Rosai-Dorfman disease (RDD) previously known as sinus histiocytosis with massive lymphadenopathy (SHML), is a rare histiocytic disorder which involves the over-production of a type of white blood cell called non Langerhans sinus histiocyte.
RDD is characterized by accumulation of abnormal cells (histiocytes) in various tissues/organs of the body. RDD tends to affect skin and lymph nodes most commonly, although any organ system can be involved from head to toe. The reason that these cells over-produce is not known, although many possibilities have been considered, including viral, bacterial, infection, environmental, and genetic causes.
In 1969, two pathologists, Juan Rosai and Ronald Dorfman, reported a distinct histiocytic disorder in several children with massive enlargement of the lymph nodes, as well as other symptoms. They named this condition sinus histiocytosis with massive lymphadenopathy, and the name has since come to be known as RDD. In the last decade, cancer-causing genetic changes (mutations) in the MAP kinase pathway have been identified in 50% of cases with RDD. Therefore, RDD was recognized as a blood cancer by the World Health Organization in 2022. However, RDD is usually not life-threatening, and many patients do not require treatment.
The exact incidence of RDD cases is not known, although it does occur worldwide and seems to affect equal numbers of males and females. It can affect children as well as adults. Because this disease is so rare, no large studies have been performed, and there is no approved, widely accepted treatment.
The Histiocytosis Association continues to work closely with an international group of physicians, known as the Histiocyte Society, who are dedicated to studying histiocytic disorders. Through their combined efforts, awareness about the disease has increased, more research has been undertaken, and progress has been made in the understanding of this disease.
The following is a recent talk by Dr. Gaurav Goyal at an international conference hosted by the Mumbai Hematology Group. Over 650 participants from 25+ countries were present on for the talk. The Histiocytosis Association hopes to host a similar webinar for the histio community soon.
Rosai-Dorfman may affect skin or lymph nodes most commonly. It can involve a single-site or multiple sites of the body. Skin involvement is in the form of nodules or lumps under the skin that can occasionally be itchy and painful. Lymph node involvement can present as neck swelling, although RDD can involve any lymph nodes of the body (chest, groin, armpits).
By frequency, RDD can involve the skin (50%), lymph nodes (30-50%), bones (15%), respiratory system including nasal sinuses and airways (10-20%), skull and nervous system (10%), eye/eye socket (5%), salivary glands (5%), breasts (1-2%), and liver/spleen (1-2%). RDD can also occur in association with autoimmune conditions including lupus, rheumatoid arthritis, or other blood cancers including lymphoma or other histiocytic disorders such as Erdheim-Chester disease or Langerhans cell histiocytosis.
Symptoms of RDD depend on the site of involvement and can include:
- Skin nodules
- Lymph node enlargement (with or without pain)
- Weight loss
- Shortness of breath
- Blockage/discharge of the nose
- Deformity of the nose (saddle-nose)
- Inflammation of the tonsils/sinuses
- Difficulty swallowing or speaking
- High-pitched breathing
- Eye bulging/decreased vision
- Night sweats
- Decreased sensation
- Blood abnormalities (low red blood cells, white cell abnormalities, increased sedimentation/inflammatory cell rate, abnormal protein levels, etc.)
- Joint pain
- Slowly growing, painless mass
It is important to remember that symptoms alone do not make the diagnosis of RDD. Thus, it is important to consult a physician to receive a thorough workup and accurate diagnosis.
Diagnosis and Treatment
The National Comprehensive Cancer Network® (NCCN®) - an alliance of leading cancer centers - announced the publication of new NCCN Guidelines® for histiocytosis. These clinical practice guidelines provide the latest evidence and expert-consensus for diagnosing and treating the three most common forms of histiocytosis in adults: Langerhans cell histiocytosis (LCH), Erdheim-Chester Disease (ECD,) and Rosai Dorfman Disease (RDD). Although the guidelines are focused on adult patients, there may be insight for pediatric physicians as well. The Guidelines are listed as "histiocytic neoplasms" and can be found on NCCN's website.
On November 1st, 2022, Memorial Sloan Kettering Cancer Center (MSK) announced that the U.S. Food and Drug Administration (FDA) has approved the oral MEK inhibitor drug cobimetinib (Cotellic®) for the treatment of adult patients with the family of blood diseases known as histiocytic neoplasms (HN). These diseases include Erdheim-Chester disease, Rosai-Dorfman disease, and Langerhans cell histiocytosis. Cobimetinib is an oral inhibitor of MEK1 and MEK2, currently approved to treat melanoma. Gratitude and congratulations to the Principal Investigator of this study, Dr. Eli Diamond, neuro-oncologist and neurologist at MSK and Chair of the Scientific Committee for the Histiocytosis Association. We applaud the efforts of Dr. Diamond and the entire study team for this tremendous advancement. Read more here.
The diagnosis of RDD is made following a biopsy of the affected tissue. This procedure can be performed of the lymph nodes, skin, bone, liver, lung, or bone marrow. A small piece of the tissue is obtained so that it can be viewed under a microscope by a pathologist. If the cells in the tissue have certain specific characteristics, the diagnosis of RDD can be made. RDD cells stain with specific dyes- S100, CD68, and OCT2.
Baseline Evaluation and Testing
Once the diagnosis of RDD is made, detailed history, physical exam, and tests are undertaken to determine the extent of the disease, i.e., determining what organs are involved with the disease:
- History: A detailed health history is undertaken including the onset and duration of symptoms, past illnesses, health and lifestyle habits, and medical conditions experienced by the family.
- Physical examination: Includes a detailed exam of the body to search for signs of RDD, with special attention to skin, nose, mouth, and lymph node regions.
- Blood tests:
- Complete blood count with differential: To check for hemoglobin, platelets, and different types of white blood cells
- Chemistries, including kidney and liver function tests: To evaluate the function of kidney and liver
- C-reactive protein (CRP) - a marker of inflammation which can be elevated in RDD
- Immunoglobulin (antibody) levels
- Tests on the biopsy specimen:
- Immunohistochemistry: This test uses various types of dyes to find markers that can help in the diagnosis of RDD and differentiate it from other diseases.
- Molecular testing for MAP kinase pathway mutations: This test involves testing the tissue for changes in the genes that can be driving the RDD (KRAS, NRAS, etc.). Some of these tests require sending the biopsy sample to a specialized laboratory that can take several days to weeks to result. Knowledge of these mutations can help with the diagnosis and treatment of RDD
- PET (positron emission tomography) scan: To check for tumor cells in the body, a small amount of radioactive sugar is injected into a vein followed by taking pictures in a PET-scanning machine. The disease-causing cells look brighter than surrounding cells due to increased uptake of glucose
- CT (computed tomography) scan: This is an x-ray that takes a number of detailed pictures of various organs and structures within the body, often conducted in combination with a PET scan. Dye may be injected into a vein or taken by mouth to make the images more clear
- MRI (magnetic resonance imaging): A special type of scan that used magnetic waves to obtain detailed pictures of various body parts. A substance called gadolinium may be injected into a vein to get clearer pictures
- Ultrasound: This is a procedure where sound waves are used to create echoes and collect pictures of organs
- Electrocardiogram: This is a tracing of the heart rate and rhythm
- Echocardiogram: Uses sounds waves to provide pictures of the heart in order to evaluate blood flow and heart function
- Bone marrow aspiration and biopsy: This procedure involves suctioning of a small amount of bone marrow and taking a small piece of the bone by inserting a hollow needle in the hip bone
In many diseases or cancers, there is the concept of “staging” which refers to the extent or severity of the disease within the body (for example, “stage 4 lung cancer”). There is no standard staging system for RDD. The severity of the disease is determined by how widespread the involvement occurs outside of bone and whether internal organs are affected.
General Principles of Treatment
Not all patients with RDD will require treatment at diagnosis. A small proportion of patients may have waxing and waning disease that does not interfere with life expectancy or symptoms. In these cases, close monitoring (wait and watch) strategy can be utilized, with institution of treatment at the onset of symptoms or involvement of one of the internal organs (liver, kidney, heart, lungs, brain). RDD involving a single-site or organ can be treated by surgery or local treatments (injections, creams, ointments). Patients with RDD involving more than one site or organ should have their treatment planned by a team of health care providers who are experts in the disease, including and not limited to the following:
- Cancer specialist (hematologist/oncologist)
- Autoimmune disease specialist (rheumatologist)
- Brain and nervous system specialist (neurologist)
- Skin specialist (dermatologist)
- Ophthalmologist (Eye Specialist)
- Psychologist and supportive care specialist
Treatments Available for RDD
For single-site disease involving the skin, injectable steroids (triamcinolone) or surgery can be utilized. For single-site lymph node disease causing symptoms, surgical removal may be sufficient. For multiple skin or other disease sites, alternate treatments using oral pills or through the veins can be used as listed below. The treatment approach for multi-system RDD has evolved significantly due to discovery of mutations in the MAPK pathway genes, leading to the successful use of targeted therapies. Treatments for RDD can be divided into two categories- targeted and conventional treatments. Patients may also consider enrolling in a clinical trial if available near them.
- MEK-inhibitors (cobimetinib, trametinib, binimetinib):
- These drugs are typically used when there are MAP kinase pathway mutations (KRAS, MAP2K1, etc.) in the tumor cells. However, in some instances, testing for a mutation may not be possible in which case these agents can also be used empirically. These drugs are taken by mouth and the dose can vary based on side effects and response to treatment. Common side effects include skin rash, and patients may need to see a skin doctor for management. These drugs can also reduce the heart function, and sometimes an echocardiogram may be needed to monitor the effects on heart. Another notable side effect is changes in the layer of the tissue in the back of eye that senses light (retina) leading to blurry vision or loss of vision. It may be necessary to get regular eye exams while on treatment with these drugs.
- Immunosuppressants and modulators (corticosteroids, 6-mercaptopurine, azathioprine, lenalidomide, thalidomide):
- These drugs are given through mouth and work by suppressing the immune system. Most commonly used corticosteroid is prednisone, and usually administered over 2-3 months with gradual tapering. Common side effects with prednisone include weight gain, worsening diabetes, mood disturbances, risk of infections, stomach upset/ulcers, and delayed wound healing. Corticosteroids can also be given as a cream/ointment or local skin injections (e.g., triamcinolone). Other immunosuppressants like 6-mercaptopurine and azathioprine can lead to abnormalities of bone marrow and liver function, nausea, inflammation of pancreas (pancreatitis), or infections. Immunomodulators like thalidomide and lenalidomide can cause nausea, fatigue, diarrhea, suppression of bone marrow function, and blood clots. Due to the risk of blood clots, aspirin is usually given alongside these drugs.
- Chemotherapy (cladribine, cytarabine, vinblastine, hydroxyurea, methotrexate)
- These drugs are given through the vein or mouth (hydroxyurea, methotrexate). Chemotherapy works by slowing the growth of or killing rapidly dividing tumor cells. These drugs have the potential to weaken the immune system and can lead to infectious complications. Vinblastine can cause damage to the nerves leading to neuropathy, manifesting as numbness, tingling, or pain of fingers and toes. Cladribine can increase the risk of a particular type of pneumonia (pneumocystis pneumonia) so preventative antibiotics may need to be administered alongside.
- Other inhibitors: mTOR inhibitors (sirolimus), imatinib
- These are less commonly used targeted therapies but can occasionally result in disease remission. These drugs are taken by mouth and the dose can vary based on side effects and response to treatment. Side effects with mTOR inhibitors include abnormal cholesterol levels, lung inflammation (pneumonitis), and worsening of diabetes mellitus. Side effects with imatinib include rash, fatigue, and diarrhea.
- Other treatments (surgery, radiation, siltuximab, rituximab)
- Surgery may be used to remove RDD lesions or to reduce the pressure from a large lesion behind the eye. Occasionally, radiation therapy using high energy x-rays or protons may be used to kill tumor cells. The side effects of radiation can depend on the site of radiation and the amount of normal tissue exposed to the radiation. Siltuximab is given through the vein and works by reducing the inflammation generated by RDD cells. Common side effects of siltuximab include itching, weight gain, rash, allergic reaction (chest pain, nausea, racing heart), or upper respiratory infections. Rituximab can be given as an injection through the vein or under the skin. The side effects of rituximab include allergic reactions (scratchy throat, chest pain, heart racing, breathing difficulties, rash) and increased risk of infections.
Monitoring on Treatment
Once treatment is initiated, patients will likely need monitoring for assessing the response to therapy and also management of side effects of treatments. Some of the tests that may be undertaken include:
- Physical exam, including neurological exam
- Skin exams in patients on MEK-inhibitor treatment.
- PET scan to check for reduced brightness and size of the tumor sites.
- Additional imaging studies (CT, MRI) may be undertaken based on organs involved at diagnosis. Imaging (PET, CT, MRI) is usually repeated every few months and can be variable for each patient.
- Blood tests to assess for changes from the disease or the treatments.
Treatment of Relapsed RDD
If the tumor grows back after treatment, it is called as relapsed disease. In such cases, one of the other targeted or conventional treatments than used previously may be utilized. In some cases, a repeat biopsy of tumor cells may be needed for confirmation of diagnosis and mutation testing. If a clinical trial is available, that may be a consideration as well.
Despite improvement in treatments, patients with RDD may struggle with many symptoms such as extreme tiredness, body pain, depressed mood, anxiety, and memory difficulty. In many cases, getting additional input from psychology, supportive/palliative care, psychiatry, and pain specialists may be helpful. Leading a healthy lifestyle (exercise, balanced diet) may help improve some of these symptoms in addition to medications.
RDD does not usually threaten life or organ function, and the risk of mortality from the disease is extremely low. Among patients who need treatment due to involvement of critical organs or symptoms, the prognosis has continued to improve with introduction of targeted drugs. It is important for patients to continue to follow up with their healthcare provider to ensure no complications such as second cancers or side effects of treatment develop. If there is development of any new symptoms, it is critical to notify the healthcare team to catch these problems in a timely manner.
What Do I Do Now?
A new diagnosis of a histiocytic disorder can bring feelings of being overwhelmed, bewildered, scared, angry, sad, disappointed, helpless, and sometimes even feelings of guilt. It is a time filled with unknowns, change, and new people and situations. Most parents feel ill-equipped to understand what is happening to their child and how to navigate through the illness to recovery. There are, however, strategies and resources that can help you, your child, and other family members get through the uncertain times that lie ahead. One step at a time, you can gather information, create a support system, learn how to cope with stress, and become a strong advocate for your Histio Warrior as part of the medical team. The following tips and suggestions are provided to help guide you through this journey toward your Histio Warrior's good health.
Articles and Links
- Overview of Histiocytosis
- The Importance of Clinical Trials in the Fight Against Histiocytosis
- LCH Information from the National Cancer Institute
- Histiocitosis de células de Langerhans - del Instituto Nacional del Cáncer (en Español)
- Improved Outcome of Treatment-Resistant High-Risk Langerhans Cell Histiocytosis After Allogenic Stem Cell Transplantation with Reduced-Intensity Conditioning
- Improved Outcome in Multisystem LCH
- Health-Related Quality of Life, Cognitive Functioning, and Behaviour Problems in Children with Langerhans Cell Histiocytosis
- Neuropathology of CNS Disease in Langerhans Cell Histiocytosis
- Central Nervous System Disease in Langerhans Cell Histiocytosis
- Dermatology Online Journal: LCH
- BRAF, A Piece of the LCH Puzzle
- Notch is Active in Langerhans Cell Histiocytosis and Confers Pathognomic Features on Dendritic Cells
Printable Fact Sheets
Learn more about the different types of histiocytic disorders from these helpful fact sheets. Printing these for family and friends is a quick and easy way to teach them about the disease. More extensive information can be found in the Disease Information section of our website.
Choose from the following Fact Sheets: