A granuloma (pl. granulomata) is an aggregation of macrophages (along with other cells) that forms in response to chronic inflammation. This occurs when the immune system attempts to isolate foreign substances that it is otherwise unable to eliminate. Such substances include infectious organisms including bacteria and fungi, as well as other materials such as foreign objects, keratin, and suture fragments.
Definition In pathology, a granuloma is an organized collection of macrophages. In medical practice, doctors occasionally use the term granuloma in its more literal meaning: "a small nodule". Since a small nodule can represent any tissue from a harmless nevus to a malignant tumor, this use of the term is not very specific. Examples of this use of the term granuloma are the lesions known as vocal cord granuloma (known as contact granuloma), pyogenic granuloma, and intubation granuloma, all of which are examples of granulation tissue, not granulomas. "Pulmonary hyalinizing granuloma" is a lesion characterized by keloid-like fibrosis in the lung and is not granulomatous. Similarly, radiologists often use the term granuloma when they see a calcified nodule on X-ray or CT scan of the chest. They make this assumption since granulomas usually contain calcium, although the cells that form a granuloma are too tiny to be seen by a radiologist. The most accurate use of the term granuloma requires a pathologist to examine surgically removed and stained (specially colored) tissue under a microscope. Macrophages, specifically histiocytes, are the cells that define a granuloma. They often fuse to form multinucleated Langhans giant cells. The macrophages in granulomas are often referred to as "epithelioid", referring to the vague resemblance of these macrophages to epithelial cells. Epithelioid macrophages differ from ordinary macrophages in that they have elongated nuclei that often resemble the sole of a slipper or shoe. They also have larger nuclei than ordinary macrophages, and their cytoplasm is typically pinker when stained with eosin. These changes are thought to be a consequence of "activation" of the macrophage by the offending antigen. The other key term in the above definition is the word "organized" which refers to a tight, ball-like formation. The macrophages in these formations are typically so tightly clustered that the borders of individual cells are difficult to distinguish. Loosely dispersed macrophages are not considered to be granulomas. All granulomas, regardless of cause, may contain additional cells and matrix. These include lymphocytes, neutrophils, eosinophils, multinucleated giant cells, fibroblasts, and collagen (fibrosis). The additional cells are sometimes a clue to the cause of the granuloma. For example, granulomas with numerous eosinophils may be a clue to coccidioidomycosis or allergic bronchopulmonary fungal disease, and granulomas with numerous neutrophils suggest blastomycosis, granulomatosis with polyangiitis, aspiration pneumonia, or cat-scratch disease. In terms of the underlying cause, the difference between granulomas and other types of inflammation is that granulomas form in response to antigens that are resistant to "first-responder" inflammatory cells such as neutrophils and eosinophils. The antigen causing the formation of a granuloma is most often an infectious pathogen or a substance foreign to the body, but sometimes the offending antigen is unknown, as in sarcoidosis. Granulomas are seen in a wide variety of diseases, both infectious and non-infectious. Infections characterized by granulomas include tuberculosis, leprosy, histoplasmosis, cryptococcosis, coccidioidomycosis, blastomycosis, and cat-scratch disease. Examples of non-oninfectious granulomatous diseases are sarcoidosis, Crohn's disease, berylliosis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, pulmonary rheumatoid nodules, and aspiration of food and other particulate material into the lung.
Caseating vs non-caseating An important feature of granulomas is whether or not they contain necrosis, which refers to dead cells that, under the microscope, appear as a mass of formless debris with no nuclei present. A related term, caseation (literally: turning to cheese), refers to a form of necrosis that, to the unaided eye, appears cheese-like ("caseous"), and is typically a feature of the granulomas of tuberculosis. The identification of necrosis in granulomas is important because granulomas with necrosis tend to have infectious causes. There are several exceptions to this general rule, but it nevertheless remains useful in day-to-day diagnostic pathology.
Diseases with granulomas
Tuberculosis Mycobacterium tuberculosis can cause the granulomas of tuberculosis which tend to contain necrosis ("caseating tubercules"), but non-necrotizing granulomas may also be present. Multinucleated giant cells with nuclei arranged like a horseshoe (Langhans giant cell) and foreign body giant cells are often present, but are not specific for tuberculosis. A definitive diagnosis of tuberculosis requires identification of the causative organism by microbiologic cultures.
Leprosy In leprosy, granulomas are found in the skin and tend to involve nerves. The appearance of the granulomas differs according to the precise type of leprosy.
Aquarium granuloma The other Mycobacterium species, Mycobacterium marinum, can cause a rare infection known as "aquarium granuloma".
Schistosomiasis Some schistosome ova that are laid in intestinal and urinary venules backwash into the liver via the portal vein, causing granuloma formation in the liver.
Histoplasmosis Granulomas are seen in most forms of histoplasmosis (acute histoplasmosis, histoplasmoma, chronic histoplasmosis). Histoplasma organisms can sometimes be demonstrated within the granulomas by biopsy or microbiological cultures.
Cryptococcosis When Cryptococcus infection occurs in persons whose immune systems are intact, granulomatous inflammation is typically encountered. The granulomas can be necrotizing or non-necrotizing. Using a microscope and appropriate stains, organisms can be seen within the granulomas.
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