Rosai-Dorfman Syndrome
Rosai-Dorfman disease, sinus histiocytosis with massive lymphadenopathy, Destombes-Rosai-Dorfman disease
Rosai-Dorfman syndrome is a rare condition where the body produces too many white blood cells called histiocytes, which can accumulate in lymph nodes and other parts of the body, causing swelling and various symptoms depending on where these cells collect.
Table of contents
- What is Rosai-Dorfman syndrome?
- Types of the disease
- Who is affected?
- Symptoms and how they vary
- What causes this condition?
- How is it diagnosed?
- Treatment approaches
- Outlook and prognosis
What is Rosai-Dorfman syndrome?
Rosai-Dorfman syndrome, also known as Rosai-Dorfman disease (RDD), is a rare condition that involves an overgrowth of special white blood cells called histiocytes.[1] Histiocytes are an important type of cell in your immune system that normally fight germs that may make you sick. However, when you have too many of these cells, as happens in Rosai-Dorfman syndrome, they can cause problems.[1]
The condition was first described in 1969 by two pathologists, Juan Rosai and Ronald Dorfman, who reported several children with massive enlargement of lymph nodes.[2] The excess histiocytes typically cause enlarged lymph nodes (small glands that are part of your immune system), especially in the neck, but these cells can also collect in other parts of your body.[1]
In recent years, scientists have discovered that cancer-causing genetic changes (mutations) in the MAP kinase pathway have been identified in about 50% of cases with Rosai-Dorfman syndrome. Because of this finding, the World Health Organization recognized it as a blood cancer in 2022.[2] However, the condition is usually not life-threatening, and many patients do not require treatment.[2]
Types of the disease
Rosai-Dorfman syndrome looks and behaves differently in different people. The disease is classified based on where the excess histiocytes accumulate in the body.[1]
Classic (nodal) Rosai-Dorfman disease is the most common type. It causes lymph nodes to swell, especially the lymph nodes in the neck. Your symptoms depend on how many lymph nodes are affected by excess histiocytes.[1]
Extranodal Rosai-Dorfman disease affects tissue in your body other than your lymph nodes. The most common site is the skin, and this type is called cutaneous RDD (CRDD). Other types of extranodal disease involve histiocyte overgrowths in the sinuses, eyes and eyelids, bone, and central nervous system (brain and spinal cord). The disease can also impact other body systems, including the respiratory and gastrointestinal systems.[1]
About 40% of people with Rosai-Dorfman syndrome have excess histiocytes in extranodal sites in addition to their lymph nodes.[1] Studies have shown that 8% of patients had classical (nodal only) disease and 92% had extranodal disease, with 67% having extranodal disease only.[3]
Who is affected?
Rosai-Dorfman syndrome is a rare condition. About 1 in every 200,000 people get the disease. In the United States, about 100 new cases are diagnosed annually.[1]
The disease mainly affects children, teens, and young adults. Most diagnoses occur at about age 20, but there are recorded cases involving people in their 70s.[1] Research from a major medical center found that the median age at diagnosis was 50 years, with a range from 2 to 79 years.[3]
The disease that affects the lymph nodes occurs most frequently in people of African descent who are male. Cutaneous Rosai-Dorfman syndrome is typically diagnosed in people of Asian descent who are female. The skin form mostly affects people in their 20s, 30s, and 40s.[1]
Symptoms and how they vary
Your symptoms will depend on where the excess histiocytes accumulate in your body. You may experience mild symptoms or even no symptoms if the histiocytes only affect lymph nodes in your neck. You may experience more severe symptoms if the histiocytes prevent an organ from functioning correctly.[1]
Classical (nodal) symptoms
Usually, histiocytes grow in the lymph nodes in your neck. As a result, the most common symptom is painless, swollen lumps on both sides of your neck. Swelling may appear in another place, depending on the affected lymph nodes.[1]
Lymph node sites that may be swollen because of histiocyte overgrowth include your neck, your groin, your armpits, and the center of your chest (mediastinum).[1] In one study, among 358 cases where the location of lymph node swelling was specified, 87.3% had cervical (neck) lymph node swelling.[5]
You may not notice symptoms other than the swelling, or you may notice symptoms like fever, pale skin, fatigue, night sweats, runny nose, and unexplained weight loss.[1]
Extranodal symptoms
Skin involvement appears in the form of nodules or lumps under the skin that can occasionally be itchy and painful.[2] In about 40% of patients, the disease occurs outside of the lymph nodes, affecting skin and soft tissue, nasal cavities, eyes and eyelids, bones, salivary glands, and central nervous system. In rare instances, it affects the kidneys, lungs, liver, breast, heart, and digestive tracts.[4]
The most common organs involved were skin and subcutaneous tissue (52%), followed by lymph nodes (33%).[3] The most common presentation was subcutaneous masses (40%).[3]
Less frequent symptoms may include low blood counts. As the number of oxygen-carrying red blood cells declines, patients may develop anemia, appearing pale, tired, or short of breath. A decline in platelets that normally help blood clot can lead to easy bruising or bleeding.[4]
What causes this condition?
The exact cause of Rosai-Dorfman syndrome is not known. The reason that histiocytes over-produce is unclear, although many possibilities have been considered, including viral, bacterial, infection, environmental, and genetic causes.[2]
Possible but unproven infectious causes include Klebsiella, polyomaviridae, Epstein-Barr virus, parvovirus B19, and human herpesvirus 6.[5] Researchers have suggested that monocytes (a type of white blood cell) recruited to inflammatory lesions could produce macrophage colony-stimulating factor, which leads to a complex signal transduction that results in the histiocytosis characteristic of the disease.[5]
In the last decade, cancer-causing genetic changes (mutations) in the MAP kinase pathway have been identified in 50% of cases with Rosai-Dorfman syndrome.[2]
How is it diagnosed?
The diagnosis of Rosai-Dorfman syndrome can be challenging. The median duration from symptom onset to diagnosis was seven months (range, 0-128), which was also reflected in the number of biopsies required to establish the diagnosis (median 2; range, 1-6).[3]
The disease is diagnosed by biopsy of affected tissues. A biopsy is a procedure where a small sample of tissue is removed and examined under a microscope.[5] Microscopic examination of stained specimens will show histiocytes with lymphocytes and possibly other types of cells trapped within them, a phenomenon known as emperipolesis.[5]
Upon special staining (immunohistochemical staining), the histiocytes will be positive for S100, CD68, and CD163 but negative for CD1a.[5] These markers help doctors distinguish Rosai-Dorfman syndrome from other similar conditions.
The differential diagnosis (other conditions that might be confused with this disease) includes both malignant and nonmalignant diseases, such as granulomatosis with polyangiitis, Langerhans cell histiocytosis, Langerhans cell sarcoma, lymphoma, sarcoidosis, IgG4-related disease, and tuberculosis.[5]
Treatment approaches
Because Rosai-Dorfman syndrome is so rare, no large studies have been performed, and there is no approved, widely accepted treatment.[2] The disease is seldom life-threatening, and in many instances, the patient’s symptoms resolve on their own.[4] Many patients do not require treatment.[2]
When treatment is needed, the approach depends on the location and severity of the disease. Commonly utilized first-line treatments were surgical excision (38%) and systemic corticosteroids (27%).[3] Corticosteroids are medications that reduce inflammation in the body. They led to a response in 56% of the cases.[3]
Some patients with severe or persistent disease may need treatment with surgery, steroids, and/or chemotherapy. Rarely, radiation therapy is used.[17] The most commonly used systemic agent was cladribine (used in 6 patients), with 67% overall response rate.[3]
Research has shown that patients showing a clinical response to cladribine had normalization of interleukin-6 (IL-6) levels post-treatment from elevated levels at pre-treatment.[11] Based on this finding, one case report documented successful treatment of disseminated Rosai-Dorfman disease with siltuximab, an IL-6 chimeric monoclonal antibody.[11]
Three patients in one study had an overlap with Erdheim-Chester disease, which had not been described before. Two of these were found to have MAP2K1 mutations.[3]
Outlook and prognosis
Rosai-Dorfman syndrome has diverse clinical manifestations and outcomes. While this disease has been historically considered a benign entity, a subset of patients endures an aggressive course necessitating the use of systemic therapies.[3]
Of those treated initially, 30% of patients developed recurrent disease.[3] Bone involvement is especially rare and predicts a chronic course with decreased likelihood of spontaneous remission.[11]
The disease is usually not life-threatening, and many patients do not require treatment.[2] The disease can be limited to the lymph nodes or affect other body systems beyond the nodes. Symptoms, treatment options, and likely outcomes vary from person to person.[1]
