Granuloma
Overview
 
Granuloma is a medical term for a tiny collection of immune cells known as macrophages. Granulomas form when the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...

 attempts to wall off substances that it perceives as foreign but is unable to eliminate. Such substances include infectious organisms such as bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...

 and fungi as well as other materials such as keratin
Keratin
Keratin refers to a family of fibrous structural proteins. Keratin is the key of structural material making up the outer layer of human skin. It is also the key structural component of hair and nails...

 and suture fragments. A granuloma is therefore a special type of inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...

 that can occur in a wide variety of diseases.
Encyclopedia
Granuloma is a medical term for a tiny collection of immune cells known as macrophages. Granulomas form when the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...

 attempts to wall off substances that it perceives as foreign but is unable to eliminate. Such substances include infectious organisms such as bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...

 and fungi as well as other materials such as keratin
Keratin
Keratin refers to a family of fibrous structural proteins. Keratin is the key of structural material making up the outer layer of human skin. It is also the key structural component of hair and nails...

 and suture fragments. A granuloma is therefore a special type of inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...

 that can occur in a wide variety of diseases. The adjective granulomatous means characterized by granulomas.

Definition

In medical practice, doctors occasionally use the term "granuloma" loosely to mean "a small nodule". Since a small nodule can represent anything from a harmless nevus
Nevus
Nevus is the medical term for sharply-circumscribed and chronic lesions of the skin. These lesions are commonly named birthmarks and moles. Nevi are benign by definition...

 to a malignant tumor, this usage of the term is not very specific. 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 often 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 specially colored (stained) tissue under a microscope. The following is a more technical definition of a granuloma.

In pathology
Pathology
Pathology is the precise study and diagnosis of disease. The word pathology is from Ancient Greek , pathos, "feeling, suffering"; and , -logia, "the study of". Pathologization, to pathologize, refers to the process of defining a condition or behavior as pathological, e.g. pathological gambling....

, a granuloma (classical Greek plural granulomata; modern anglicized plural granulomas) is an organized collection of macrophages.

Macrophages (also known as histiocytes) are the cells that define a granuloma. They often, but not invariably, fuse to form multinucleated giant cells (Langhans giant cell
Langhans giant cell
Langhans giant cells are large cells found in granulomatous conditions.They are formed by the fusion of epithelioid cells , and contain nuclei arranged in a horseshoe-shaped pattern in the cell periphery....

). The macrophages in granulomas are often referred to as "epithelioid
Epithelioid
An epithelioid cell is a cell that resembles epithelial cells in that it directly contacts its neighboring cells via cell surface molecules or junctions. Unlike epithelial cells, however, epithelioid cells make contacts over their entire surface, rather than at restricted portions. The term...

". This term refers 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 more pink when stained with eosin
Eosin
Eosin is a fluorescent red dye resulting from the action of bromine on fluorescein. It can be used to stain cytoplasm, collagen and muscle fibers for examination under the microscope. Structures that stain readily with eosin are termed eosinophilic....

. 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" that 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 appreciate. 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
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...

 (fibrosis
Fibrosis
Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This is as opposed to formation of fibrous tissue as a normal constituent of an organ or tissue...

). 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, Wegener's granulomatosis, 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 often the offending antigen is unknown (as in sarcoidosis).

Granulomas are seen in a wide variety of diseases, both infectious and non-infectious. Infections that are characterized by granulomas include tuberculosis
Tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...

, leprosy
Leprosy
Leprosy or Hansen's disease is a chronic disease caused by the bacteria Mycobacterium leprae and Mycobacterium lepromatosis. Named after physician Gerhard Armauer Hansen, leprosy is primarily a granulomatous disease of the peripheral nerves and mucosa of the upper respiratory tract; skin lesions...

, histoplasmosis
Histoplasmosis
Histoplasmosis is a disease caused by the fungus Histoplasma capsulatum. Symptoms of this infection vary greatly, but the disease primarily affects the lungs...

, cryptococcosis
Cryptococcosis
Cryptococcosis, or cryptococcal disease, is a potentially fatal fungal disease. It is caused by one of two species; Cryptococcus neoformans and Cryptococcus gattii. These were all previously thought to be subspecies of C...

, coccidioidomycosis
Coccidioidomycosis
Coccidioidomycosis is a fungal disease caused by Coccidioides immitis or C. posadasii. It is endemic in certain parts of Arizona, California, Nevada, New Mexico, Texas, Utah and northwestern Mexico.C...

, blastomycosis
Blastomycosis
Blastomycosis is a fungal infection caused by the organism Blastomyces dermatitidis...

 and cat scratch disease
Cat scratch disease
Cat scratch disease is a usually benign infectious disease caused by the intracellular bacterium Bartonella. It is most commonly found in children following a scratch or bite from a cat by about one to two weeks...

. Examples of non-infectious granulomatous diseases are sarcoidosis
Sarcoidosis
Sarcoidosis , also called sarcoid, Besnier-Boeck disease or Besnier-Boeck-Schaumann disease, is a disease in which abnormal collections of chronic inflammatory cells form as nodules in multiple organs. The cause of sarcoidosis is unknown...

, Crohn's disease
Crohn's disease
Crohn's disease, also known as regional enteritis, is a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract from mouth to anus, causing a wide variety of symptoms...

, berylliosis
Berylliosis
Berylliosis, or chronic beryllium disease , is a chronic allergic-type lung response and chronic lung disease caused by exposure to beryllium and its compounds. As an occupational lung disease, it is most classically associated with beryllium mining or manufacturing of fluorescent light bulbs...

, Wegener's granulomatosis
Wegener's granulomatosis
Wegener's granulomatosis , more recently granulomatosis with polyangiitis , is an incurable form of vasculitis that affects the nose, lungs, kidneys and other organs. Due to its end-organ damage, it is life-threatening and requires long-term immunosuppression...

, Churg-Strauss syndrome
Churg-Strauss syndrome
Churg–Strauss syndrome is a medium and small vessel autoimmune vasculitis, leading to necrosis. It involves mainly the blood vessels of the lungs , gastrointestinal system, and peripheral nerves, but also affects the heart, skin and kidneys. It is a rare disease that is non-inheritable and...

, pulmonary rheumatoid nodules and aspiration of food and other particulate material into the lung.

An important feature of granulomas is whether or not they contain necrosis
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...

. Necrosis 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 (i.e., without a microscope), appears cheese-like ("caseous"), and is typically (but not uniquely) 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.

Tuberculosis

The granulomas of tuberculosis
Tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...

 tend to contain necrosis
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...

 ("caseating tubercules"), but non-necrotizing granulomas may also be present. Multinucleated giant cells with nuclei arranged like a horseshoe (Langhans giant cell
Langhans giant cell
Langhans giant cells are large cells found in granulomatous conditions.They are formed by the fusion of epithelioid cells , and contain nuclei arranged in a horseshoe-shaped pattern in the cell periphery....

) are often present, but are not specific for tuberculosis. The diagnosis of tuberculosis requires identification of the causative organism by microbiologic cultures.

Leprosy

In leprosy
Leprosy
Leprosy or Hansen's disease is a chronic disease caused by the bacteria Mycobacterium leprae and Mycobacterium lepromatosis. Named after physician Gerhard Armauer Hansen, leprosy is primarily a granulomatous disease of the peripheral nerves and mucosa of the upper respiratory tract; skin lesions...

, granulomas are found in the skin and tend to involve nerves. The appearance of the granulomas differs according to the precise type of leprosy.

Schistosomiasis

Some schistosome ova that are laid in intestinal and urinary veinules backwash into the liver via the portal vein causing granuloma formation in the liver.

Histoplasmosis

Granulomas are seen in most forms of histoplasmosis
Histoplasmosis
Histoplasmosis is a disease caused by the fungus Histoplasma capsulatum. Symptoms of this infection vary greatly, but the disease primarily affects the lungs...

 (acute histoplasmosis, histoplasmoma, chronic histoplasmosis). Histoplasma organisms can sometimes be demonstrated within the granulomas by biopsy or microbiological cultures.

Cryptococcosis

When Cryptococcus
Cryptococcus
Cryptococcus is a genus of fungus. Species grow in culture as yeasts. The perfect forms or teleomorphs of Cryptococcus species are filamentous fungi in the genus Filobasidiella...

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.

Cat-scratch disease

Cat-scratch disease is an infection caused by the bacterial organism Bartonella henselae, typically acquired by a scratch from a kitten infected with the organism. The granulomas in this disease are found in the lymph nodes draining the site of the scratch. They are characteristically "suppurative", i.e., pus
Pus
Pus is a viscous exudate, typically whitish-yellow, yellow, or yellow-brown, formed at the site of inflammatory during infection. An accumulation of pus in an enclosed tissue space is known as an abscess, whereas a visible collection of pus within or beneath the epidermis is known as a pustule or...

 forming, containing large numbers of neutrophils. Organisms are usually difficult to find within the granulomas using methods routinely used in pathology laboratories.

Sarcoidosis

Sarcoidosis
Sarcoidosis
Sarcoidosis , also called sarcoid, Besnier-Boeck disease or Besnier-Boeck-Schaumann disease, is a disease in which abnormal collections of chronic inflammatory cells form as nodules in multiple organs. The cause of sarcoidosis is unknown...

 is a disease of unknown cause characterized by granulomas in multiple organs and body sites , most commonly the lungs and lymph nodes within the chest cavity. Other common sites of involvement include the liver, spleen, skin and eyes. The granulomas of sarcoidosis
Sarcoidosis
Sarcoidosis , also called sarcoid, Besnier-Boeck disease or Besnier-Boeck-Schaumann disease, is a disease in which abnormal collections of chronic inflammatory cells form as nodules in multiple organs. The cause of sarcoidosis is unknown...

 are similar to the granulomas of tuberculosis and other infectious granulomatous diseases. However, in most cases of sarcoidosis, the granulomas do not contain necrosis and are surrounded by concentric scar tissue (fibrosis
Fibrosis
Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This is as opposed to formation of fibrous tissue as a normal constituent of an organ or tissue...

). Sarcoid granulomas often contain star-shaped structures termed asteroid bodies or lamellar structures termed Schaumann bodies
Schaumann bodies
In pathology, Schaumann bodies are calcium and protein inclusions inside of Langhans giant cells as part of a granuloma.Many conditions can cause Schaumann bodies, including:*Sarcoidosis,*Hypersensitivity pneumonitis, and*Berylliosis....

. However, these structures are not specific for sarcoidosis . Sarcoid granulomas can resolve spontaneously without complications or heal with residual scarring. In the lungs, this scarring can cause a condition known as pulmonary fibrosis
Pulmonary fibrosis
Pulmonary fibrosis is the formation or development of excess fibrous connective tissue in the lungs. It is also described as "scarring of the lung".-Symptoms:Symptoms of pulmonary fibrosis are mainly:...

 that impairs breathing; in the heart, it can lead to rhythm disturbances, heart failure and even death.

Crohn's disease

Crohn's disease
Crohn's disease
Crohn's disease, also known as regional enteritis, is a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract from mouth to anus, causing a wide variety of symptoms...

 is an inflammatory condition of uncertain cause characterized by severe inflammation in the wall of the intestines and other parts of the abdomen. Within the inflammation in the gut wall, granulomas are often found, and are a clue to the diagnosis.

Pneumocystis pneumonia

Pneumocystis infection in the lungs is usually not associated with granulomas, but rare cases are well documented to cause granuomatous inflammation. The diagnosis is established by finding Pneumocystis yeasts within the granulomas on lung biopsies .

Aspiration pneumonia

Aspiration pneumonia
Aspiration pneumonia
Aspiration pneumonia is bronchopneumonia that develops due to the entrance of foreign materials into the bronchial tree, usually oral or gastric contents...

 is typically caused by aspiration of bacteria from the oral cavity into the lungs, and does not result in the formation of granulomas. However, granulomas may form when food particles or other particulate substances like pill fragments are aspirated into the lungs. Patients typically aspirate food because they have esophageal, gastric or neurologic problems. Intake of drugs that depress neurologic function may also lead to aspiration. The resultant granulomas are typically found around the airways (bronchioles) and are often accompanied by foreign-body-type multinucleated giant cells, acute inflammation or organizing pneumonia. The finding of food particles in lung biopsies is diagnostic.

Granulomas associated with vasculitis

Certain inflammatory diseases are characterised by a combination of granulomatous inflammation and vasculitis
Vasculitis
Vasculitis refers to a heterogeneous group of disorders that are characterized by inflammatory destruction of blood vessels. Both arteries and veins are affected. Lymphangitis is sometimes considered a type of vasculitis...

 (inflammation of the blood vessels). Both the granulomas as well as the vasculitis tend to occur in association with necrosis
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...

. Classic examples of such diseases include Wegener's Granulomatosis
Wegener's granulomatosis
Wegener's granulomatosis , more recently granulomatosis with polyangiitis , is an incurable form of vasculitis that affects the nose, lungs, kidneys and other organs. Due to its end-organ damage, it is life-threatening and requires long-term immunosuppression...

 and Churg-Strauss Syndrome
Churg-Strauss syndrome
Churg–Strauss syndrome is a medium and small vessel autoimmune vasculitis, leading to necrosis. It involves mainly the blood vessels of the lungs , gastrointestinal system, and peripheral nerves, but also affects the heart, skin and kidneys. It is a rare disease that is non-inheritable and...

.

External links

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