Rosai-Dorfman-Destombes Disease – The Current View on Pathogenesis, Clinical Characteristics, Differential Diagnosis and Treatment

1. Introduction

Rosai–Dorfman–Destombes (RDD) disease, also known as sinus histiocytosis with massive lymphadenopathy (SHML), is an idiopathic histiocytic proliferative disorder based in the lymph nodes [1,2]. In most patients, it manifests as a benign lymphoproliferative disorder of unknown etiology. The disease can be sporadic or familial, and is considered a distinct entity from cutaneous RDD, which is strictly limited to the skin [3,4]. While the condition was first described by Destombes in 1965 [5], it was later reclassified by Rosai and Dorfman as a distinct entity characterized by sinus histiocytosis and massive lymphadenopathy [6].

In the revised 2016 classification of histiocytoses, classic RDD is classified as part of the R-group of non-Langerhans cell histiocytosis, while cutaneous RDD is included in the C-group. In the former, RDD can be further divided into five subgroups: classical (nodal), familial, extranodal, neoplasia-associated, and immune disease-associated RDD [1,7]. This classification underscores the clinical heterogeneity of the condition, and highlights its hallmark characteristics, viz. histiocytes that exhibit emperipolesis and are positive for S-100, CD68, and CD163, without CD1a or CD207 expression. This classification encompasses the classical, sporadic and extranodal forms of RDD, and includes variants associated with immune-mediated conditions, such as systemic lupus erythematosus, idiopathic juvenile arthritis, autoimmune hemolytic anemia, HIV and neoplasia. In contrast, familial RDD includes H syndrome (Faisalabad syndrome) and autoimmune lymphoproliferative syndrome (ALPS)-related RDD with FAS deficiency. H syndrome is caused by mutations in the SLC29A3 gene and is inherited in an autosomal manner. ALPS-related RDD is caused by germline mutations in the TNFRSF6 gene [8].

Rosai-Dorfman-Destombes disease is now included in the 5th Edition of the World Health Organization (WHO) Classification of Myeloid and Histiocytic/Dendritic Neoplasms [9]. Its proliferating histiocytes, known as Rosai-Dorfman cells, are polyclonal, which suggests their reactive character [3]. The disovery of recurrent and somatic mutations in the MAPK signaling pathway in some patients led to a reclassification of RDD from an inflammatory disorder to a neoplastic process. Indeed, RDD has been found to follow a variable clinical course, with spontaneous remissions or progression that may require treatment.

2. Epidemiology

The prevalence of RDD is very rare, occurring with a frequency of 1 in 200,000, with about 100 new cases reported annually in the USA [10]. Only 1000 cases were reported worldwide as of 2020 [11]. The disease can appear at any age but is most common in children and adolescents, with a male-to-female ratio of 2:1. The mean age at presentation is 20.6 years, and 80% of cases have been diagnosed in patients 20 years old and younger, however, patients 70 years of age and older have also been observed [12]. The mean age of patients with cutaneous RDD is 45 years [10]. While RDD is equally common in African and White populations, it has been observed less frequently in Asian populations [13]. In contrast, cutaneous RDD is more common in White and Asian populations.

3. Etiology and Pathogenesis

It has been postulated that RDD originates from a monocyte-derived cell that develops along the macrophage differentiation pathway. The cells are large, with abundant eosinophilic cytoplasm and round-to-oval, cytologically bland nuclei. The vast majority of RDD cases are considered benign reactive proliferations, and molecular evidence of clonality has been documented in a subset. While the precise etiology of RDD remains unclear [3], infections and immunodeficiency are believed to play a part. Fro exaple, cases have been associated with human pathogens such as Brucella and Klebsiella spp., or viruses such as Epstein–Barr virus (EBV), human herpesvirus (HHV)-6, Varicella zoster virus, Cytomegalovirus (CMV), human immunodeficiency virus (HIV), and Parvovirus B19; however, no definite etiological link with RDD has been confirmed [14,15,16]. Moreover, familial cases have also been reported [17].

For many years, RDD was considered a polyclonal, reactive, and non-neoplastic disease. Molecular studies in a subset of patients have identified somatic mutations activating the mitogen-activated protein kinase (MAPK) signaling pathway. These include mutations in KRAS (KRAS proto-oncogene, GTPase), NRAS (NRAS proto-oncogene, GTPase), MAP2K1 (mitogen-activated protein kinase kinase 1), and ARAF (A-Raf proto-oncogene, serine/threonine kinase); in some patients, they have also been associated with alterations in PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha), which functions in the phosphoinositide 3-kinase–protein kinase B signaling pathway instead of the MAPK pathway [1,18,19].

In one study, one-third of RDD patients were found to dmeonstrate KRAS or MAP2K1 mutations, suggesting that a subset of cases may be clonal [20]; KRAS or MAP2K1 mutations have been found to be more common in younger patients with head and neck lymph node involvement and multifocal disease [19]. In addition, the MAPK pathway is involved in cell proliferation, differentiation and apoptosis [20]. These observations indicate that a molecularly-defined subset of RDD. BRAF, ARAF, CSF1R (Colony Stimulating Factor 1 Receptor) demonstrates clonality, and NRAS mutations have also been described in nodal and extranodal (but not cutaneous) cases [2,20,21]. Abnormal activation of the MAPK pathway can trigger the production of mammalian target of rapamycin (mTOR) and induce TNF-α production [22]. Ome reports suggest that RDD may be associated with neoplastic diseases, including Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), acute leukemia and sarcoma [1,23,24].

The most common lymphoma types associated with RDD include follicular lymphoma (FL) and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) [3,23,24]. Reports also suggest a relationhip between RDD and IgG4-related diseases, with IgG4-related disease noted in up to 30% of RDD patients, and some patients presenting increased numbers of IgG4-related plasma cells in the affected organs [25,26,27,28]. Despite this, the relationship between IgG4-related disease and RDD remains unclear [3,25]. In addition, approximately 10% of cases, RDD coexists with immunological disorders, such as idiopathic juvenile arthritis, lupus or autoimmune hemolytic anemia [29]. In familial RDD, SLC29A3 (Solute Carrier Family 29 Member 3) mutations may play a role [30]. However, it should be noted that increased IgG4-positive plasma-cell counts or an elevated IgG4/IgG ratio alone do not establish IgG4-related disease in an RDD lesion.

4. The Diagnosis of RDD

A diagnosis of RDD requires an approach that integrates compatible histopathology with the clinical and radiologic setting, and that excludes dominant malignant or infectious mimics (Table 1).

4.1. Clinical Characteristics

While the clinical presentation of RDD is variable [1,2,3], it can be classified into two general clinical forms: a typical systemic form and a cutaneous form [2,31]. In around 80 % of cases, the most common symptom is massive painless cervical lymphadenopathy [2]. The classic nodal phenotype of RDD presenting as persistent cervical lymphadenopathy is illustrated in a recent Polish pediatric report of a two-year-old child [32]. However, head and neck lymph nodes, or any nodal region, may also involve other tissues and organs, including the skin, central nervous system (CNS) and gastrointestinal tract.

The most common classical type of RDD is characterized by painless cervical lymphadenopathy and systemic lymph node involvement (Figure 1 and Figure 2) [1,33,34]. However, RDD can present as either a single mass or as multiple incidences at various anatomical sites. Axillary, inguinal, and mediastinal nodes are also affected, though less frequently than cervical nodes. In one study, around 40% of patients reported extranodal involvement in a single organ system [1]. The condition is often accompanied by systemic symptoms such as fever, night sweats, fatigue and weight loss, and by laboratory abnormalities including leukocytosis, polyclonal hyperglobulinemia, an elevated erythrocyte sedimentation rate, and immunological dysfunction. Other clinical symptoms at diagnosis include neutrophilia, anemia, hypergammaglobulinemia, and an elevated erythrocyte sedimentation rate (ESR) [35,36]. Anemia is observed in 40%-50% of patients [1]; while it is usually related to chronic inflammation, other potential causes include bone marrow infiltration and autoimmune hemolysis. In 40% of patients with RDD, extranodal involvement is observed and is commonly associated with a poor prognosis [34].

4.2. Histopathological Evaluation

RDD is diagnosed by correlating tissue morphology and immunophenotype with the clinical and imaging findings (Figure 1) [2,6,37]. In lymph nodes, the sinuses are widened and filled by characteristic large histiocytes. They have round to oval vesicular nuclei, visible nucleoli, and abundant pale cytoplasm with poorly demarcated borders. Significant nuclear atypia, atypical mitotic activity, and multinucleated forms are unusual. The residual and intersinusoidal tissue commonly contains abundant polytypic plasma cells, most conspicuous in medullary cords. Neutrophils may occur, at times forming small abscesses, whereas eosinophils are usually sparse. Variable capsular and intranodal fibrosis may extend into adjacent soft tissue. In extensively involved nodes, the original architecture can be largely lost.

A typical, although variable, finding is emperipolesis: intact inflammatory cells are present within the cytoplasm of the lesional histiocytes. Lymphocytes predominate, but plasma cells, neutrophils, and erythrocytes can also be seen. This differs from phagocytosis because the internalized cells remain viable. Its presence is diagnostically helpful, but it is neither required nor unique to RDD. In particular, it may be focal or difficult to identify in extranodal lesions.

The morphology of extranodal RDD is less uniform. Pale collections of histiocytes are interspersed with plasma cell-rich and lymphocyte-rich areas, producing a light and dark appearance at low power. As true sinuses are absent, the resemblance to nodal RDD is only partial. Fibrosis, foamy histiocytes, and scant emperipolesis may dominate the biopsy and obscure the diagnosis.

The lesional histiocytes are S100-positive and express OCT2 or Cyclin D1; S100 staining may make emperipolesis easier to recognize (Figure 1 E-F). CD68 and CD163 are variably expressed. CD4, CD11c, and CD14 can also be expressed. Of note, CD1a, langerin (CD207) and ALK are absent [1,23].

According to the WHO 5th Edition Classification, the diagnosis rests on the combination of typical pale histiocytes, a plasma cell-rich inflammatory background, and S100 expression; emperipolesis is frequent but not obligatory. IgG and IgG4 stains may be useful when plasma cells are numerous. However, increased IgG4-positive plasma cells or a high IgG4/IgG ratio alone is insufficient for a diagnosis of IgG4-related disease [2,25,29,38]. RDD may occur together with lymphoma or Langerhans cell histiocytosis, and a coexisting lesion should be actively excluded.

4.3. Imaging

The initial indication of RDD is often obtained radiologically, by detecting nonspecific lymphadenopathy or identifying extranodal disease; moreover, imaging can be used to identify biopsy targets, inform prognosis, and assess treatment response [39,40]. While ultrasonography and CT are recommended as initial imaging modalities, PET-CT plays an important role in managing patients with RDD and is increasingly used to detect subclinical involvement. The technique can allow rapid initial disease characterization by revealing other potential sites of involvement and should be considered as routine in patients with suspected systemic histiocytosis. Furthermore, PET-CT has been found to provide additional diagnostic information in 30 percent of cases where CT or MRI has proven inconclusive [39]. In the scanes, RDD lesions appear hypermetabolic and are FDG-avid. The technique plays a pivotal role in characterizing disease at diagnosis and in evaluating treatment response [39,41].

4.4. Differential Diagnosis

Rosai-Dorfman-Destombes disease should be differentiated from other histiocytic disorders with similar clinical presentations, such as Langerhans Cell Histiocytosis (LCH) and Erdheim-Chester Disease (ECD) [42]. The differential diagnosis should also include infectious lymphadenopathies and atypical chronic infections (mycobacterial or fungal), certain indolent low-grade lymphomas, immunoglobulin G4 (IgG4)-related interstitial lung disease, as well as hemophagocytic syndrome, and malignant histiocytosis/histiocytic sarcoma [43]. Unlike RDD, LCH is defined by lesional cells expressing CD1a and langerin (CD207), usually with S100 positivity; emperipolesis is not characteristic [23,44]. In addition, LCH may be unifocal or multisystemic and commonly involves bone, skin, the pituitary, or lung; isolated pulmonary LCH in adults is strongly associated with smoking. Mixed histiocytosis involving Langerhans cells and Rosai-Dorfman disease was recently reported [11].

Erdheim-Chester disease is a non-LCH histiocytosis characterized by MAPK pathway hyperactivation and inflammatory symptoms [45]. Common manifestations include xanthelasma, perirenal infiltration, and sclerotic lesions in the femora and tibiae, as well as histiocyte infiltration of various organs that causes organ damage [42]. Approximately one-half of cases present BRAF V600E, and most of the remainder indicate another MAPK–ERK pathway alteration when sensitive testing is used. While ECD belongs to the L-Group of histiocytoses [23], cases with features of both ECD and RDD have also been described as a new entity [46].

5. Extranodal Localization of RDD

Over 40% of patients with RDD exhibit extranodal involvement which may involve multiple sites. The most frequent extranodal sites are skin and soft tissue (10-16%), nasal cavity and paranasal sinuses (16%), eye, orbit, and ocular and orbital tissue (11%), bone (5-10%), salivary gland (7%), central nervous system (7%), oral cavity (4%), kidney and genitourinary tract (3%), respiratory tract (3%), intrathoracic localization (2%), liver (1%), tonsil (1%), breast (0.1 to 0.2%), heart (0.1 to 0.2%), pancreas and gastrointestinal involvement (<1% ) (Figure 2) [1,34,47]. Another study found extranodal involvement in at least one site in 43% of RDD patients: these sites included the skin (20.8%), the oral cavity (27.3%), the nasal cavity/paranasal sinuses (22.9%), the lower respiratory tract (22.3%), the eyelid/orbit (22.3%), and the larynx in 16.7% [2,34,47]. Extranodal manifestations are more common in adults than in children.

5.1. Cutaneous RDD

Skin changes occur in about 10%–20% of patients with RDD. In contrast, only 3% of RDD cases demonstrate primary cutaneous RDD (CRDD); such cases lack nodal involvement and are limited to the skin [7,48,49]. CRDD is classified as a distinct entity within the ‘C group’ of histiocytoses, with different epidemiology and clinical features [23]. CRDD usually presents as asymptomatic single or multiple yellow-red to brown or purple papules, nodules, and/or plaques (Figure 3). Lesions most often arise on the face, cheeks, periorbital area, trunk, or extremities [48,50,51]. When RDD is limited to the skin, the long-term prognosis is favorable, with spontaneous regression in most patients. CRDD typically has an indolent course and may improve without treatment. In such cases, it is recommended to use conservative management with observation only, unless the lesions become disfiguring or symptomatic. Other treatment options are available, such as surgery, radiotherapy, cryotherapy, retinoids, dapsone, thalidomide, oral or intralesional corticosteroids, and low-dose methotrexate, but the strategy is not standardized [52,53]. Localized CRDD lesions can be observed or treated with local therapies, including topical or intralesional steroids, or surgery can be applied if necessary [7]. Systemic therapies are recommended for patients with extensive symptoms, multisite disease, or refractory localized disease; in such cases, corticosteroids, methotrexate, thalidomide, isotretinoin, dapsone, or cytotoxic agents are indicated [51,54].

5.2. RDD in Central Nervous System

Central nervous system (CNS) involvement is observed in less than 5% of cases [55,56]. While CNS RDD represents a particularly challenging form of RDD, both diagnostically and therapeutically, 65.5% of cases of RDD with CNS involvement are isolated, i.e. without lymphadenopathy or other extranodal sites involved [56,57]. Symptoms of CNS-localized RDD are related to the location and size of the lesion and include headache, seizures, focal neurological deficits, or cognitive impairment. Most frequently, changes present as a dural-based mass, often showing homogeneous enhancement and the dural tail sign on MRI [58,59]. This feature should be differentiated from meningioma, sarcoidosis, or infectious granulomas.

Spinal involvement is very rare and has been observed either as an isolated infiltration or in association with disseminated disease. This form of RDD is estimated to occur in only 0.6%-1% of all RDD cases and in 20-25% of CNS RDD patients [60,61]. In one report of 60 patients with spinal RDD, an epidural mass was reported in 28 (45.9%) cases, an intradural extramedullary mass in 18 (29.5%) patients, and an intramedullary mass in four (6.6%) patients [61]. One patient had both epidural and intradural extramedullary masses (1.6%), and another had both epidural and intramedullary masses. In a recent analysis of 67 studies reporting 85 patients, thoracic (61.2%) and cervical (43.5%) lesions were most common [62]. Extradural infiltration was observed in 40%, intradural-extramedullary infiltration in 24.7%, and intramedullary involvement in 31.8%. Patients with spinal localization of RDD often present with neurological symptoms involving any region of the neuraxis and typically present with symptoms related to spinal cord or nerve root compression, including back pain, radiculopathy, paraparesis or paraplegia, and tendon hyperreflexia of the lower limbs.

On CT and MRI, RDD lesions resemble meningiomas and show a characteristic dural tail sign [63]. The treatment of choice for CNS RDD is controversial and depends on extent and clinical presentation. Options include surgical resection, corticosteroids, immunomodulatory agents, chemotherapy, radiotherapy, cryosurgery, and radiosurgery. In localized disease, surgical resection and/or radiotherapy are most commonly used. However, the recurrence rate of CNS RDD after surgery is 15% [57,64]. If resection is incomplete or relapse occurs, additional treatment with corticosteroids, chemotherapy, radiotherapy, or cryosurgery should be used. Systemic therapy is also indicated in patients with multifocal, progressive, or unresectable disease [65,66]. While cases with isolated CNS RDD have a similar prognosis to those with intracranial lesions or with isolated spinal RDD [61], extramedullary spinal disease is associated with better postoperative neurological recovery and a better prognosis than intramedullary involvement [62].

5.3. Oral and Nasal Cavity

The most common extranodal sites of RDD are located around the head and neck, including the nasal cavity, oral cavity, tonsil, salivary glands, orbit, and parotid. Typical initial lymph node involvement has also been reported [67,68]. In one study, the oral cavity was involved in 27.3% of extranodal locations, the nasal cavity/paranasal sinuses in 22.9%, the eyelid/orbit in 22.3%, and the larynx in 16.7% [34]. Another report found the most common presenting symptoms to be a neck mass, nasal obstruction, and epistaxis [69]. Less commonly, loss of vision, proptosis, eye tearing, hoarseness, and hyposmia were also reported.

As RDD may originate from both the nasal cavity and the paranasal sinuses, one of the first symptoms may be sinonasal changes [70,71]. Indeed, sinonasal involvement has been noted in 11% of cases and can be difficult to diagnose because it can resemble other diseases in this location [72]. Xu et al. report a higher frequency, with nasal presentations of Rosai–Dorfman disease observed in up to 54.2% of all confirmed cases [70]. While full-body FDG-PET-CT is recommended as part of the baseline evaluation of RDD, MRI of the head may be advantageous for evaluating the sinuses and nasal skull base [73]. Ultrasonography should be used as the initial imaging modality for children up to 14 years presenting with a neck mass [74].

The most commonly-used treatment (92%) for nasal RDD is endoscopic surgery [70]. If complete resection is not feasible, laser excision is a useful therapeutic option for nasal lesions, while corticosteroids and endoscopic surgery are useful in recurrent or compressive cases. Adjuvant chemotherapy or radiotherapy may help control the disease [75]. The optimal surgical approach remains undefined.

5.4. Ophthalmologic Manifestations

Ophthalmic manifestations of RDD occur in less than 10% of cases [34]. Ophthalmic RDD symptoms involve the eye and periocular region, most commonly as an orbital mass, epibulbar mass, scleritis, corneal lesion, uveitis, choroidal mass, serous retinal detachment, and lacrimal duct obstruction [76,77,78]. Foucar et al. analyzed 36 cases with periocular involvement, including 26 in the orbit, five in the eyelid, four in the uvea, and conjunctival involvement in one case [34]. The clinical behavior of ocular RDD is chronic and unpredictable. The most common involvement includes painless orbital soft-tissue masses or rubbery, yellowish-white conjunctival/epibulbar nodules. Patients may experience proptosis, eyelid swelling, diplopia, and sometimes uveitis or optic nerve compression [76,78]. Approximately 50% of patients with ophthalmologic manifestations require treatment, most commonly surgical excision as first-line therapy. Radiotherapy, corticosteroids and chemotherapy are used in recurrent and disseminated disease [78].

5.5. Intrathoracic Localization

Intrathoracic lymphadenopathy is the most common intrathoracic localization of RDD, reported in up to 66% of patients in some series [79]. Other symptoms, such as pulmonary nodules, pleural effusion, cystic changes and interstitial lung disease, are reported in less than 3% of patients [34,80]. Diagnosis is based on imaging findings and histologic evaluation. 18FDG PET-CT may show pathologic uptake in involved organs and help assess disease extent.

Cardiac involvement is a rare manifestation of RDD, occurring in 0.1% to 0.2% of patients [80,81,82,83]. In reported cases, RDD involvement was located in the atria (more commonly the right atrium), interatrial septum, left ventricle, endocardium, myocardium, and pericardium [82,84]. The right atrium is the most commonly-affected site, followed by the left atrium, interatrial septum and left ventricle [84]. Cardiac symptoms present as chest pain, palpitations, arrhythmias, dyspnea, chest discomfort, or even severe cardiac obstruction and cardiac shock. In patients with pericardial involvement, pericardial effusion was observed [84]. Echocardiography can show intracardiac masses. However, cardiac involvement of RDD is based on histopathologic features of the excised tissue and should be differentiated from other cardiac tumors, including lymphoma [85].

5.6. Bone

Bone involvement in RDD is observed in approximately 5 to 10% of cases [86], and primary RDD of the bone without lymphadenopathy or other locations in approximately 2 to 8% [87]. Bone RDD presents as solitary or multifocal lytic lesions [86,87,88]. In approximately 75% of patients with bone lesions, extrabony manifestations were reported, mainly in soft tissues, lymph nodes, sinuses and the orbital cavity [89]. RDD is most commonly diagnosed in long bones, especially the metaphyseal heads of the femur and humerus, as well as in the pelvis, vertebrae, ribs and skull [88]. Clinical symptoms may include pain or swelling. On radiographs and CT, skeletal lesions usually appear as lytic and intramedullary, sometimes with surrounding sclerosis. Cortical destruction, periosteal reaction, and sclerosis have also been reported [90]. Primary bone RDD has been diagnosed in the axial and appendicular skeleton, including the skull, clavicle, femur, tibia, sacrum and small bones of the hands and feet [91]. The most common treatments in patients with bone RDD are surgical interventions and steroids [88,91], while less common treatments include other immunosuppressive drugs and chemotherapy. Radiotherapy in the 10-30 Gy range can induce complete resolution of bone symptoms in some patients; however, the optimal dose has not yet been established.

5.7. RDD of the Breast

Breast involvement in RDD is very uncommon. It occurs mostly in women, but a few cases have been noted in men [92]. If present, RDD in the breast manifests as a solid infiltrative mass on radiologic examination. Findings are often non-specific, resembling either tumorous or non-tumorous diseases, and are usually indistinguishable from breast cancer. An accurate diagnosis requires pathological analysis [93]. For isolated breast RDD lesions, complete surgical excision is the treatment of choice, with low recurrence rates [92]; however, in some cases with disseminated or treatment-resistant disease, systemic therapy is needed.

5.8. Other Clinical Presentations of RDD

Several other extranodal presentations of RDD have been reported, albeit as single cases. Gastrointestinal manifestations have been noted in fewer than 1% of RDD cases, with most being located beyond the pylorus, involving the ileocecal area, appendix, and distal colon [94,95]. Individual cases have been reported of pancreatic and hepatic infiltration [96], and bone marrow and spleen infiltration [97], as well as cases involving the thyroid gland, parotid gland and salivary gland [98,99,100].

6. Treatment

Largely due to the rarity of the disease, its variable clinical course, and the fact that spontaneous clinical remission occurs in 20-50% of patients, the treatment of RDD remains individualized. For asymptomatic patients or those with limited nodal involvement, observation may be appropriate [65,101], as well in patients with uncomplicated lymphadenopathy. While treatment is indicated in symptomatic patients and in those with critical organ dysfunction, no established standard management exists for symptomatic patients who require systemic therapy. In such cases, therapeutic options include surgical resection, corticosteroids, chemotherapy, immunomodulatory drugs, targeted therapies, and radiotherapy [1,47]. Localized symptomatic disease is generally treated with surgery or radiotherapy. Systemic therapy is indicated for multifocal, relapsed, or organ-threatening disease, such as central nervous system involvement or upper airway obstruction [1]. Asymptomatic cases can be observed and monitored only. Patients with symptomatic, multifocal, irresectable nodal or extranodal disease should be treated with systemic therapy.

However, realtively litte information exists regarding commonly-accepted regimens and their sequences. As such, treatment and maintenance duration vary widely, and depend on disease dissemination, organ involvement, response to therapy and relapse risk. Table 2 summarizes prospective trials and ongoing interventional studies, as well as informative retrospective treatment cohorts.

6.1. Surgery

Surgical resection can be curative, and is suitabl for isolated, extranodal, and accessible lesions, particularly in cutaneous or solitary intracranial disease [1,65,101]. It is the most effective therapy for solid CRDD, with cure rates of around 80% [1,102]. Excision is also useful for diagnosis because it provides tissue for histopathological examination.

6.2. Radiotherapy

While the effectiveness of radiatiotherapy is usually limited, it is primarily recommended for palliative care in patients with isolated, refractory disease [33]and in patients with cosmetically-sensitive or difficult-to-resect areas [103]. It is also recommended for palliative care in patients with multifocal, symptomatic disease [104]. However, data on radiation therapy doses, fractionation, technique and effectiveness in RDD are limited and no standard doses for radiotherapy in RDD have been established. Even so, doses ranging from 30 to 50 Gyhave been used in clinical practice [99,105].

6.3. Corticosteroids

Corticosteroids are commonly used as first-line treatment, but their efficacy varies. In some cases, treatment transiently decreases lymph node size and reduces fever within five days to six months [71]. Optimal steroid doses and treatment duration are unknown. Most commonly, the starting dose of oral prednisolone is 1 mg/kg of body weight [106]. Treatment should be first continued until an optimal response is achieved; following this, the dose can be reduced to 0.5 mg/kg/day in the first month, then to 0.3 mg/kg/day, and maintained for three months, and then gradually reduced to 0.1 mg/kg/day [1]. Dexamethasone can also be used in some cases, with 8 to 20 mg daily doses. Steroids are used until the best response, followed by a slow taper. The adverse effects of steroids should be carefully monitored [106,107]: in many cases, symptoms rebound after treatment, especially in patients requiring prolonged therapy or experiencing relapse, and other treatments are needed. Furthermore, steroids are often poorly tolerated and have limited activity in more advanced disease [107]. Corticosteroids should be used until the best response is achieved, followed by a slow taper. Again, it is essential to monitor patients treated with steroids for efficacy and potential side effects, as relapses of RDD lesions have often been reported shortly after treatment is discontinued [104]. In steroid-dependent and relapsing patients, prolonged low-dose immunosuppressive therapy with methotrexate, 6-mercaptopurine, azathioprine, or vinblastine should be considered to maintain remission and prevent disease reactivation [1].

6.4. Chemotherapy

Chemotherapy is recommended in selected, more advanced cases with severe symptoms and vital organ or system involvement. In such cases, the most commonly-used agents include methotrexate, vinblastine, 6-mercaptopurine (MP) and cladribine (CDA). Evidence from prospective trials and informative retrospective treatment cohorts is summarized in Table 2; outcomes not reported for an RDD subgroup should not be generalized to RDD. Prolonged low-dose immunomodulatory therapy, particularly with inter alia methotrexate, 6-mercaptopurine, azathioprine or vinblastine, has commonly been used to maintain remission and prevent relapse in steroid-dependent, relapsing or chronic disease. Methotrexate alone or in combination with other agents has been reported to achieve complete to partial responses in many cases of systemic or CRDD [108,109,110]. In patients with cutaneous RDD, oral methotrexate is given at a dose of 15- 20 mg once weekly. In some patients who obtained a CR, methotrexate was reduced to 5 mg weekly as maintenance for several months [109,110]. Methotrexate can be combined with MP, vinblastine or vinorelbine [111,112,113].

Purine analogs (mercaptopurine, azathioprine, cladribine, and clofarabine) and pyrimidine analogs (cytarabine) have also been used in RDD, mainly in relapsed patients [114,115]. Riller et al. retrospectively evaluated cladribine in 21 consecutive adults with Erdheim–Chester disease, RDD, or unclassified non-Langerhans cell histiocytosis. The respective overall clinical and radiological response rates were 62% and 43% among the whole group and 70% and 30% among the patients with RDD. Relapse occurred in four of nine radiological responders after a median of 18 months. Although all evaluable patients developed lymphopenia, clinical infections occurred in only two of nineteen, suggesting clinically-relevant activity with manageable toxicity [116].

Degar et al. conducted a phase II study of clofarabine in 25 patients, including four with non-Langerhans cell histiocytosis: two with RDD and two with malignant histiocytosis [117]. Clofarabine showed partial responses in three of foru patients, however disease-specific conclusions should be drawn cautiously due to the small size of the RDD subgroup. Of the two RDD patients, one stopped after two cycles due to illness and died from infection; the other completed six cycles and recurred after a year. Also, 80% of patients exhibited grade ≥3 toxicity, mainly hematological, indicating that the regimen has potential activity but requires close toxicity monitoring. Mercaptopurine (MP) is usually started at a daily dosage of 2.5 mg/kg [111] and is commonly used with methotrexate or methotrexate and vinblastine [111,113]. Another purine analog, azathioprine, is also effective in selected patients with RDD [114].

Cladribine has been used for many years to treat lymphoid and myeloid malignancies. It is also one of the most effective drugs for histiocytoses, including LCH, ECD, and RDD [118,119,120]. A retrospective analysis of five patients with RDD at MD Anderson Cancer Center found an 80% response rate and a median progression-free survival (PFS) of 29 months [120]. Other reports have demonstrated rapid response and durable complete remission [121,122,123]. Most commonly, cladribine is administered at 5 mg/m2 in a continuous infusion on days 1-5 every 28 days for three to six courses, although another option is 0.12 mg/kg in a two-hour infusion for five days every four weeks [122]. Patients with a clinical response to cladribine demonstrated normalization of interleukin-6 (IL-6) levels if pretreatment levels were elevated [124]. These reports support the use of cladribine in patients with high-risk, extranodal multifocal disease and organ damage. However, several side effects can complicate treatment, including severe, prolonged bone marrow aplasia [122]. In a separate Mayo Clinic cohort, four of six cladribine-treated patients responded (67%), with no relapse among responders at a median follow-up of 16 months [33].

Cytarabine and clofarabine were also active in RDD, particularly in patients with CNS involvement, as these drugs penetrate the blood–brain barrier and achieve cytotoxic concentrations in cerebrospinal fluid. In one report, cytarabine was used in two patients with CNS RDD at 1.0-1.5 g IV q12h d1-2, with dexamethasone 20 mg IV qd d1-4 for six cycles [125]. At the end of treatment, patients became asymptomatic, and repeat MRI found the brain lesions to have decreased in size. In another study, clofarabine was given at 25 mg/m2/day for 5 days every 28 days for 4-6 cycles to three patients with RDD, with good efficacy and acceptable tolerability [126]. In the retrospective clofarabine series, all three RDD patients responded and two achieved CR; a later phase II study reported non-LCH-stratum outcomes but did not provide RDD-specific efficacy.

6.5. Immunomodulatory and Immunosuppressive Agents

The immunomodulatory drugs thalidomide and lenalidomide are commonly used to treat multiple myeloma. Both agents also have therapeutic activity in some patients with RDD, and exert anti-inflammatory effects by inhibiting TNF-α and IL-6 and regulating T-helper cells. Thalidomide and lenalidomide have also been used in several cases of RDD with high response rates [1]. Among seven patients treated with thalidomide by Chen et al., five showed clinical improvement, and two showed minimal response [127]. Shahidi-Dadras et al. report an atypical case with massive cutaneous manifestation of RDD that responded well to thalidomide [128]. The starting dose of thalidomide was 100 mg/day, but was reduced to 100 mg every other day and then to 50 mg every other day due to adverse events. Response was observed during the 14 months of follow-up. The National Comprehensive Cancer Network (NCCN) recommends thalidomide for RDD patients with skin involvement (NCCN Guidelines, Version 3, 2026. Histiocytic Neoplasms).

Lenalidomide is less toxic than thalidomide and has demonstrated high activity in patients with multifocal recurrent RDD. The drug is active as a single agent [129]. However, it is more commonly used in combination with dexamethasone [130,131,132]. Chang et al. report the results of lenalidomide and dexamethasone treatment in a group of 23 patients with RDD, 13 with newly-diagnosed disease and 10 with recurrent disease [131]. Lenalidomide was administered at 25 mg/day on days 1–21, and dexamethasone 40 mg on days 1, 8, 15, and 22, in 28-day cycles for 12 cycles. The ORR was 87% (20 of 23 patients), including CR in 7 (30%). Lenalidomide and dexamethasone are well tolerated in most patients, and adverse events and toxicities are consistent with the known safety profile of these agents [132]. Median PFS and OS were not reached; the reported 2-year PFS and OS values were 69% and 100%, respectively [132].

Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor that inhibits the normal development of histiocytes. It has been reported to be active in treating RDD in single cases [133,134]. In one study, sirolimus was used to treat systemic RDD complicated by multiple autoimmune manifestations refractory to several chemotherapy regimens, resulting in a CR that lasted for 23 months [134]. Elsewhere, two cases of RDD involving lymph nodes were treated with sirolimus, with good efficacy [133]. Finally, Tirado-Sánchez reported a patient with disseminated, cutaneous RDD who had previously been treated with various immunosuppressive agents, including systemic steroids, chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone) and radiotherapy [135]. The patient responded well to sirolimus and methylprednisolone, with a reduced incidence of new lesions and decreased size of preexisting lesions. Sirolimus is recommended for patients with ALPS and/or PIK3CA mutations [133]. While a few case reports describe the use of alpha-interferon [136,137] its role in treating RDD remains unclear.

6.6. Monoclonal Antibodies

The CD20 monoclonal antibody (Mab) rituximab was effective in some patients with autoimmune-related RDD and IgG4 disease [138,139,140]. Its mechanism of action is unclear, but is believed to be related to antibody-mediated pathogenesis. Rituximab can be used for RDD with IgG4-related RDD, RDD with nodal involvement, and coexisting cytopenias (NCCN Guidelines, Version 3, 2026. Histiocytic Neoplasms).

Interleukin-6 is a proinflammatory cytokine that stimulates the production of acute-phase reactant proteins and neutrophils and supports B-cell development. Overexpression of IL-6 has been reported in several studies of RDD patients and may play a role in disease progression [1]. The anti-IL-6 mAbs siltuximab and tocilizumab have been used in a few patients with RDD [141,142]. Siltuximab is an anti-IL-6 chimeric monoclonal antibody that reduces inflammation and acute-phase reactants and has antiangiogenic effects [141]. Siltuximab tretament achieved a CR in one heavily-pretreated patient with refractory disseminated RDD [141]. In another study, tocilizumab was found to achieve significant and durable clinical improvement in one patient with sporadic RDD and elevated IL-6 [142]. Tocilizumab is a direct IL-6 receptor inhibitor, generally well tolerated, with toxicities including upper respiratory infections, elevated transaminases, and neutropenia.

6.7. Targeted Drugs

In RDD patients with a mitogen-activated protein kinase mutation, targeted therapy with MEK pathway inhibitors, such as cobimetinib or trametinib, can be highly effective [43,143,144]. Abeykoon et al. analyzed 16 patients with RDD treated with cobimetinib at 20 to 60 mg/day for 21 days in a 28-day cycle [145]. The ORR was 63% (10 patients), including CR in five patients and partial response (PR) in another five. Somatic alterations in the KRAS or MEK genes were detected in eight (50%) patients. Eight patients with KRAS or MEK alterations had significantly higher ORR (88% vs 38%; P = 0.03) and a higher CR rate (71% vs 0%; P = 0.002). PFS was also longer in patients with KRAS or MEK mutations (one year: 100% vs 29%). Other reports have also indicated good responses to cobimetinib in RDD, particularly in patients with an activating KRAS mutation [146]. Finally, Moyon et al. treated two patients with cobimetinib for severe lung disease, with excellent pulmonary responses, confirmed by PET scan [144].

The US Food and Drug Administration approved cobimetinib in 2022 for treatment in histiocytic neoplasms. In NCCN recommendations, cobimetinib is the preferred drug for RDD with MAP kinase pathway mutation. (NCCN Guidelines, Version 3, 2026. Histiocytic Neoplasms). It should be noted, however, that the prospective cobimetinib basket trial (NCT02649972) did not report RDD-specific final efficacy; the RDD-specific 63% ORR cited above is from the separate retrospective cohort.

Another highly selective, potent MEK inhibitor is trametinib. In one study, the drug was used to treat three patients with RDD and five with ECD/RDD [147]. Trametinib was started at 1 mg orally daily and was mostly reduced to 0.5 mg daily. Two patients with ECD/RDD achieved CR, another patient PR, and another SD. Only one patient with RDD was evaluable and achieved SD. Recently, another selective MEK1/2 inhibitor, luvometinib, was used in two patients with RDD, and one responded [148].

Another potential therapeutic option involves the use of the oral JAK1/3 inhibitor tofacitinib. The JAK-STAT signaling pathway (Janus kinase-signal transducer and activator of transcription) plays an important role in various immune processes, including the synthesis of inflammatory mediators IL-6 and IFN-γ [149]. Tofacitinib was recently found to be effective in a patient with RDD [150]. Zhang et al. administered tofacitinib to patients with anaplastic lymphoma kinase (ALK)-positive histiocytosis, a unique subtype of clonal histiocytic neoplasm driven by ALK amplification and translocation [151]. The ALK gene is located on chromosome 2p23 and encodes the ALK receptor tyrosine kinase (CD246) [21].

In a few cases, ALK-positive histiocytosis has been successfully treated with crizotinib [152]. Crizotinib (Xalkori) is approved by the FDA for the treatment of ALK- or ROS1-positive lung cancer and ALK-positive relapsed or refractory systemic anaplastic large cell lymphoma. The drug is usually administered at a dose of 250 mg PO twice daily. The NCCN recommends crizotinib for patients with ALK fusion (NCCN Guidelines, Version 3, 2026. Histiocytic Neoplasms). Administering 5 mg twice daily in cases of multiple relapsed CRDD resulted in a significant reduction of skin changes [150]. ALK-positive histiocytosis is a unique subtype of clonal histiocytic neoplasm driven by ALK amplification and translocation, and is distinct from RDD subtypes [150], as such crizotinib should be discussed only in the context of a confirmed ALK fusion.

Pexidartinib (Turalio) is active in patients with CSF1R mutations, including those with a CSF1R in-frame deletion (p.S560_P566del) [21,153]. Few cases of histiocytosis and CSF1R mutation have been reported so far [143,153]. Any consideration of pexidartinib in RDD should be restricted to a confirmed CSF1R alteration and described as mutation-directed extrapolation rather than established RDD efficacy (NCCN Guidelines, Version 3, 2026. Histiocytic Neoplasms).

Larotrectinib (Vitrakvi) is an oral targeted drug for patients with a tropomyosin-positive neurotrophic tyrosine kinase receptor 1 (NTRK1) gene fusion [154]. The NCCN recommends larotrectinib for patients with an NTRK1 fusion. (NCCN Guidelines, Version 3, 2026. Histiocytic Neoplasms).

Entrectinib was designed to be active against NTRK fusion-positive tumors and to cross the blood–brain barrier. It is also a potent inhibitor of TRKA, TRKB, TRKC, ROS1, and ALK-positive cancers [155,156]. Entrectinib is active in patients with advanced or metastatic NTRK fusion-positive solid tumors [156]. For RDD, entrectinib should only be considered when a validated NTRK1/2/3 or ROS1 fusion provides a molecular rationale [155,156]. The NCCN recommends entrectinib for patients with a confirmed NTRK gene fusion (NCCN Guidelines, Version 3, 2026. Histiocytic Neoplasms).

Repotrectinib (Augtyro) inhibits TRK fusion proteins and resistant mutations. Repotrectinib was evaluated in a phase 1/2 trial of patients with a diverse range of NTRK+ solid tumors [157]. The drug showed clinical activity regardless of tumor type, NTRK gene, intracranial disease status, prior treatment or NTRK resistance mutation status. Based on the registrational phase 1/2 TRIDENT-1 study (NCT03093116) [158], the FDA granted accelerated approval of repotrectinib for patients with locally-advanced or metastatic solid tumors harboring an NTRK gene fusion. The NCCN recommends repotrectinib for RDD patients with an NTRK1 fusion (NCCN Guidelines, Version 3, 2026. Histiocytic Neoplasms).

Selpercatinib (Retevmo, Eli Lilly) is a highly-selective, potent RET inhibitor capable of penetrating the central nervous system. It has been approved by the FDA for RET fusion–positive, locally advanced or metastatic solid tumors. Rearrangements in RET (fusion gene NCOA4-RET) have been identified in a few patients with histiocytic neoplasms, including RDD [21,54]. The NCCN recommends selpercatinib for patients with RDD who have a RET fusion (NCCN Guidelines, Version 3, 2026. Histiocytic Neoplasms).

7. Prognosis

In most cases, the outcomes of Rosai-Dorfman disease are favorable; indeed, about half of all patients, particularly those with nodal or cutaneous involvement, experience spontaneous remission. However, the disease has an unpredictable course, and treatment is indicated for symptomatic patients, or those with vital organ or system involvement [1,2]. Many patients can also experience spontaneous exacerbation or remission. In some studies, 33% show residual asymptomatic lymphadenopathy, and 17% exhibit persistent disease [159].

Furthermore, central nervous system involvement and residual metabolic activity are sometimes observed after initial therapy, which is associated with an increased risk of early progression [65]. More worryingly, residual symptoms can persist for five to ten years after diagnosis, and the disease is fatal in up to 10% of patients, primarily due to direct disease, infections and amyloidosis [34]. Approximately 10% of patients have poor outcomes due to organ dysfunction, disease-related complications, infections, or amyloidosis [34,91], with unfavorable or fatal outcomes being reported mainly in patients with multiorgan involvement.

Therefore, patients should receive long-term follow-up to monitor disease progression. Clinical assessment and imaging should also be performed every six to twelve months, particularly in patients with persistent disease or incomplete resection [1,71].

8. Conclusion

Classic RDD is a rare histiocytosis most commonly presenting as bilateral cervical lymphadenopathy, with the cutaneous form considered a separate entity. While the treatment of asymptomatic RDD is usually based on observation and monitoring, various systemic and local treatment options exist for symptomatic disease. However, despite this broad theraputic armory, the optimal treatment for RDD remains uncertain, and further studies are needed to standardize management of this rare disease and to identify the cell of origin of neoplastic RDD.