Over the last 20 years, the prognosis for those with Erdheim-Chester disease, a histiocytic neoplasm, has improved dramatically due to the increased speed at which doctors can identify and treat the condition. Although great strides have been made, the pace at which doctors are able to diagnose the condition is still considered extremely slow. The slow speed is supported by a 4.2-year mean diagnosis time which is associated with higher mortality rates and a smaller 5-year survival percentage. Ultimately, the lack of awareness, generalized symptoms, and ambiguous lab work contribute immensely to the extremely long time until diagnosis. This article will serve as an outline of the numerous hindrances that contribute to the diagnostic difficulty associated with Erdheim-Chester disease.
What is Erdheim-Chester disease and how does it affect the body?
Erdheim-Chester disease is a rare type of slow-growing blood cancer called a histiocytic neoplasm.¹² Essentially, this means that Erdheim-Chester disease is a part of a group of blood cancers that are characterized by the abnormal growth of tissue caused by the build-up of macrophages, dendritic cells, or monocyte-derived cells in various organs and tissues. More than fifty percent of people with Erdheim-Chester disease share a specific mutation on the BRAF gene.¹² The role of the BRAF gene is to provide the instructions for making proteins that transmit chemical signals from outside the cell to the nucleus. These proteins are a part of the RAS/MAPK pathway which us responsible for the regulation of cellular growth, proliferation, differentiation, migration, and apoptosis.¹² The mutation that occurs on the BRAF gene is somatic, meaning that it only occurs in specific cells and is present throughout the entirety of a person’s life. Additionally, the mutation only occurs in histiocytes and precursor cells that eventually develop into histiocytes. In the case of Erdheim-Chester disease, this mutation leads to the production of an abnormally active BRAF protein which disrupts the regulation of cell growth and division. Without any regulation, histiocytes continue to grow and divide uncontrollably and therefore, result in a surplus of histiocytes in the patient’s organs and tissues. This phenomenon is called histiocytosis, and it is responsible for the reduced kidney function, bone pain, and diabetes insipidus (the imbalance of fluid in the body leading to excessive urination) associated with the disease.¹
What Makes Erdheim-Chester disease Diagnostically Unique?
The diagnostic uniqueness of Erdheim-Chester disease lies in its immune-histopathological characteristics. The key difference between Erdheim-Chester disease and other types of histiocytic neoplasms is that the histiocytes that are overproduced are CD1a negative, meaning that the histiocytes in people with Erdheim-Chester disease lack any CD1a antigen markers. Antigen markers serve as a form of communication between cells and function as a way that the body identifies and classifies certain cells. CD1a is a type of T-cell antigen marker responsible for presenting glycolipids and lipopeptide.⁸ Glycolipids are tasked with maintaining cellular stability in the cell membrane while lipopeptide is a molecule expressed by bacteria.¹¹
What Makes Erdheim-Chester Disease so Hard to Diagnose?
The main difficulties while diagnosing Erdheim-Chester disease are differentiating between different histiocytic neoplasms. Specifically, histopathologically it is difficult to discern between Erdheim-Chester disease and Langerhans Cell histiocytosis.¹⁰ Langerhans Cell histiocytosis often presents with the same symptoms as Erdheim-Chester disease, but its impact is limited to only the dendritic or antigen-presenting cells while Erdheim-Chester disease’s impact is limited to macrophages.⁵ Despite the clear histopathological difference between the two histiocytic neoplasms, they are often hard to differentiate from one another because both can be present simultaneously. In fact, 20% of patients with Erdheim-Chester disease also have LCH lesions, sometimes within the same biopsy.⁶ The possible coexistence of the two histiocytic neoplasms in the same biopsy means that it can be hard to discern a diagnosis even from the immune-histopathological characteristics. The other factor that makes diagnosing Erdheim Chester extremely difficult is the non-specific symptoms shared between Erdheim-Chester disease and a myriad of other conditions. Symptoms of Erdheim-Chester disease include bone pain, leg pain, upper arm pain, weight loss, fever, night sweats, fatigue, diabetes insipidus, balance issues, ataxia (a lack of muscle coordination and voluntary motor control), dysarthria (slurred speech), involuntary rapid eye movement, reduced kidney function, exophthalmos or the bulging of the eye, and increased susceptibility to infections.² Unlike some other genetic conditions characterized by specific symptom presentation, Erdheim-Chester disease symptom presentation is too general to use as a basis for a diagnosis. These symptoms are shared by many conditions like Multiple Sclerosis, Lymphoma, Vasculitis, and even Sarcoidosis. However, there is not just one way to arrive at a diagnosis. Ultimately, depending on the presenting symptoms and the course the condition takes, the way to make a definitive diagnosis changes. This is often due to a lack of diagnostic advancement and identification. With an indecipherable constellation of symptoms, the possibility of ambiguous lab work, and the limited awareness of Erdheim-Chester disease doctors often are unable to make a definitive diagnosis for years.
What are the implications of the diagnostic difficulty associated with Erdheim-Chester Disease?
As with any serious medical condition, the real-life ramifications of delayed diagnosis are drastic. In conditions like Erdheim-Chester disease, the time to diagnose is vital in managing and slowing down its progression. In a study conducted by Blood Advances consisting of 60 confirmed Erdheim-Chester disease patients, they found that the most common misdiagnosis for Erdheim-Chester disease was sarcoidosis, an inflammatory disease in which nodules of inflamed tissues form in multiple organs throughout the body. Other misdiagnoses included lymphoma, bone cancer, brain cancer, orbital lymphoma, autoimmune diseases, large vessel vasculitis, immunoglobulin IgG-4 related disease, and multiple sclerosis.⁷ With such a large array of different types of cancers, autoimmune diseases, vascular diseases, and infectious diseases as the working diagnoses in these cases, the mean time for an accurate diagnosis was 4.2 years.⁷ The patient impact of such a large time for diagnosis lies in the lack of treatments available for Erdheim-Chester disease. As of now, the main treatment is Interferon Alpha (IFN-alpha), a form of immunotherapy.³ IFN-alpha works by stimulating T-cells to attack the cancerous cells, as it causes the cancer cells to emit chemicals that attract T-cells to them.
Unfortunately, Interferon Alpha is only effective in the early stages of the condition meaning that it is crucial to catch Erdheim-Chester disease early. After Erdheim-Chester disease has progressed, treatment is futile as the cancer and lesions have most likely already spread to the vital organs. In fact, before the use of IFN-alpha, the mean survival time after diagnosis was 19.2 months. However, with early IFN-alpha treatments, the mortality rate is only 26%, and 5-year survival is 68%.⁹ Identifying Erdheim-Chester disease early can help to increase the survival rate and the quality of life drastically for patients, but unfortunately, with a mean diagnosis time of more than 4 years, patients are often unable to receive the necessary treatment in the early stages of the disease.
In order to further diagnostic advancements for Erdheim-Chester disease, we must establish a standardized treatment plan and look into new forms of immunotherapies that can further help to curb the mortality rate. Furthermore, we need to expand the approved treatments for Erdheim-Chester disease. New drugs like Zelboraf will provide the gateway to finding new treatments. In terms of increasing the diagnostic efficiency, more awareness is needed so that doctors become more familiar with the condition and can therefore include Erdheim-Chester disease in their differential.
 “About Histiocytosis – Dana-Farber Cancer Institute | Boston, MA.” Accessed September 19, 2020. https://www.dana-farber.org/histiocytosis/about/.
 admin. “Symptoms.” Accessed September 19, 2020. https://erdheim-chester.org/symptoms/.
 ———. “Treatments.” Accessed September 19, 2020. https://erdheim-chester.org/treatments/.
 “CD1a.” www.pathologyoutlines.com. Accessed September 19, 2020. https://www.pathologyoutlines.com/topic/cdmarkerscd1a.html.
 Emile, Jean-François, Oussama Abla, Sylvie Fraitag, Annacarin Horne, Julien Haroche, Jean Donadieu, Luis Requena-Caballero, et al. “Revised Classification of Histiocytoses and Neoplasms of the Macrophage-Dendritic Cell Lineages.” Blood 127, no. 22 (2016): 2672–81. https://doi.org/10.1182/blood-2016-01-690636.
 ———. “Revised Classification of Histiocytoses and Neoplasms of the Macrophage-Dendritic Cell Lineages.” Blood 127, no. 22 (2016): 2672–81. https://doi.org/10.1182/blood-2016-01-690636.
 Estrada-Veras, Juvianee I., Kevin J. O’Brien, Louisa C. Boyd, Rahul H. Dave, Benjamin H. Durham, Liqiang Xi, Ashkan A. Malayeri, et al. “The Clinical Spectrum of Erdheim-Chester Disease: An Observational Cohort Study.” Blood Advances 1, no. 6 (February 9, 2017): 357–366. https://doi.org/10.1182/bloodadvances.2016001784.
 “Glycolipids – an Overview | ScienceDirect Topics.” Sciencedirect.com, 2010. https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/glycolipids.
 “Interferon Alfa – Drug Information – Chemocare.” chemocare.com. Accessed September 19, 2020. http://chemocare.com/chemotherapy/drug-info/interferon-alfa.aspx.
 “Langerhans Cell Histiocytosis.” WebMD, n.d. https://www.webmd.com/cancer/cancer-langerhans-cell-histiocytosis#1.
 “Lipopeptide – an Overview | ScienceDirect Topics.” Science Direct. Accessed September 19, 2020. https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/lipopeptide.
 Reference, Genetics Home. “Erdheim-Chester Disease.” Genetics Home Reference. Accessed September 19, 2020. https://ghr.nlm.nih.gov/condition/erdheim-chester-disease#genes.
About the Author
Jonathan Colaco is a 17 year old student, currently in 12th grade. He has a great passion for investigating the practice of medicine and all of the human body’s complex processes and mechanisms. Jonathan’s ultimate goal is to go to medical school and become a practicing physician.