Malignant histiocytosis (MH) is an ultra-rare subtype of histiocytic neoplasms, with estimated incidence of less than 1 case per million population. MH can affect children as well as adults, although it is more commonly seen among adult population.
Malignant histiocytosis (MH) is an ultra-rare subtype of histiocytic neoplasms, with estimated incidence of less than 1 case per million population. MH can affect children as well as adults, although it is more commonly seen among adult population. MH can occur by itself (primary MH) or in relation to another blood cancer like leukemia or lymphoma (secondary MH). MH encompasses 3 entities - histiocytic sarcoma (HS), Langerhans cell sarcoma (LCS), and interdigitating dendritic cell sarcoma (IDCS); however, histiocytic sarcoma (HS) represents the vast majority of MH cases.
The average age at diagnosis is around 60 years, although malignant histiocytosis (MH) has been diagnosed in children as well as elderly. MH can involve any organ system of the body, with most common organs involved being lymph nodes, bone, lung, skin, bone marrow, and central nervous system. About a third of patients with MH present with single site of disease (unifocal MH) and the rest present with multiple sites (multifocal MH). The term “malignant” generally suggests aggressive disease, although there are several cases of unifocal MH that do not behave aggressively and have good outcomes.
Symptoms of malignant histiocytosis can vary depending on what type of histiocytoma you have. Symptoms may include:
- A lump that grows larger
- Swelling in your hand or foot
- Loss of appetite
Diagnosis and Treatment
The diagnosis of malignant histiocytosis (MH) relies on the review of the biopsy of a tumor specimen under the microscope by a pathologist. The pathologists usually conduct several tests on the sample, including dye testing (called as immunohistochemistry), to arrive at the diagnosis of MH and further classify its subtype. In some cases, the appearance of the cells is not classic for MH and additional consultations and testing may be necessary to ensure that the tumor is not related to another form of cancer. Often, the number of cells in biopsy specimens is not enough to run all the necessary tests, in which case a repeat biopsy can be recommended. In addition, testing for mutations of the BRAF and other genes through special tests called as next generation sequencing (NGS) studies on the biopsy specimen or blood may be undertaken to help aid in the diagnosis or treatment. In cases of MH arising after another blood cancer (secondary MH), the pathologist might order genetic testing to test whether the two cancers are related to each other and arising from the same parent cell type.
Once the diagnosis of MH 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 MH.
- 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 MH.
- BRAF and other mutation testing- to check for BRAF-V600E and other mutations in the blood.
- Tests on the Biopsy Specimen:
- Immunohistochemistry: This test uses various types of dyes to find markers that can help in the diagnosis of MH and differentiate it from other diseases. At times, BRAF-mutation testing can also be achieved relatively quickly using immunohistochemistry methods.
- Molecular testing for MAPK and other pathway mutations: This test involves testing the tissue mutations that can be driving the MH (BRAF, 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 treatment of MH.
- 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 clearer.
- MRI (magnetic resonance imaging): A special type of scan that used magnetic waves to obtain detail pictures of various body parts. A substance called gadolinium may be injected into a vein to get clearer pictures. Sometimes, an MRI of the brain is conducted if there is suspicion of MH involvement.
- 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 MH. The severity of the disease is determined by how widespread the involvement is, including whether the disease is unifocal or multifocal.
Treatment of Primary Malignant Histiocytosis (MH)
Given the rarity of the disease, large studies examining treatments and outcomes are lacking, and treatment guidelines rely on individual reports of cases or expert opinion, borrowing from other histiocytic disorders. The treatment of MH often depends on the degree of organ involvement at diagnosis.
- Unifocal MH: For select cases of MH involving a single site that is easily removable/resectable by surgery (e.g., bone, skin, or lymph node), the outcomes can be very good by complete surgical resection. In some cases, a complete resection is not possible, and additional (adjuvant) radiation therapy is employed. Other cases that involve organs or sites where surgery is not considered safe or feasible are treated similar to multifocal MH.
- Multifocal MH: Patients with multifocal MH tend to have a more aggressive presentation and clinical course, with a lack of effective treatments. If a clinical trial is available, it is highly encouraged to enroll in one to try novel therapies. There is no established standard of care for multifocal MH, and treatments are adopted from other blood cancers, including histiocytic disorders like Erdheim-Chester disease and Langerhans cell histiocytosis. It is unknown at this time which of the treatments work best for cases with MH. Some of the treatments that have been utilized so far include the following:
- Chemotherapy: Commonly used regimens for MH include combination chemotherapy drugs like ifosfamide, carboplatin, and etoposide (ICE) or Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). These treatments are typically administered in “cycles”, which each dose considered as 1 cycle, repeated up to 6 times every 3 weeks apart. Important side effects of these regimens includes lowering of blood cells (red blood cells, white blood cells, and platelets), risk of infections, kidney failure, and nerve damage. Other less studied chemotherapy drugs include vinblastine with prednisone, cladribine, or cytarabine as used in LCH.
- Targeted therapy: Borrowing from ECD and LCH, targeted treatments like BRAF-inhibitors (vemurafenib, dabrafenib) or MEK-inhibitors (cobimetinib, trametinib) are sometimes utilized especially if there is a mutation in the MAPK pathway (BRAF, KRAS, MAP2K1, etc.). The effectiveness of such treatments for MH is currently unknown and available case reports suggest mixed results.
- Other treatments: There are a handful of case reports of use of immunotherapy drugs (pembrolizumab and nivolumab), thalidomide, and alemtuzumab. The role of these therapies in MH treatment remains unclear.
Treatment of Secondary Malignant Histiocytosis (MH)
The optimal treatment for secondary MH, i.e., MH arising after a blood cancer such as leukemia or lymphoma, is unknown. In many such instances, MH occurs along with the other blood cancer, where the treatment is focused on the underlying lymphoma or leukemia. In other cases, if an active blood cancer other than MH is not found, such cases are treated similar to primary MH as described above.
Monitoring on Treatment
Once treatment is initiated,
patients need follow-up tests, or 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 BRAF- and MEK-inhibitor treatments.
- 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 or Refractory Malignant Histiocytosis (MH)
If the MH grows back after treatment, it is called relapsed disease and if it does not respond to treatment at all, it is called refractory disease. In case of unifocal MH that recurs after initial surgery in a localized spot, a repeat surgery and/or radiation therapy can be considered. In some cases, a stem cell transplant from a donor (allogeneic transplant) is utilized as an aggressive treatment option if the patients respond to chemotherapy. In other cases, one of the targeted or other treatments than used previously are 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.
The prognosis of MH appears to be strongly tied to the extent of the disease and relationship to another blood cancer (primary vs. secondary MH). Many patients with unifocal MH who undergo complete surgical resection can have long-term remissions and often are cured of the MH. There are also very rare reports of unifocal MH undergoing spontaneous regression without treatment. Multifocal and secondary MH, on the other hand, generally tend to be associated with a poor prognosis, especially in cases with “aggressive presentation” leading to illness from rapid tumor growth.
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 (Including Diabetes Insipidus)
- The Importance of Clinical Trials in the Fight Against Histiocytosis
- Diabetes Insipidus (National Institutes of Health)
- Risk Factors for Diabetes Insipidus in Langerhans Cell Histiocytosis
- Central Diabetes Insipidus: Is it Langerhans Cell Histiocytosis of the Pituitary Stalk?
- Central Diabetes Insipidus in Children and Young Adults
- Management of Langerhans Cell Hisitocytosis (LCH)-Induced Central Diabetes Insipidus and Its Associated Endocrinological/Neurological Sequelae
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: