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Granulomas

What Is It, Types, Causes, and More

Author: Corinne Tarantino, MPH

Editors: Alyssa Haag, Emily Miao, PharmD

Illustrator: Jillian Dunbar

Copyeditor: David G. Walker


What is a granuloma?

A granuloma is a small area of chronic inflammation, characterized by a collection of macrophages, typically accompanied by helper T-cells. There are two types of immune system responses, innate and active. The innate immune response is non-specific and is the first line of defense to protect the body from invading pathogens. Macrophages, a type of white blood cell used in the innate defense, engulf and kill foreign substances. If the foreign pathogen continues to invade, the active immune response is activated, producing a stronger and more targeted response. During this secondary defense, a specific type of white blood cells called CD4+ helper T-cells are involved. There are several types of CD4+ helper T-cells; however, the TH1 subtype, a lineage of T-cells involved in macrophage proliferation, is involved in granuloma formation. 

Formation of granulomas may occur when there is either a continuous T-cell response or when the body attempts to contain a pathogen it is unable to eliminate. The consequent chronic inflammation may damage organ tissue and cause tissue death (i.e., necrosis) or scarring (i.e., fibrosis).

What are the types of granulomas?

Granuloma types can be split into two categories: caseating and noncaseating. Caseating granulomas have a central region of necrosis and classically appear “cheese-like” upon biopsy. These typically form in the lungs in response to tuberculosis and fungal infections. On the other hand, noncaseating granulomas do not have a central region of necrosis and occur more commonly. They may be formed in response to contact with foreign material, sarcoidosis, and Crohn’s disease.

Granulomas may be further classified by the cause. For example, noncaseating granulomas caused by exposure to foreign objects, such as breast implants, are called foreign body granulomas.

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What causes granulomas to form?

Granulomas form in response to chronic inflammation. Accordingly, the most common cause of granulomas are infections. Caseating granulomas are formed by infections, such as tuberculosis and fungal infections. Noncaseating granulomas may be formed by an inflammatory condition (e.g., sarcoidosis and Crohn disease), vasculitis, and exposure to foreign objects.

Formation of granulomas is characteristic of certain diseases. Most commonly, in chronic granulomatous disease (CGD), an inherited genetic mutation reduces the ability of white blood cells to kill certain bacteria and fungi, like Staphylococcus aureus and Aspergillus. Individuals with CGD are highly susceptible to infections that lead to granuloma development throughout the body. Similarly, granuloma annulare is a chronic skin disorder characterized by granulomas appearing as small red or yellow bumps in a ring shape on the skin. Finally, granulomatosis with polyangiitis (GPA) is a rare autoimmune-induced vasculitis characterized by granuloma formation, causing inflammation of the blood vessels (primarily small-sized arteries) and, ultimately, affecting blood flow.

How do granulomas form?

Granulomas form when the immune system responds to the causative agents (e.g., infections and foreign objects). First, an antigen (i.e., a foreign substance that stimulates an immune response) from the causative pathogen is taken up by an antigen presenting cell, like a macrophage. These antigen presenting cells can then present the foreign antigen on their major histocompatibility complex (MHC) class II to the CD4+ helper T-cells. This induces the secretion of cytokines, which results in the conversion of a CD4+ helper T-cell to the TH1 subtype. 

Granulomas may form when TH1 cells accumulate and secrete cytokines and chemokines. In particular, the secretion of interleukin 2 (IL-2) further induces T-cell proliferation, and interferon gamma (INɣ) secretion activates macrophages. Tumor necrosis factor alpha (TNFɑ) may then be released by macrophages and T-cells increasing attraction and stimulation of macrophages, leading to a stable and dynamic accumulation of inflammatory cells.

Typically, during this process, macrophages will develop a large cytoplasm and begin to resemble epithelial cells, now called epithelioid cells. These cells are often then surrounded by lymphocytes and, occasionally, plasma cells. Multiple macrophages may then fuse together forming multinucleated cells called giant cells. Granulomas form when these giant cells pack tightly together.

How are granulomas diagnosed?

Diagnosing granulomas begins with a medical examination, including a history of the individual’s present illness, the individual’s medical history, and the conduction of a thorough physical examination. Afterwards, imaging may be conducted, such as X-rays or CT scans. If a mass is present in the initial imaging, biopsy of the suspected tissue will typically be conducted to confirm a diagnosis and determine if the granuloma is non-caseating or caseating. If caseating granulomas are discovered in the lungs, the individual may be tested for tuberculosis (TB) by either a blood or a skin test. Other types of blood tests may also be performed to diagnose the underlying cause of the granulomas, such as an antineutrophil cytoplasmic antibody (ANCA) test for diagnosing Granulomatosis with Polyangiitis.

How are granulomas treated?

Granulomas are typically treated with medications that target the underlying inflammation, like anti-TNF therapy. Prior to receiving therapy, individuals will often be tested for active TB, as TB stored within the granuloma can be released when treated with anti-TNF medications, causing a disseminated infection. If the TB test is positive, the TB will be treated with a medication regimen often involving isoniazid, rifampin, ethambutol, and pyrazinamide. Other underlying conditions will also be treated accordingly, such as prescribing anti-inflammatory corticosteroids for sarcoidosis.

Do granulomas go away?

Depending on the underlying cause of the granuloma, they may go away on their own (e.g., granuloma annulare) or may require treatment to fully regress (e.g., tuberculosis).

What are the most important facts to know about granulomas?

Granulomas are a tight collection of macrophages, often surrounded by helper T-cells. Most granulomas fall into one of two categories: caseating, with a necrotic center, or non-caseating, without any necrosis. Caseating granulomas are often caused by infections, while the non-caseating type is typically caused by an inflammatory condition. Granulomas form when the immune system responds to a causative agent, eventually leading macrophage transformation to epithelioid cells, which may bind tightly together, forming the granuloma. Granulomas are typically diagnosed by a medical evaluation, imaging, biopsy, and blood tests. Generally, granulomas are treated with medications, like anti-TNF therapy, that decrease inflammation. Treatment also consists of treating the underlying cause. Granulomas may go away on their own or require treatment depending on the underlying cause.

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Related links

Tuberculosis: Pathology review
Chronic granulomatous disease
Vasculitis: Clinical practice
Sarcoidosis
Hypopigmentation skin disorders: Clinical practice

Resources for research and reference

Centers for Disease Control and Prevention. (2016). Tuberculosis (TB). https://www.cdc.gov/tb/topic/treatment/tbdisease.htm 

Facco, M., Miorin, M., Agostini, C., & Semenzato, G. (2007). Granuloma Formation. In U. Costabel, R.M. du Bois, & J.J. Egan (eds), Diffuse Parenchymal Lung Disease, 36: 87-100. Karger. DOI:10.1159/000102629

Kumar, V., Abbas, A. K., & Aster, J. C. (2015). Robbins and Cotran Pathologic Basis of Disease (9th ed.). Suanders.

National Organization for Rare Disorders. (2003). Granuloma Annulare. Retrieved from https://rarediseases.org/rare-diseases/granuloma-annulare/

National Organization for Rare Disorders. (2020). Granulomatosis with polyangiitis. Retrieved from https://rarediseases.org/rare-diseases/granulomatosis-with-polyangiitis/

National Organization for Rare Disorders. (2020). Chronic Granulomatous Disease. Retrieved from https://www.niaid.nih.gov/diseases-conditions/chronic-granulomatous-disease-cgd

Williams, O., & Fatima, S. (2021). Granuloma. In StatPearls. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK554586/