Abstract:
Over the last 20 years, the prognosis for those with Erdheim-Chester disease has improved dramatically due to the increased speed at which doctors can identify and treat the condition. Although great strides have been made, the speed and ease at which doctors are able to identify the condition are still considered extremely slow in comparison to other similar diseases. 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.
Introduction:
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 regulates growth, proliferation, differentiation, migration, and apoptosis in the cell.¹² The mutation that occurs on the BRAF gene is somatic, meaning that it only occurs in certain cells and occurs throughout the entirety of a person's life. The mutation only occurs in histiocytes and precursor cells that eventually develop into histiocytes. Specifically, the mutation leads to the production of an abnormally active BRAF protein which, as a result, disrupts the regulation of cell growth and division. Without any regulation, histiocytes will 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 associated with Erdheim-Chester disease.¹
Method/Discussion/Results:
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 forms 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, 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 they appear the same in biopsy. In fact, 20% of patients with Erdheim-Chester disease also have LCH lesions, sometimes within the same biopsy.⁶ The possible coexistence between the two histiocytic neoplasms within the same biopsy means that it is hard to discern a diagnosis from even 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, dysarthria or slurred speech, involuntary rapid eye movement, reduced kidney function, exophthalmos or the bulging of the eye, and increased susceptibility to infections.² Unlike some genetic conditions characterized by specific symptom presentation Erdheim-Chester disease symptom presentation is too general to use for a basis for a diagnosis. These symptoms are shared by many conditions like Multiple Sclerosis, Lymphoma, Vasculitis, and even Sarcoidosis. There is not one way to arrive at a diagnosis. 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 such an indecipherable constellation of symptoms and the possibility of unreliable lab work, 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 certain conditions, including 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. 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 IFN-alpha, the mean survival 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 treatment in the early stages of the disease.
Conclusion:
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. 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 conditions and can identify possible testing errors in their differential.
Full References:
[1] “About Histiocytosis - Dana-Farber Cancer Institute | Boston, MA.” Accessed September 19, 2020. https://www.dana-farber.org/histiocytosis/about/.
[2] admin. “Symptoms.” Accessed September 19, 2020. https://erdheim-chester.org/symptoms/.
[3] ———. “Treatments.” Accessed September 19, 2020. https://erdheim-chester.org/treatments/.
[4] “CD1a.” www.pathologyoutlines.com. Accessed September 19, 2020. https://www.pathologyoutlines.com/topic/cdmarkerscd1a.html.
[5] 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.
[6] ———. “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.
[7] 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.
[8] “Glycolipids - an Overview | ScienceDirect Topics.” Sciencedirect.com, 2010. https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/glycolipids.
[9] “Interferon Alfa - Drug Information - Chemocare.” chemocare.com. Accessed September 19, 2020. http://chemocare.com/chemotherapy/drug-info/interferon-alfa.aspx.
[10] “Langerhans Cell Histiocytosis.” WebMD, n.d. https://www.webmd.com/cancer/cancer-langerhans-cell-histiocytosis#1.
[11] “Lipopeptide - an Overview | ScienceDirect Topics.” Science Direct. Accessed September 19, 2020. https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/lipopeptide.
[12] Reference, Genetics Home. “Erdheim-Chester Disease.” Genetics Home Reference. Accessed September 19, 2020. https://ghr.nlm.nih.gov/condition/erdheim-chester-disease#genes.
Comments