Rosai Dorfman Disease: Symptoms, Types, Causes and Treatment

Rosai Dorfman Disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, is a rare and fascinating disorder that can present with a wide range of symptoms and affect multiple organ systems. First described in the late 1960s, RDD is now recognized as part of the spectrum of histiocytic disorders, with new insights into its causes, types, and management emerging over recent years. Understanding RDD can be challenging due to its rarity, variable presentations, and evolving classification. In this article, we’ll explore the symptoms, forms, underlying mechanisms, and current approaches to treatment, offering a comprehensive overview for patients, families, and clinicians.

Symptoms of Rosai Dorfman Disease

Rosai Dorfman Disease is notorious for its diverse and sometimes confusing array of symptoms. While some patients present with classic signs, others may have subtle or atypical complaints, making diagnosis a puzzle. Recognizing these symptoms is crucial for early detection and management.

Symptom	Description	Frequency/Features	Sources
Lymphadenopathy	Massive, painless, often bilateral nodes	Most common; cervical region	1 4 5 7
Fever	Low to high grade, persistent or episodic	Common, often with fatigue	1 4 7
Skin lesions	Nodules, plaques, or rashes	Seen in extranodal/cutaneous RDD	5 15
Neurological signs	Headache, seizures, vision changes	Rare, in CNS involvement	2 8 16
Respiratory issues	Cough, shortness of breath	When lungs are involved	3
Laboratory findings	Elevated ESR, leukocytosis, hypergammaglob.	Non-specific, supportive	4 5 7

Table 1: Key Symptoms

Classic Presentations

The hallmark of RDD is massive, painless, bilateral cervical lymphadenopathy. This means patients frequently present with enlarged lymph nodes in the neck, which can be mistaken for infections or malignancies such as lymphoma or tuberculosis, especially in children and young adults. Fever and systemic symptoms like fatigue and weight loss are also common, contributing to diagnostic confusion 1 4 7 13.

Extranodal and Systemic Symptoms

RDD isn’t limited to lymph nodes. In fact, extra-nodal involvement occurs in a significant number of cases—sometimes as the only manifestation. The skin is the most commonly affected extranodal site, leading to nodules, plaques, or rashes, often without any lymphadenopathy 5 7 15. Other organs that may be involved include:

• Central nervous system (CNS): Symptoms such as headaches, seizures, or focal neurological deficits may occur, though this is rare 2 8 16.
• Respiratory tract: Patients may report cough, shortness of breath, or even parotid gland swelling 3.
• Other sites: Eyes (dry, itchy), joints (pain or mild limitation), and bones may also be affected 3 15.

Laboratory and Systemic Features

Laboratory findings can support the diagnosis but are non-specific. Common abnormalities include:

• Elevated erythrocyte sedimentation rate (ESR)
• Leukocytosis (increased white blood cells)
• Polyclonal hypergammaglobulinemia (increased antibodies)
• Occasionally, anemia or other immune-related changes 4 5 7

Atypical and Overlapping Symptoms

Some patients may present with highly unusual or multisystem complaints, including associations with autoimmune diseases. In these cases, RDD should be considered in the differential diagnosis of unexplained lymphadenopathy and multisystem symptoms 3.

Types of Rosai Dorfman Disease

RDD is not a one-size-fits-all disease. Classification has evolved, and understanding the different types helps guide diagnosis and management.

Type	Main Features	Typical Sites	Sources
Nodal	Classic; lymph nodes only	Cervical, axillary nodes	1 4 7 12
Extranodal	Involves organs outside lymph nodes	Skin, CNS, bone, others	1 7 8 15 16
Cutaneous	Limited to skin, no lymph node involvement	Thighs, buttocks, trunk	5 7 10
Mixed	Both nodal and extranodal	Lymph nodes + any extranodal	10 15

Table 2: RDD Types and Key Characteristics

Nodal (Classic) Rosai Dorfman Disease

The classic form primarily affects lymph nodes, most often in the neck (cervical area). This presentation is what gave RDD its original name: sinus histiocytosis with massive lymphadenopathy. Nodal disease is more common in children and young adults, and often resolves spontaneously 1 4 7 12.

Extranodal Rosai Dorfman Disease

Extranodal disease involves tissues and organs other than lymph nodes and is seen in more than half of patients in some series 7 15. Common sites include:

• Skin and subcutaneous tissues: Nodules or plaques, sometimes as the only sign.
• Central nervous system (CNS): Rare but can mimic tumors like meningioma; symptoms depend on location 2 8 16.
• Bone, eyes, respiratory tract, salivary glands: Symptoms vary according to the organ involved 3 15.

Cutaneous Rosai Dorfman Disease (CRDD)

This rare subtype is limited to the skin without any lymph node or systemic involvement. CRDD typically presents as painless nodules or plaques, often on the thighs, buttocks, or trunk, and is more common in adults 5 7 10. It is now considered a separate entity in the latest classification systems.

Mixed (Nodal + Extranodal)

Some patients have both nodal and extranodal involvement, showing the disease’s variability. While less common, this mixed form can make diagnosis and management more complex 10 15.

Classification Evolution

The Histiocyte Society revised its classification in 2016, highlighting the distinction between classic RDD, extranodal forms, and pure cutaneous RDD. This distinction is important for prognosis and treatment planning 7 14.

Causes of Rosai Dorfman Disease

The question of "why does RDD occur?" has puzzled clinicians and researchers for decades. Although the exact cause remains elusive, recent advances have shed light on possible mechanisms.

Cause/Mechanism	Description	Evidence/Notes	Sources
Immune Dysregulation	Overactive immune response, possible triggers	Associations with autoimmune cases	3 7 14
Genetic Mutations	Somatic mutations in MAPK/ERK pathway genes	KRAS, NRAS, MAP2K1, ARAF detected	6 11 14 15
Infectious Triggers	Viral or bacterial infections as possible triggers	Unproven, hypothesized	7 9
Clonal Proliferation	Subset of cases suggested to be neoplastic	Clonality found in some patients	6 11 14

Table 3: Potential Causes and Mechanisms

Immune System Dysregulation

RDD has long been considered a disorder of immune system dysfunction. Overproduction of monocytes/macrophages—the immune cells involved—leads to their accumulation in tissue, resulting in swelling and organ involvement. RDD can sometimes occur alongside autoimmune diseases, suggesting that abnormal immune regulation plays a significant role 3 7 14.

Genetic and Molecular Insights

Recent genetic studies have revolutionized our understanding of RDD. About one-third of cases show somatic mutations in genes associated with the MAPK/ERK signaling pathway, including KRAS, NRAS, MAP2K1, and ARAF 6 11 14 15. These mutations drive the proliferation of histiocytes and suggest that some cases of RDD are clonal—meaning they behave more like a neoplasm (tumor) rather than a purely reactive process.

• KRAS and MAP2K1 mutations: Mutually exclusive, more common in pediatric and head/neck cases, often multifocal 6.
• Clonality: The presence of these mutations supports a neoplastic (tumor-like) origin in a subset of patients, changing how we think about the disease.

Infectious and Environmental Triggers

Some researchers have proposed that infections, particularly viruses or bacteria, might trigger RDD in susceptible individuals. However, no single pathogen has been definitively linked to the disease, and this remains a hypothesis 7 9.

Other Factors

RDD is classified as a non-Langerhans cell histiocytosis, but it sometimes overlaps with other rare histiocytic disorders (like Erdheim-Chester disease), especially in cases with detected mutations. The role of IgG4-positive plasma cells is debated and may not be central to the cause 7 14.

Treatment of Rosai Dorfman Disease

Managing RDD is as complex as understanding its causes. Treatment depends on the disease's severity, location, and progression, with many patients requiring little or no intervention.

Treatment Modality	Indication/Usage	Response/Outcome	Sources
Observation	Mild, asymptomatic, self-limited cases	Often spontaneous resolution	4 12 13 14
Surgical Resection	Symptomatic, localized, accessible lesions	Mainstay for focal disease	1 8 15 16
Corticosteroids	Systemic, multifocal, or refractory disease	Response in ~56% cases	1 15 14
Chemotherapy	Advanced, multifocal, or refractory disease	Partial/complete response	1 2 15 17
Radiation Therapy	Residual disease after surgery or inoperable	Variable response	1 2 16
Targeted Therapies	Mutation-positive or refractory disease	Promising partial responses	6 14 17

Table 4: RDD Treatment Options

Observation and Supportive Care

Because RDD is often benign and self-limiting, watchful waiting is the recommended approach for many patients, especially those with mild or asymptomatic disease. Spontaneous resolution is common, and unnecessary treatment can be avoided 4 12 13 14.

Surgical Management

For patients with symptomatic, localized disease—such as compressive lymph nodes or CNS lesions—surgical excision is usually the first line of treatment. Surgery can provide rapid relief from symptoms and is particularly effective when complete resection is possible 1 8 15 16. However, recurrence can occur, especially with incomplete removal or multifocal disease.

Systemic Therapies

When surgery is not feasible or the disease is multifocal/systemic, other treatments are considered:

• Corticosteroids: These can reduce inflammation and histiocyte proliferation. Around half of patients respond, but relapses are possible 1 15.
• Chemotherapy: Agents like cladribine and others may be used, particularly in refractory cases or when vital organs are involved. Response rates vary, but these treatments are typically reserved for aggressive disease 1 2 15 17.
• Radiation Therapy: Used for residual or inoperable lesions, particularly in the CNS or spine. Effectiveness varies, and it's often an adjunct to surgery 1 2 16.

Targeted Molecular Therapies

With the discovery of mutations in the MAPK/ERK pathway, targeted therapies (e.g., small molecule inhibitors) are being explored, especially for mutation-positive or refractory cases. Early data suggest higher partial response rates compared to conventional therapies, but long-term outcomes are still under investigation 6 14 17.

Special Considerations and Multidisciplinary Care

Due to the rarity and complexity of RDD, referral to specialized or tertiary centers is recommended for challenging cases, especially those with unusual presentations or requiring systemic therapy 1 14. A multidisciplinary team—including pathologists, oncologists, surgeons, and radiologists—is often needed to tailor management.

Conclusion

Rosai Dorfman Disease is a rare, often misunderstood disorder with highly variable symptoms, types, causes, and management options. Continued research is shedding new light on its underlying mechanisms and opening the door to more targeted therapies.

Key Takeaways:

• Symptoms: RDD typically presents with painless, massive lymphadenopathy but can affect many organs, with symptoms ranging from skin nodules to neurological deficits.
• Types: The disease exists in nodal, extranodal, cutaneous, and mixed forms, with cutaneous RDD now recognized as a separate entity.
• Causes: While immune dysregulation is central, recent discoveries of MAPK/ERK pathway mutations suggest a clonal/neoplastic process in some cases.
• Treatment: Many cases resolve without intervention; others require surgery, corticosteroids, chemotherapy, or targeted therapies, especially for aggressive or refractory disease.

Understanding RDD requires a high index of suspicion, careful diagnosis, and individualized management. As science advances, hope grows for more effective and precise treatments for this enigmatic disease.