸⁰⁾. Bone lesions typically occur in the metaphysis or diaphysis, are osteolytic or mixed lytic/sclerotic, and have a narrow zone of transition. Soft tissue extension can occur. The clinical differential diagnosis includes chronic osteomyelitis, fibrous dysplasia, lymphoma, and Ewing sarcoma. Lesions in the femurs and tibia should raise concern for Erdheim-Chester disease. The prognosis of bony Rosai-Dorfman disease is generally good ¹⁸¹⁾.

Hematologic Rosai-Dorfman disease

Normochromic normocytic anemia (in 67% of cases), leukocytosis (in 60%, typically neutrophilia), thrombocytopenia, eosinophilia, hypergammaglobulinemia, and elevated erythrocyte sedimentation rate (ESR) are common, although bone marrow infiltration is rare ¹⁸²⁾, ¹⁸³⁾.

Rosai-Dorfman disease symptoms

The symptoms and physical findings associated with Rosai-Dorfman disease vary greatly from one person to another depending upon the extent of the disorder and the specific organ systems affected ¹⁸⁴⁾. Some Rosai-Dorfman disease cases may only affect the lymph nodes and may not cause any serious complications. Less often, some Rosai-Dorfman disease cases may affect various organ systems of the body and may potentially cause serious complications. Any organ system of the body may become affected.

In most Rosai-Dorfman disease cases, affected individuals exhibit painless swelling or enlargement of affected lymph nodes (lymphadenopathy), most often those of the neck (cervical lymphadenopathy) ¹⁸⁵⁾. Other locations such as inguinal (26%), axillary (24%) and mediastinal lymph nodes (15%) are also reported to be involved ¹⁸⁶⁾. Many individuals with Rosai-Dorfman disease do not develop any additional symptoms of the disorder (asymptomatic).

In some cases, affected individual may experience nonspecific symptoms that are common to many different conditions including fever, paleness of the skin (pallor), unintended weight loss, a general feeling of ill health (malaise) and a chronically runny nose (rhinitis). In extremely rare cases, affected individuals may experience abnormal enlargement of the liver and/or spleen (hepatosplenomegaly).

In approximately 43 percent of patients, other areas of the body besides the lymph nodes may also be affected (extranodal disease). Some individuals may have extranodal disease without the presence of lymphadenopathy ¹⁸⁷⁾. The skin is the most common extranodal site. Skin lesions associated with Rosai-Dorfman disease are usually yellow or purple. A reddish rash-like inflammation of the skin (erythema), small solid elevations on the skin (papules), or knots visible under the skin (nodules) may be present. Skin lesions may occur anywhere on the body, but most often affect the head and neck. In some cases, skin abnormalities precede the development of lymphadenopathy.

The salivary glands, nasal cavity, upper respiratory tract, various bones, and the eyes and eye sockets (orbits) may also be affected. In rare cases, the central nervous system (CNS), digestive system, or the kidneys may be affected. Hepatosplenomegaly is uncommon ¹⁸⁸⁾. Central nervous system (brain and spinal cord) can be involved less than 5% of Rosai-dorfman disease ¹⁸⁹⁾, ¹⁹⁰⁾. In 70% of central nervous system-Rosai-Dorfman disease, the presentation is limited to the brain or to the spinal cord and is not associated with lymphadenopathy ¹⁹¹⁾. Approximately, 75% of central nervous system (CNS) afflictions are intracranial, whereas 25% involve the spine ¹⁹²⁾. Over 90% of central nervous system Rosai-Dorfman disease leptomeninges are only involved ¹⁹³⁾. Involvement of these areas may result in additional (secondary) symptoms. For example, loss of vision may occur secondary to the involvement of the eyes, and seizures, headache, ataxia, motor or sensory abnormalities, dizziness and cranial nerve deficits may occur secondary to involvement of the central nervous system (CNS) ¹⁹⁴⁾. In some cases of Rosai-Dorfman disease, the accumulation of histiocytes into masses may cause compression of vital organs potentially resulting in serious complications ¹⁹⁵⁾, ¹⁹⁶⁾, ¹⁹⁷⁾, ¹⁹⁸⁾, ¹⁹⁹⁾, ²⁰⁰⁾, ²⁰¹⁾.

In some cases, the lymph nodes may not be affected. Instead a specific area of the body such as the skin, a solitary bone, or the central nervous system may be affected. These cases may be known as isolated Rosai-Dorfman disease. A distinct type of isolated Rosai-Dorfman disease has been identified called cutaneous Rosai-Dorfman disease, in which only the skin is affected. Initial reports indicate that cutaneous Rosai-Dorfman disease is more common in female adults.

Table 2. Rosai-Dorfman disease signs and symptoms

Site	Incidence	Symptoms/Signs	Radiologic Findings
Nodal
Lymph node	57% of cases	Bilateral cervical lymphadenopathy or other lymph node sites, manifested with palpable masses	Enlarged lymph nodes
Extranodal
Skin	10% of cases	Painless, macular, slow-growing papules, subcutaneous nodules. Any skin site can be affected.	Nodule(s) or mass(es)
Central nervous system (CNS)	<5% of cases (75% intracranial and 25% spinal lesions), more than 300 cases have been reported. Cervical and thoracic regions are the most common areas affected in spinal-dural or epidural lesion	Headaches, seizures, gait difficulty. In familial cases, there is an association with damage to the auditory nerve pathway and deafness.	Dural lesion, extra-axial, homogeneously enhancing, mimicking nodular meningioma; or parenchymal (infratentorial) involvement
Orbit	11% of cases	Presents as a mass in different part of the orbit, e.g., conjunctiva, lacrimal glands, and cornea. It can also present as uveitis.	Orbital mass
Head and neck	11% of cases involving nasal cavity, more common among Asians	Nasal obstruction, epistaxis, and nasal dorsum deformity	Nodules, swelling, mass(es)
Intrathoracic	2% of patients, with pulmonary disease concurrent lymphadenopathy or systemic disease. Cardiac involvement is extremely rare ~0.1–0.2% of cases.	Chronic dry cough, progressive dyspnea, or acute respiratory failure. Rosai-Dorfman disease affecting lower respiratory tract have a high mortality rate, reaching 45%.	Pulmonary nodular consolidation in all lobes of the lungs; pleural effusion with fibrosis or nodules
Retroperitoneal /genitourinary tract	Kidneys are affected in approximately 4% of cases.	Abdominal or flank pain, fullness, hematuria, renal failure, hypercalcemia, and/or nephrotic syndrome	Mass(es), hydronephrosis, urethral obstruction
Gastrointestinal tract	<1% of cases, commonly in middle-aged women with concurrent nodal or extranodal affection	Abdominal pain, constipation, hematochezia, and intestinal obstruction	Mass(es)
Bone	5% to 10% of cases, usually with concurrent nodal affection	Bone pain and, rarely, pathologic fractures	Cortex-based osteolytic lesion, commonly long bones, vertebrae, and sacrum

[Source ²⁰²⁾ ]

Rosai-Dorfman disease diagnosis

The diagnostic and staging evaluation of patients with newly diagnosed Rosai-Dorfman disease should include an assessment of disease extent, as well as evaluation for conditions either known to be associated with Rosai-Dorfman disease, particularly autoimmune disorders, or known to contain an Rosai-Dorfman disease-like reactive component secondary to malignancies (Table 3).

According to the international expert consensus at the 32nd Histiocyte Society Meeting in 2018 and National Comprehensive Cancer Network (NCCN) Guidelines for Histiocytic Neoplasms 2020, A comprehensive medical history and physical and neurologic examinations should be performed, including head and neck, intrathoracic/pulmonary/cardiovascular, gastrointestinal (GI), renal, genitourinary (GU) system, neuroendocrine, central nervous system (CNS), and cutaneous symptoms ²⁰³⁾.

The following recommendations are used for baseline evaluation of new/suspected cases of Rosai-Dorfman disease ²⁰⁴⁾, ²⁰⁵⁾:

1. Medical history
   • Constitutional symptoms;
   • Organ affection (head, eyes, ears, nose, and throat; cardiovascular; pulmonary; gastrointestinal (GI); genitourinary (GU); skin; central nervous system (CNS); and endocrine);
   • History of autoimmune disease, Langerhans cell histiocytosis (LCH), or other histiocytic lesions, as well as hematologic malignancies;
   • Family history for children.
2. Physical examination
   • Lymphadenopathy;
   • Organomegaly;
   • Cutaneous and extranodal lesions;
   • Neurologic changes.
3. Radiological evaluation
   • All patients should have whole-body positron emission tomography (PET)/computed tomography (CT);
   • Selected patients should have CT sinuses with contrast, high-resolution CT chest, magnetic resonance imaging of orbit/brain with contrast and magnetic resonance imaging of spine with contrast;
   • Selected patients for organ-specific ultrasound.
4. Laboratory evaluation
   1. Complete blood cell count, complete metabolic panel, erythrocyte sedimentation rate;
   2. Serum immunoglobulins;
   3. Coagulation studies, C-reactive protein, uric acid, and lactate dehydrogenase (LDH);
   4. Hemolysis panel (Coombs, haptoglobin, reticulocytes, and blood smear);
   5. Panel for autoimmune diseases (autoimmune lymphoproliferative syndrome (ALPS) panel, antinuclear antibody, rheumatoid factor, HLA B27);
   6. Next-generation sequencing (NGS) targeted gene mutations in RAF-RAS-MEK-ERK pathway;
   7. If familial form is suspected, then NGS test for SLC29A3 (germline mutations);
   8. Bone-marrow biopsy (if cytopenia or abnormal peripheral blood smear are present);
   9. Lumbar puncture for CNS involvement.
5. Subspecialty consultation as needed
   • Dermatology and ophthalmology evaluation before initiating MEK-inhibitor therapy.

Rosai-Dorfman disease diagnosis is made by a biopsy. Grossly, the excised lymph node is usually very large and is often matted to overlying soft tissues or adjacent lymph nodes. The lymph node architecture is dominated by a striking sinus expansion, filled with characteristic histiocyte-like cells. The cytoplasm of these histiocyte-like cells often contains phagocytosed intact small lymphocytes (lymphophagocytosis) or a variety of cells, including red blood cells, neutrophils, or plasma cells (emperipolesis). Typically, there are multiple ingested cells forming a partial or complete ring around the nuclei. Late lesions may show extensive fibrosis. Immunohistochemical studies show that the proliferating cells express the histiocytic markers CD163 and CD68 as well as S-100 protein. They are negative for the Langerhans cell marker CD1a as well as the dendritic markers CD21 and CD35. They lack almost all lymphoid markers, although they may express CD30 in up to 50% of cases and show a germline configuration of their antigen receptor genes. They lack Birbeck granules on ultrastructural examination.

Although Rosai-Dorfman disease has many prominent features, which can help to distinguish this entity from other histiocytic disorders, certain features are nonspecific, e.g., emperipolesis can be identified in Erdheim-Chester disease, juvenile xanogranuloma, and malignant histiocytosis ²⁰⁶⁾. In addition to S100, histiocytic markers (Fascin, CD68, CD163, CD4, CD14) positive for Rosai-Dorfman disease can be seen with numerous histiocytic disorders, especially when Rosai-Dorfman disease concurs with other histiocytic lesions. Differentiation between Rosai-Dorfman disease and other histiocytic disorders is sometimes challenging. For nodal Rosai-Dorfman disease, differential diagnoses mainly include Langerhans cell histiocytosis, Erdheim-Chester disease, and ALK1-positive histiocytosis and infection or other malignancies associated with reactive histiocytosis.

Table 3. Baseline clinical evaluation for patients with Rosai-Dorfman disease

Recommendation
Medical history
Constitutional: fevers, night sweats, fatigue
Head, eyes, ears, nose, and throat: cervical swelling, double vision, retroorbital pain, eyelids/lacrimal swelling, nasal obstruction, epistaxis, hyposmia, oral sores, or pain
Cardiovascular: dyspnea, orthopnea
Lung: dyspnea, cough
Gastrointestinal: abdominal pain, constipation, hematochezia
Kidney: hematuria, flank pain
Musculoskeletal: bone pain
Skin: rash, pruritus
Endocrine: polydipsia/polyuria
Nervous system: headaches, seizures, gait difficulty, limb or facial weakness, sensory changes, hearing impairment, new or focal back pain
History of: autoimmune disease, autoimmune lymphoproliferative syndrome (ALPS), malignancy, Langerhans cell histiocytosis (LCH), or another histiocytic disorder
Family history (pediatric patients): consanguineous parents, autoimmune disease, Turkish/Pakistani or Middle Eastern background
Physical examination
Head, eyes, ears, nose, and throat: dysmorphic face and hearing abnormalities (familial Rosai-Dorfman disease), enlarged cervical nodes, proptosis, lesions of oral mucosa, enlarged tongue or tonsils
Cardiac: hypertension, irregular pulse, cardiomegaly, murmurs
Thoracic: diminished lung aeration, rales, axillary nodes, breast mass
Skin: nodules, papules, or plaques
Abdominal: flank mass, hepatosplenomegaly, enlarged inguinal nodes
Genital: testicular mass or enlargement
Musculoskeletal: osseous mass
Neurologic: disconjugate gaze, cranial nerve palsies, dysarthria, ataxic gait, hemiparesis, hyperreflexia
Radiological evaluation
All patients
PET/CT: recommended by some authors for all patients, including children (judicious use is recommended in this age group), but no universal consensus was reached
Ultrasound neck/abdomen, chest X-ray or whole-body MRI: reasonable alternatives
Selected patients based on symptoms or organ involvement
CT sinuses with contrast
MRI orbit/brain with contrast
MRI spine with contrast
High-resolution CT chest
Pulmonary function tests
Thyroid ultrasound
Testicular ultrasound
Laboratory evaluation
Complete blood count with differential
Serum immunoglobulins
Autoimmune lymphoproliferative syndrome (ALPS) panel, antinuclear antibody (ANA), rheumatoid factor (RF), HLA-B27: if autoimmune disease is suspected
Erythrocyte sedimentation rate (ESR)
Complete metabolic panel, coagulation parameters, uric acid, lactate dehydrogenase (LDH)
Patients with anemia: Coombs test, haptoglobin, reticulocyte count and blood smear
Targeted-capture, next-generation sequencing of lesional tissue for mutations in RAF-RAS-MEK-ERK pathway (eg, KRAS, MAP2K1): in severe or refractory cases
Bone marrow aspirate/biopsy (if cytopenias or abnormal peripheral blood smear are present)
Lumbar puncture (for brain lesions inaccessible to biopsy);  cerebrospinal fluid (CSF) pleocytosis with emperipolesis visible upon cytologic examination is indicative of Rosai-Dorfman disease
Check lesional tissue for PDGFR-α/β and c-kit
Germ line mutations in SLC29A3: if familial Rosai-Dorfman disease is suspected

Abbreviations: CSF = cerebrospinal fluid; LDH = lactate dehydrogenase

[Source ²⁰⁷⁾ ]

Imaging studies

In children, a chest X-ray with neck and abdominal ultrasounds are routinely performed initially. For older patients, CT of the neck/chest/abdomen and pelvis is recommended. Rosai-Dorfman disease lesions are known to be FDG-avid, including extranodal areas ²⁰⁸⁾ and FDG-PET/CT is used by some investigators for initial staging when possible, similarly to patients with Erdheim-Chester disease ²⁰⁹⁾. Of note, Rosai-Dorfman disease lesions can have appearance and avidity on FDG-PET similar to those of intermediate- and high-grade lymphomas, and these should be diagnostic considerations. Rather than skull-to-thigh scanning, full-body PET including the distal extremities should be performed for comprehensive osseous evaluation. However, there is no consensus among the authors about the benefits of PET/CT in patients with Rosai-Dorfman disease as compared with anatomic imaging ²¹⁰⁾. In children, efforts must be made to minimize radiation exposure and need for anesthesia. Whole-body MRI is usually recommended instead of CT scans, and PET scans should be used judiciously ²¹¹⁾. Patients with orbital or neurologic symptoms should have a gadolinium-enhanced MRI of the brain, orbits, or total spine depending on the localizing symptoms; screening MRI of the brain and spine with contrast may be appropriate to identify asymptomatic neurologic involvement ²¹²⁾. Dedicated organ-specific imaging (ie, MRI of the heart or abdomen) may be necessary to evaluate structural lesions identified but poorly characterized by CT or PET ²¹³⁾.

Laboratory tests

Laboratory tests should include comprehensive metabolic panel, a complete blood count with differential, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and quantitative immunoglobulin levels. Serologies for HIV and hepatitis B and C are suggested to exclude these as associated diagnoses. Testing for antinuclear antibodies (ANA) and rheumatoid factor (RF) is suggested, because screening for associated systemic lupus erythematous (SLE) or idiopathic juvenile arthritis and further evaluation for evidence of autoimmunity should be carried out if other diagnoses are considered on the basis of medical history and physical examination. Bone marrow aspirate and biopsy are required only for patients with unexplained cytopenias or abnormal peripheral blood cells.

Laboratory evaluation of Rosai-Dorfman disease patients shows approximately 2/3 of patients present with normochromic normocytic anemia, leukocytosis (neutrophilia most commonly) ²¹⁴⁾. Poly-clonal hypergammaglobulinemia was reported in approximately 90% of patients; increased erythrocyte sedimentation rate in approximately 90%; and hypoalbuminemia in approximately 60%. The CD4:CD8 ratio was found to be decreased. Other laboratory findings are present, such as elevated ferritin level and autoimmune hemolytic anemia ²¹⁵⁾.

Tissue biopsy

It is important that sufficient tissue be acquired to establish a Rosai-Dorfman disease diagnosis and that biopsies be reviewed by a pathologist familiar with Rosai-Dorfman disease ²¹⁶⁾. Flow cytometry and cytogenetic testing may be required to rule out a lymphoproliferative disorder. Immunohistochemistry for IgG4 should be performed when pathology samples show an enriched plasma-cell presence ²¹⁷⁾. In the event of severe or refractory Rosai-Dorfman disease, lesional tissue should be analyzed to detect gain-of-function mutations of genes of the MAPK pathway amenable to targeted therapies (including at least KRAS, NRAS, HRAS, ARAF, BRAF, and MAP2K1) ²¹⁸⁾.

Histopathology

Histologic examination shows enlarged, matted, grossly involved lymph nodes and capsular fibrosis. Under microscopic examination, lymph nodes have a thickened capsule, abnormal architecture, and massive sinus expansion. Sinuses are obstructed by a mixed population of cells, including histiocytes, lymphocytes, plasma cells, and Rosai-Dorfman disease histiocytes. Rosai-Dorfman disease histiocytes are usually large with round-to-oval nuclei, dispersed chromatin, prominent nucleoli, and abundant clear-to-foamy or vacuolated cytoplasm. The hallmark of Rosai-Dorfman disease histiocytes is lymphophagocytosis or emperipolesis – the phagocytosis of a variety of intact cells, including red blood cells, neutrophils, or plasma cells ²¹⁹⁾. During the process of emperipolesis, Rosai-Dorfman disease histiocytes engulf intact cells and sometimes nuclear debris and lipids. The engulfed cells remain viable and can exit histiocytes in contrast to the process of phagocytosis (Figure 7). These findings are observed in both nodal and extranodal sites; however, there is a greater degree of fibrosis and Rosai-Dorfman disease histiocytes with less frequent or absent emperipolesis on extranodal sites. Extranodal Rosai-Dorfman disease also appears more frequently to be fibrosis and less frequently to be histiocytosis. Rosai-Dorfman disease is often associated with abundant plasma cells in the medullary cords and around the venules ²²⁰⁾.

Fine-needle aspiration–smears and touch imprints are typically highly cellular with many histiocytes and engulfed lymphocytes (emperipolesis) against a background of mixed inflammatory cells, including plasma cells and lymphocytes ²²¹⁾. Histiocytes tend to be large with abundant cytoplasm and a round, vesicular nucleus with a small central nucleolus. In smear and imprint preparations, there tends to be a diagnostic dilemma; overlapping lymphocytes can be mistaken for emperipolesis as engulfed lymphocytes do not appear surrounded by a halo, as seen in tissue sections. In later stages of Rosai-Dorfman disease, there tends to be increased plasma cells and cytoplasmic immunoglobulin inclusion (Russell bodies) ²²²⁾.

Immunohistochemical stains are crucial in confirming a diagnosis. The typical Rosai-Dorfman disease histiocytes express S100+, CD4+, CD11c+, CD14+, CD68+, CD163+, α-1-antitripsin+, α-1-antichymotripsin+, and CD1a negative ²²³⁾, ²²⁴⁾, ²²⁵⁾, ²²⁶⁾, ²²⁷⁾. Uniquely, in Rosai-Dorfman disease, the histiocytes express S100, which is a useful feature for visualizing the emperipolesis, as first described in a single case by Aoyama et al. ²²⁸⁾ and confirmed in a larger series by Miettinen et al. ²²⁹⁾ (see Figure 8). Rosai-Dorfman disease is usually negative for pan B- or T-cell antigens, markers for Langerhans cells (CD1a and langerin/CD207), and follicular dendritic cell markers (CD21, CD23, CD35, and clusterin) ²³⁰⁾. Rosai-Dorfman disease histiocytes are also reactive to α1-antichymotrypsin and α1-antitrypsin, which might suggest lysosomal activity ²³¹⁾.

Recent studies have shown that 1/3 of Rosai-Dorfman disease cases harboring mutations in the MAPK/ERK pathway that were found to be gain-of-function mutations leading to the upregulation of p-ERK and cyclin D1/BCL-1 in the histiocytes ²³²⁾, ²³³⁾, ²³⁴⁾. Cyclin D1/BCL-1, a key cell-cycle regulator, represents a major downstream target of the MAPK/ERK pathway. Expression that is positive for Cyclin D1/BCL-1 can be associated with phosphorylated -ERK (p-ERK), reflecting the constitutive activation of MAPK pathway ²³⁵⁾. However, some cases show cyclin D1 upregulation and absence of p-ERK expression; hence, cyclin D1 might be regulated by other oncogenic mechanisms bypassing the ERK pathway ²³⁶⁾. Positive cyclin D1/BCL-1 staining in Rosai-Dorfman disease is not associated with an underlying translocation of the CCND1 gene. Be cautious: some reactive histiocytes also express cyclin D1/BCL-1; however, this is usually dimly expressed. The marker becomes less specific for Rosai-Dorfman disease if it is weakly expressed on histiocytes ²³⁷⁾, ²³⁸⁾. Besides cyclin D1/bcl-1, the Mayo group study showed a subset of Rosai-Dorfman disease cases also expressed p16 (64%), Factor XIIIa (30%) and phosphorylated extracellular signal-related kinase (45%) ²³⁹⁾. The latter two parameters appeared to be associated with multifocality of Rosai-Dorfman disease ²⁴⁰⁾. As Factor XIIIa is also seen with Erdheim-Chester disease, this should be interpreted with caution.

Another marker that was frequently expressed in many Rosai-Dorfman disease cases is BCL-2. Since Rosai-Dorfman disease cases usually have low Ki-67 proliferation index, the expression of BCL-2 might be caused by the activation of the anti-apoptotic process ²⁴¹⁾, ²⁴²⁾. OCT2, a unique monocyte-macrophage marker, has also been found to be expressed in most cases of Rosai-Dorfman disease, in contrast to other histiocytic disorders, such as Langerhans cell histiocytosis and Erdheim-Chester disease ²⁴³⁾. Plasma cell markers (IgG, IgG4, kappa and lambda) are used to identify concurrent IgG4 disease (Figure 10).

BRAF-V600E mutation and Birbeck granules, both found in Langerhans cell histiocytosis (LCH), are negative in Rosai-Dorfman disease ²⁴⁴⁾. BRAF-V600E is more common in Rosai-Dorfman disease overlapped with Langerhans cell histiocytosis or Erdheim-Chester disease ²⁴⁵⁾.

Figure 8. Rosai-Dorfman disease histopathology

Footnotes: The selected images show a case of nodal Rosai–Dorfman disease with concurrent IgG4-related disease. (A) Low-power magnification shows effacement of normal lymph-node architecture by histiocytes (H & E, magnification 40×). (B) Higher-power magnification demonstrates increased plasma cells arranged in nests and singly associated with background fibrosis and histiocytes (immunoperoxidase, magnification 200×). (C) Loaded histiocytes with emperipolesis and (D) an increased number of plasma cells (immunoperoxidase, magnification 600× and 600×, respectively).

[Source ²⁴⁶⁾ ]

Figure 9. Rosai–Dorfman disease immunohistochemical stains

Footnotes: (A) S100 immunohistochemical stain highlighting the histiocytes, which also demonstrates emperipolesis (immunoperoxidase, magnification 600×). (B) CD68 immunohistochemical stain highlighting the histiocytes (immunoperoxidase, magnification 600×). (C,D) BCL-1 and Oct2 immunohistochemical stains are positive for histiocytes of Rosai–Dorfman disease (immunoperoxidase, magnification 600×).

[Source ²⁴⁷⁾ ]

Figure 10. Rosai–Dorfman disease with IgG4 disease

Footnotes: IgG4 disease in a patient with Rosai–Dorfman disease. Increased plasma cells in a background of fibrosis. (A,B) Immunohistochemical stains demonstrate plasma cells positive for IgG and proportionally positive forIgG4 (A,B). immunoperoxidase 100×, respectively). (C,D) In situ hybridization using kappa and lambda light chain probes reveal the plasma cells to be polyclonal (in situ hybridization 100×, respectively).

[Source ²⁴⁸⁾ ]

Gene mutations

Approximately 50% of cases of Rosai-Dorfman disease do not have a known distinct genetic mutation profile ²⁴⁹⁾. From 30% to 50% of patients with Rosai-Dorfman disease-harboring somatic mutations are frequently involved in ARAF, NRAS, KRAS, MAP2K1, CSF1, and CBL genes, of which MA2P2K1 and KRAS were the most frequent, making up 14% and 12.5% of all Rosai-Dorfman disease, respectively (see Table 4) ²⁵⁰⁾, ²⁵¹⁾, ²⁵²⁾, ²⁵³⁾, ²⁵⁴⁾. Garces et al. ²⁵⁵⁾ showed mutually excluded KRAS and MAP21 gene mutations in Rosai-Dorfman disease, together making up 33% of cases. NRAS mutation was detected in numerous cases of purely cutaneous Rosai-Dorfman disease. A study of Wu et al. ²⁵⁶⁾ showed NRAS (A146T) mutation was the most common among point mutants, followed by NRAS G13S, suggesting that the mutations may play a role in pathogenesis of cutaneous Rosai-Dorfman disease. PTPN11, NF1 mutations have also occasionally been reported ²⁵⁷⁾. BRAF mutations can occasionally occur in Rosai-Dorfman disease, and not just V600E mutations; other mutations were reported (BRAF Y472C and BRAF R188G, deletion in exon 12 of BRAF) ²⁵⁸⁾, ²⁵⁹⁾, ²⁶⁰⁾. BRAF-V600E is more common in Rosai-Dorfman disease overlapped with Langerhans cell histiocytosis or Erdheim-Chester disease ²⁶¹⁾. Given the low frequency of BRAF mutations in cases of Rosai-Dorfman disease, one should pay an attention to Rosai-Dorfman disease-overlapping diseases.

There are many other genes that are mutated in Rosai-Dorfman disease, including SNX24, and are involved in intracellular trafficking. INTS2, CIC, SFR1, BRD4, and PHOX2B genes play roles in the transcriptional regulation as well as cell-cycle regulation genes (PDS5A, MUC4); ubiquitin-proteasome pathway (USP35); and DNA-mismatch repair genes (BRCA1, LATS2, ATM) ²⁶²⁾, ²⁶³⁾.

Some gene mutations frequently identified in myeloid or lymphoid neoplasms have also been observed in Rosai-Dorfman disease, e.g., ASXL1, TET2, and DNMT3A ²⁶⁴⁾. A large cohort of 28 patients reported many mutations, which are implicated in other myeloid malignancies, e.g., TET2, MLL4, NF1, ALK, and ASXL1; many of these genes are driver mutations in different myeloid and lymphoid neoplasms ²⁶⁵⁾. Whether they might play a role in the pathogenesis of Rosai-Dorfman disease or if they might cause transformation or transdifferentiation to these neoplasms has yet to be determined. Many other mutations have been reported: SEC62, FCGBP, PIK3R2, PIK3CA, VCL, EGFR, ERBB2 and TLR8 (minimum variable allele frequency in these mutations is 2%) ²⁶⁶⁾. The exact roles of these genes are of further exploration.

Cytogenetic testing usually does not have a role in Rosai-Dorfman disease; however, testing can be conducted to rule out a neoplastic process. One case was reported to have a normal karyotype with a minor clone lacking chromosome 20 ²⁶⁷⁾.

Table 4. Certain gene mutations identified in Rosai-Dorfman disease

Gene	Molecular Alteration
ARAF	N217K
MAP2K1	F53V, L115V, P124R, G128D, V50M, D65M
KRAS	A146T, A146V, K117N, G12D, G12R, G13S, Q22K,
NRAS	G13D
CBL	C384Y, GNAQ Q209H
KDM5A	amplification
FBXW7	E113D
BRAF	V600E, deletion (p. 486–491), Y472C and R188G
SMAD4	T521I (variant of unknown significance, 1 case)

[Source ²⁶⁸⁾ ]

Rosai Dorfman disease treatment

In many cases, Rosai-Dorfman disease is a self-limited and seldom life-threatening disease which commonly does not require therapy. The “watch and wait” approach is used without treatment is preferred for individuals with Rosai-Dorfman disease whenever possible ²⁶⁹⁾, ²⁷⁰⁾.

In some cases, various treatment options may become necessary. In these cases, the treatment of Rosai-Dorfman disease is directed toward the specific symptoms that are apparent in each individual. Several different treatment options have been used to treat individuals with Rosai-Dorfman disease including surgical removal of histiocytic lesions. In more serious cases, additional treatment options have included therapy with certain drugs including steroids (e.g., prednisone), interferon-alpha (IFN-α) ²⁷¹⁾, rituximab ²⁷²⁾, ²⁷³⁾, imatinib ²⁷⁴⁾ and retinoids ²⁷⁵⁾ and a regimen of certain anticancer drugs (chemotherapy). Numerous chemotherapeutic agents were used, i.e. vinca alkaloids, alkylating agents, anthracyclines, cladribine ²⁷⁶⁾, clofarabine ²⁷⁷⁾, methotrexate ²⁷⁸⁾, mercaptopurine ²⁷⁹⁾, azathioprine ²⁸⁰⁾ and chlorodeoxyadenosine ²⁸¹⁾. In some cases, affected individuals have shown improvement of symptoms with these treatments. In other cases, drug therapies have been ineffective.

Other treatment is symptomatic and supportive. Radiotherapy was considered a palliative method in patients with symptomatic Rosai-Dorfman disease ²⁸²⁾, but according to the latest findings it can give better results than chemotherapy in some cases ²⁸³⁾. Radiotherapy appears to be an alternative in steroid-resistant patients ²⁸⁴⁾, ²⁸⁵⁾.

There are reports describing Rosai-Dorfman disease patients with a high level of HHV-6/VZV antibody titres, in which there was significant improvement after the application of acyclovir ²⁸⁶⁾, ²⁸⁷⁾. In other cases, complete remission was observed after using thalidomide ²⁸⁸⁾.

Figure 11. Rosai-Dorfman disease treatment algorithm

[Source ²⁸⁹⁾ ]

Figure 12. Rosai-Dorfman disease with nervous system disease treatment algorithm

[Source ²⁹⁰⁾ ]

Table 5. Treatment options for Rosai-Dorfman disease

Treatment	Dose/schedule	Indication	Supportive evidence	Comments
Observation	NA	Uncomplicated adenopathy	Case series of 80 patients showed 50% spontaneous remission 291)	Can consider observation for near-complete resection of unifocal lesions with minimal residual disease after surgery
		Asymptomatic cutaneous Rosai-Dorfman disease
		Postoperatively for resected unifocal disease
Corticosteroids	Prednisone: 40-70 mg or 1 mg/kg per day followed by taper	Symptomatic nodal or cutaneous disease	Several case reports and case series with prednisone showing responses in orbital, central nervous system (CNS), and bone Rosai-Dorfman disease and autoimmune hemolytic anemia-associated disease 292), 293)	Responses, when favorable, are unpredictable in their durability
	Dexamethasone: 8-20 mg per day followed by taper	Nonresectable or multifocal extranodal disease requiring systemic treatment	Dexamethasone was effective in central nervous system (CNS) and nodal Rosai-Dorfman disease in case reports 294), 295)	Optimal duration of treatment is not known because early relapse can occur
			Case report of intralesional steroids in orbital Rosai-Dorfman disease 296)	One reasonable approach is to treat to optimal response followed by slow taper
			No response to steroids in other case reports of orbital, tracheal, renal, or soft tissue Rosai-Dorfman disease 297), 298)	After successful steroid treatment: consider second-line agents to maintain response
Surgical resection	NA	Unifocal extranodal disease	Case series with long-term remission after resection of isolated cutaneous and intracranial disease 299), 300)	Local recurrences can occur 301), 302), for which case systemic treatment should be considered
		Symptomatic cranial, spinal, sinus, or airway disease
Sirolimus	2.5 mg/m2 per day for 18 months, then taper off over 6 months		Prolonged complete response in Rosai-Dorfman disease with autoimmune cytopenia 303)	Reasonable first choice in Autoimmune lymphoproliferative syndrome (ALPS)-associated Rosai-Dorfman disease
Radiotherapy	30-50 Gy, lymphoma-like schedule 304)	Refractory or symptomatic disease not amenable to resection, recurrent after resection, or with a contraindication to systemic therapy	Palliative benefit in case reports, including refractory soft tissue and orbital Rosai-Dorfman disease with visual compromise 305) and for mass effect causing airway obstruction 306), 307)	No established fractionation schedule
				Can also be considered as adjuvant treatment after resection of cranial or spinal lesions with residual but not bulky disease
Chemotherapy
Cladribine	5 mg/m² per day for 5 days, every 28 days for up to 6 cycles	Severe, disseminated, or refractory disease	11 patients reported: 7 with complete response, 1 with partial response, and 3 with progressive disease 308), 309), 310), 311), 312)	Can cause myelosuppression with associated infections
		CNS involvement
methotrexate or 6-mercaptopurine/methotrexate	20 mg/m² per week of methotrexate, alone or with 6-mercaptopurine (50 mg/m² per day) or steroids	Multifocal, skin, or CNS Rosai-Dorfman disease	Partial response or complete response in refractory cases 313), 314), 315), 316), 317), 318), 319)	Reasonable as maintenance therapy after surgery or steroids
				Optimal duration unknown
Vinca alkaloids	Standard doses; vinblastine usually combined with prednisone		Vincristine effective in 1 report of skin Rosai-Dorfman disease 320)	Variable responses
			Several reports showing prolonged complete response when combined with other agents 321), 322), 323)	Optimal duration unknown
Immunomodulatory
Thalidomide	50-300 mg per day; variable duration	Refractory cutaneous Rosai-Dorfman disease	Recent review: several reports with prolonged complete response 324)	Notable toxicities include skin rash and neuropathy
			Variable responses	Optimal dose and duration unknown
Lenalidomide	Not known	Refractory disease	Sustained complete response in an adult with multiply relapsed Rosai-Dorfman disease 325)	Myelosuppressive but less neuropathy and skin rash than thalidomide
Rituximab	500 mg/m² per dose every 1 or 2 week for 2-6 cycles	For refractory nodal and immune-related Rosai-Dorfman disease	Efficacy described in single case reports 326)	Mechanism of efficacy is not understood
	– alone or with chemotherapy			There are reports of refractoriness and relapses 327), 328) and therefore, reports of success are interpreted with caution
Imatinib mesylate	400-600 mg per day for 7 months	Refractory/relapsed Rosai-Dorfman disease	Anecdotal activity in 1 adult with refractory Rosai-Dorfman disease 329)	Variable responses
			1 case of skin Rosai-Dorfman disease was refractory 330)	May work only in progressive disease GFR α/β+ cases
Clinical trial (experimental)
Cobimetinib (NCT02649972)	Per trial guidelines	Refractory Rosai-Dorfman disease	Substantial regression of abdominal masses in a single patient with KRAS p.G12R–mutated Rosai-Dorfman disease 331)	Several case reports of successful treatment of Erdheim-Chester disease with cobimetinib 332), 333)
Clofarabine (NCT02425904)	25 mg/m² per day for 5 days, every 28 days for 6 cycles	Severe, disseminated, or refractory disease	3 patients: 2 with complete response, 1 had partial response 334)	Myelosuppressive and expensive
		CNS involvement		Prospective studies ongoing to determine optimal dosing, long-term efficacy, and toxicity

Footnote: NA = not applicable

[Source ³³⁵⁾ ]

Watch and wait

After the diagnosis of Rosai-Dorfman disease is established, observation is reasonable in many cases, because 20% to 50% of patients with nodal or cutaneous Rosai-Dorfman disease will have spontaneous remissions ³³⁶⁾, ³³⁷⁾. Watch and wait strategy is suitable for patients with uncomplicated lymphadenopathy or asymptomatic cutaneous Rosai-Dorfman disease and potentially for those with asymptomatic disease in other sites ³³⁸⁾.

Surgery

Surgery for Rosai-Dorfman disease is usually limited to biopsy, but complete surgical resection can be curative for unifocal disease, and debulking may be warranted for upper airway obstruction, spinal cord compression, or large lesions causing end-organ damage ³³⁹⁾. Long-term remissions with resection alone have been reported in isolated intracranial disease ³⁴⁰⁾. The most effective treatment of cutaneous Rosai-Dorfman disease is surgical excision ³⁴¹⁾. Endoscopic resection of sinonasal Rosai-Dorfman disease can achieve symptomatic control and restoration of function ³⁴²⁾. In cases of multifocal disease, surgical resection of single foci should be reserved for bulky disease with neurologic or end-organ dysfunction ³⁴³⁾.

Corticosteroids

Corticosteroids are usually helpful in reducing nodal size and symptoms, although responses have been variable ³⁴⁴⁾. The optimal corticosteroid (prednisone or dexamethasone) dose and duration are not clearly defined. Prednisone (40-70 mg per day) has produced complete or partial responses in cases of orbital, central nervous system (CNS), bone, and autoimmune hemolytic anemia–associated disease ³⁴⁵⁾, ³⁴⁶⁾. Compared with other immune diseases (eg, sarcoidosis), therapeutic prednisone doses are usually higher (>0.5 mg/kg per day). Similarly, dexamethasone (8-20 mg per day) was effective in cases of central nervous system (CNS) Rosai-Dorfman disease and hilar lymphadenopathy ³⁴⁷⁾, ³⁴⁸⁾. One viable approach is to treat to the best observed response, followed by slow taper ³⁴⁹⁾. An anecdotal response to intralesional steroids has been reported in an adult with orbital Rosai-Dorfman disease and optic nerve compression ³⁵⁰⁾. Nevertheless, other reports of orbital, tracheal, renal, or soft tissue Rosai-Dorfman disease have shown a failure to respond to steroids ³⁵¹⁾, ³⁵²⁾. Furthermore, relapses of Rosai-Dorfman disease lesions can sometimes occur after a short period of interruption ³⁵³⁾. Anecdotally, the experience of the authors is that patients with extranodal disease do not generally demonstrate a durable response to steroids alone ³⁵⁴⁾. A case series of 57 patients reported by Mayo Clinic group showed that corticosteroid treatment was associated with 56% overall response rate (ORR) in treatment-naïve patients ³⁵⁵⁾. Relapses occurred in 53% of patients. When steroids were used as a second-line therapy, the overall response rate (ORR) was 67% ³⁵⁶⁾.

Sirolimus

Mammalian target of rapamycin is a critical pathway for the control of proliferation and cytokine production from immune cells and has been found to be dysregulated in Rosai-Dorfman disease ³⁵⁷⁾. Sirolimus and prednisone induced objective responses and disease stabilization in 80% of patients with Erdheim-Chester disease in 1 report ³⁵⁸⁾ and sirolimus was found to be beneficial in a child with resistant Rosai-Dorfman disease and recurrent autoimmune cytopenias ³⁵⁹⁾. Sirolimus is frequently used for treating autoimmune lymphoproliferative syndrome (ALPS)- or autoimmune-associated Rosai-Dorfman disease, but further study are needed.

Chemotherapy

Treatment of Rosai-Dorfman disease with chemotherapeutic agents has shown mixed results ³⁶⁰⁾. Although chemotherapy is generally reserved for refractory or relapsed cases, sometimes it is used as initial therapy in disseminated or life-threatening disease. Anthracyclines and alkylating agents have little efficacy, whereas vinca alkaloids have shown variable responses ³⁶¹⁾. Low-dose methotrexate and 6-mercaptopurine administered in combination were effective in few patients ³⁶²⁾, ³⁶³⁾. Sustainable remissions after regimens containing vinblastine/methotrexate/6-mercaptopurine and 6-thioguanine ³⁶⁴⁾, vinblastine/prednisone/methotrexate/6-mercaptopurine ³⁶⁵⁾ or vinorelbine/methotrexate ³⁶⁶⁾ have been reported. Single-agent 6-mercaptopurine was effective in halting disease in an adult with orbital and intracranial Rosai-Dorfman disease ³⁶⁷⁾. Furthermore, long-term remission of intracranial Rosai-Dorfman disease has been reported after postsurgical maintenance with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)–like regimens ³⁶⁸⁾. A patient with multiply-relapsed nodal Rosai-Dorfman disease responded to cytarabine/prednisone/vincristine followed by methotrexate/6-mercaptopurine maintenance ³⁶⁹⁾. Successful treatment of refractory cutaneous Rosai-Dorfman disease was reported with single-agent vincristine ³⁷⁰⁾ and low-dose methotrexate ³⁷¹⁾. In addition, azathioprine and interferon-alpha (IFN-α) induced long-term remissions in patients with Rosai-Dorfman disease ³⁷²⁾, ³⁷³⁾. However, interferon-alpha (IFN-α) in combination with chemotherapy failed to induce any response in another report ³⁷⁴⁾. Therefore, these agents could be considered for steroid-refractory disease or early recurrence after interruption of steroids or when steroids are contraindicated ³⁷⁵⁾.

Nucleoside analogs cladribine and clofarabine have induced responses in Rosai-Dorfman disease ³⁷⁶⁾, ³⁷⁷⁾, ³⁷⁸⁾, ³⁷⁹⁾, ³⁸⁰⁾. They impair the function of monocytes through inhibition of interleukin-6 (IL-6), IL-1β, and tumor necrosis factor alpha (TNF-α) production. Cladribine (2.1-5 mg/m² per day for 5 days every 28 days for 6 months) induced prolonged remissions in cases of recurrent or refractory systemic Rosai-Dorfman disease ³⁸¹⁾, ³⁸²⁾, ³⁸³⁾, ³⁸⁴⁾ and clofarabine (25 mg/m² per day for 5 days every 28 days for 6 months) was effective as salvage therapy in a series of patients with refractory or relapsed Rosai-Dorfman disease ³⁸⁵⁾. These agents should be considered in severe or refractory Rosai-Dorfman disease cases when the potential benefit justifies their myelosuppressive toxicity ³⁸⁶⁾. A multicenter prospective study (NCT02425904) is being conducted by the North American Consortium for Histiocytosis to study the efficacy and safety of clofarabine salvage in patients with histiocytoses, including Rosai-Dorfman disease.

Immunomodulatory therapy

Tumor necrosis factor alpha (TNF-α) inhibitors thalidomide and lenalidomide have shown promising results in Rosai-Dorfman disease because the identification of high levels of TNF-α and IL-6 provides a rational basis for their effectiveness ³⁸⁷⁾. A recent review showed that low-dose thalidomide (100 mg per day) was effective in refractory cutaneous Rosai-Dorfman disease ³⁸⁸⁾. However, responses to thalidomide have not been universal, and optimal dosing and duration of this drug remain unknown. Lenalidomide recently showed an excellent response in an adult with multiply-refractory nodal and bone Rosai-Dorfman disease and may be more tolerable than thalidomide (fewer skin rashes and less neuropathy), although more myelosuppressive ³⁸⁹⁾.

The efficacy of rituximab has been described, especially in autoimmune-related Rosai-Dorfman disease cases ³⁹⁰⁾, although refractoriness ³⁹¹⁾ and recurrences ³⁹²⁾ have also been described.

Targeted therapies

Imatinib mesylate, a tyrosine kinase inhibitor, showed some activity in 1 patient with refractory Rosai-Dorfman disease. Lesional histiocytes were positive for the imatinib target proteins PDGFRB and KIT by immunohistochemistry, but no concurrent mutation was found ³⁹³⁾. In another case, cutaneous Rosai-Dorfman disease was refractory to imatinib ³⁹⁴⁾.

Unlike Erdheim-Chester disease and Langerhans cell histiocytosis, BRAF-V600E mutations have not been observed in Rosai-Dorfman disease ³⁹⁵⁾, ³⁹⁶⁾; therefore, the use of BRAF inhibitors is not relevant ³⁹⁷⁾. MEK inhibition has shown preliminary activity in BRAF–wild-type Erdheim-Chester disease and in an adult with KRAS-mutated Rosai-Dorfman disease ³⁹⁸⁾, ³⁹⁹⁾. A phase 2 trial of cobimetinib for patients with BRAF–wild-type histiocytoses, including Rosai-Dorfman disease, is ongoing (NCT02649972), with promising early results ⁴⁰⁰⁾. The robust activity of targeted therapies in other histiocytoses raises interest in their potential for Rosai-Dorfman disease, especially in cases with demonstrated somatic mutations; however, currently, the broad applicability of tumor sequencing and targeted treatments has not yet been established ⁴⁰¹⁾.

Radiotherapy

External-beam radiation therapy has modest efficacy in Rosai-Dorfman disease, although it can be beneficial in localized unresectable symptomatic steroid-refractory soft tissue masses and orbital bone disease with visual compromise ⁴⁰²⁾ or resistant airway obstruction or to palliate local symptoms ⁴⁰³⁾, ⁴⁰⁴⁾. Radiotherapy has also been implemented in patients whose symptoms persist or recur after resection of isolated disease and in those who are not suitable candidates for surgery and/or when other treatments are contraindicated ⁴⁰⁵⁾, ⁴⁰⁶⁾. No standard doses of radiotherapy have been established, but doses between 20 and 50 Gy with 2 Gy per fraction have been employed ⁴⁰⁷⁾. Overall response rate (ORR) was approximately 40% in patients treated with doses ranging from 30 to 49 Gy and 27% with doses less than 30 Gy ⁴⁰⁸⁾.

Treatment course and disease surveillance

The optimal duration of steroids or other systemic therapies for Rosai-Dorfman disease is not known ⁴⁰⁹⁾. Six to 12 months of systemic therapy followed by observation, assuming tolerance and a favorable response to treatment, is a reasonable approach. When initiating treatment, a first response assessment should be carried out within 4 months; if disease stabilizes or is in remission, interval of surveillance can be extended to 6 to 12 months ⁴¹⁰⁾.

Rosai Dorfman disease prognosis

To date, there has not been a large case series monitoring the prognosis of Rosai-Dorfman disease patients ⁴¹¹⁾. Prognosis is usually favorable for cutaneous, nodal, and bone Rosai-Dorfman disease. However, multiorgan involvement or dysfunction and association with immune dysfunction are poor prognostic indicators and may lead to death ⁴¹²⁾, ⁴¹³⁾. In extranodal Rosai-Dorfman disease forms, prognosis also correlated with the number of organ systems that were involved. CNS involvement with Rosai-Dorfman disease has variable outcomes ⁴¹⁴⁾, ⁴¹⁵⁾, ⁴¹⁶⁾. In most cases, Rosai-Dorfman disease has a good prognosis; however, some patients have a progressive and fatal course. Regarding gastrointestinal involvement by Rosai-Dorfman disease, a case series reported approximately 20% mortality ⁴¹⁷⁾. Genitourinary-system involvement has a worse prognosis of approximately 40% mortality in Rosai-Dorfman disease involving the kidney ⁴¹⁸⁾. The largest series of Rosai-Dorfman disease was reported by Foucar et al. in 1990 ⁴¹⁹⁾; it showed that 17 (7%) of 238 patients died because of direct complications of their disease, infections, or amyloidosis. The most common causes of reported deaths were identified immunological abnormalities, severe infections, surgical complications, complications after radiotherapy, and the compression of airways by enlarged lymph nodes ⁴²⁰⁾, ⁴²¹⁾. There are reports of Rosai-Dorfman disease leading to lymphoma, amyloidosis, and consequently death resulting from these diseases ⁴²²⁾.

In 2011 the Histiocyte Society divided Rosai-Dorfman disease patients into three major groups ⁴²³⁾:

1. Patients with sudden enlargement of the lymph nodes, in which spontaneous regression is observed, without any further recurrences – consistent with the best prognosis;
2. Patients with immunological abnormalities, in which lymphadenopathy is more generalized – the prognosis being worse; and
3. Patients with extranodal site involvement and/or multinodal disease, with repeated relapses and remissions over a period of years – the prognosis depends on the type and number of extranodal sites.

In a review by Pulsoni et al in 2002 ⁴²⁴⁾, 10 (12%) of 80 patients died as a result of Rosai-Dorfman disease. Patients with multifocal and extranodal Rosai-Dorfman disease, particularly those with kidney, liver, or lower respiratory tract disease, seem to have an unfavorable prognosis. Therefore, intensive systemic chemotherapy, targeted therapies, and investigational agents may be justified in this context. Further research of the role of these therapies in refractory Rosai-Dorfman disease may mitigate the poor prognosis of some of these cases ⁴²⁵⁾.

Classic symptoms, such as cervical lymphadenopathy, fever, and good general condition, may persist from several weeks to even a few years (the average time is 3-9 months) ⁴²⁶⁾. Twenty percent of Rosai-Dorfman disease patients have spontaneous resolution or improvement within 3–9 months. Other patients experience an unpredictable clinical course, with alternating periods of remission and reactivation that may last years ⁴²⁷⁾. The majority of Rosai-Dorfman disease patients have stable and persistent disease lasting up to several years. Without treatment, relapsing-remitting Rosai-Dorfman disease will occur in 70% of cases, spontaneous regression in 20%, and in 10% there will be a progression of the disease ⁴²⁸⁾. Seven percent of patients have a fatal outcome, especially if immunologic abnormalities and extranodal involvement are present. It is recommended that a clinical examination and laboratory tests be performed every 3-6 months during the first two years following diagnosis, then every year ⁴²⁹⁾.