Granuloma | |
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Picture of a granuloma (without necrosis) as seen through a microscope on a glass slide: The tissue on the slide is stained with two standard dyes (hematoxylin: blue, eosin: pink) to make it visible. The granuloma in this picture was found in a lymph node of a patient with a Mycobacterium avium infection. | |
Specialty | Pathology |
A granuloma 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. [1] Such substances include infectious organisms including bacteria and fungi, as well as other materials such as foreign objects, keratin, and suture fragments. [2] [3] [4] [5]
In pathology, a granuloma is an organized collection of macrophages. [1] [6]
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 specially colored (stained) tissue under a microscope.
Macrophages (specifically histiocytes) are the cells that define a granuloma. They often fuse to form multinucleated giant cells (Langhans giant cell). [7] The macrophages in granulomas are often referred to as "epithelioid". 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 pinker when stained with eosin. These changes are thought to be a consequence of "activation" of the macrophage by the offending antigen.[ citation needed ]
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 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 (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).[ citation needed ]
Granulomas are seen in a wide variety of diseases, both infectious and noninfectious. [2] [3] Infections characterized by granulomas include tuberculosis, leprosy, histoplasmosis, cryptococcosis, coccidioidomycosis, blastomycosis, and cat-scratch disease. Examples of noninfectious[ clarification needed ] 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.[ citation needed ]
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. [2] Several exceptions to this general rule exist, but it nevertheless remains useful in day-to-day diagnostic pathology.
Mycobacterium tuberculosis can cause the granulomas of tuberculosis which tend to contain necrosis ("caseating tubercules"), but non-necrotizing granulomas may also be present. [8] Multinucleated giant cells with nuclei arranged like a horseshoe (Langhans giant cell) and foreign body giant cells [9] are often present, but are not specific for tuberculosis. A definitive diagnosis of tuberculosis requires identification of the causative organism by microbiologic cultures. [10]
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.
The other Mycobacterium species, Mycobacterium marinum can cause a rare infection known as "aquarium granuloma". [11]
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.
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. [2]
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. [10]
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-forming, containing large numbers of neutrophils. Organisms are usually difficult to find within the granulomas using methods routinely used in pathology laboratories.
Rheumatic fever is a systemic disease affecting the periarteriolar connective tissue and can occur after an untreated group A, beta-hemolytic streptococcal pharyngeal infection. It is believed to be caused by antibody cross-reactivity.
Sarcoidosis is a disease of unknown cause characterized by non-necrotizing ("non-caseating") granulomas in multiple organs and body sites, [12] 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 are similar to those of tuberculosis and other infectious granulomatous diseases. In most cases of sarcoidosis, though, the granulomas do not contain necrosis and are surrounded by concentric scar tissue (fibrosis). Sarcoid granulomas often contain star-shaped structures called asteroid bodies or lamellar structures termed Schaumann bodies , but these structures are not specific for sarcoidosis. [10] 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 that impairs breathing. In the heart, it can lead to rhythm disturbances, heart failure, and even death.
Crohn's disease 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. [13]
Listeria monocytogenes infection in infants can cause potentially fatal disseminated granulomas, called granulomatosis infantiseptica, following in utero infection.
Leishmaniases are a group of human diseases caused by Leishmania genus and transmitted by a sandfly bite can lead to granulomatous inflammation [14] in skin (cutaneous form of the disease) and liver (visceral form), with research suggesting effective granuloma formation to be desirable in the resolution of the disease. [15]
Pneumocystis infection in the lungs is usually not associated with granulomas, but rare cases are well documented to cause granulomatous inflammation. The diagnosis is established by finding Pneumocystis yeasts within the granulomas on lung biopsies. [16]
Aspiration pneumonia is typically caused by aspiration of bacteria from the oral cavity into the lungs, and does not result in the formation of granulomas. Granulomas may form, though, when food particles or other particulate substances such as 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. [17]
Necrotizing granulomas can develop in patients with rheumatoid arthritis, typically manifesting as bumps in the soft tissues around the joints (so-called rheumatoid nodules) or in the lungs. [10]
Granuloma annulare is a skin disease of unknown cause in which granulomas are found in the dermis of the skin, but it is not a true granuloma. Typically, a central zone of necrobiotic generation of collagen is seen, with surrounding inflammation and mucin deposition on pathology.
A foreign-body granuloma occurs when a foreign body (such as a wood splinter, piece of metal, glass etc.) penetrates the body's soft tissue followed by acute inflammation and formation of a granuloma. [18] In some cases the foreign body can be found and removed even years after the precipitating event. [19]
Childhood granulomatous periorificial dermatitis is a rare granulomatous skin disorder of unknown cause. It is temporary and tends to affect children, usually of African descent.
Certain inflammatory diseases are characterised by a combination of granulomatous inflammation and vasculitis (inflammation of the blood vessels). Both the granulomas as well as the vasculitis tend to occur in association with necrosis. Classic examples of such diseases include granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis.
The term is from Latin grānulum 'small grain' and -oma, a suffix used to indicate tumors or masses. The plural is granulomas or granulomata. The adjective granulomatous means "characterized by granulomas".
Berylliosis, or chronic beryllium disease (CBD), is a chronic allergic-type lung response and chronic lung disease caused by exposure to beryllium and its compounds, a form of beryllium poisoning. It is distinct from acute beryllium poisoning, which became rare following occupational exposure limits established around 1950. Berylliosis is an occupational lung disease.
Sarcoidosis is a disease involving abnormal collections of inflammatory cells that form lumps known as granulomata. The disease usually begins in the lungs, skin, or lymph nodes. Less commonly affected are the eyes, liver, heart, and brain, though any organ can be affected. The signs and symptoms depend on the organ involved. Often, no, or only mild, symptoms are seen. When it affects the lungs, wheezing, coughing, shortness of breath, or chest pain may occur. Some may have Löfgren syndrome with fever, large lymph nodes, arthritis, and a rash known as erythema nodosum.
Granulomatosis with polyangiitis (GPA), previously known as Wegener's granulomatosis (WG), after the German physician Friedrich Wegener, is a rare long-term systemic disorder that involves the formation of granulomas and inflammation of blood vessels (vasculitis). It is an autoimmune disease and a form of vasculitis that affects small- and medium-size vessels in many organs but most commonly affects the upper respiratory tract, lungs and kidneys. The signs and symptoms of GPA are highly varied and reflect which organs are supplied by the affected blood vessels. Typical signs and symptoms include nosebleeds, stuffy nose and crustiness of nasal secretions, and inflammation of the uveal layer of the eye. Damage to the heart, lungs and kidneys can be fatal.
Eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as allergic granulomatosis, is an extremely rare autoimmune condition that causes inflammation of small and medium-sized blood vessels (vasculitis) in persons with a history of airway allergic hypersensitivity (atopy).
Uveitis is inflammation of the uvea, the pigmented layer of the eye between the inner retina and the outer fibrous layer composed of the sclera and cornea. The uvea consists of the middle layer of pigmented vascular structures of the eye and includes the iris, ciliary body, and choroid. Uveitis is described anatomically, by the part of the eye affected, as anterior, intermediate or posterior, or panuveitic if all parts are involved. Anterior uveitis (iridocyclitis) is the most common, with the incidence of uveitis overall affecting approximately 1:4500, most commonly those between the ages of 20–60. Symptoms include eye pain, eye redness, floaters and blurred vision, and ophthalmic examination may show dilated ciliary blood vessels and the presence of cells in the anterior chamber. Uveitis may arise spontaneously, have a genetic component, or be associated with an autoimmune disease or infection. While the eye is a relatively protected environment, its immune mechanisms may be overcome resulting in inflammation and tissue destruction associated with T-cell activation.
A chest radiograph, chest X-ray (CXR), or chest film is a projection radiograph of the chest used to diagnose conditions affecting the chest, its contents, and nearby structures. Chest radiographs are the most common film taken in medicine.
Peripheral tuberculous lymphadenitis is a form of tuberculosis infection occurring outside of the lungs. In general, it describes tuberculosis infection of the lymph nodes, leading to lymphadenopathy. When cervical lymph nodes are affected, it is commonly referred to as "Scrofula." A majority of tuberculosis infections affect the lungs, and extra-pulmonary tuberculosis infections account for the remainder; these most commonly involve the lymphatic system. Although the cervical region is most commonly affected, tuberculous lymphadenitis can occur all around the body, including the axillary and inguinal regions.
Caseous necrosis or caseous degeneration is a unique form of cell death in which the tissue maintains a cheese-like appearance. Unlike with coagulative necrosis, tissue structure is destroyed. Caseous necrosis is enclosed within a granuloma. Caseous necrosis is most notably associated with tuberculoma. The dead tissue appears as a soft and white proteinaceous dead cell mass.
Microscopic polyangiitis is an autoimmune disease characterized by a systemic, pauci-immune, necrotizing, small-vessel vasculitis without clinical or pathological evidence of granulomatous inflammation.
Scleritis is a serious inflammatory disease that affects the white outer coating of the eye, known as the sclera. The disease is often contracted through association with other diseases of the body, such as granulomatosis with polyangiitis or rheumatoid arthritis. There are three types of scleritis: diffuse scleritis, nodular scleritis, and necrotizing scleritis. Scleritis may be the first symptom of onset of connective tissue disease.
A giant cell is a mass formed by the union of several distinct cells, often forming a granuloma.
Orofacial granulomatosis (OFG) is a condition characterized by persistent enlargement of the soft tissues of the mouth, lips and the area around the mouth on the face, causing in most cases extreme pain. The mechanism of the enlargement is granulomatous inflammation. The underlying cause of the condition is not completely understood, and there is disagreement as to how it relates to Crohn's disease and sarcoidosis.
Epithelioid cells are derivatives of activated macrophages resembling epithelial cells.
A rheumatoid nodule is a lump of tissue, or an area of swelling, that appears on the exterior of the skin usually around the olecranon or the interphalangeal joints, but can appear in other areas. There are four different types of rheumatoid nodules: subcutaneous rheumatoid nodules, cardiac nodules, pulmonary nodules, and central nervous systems nodules. These nodules occur almost exclusively in association with rheumatoid arthritis. Very rarely do rheumatoid nodules occur as rheumatoid nodulosis in the absence of rheumatoid arthritis. Rheumatoid nodules can also appear in areas of the body other than the skin. Less commonly they occur in the lining of the lungs or other internal organs. The occurrence of nodules in the lungs of miners exposed to silica dust was known as Caplan’s syndrome. Rarely, the nodules occur at diverse sites on body.
Necrotizing vasculitis, also called systemic necrotizing vasculitis, is a general term for the inflammation of veins and arteries that develops into necrosis and narrows the vessels.
Granulomatous mastitis can be divided into idiopathic granulomatous mastitis and granulomatous mastitis occurring as a rare secondary complication of a great variety of other conditions such as tuberculosis and other infections, sarcoidosis and granulomatosis with polyangiitis. Special forms of granulomatous mastitis occur as complication of diabetes. Some cases are due to silicone injection or other foreign body reactions.
Actinic granuloma (AG) was first described by O'Brien in 1975 as a rare granulomatous disease. Lesions appear on sun-exposed areas, usually on the face, neck, and scalp, with a slight preference for middle-aged women. They are typically asymptomatic, single or multiple, annular or polycyclic lesions measuring up to 6 cm in diameter, with slow centrifugal expansion, an erythematous elevated edge, and a hypopigmented, atrophic center.
Chronic pulmonary aspergillosis is a long-term fungal infection caused by members of the genus Aspergillus—most commonly Aspergillusfumigatus. The term describes several disease presentations with considerable overlap, ranging from an aspergilloma—a clump of Aspergillus mold in the lungs—through to a subacute, invasive form known as chronic necrotizing pulmonary aspergillosis which affects people whose immune system is weakened. Many people affected by chronic pulmonary aspergillosis have an underlying lung disease, most commonly tuberculosis, allergic bronchopulmonary aspergillosis, asthma, or lung cancer.
Ground-glass opacity (GGO) is a finding seen on chest x-ray (radiograph) or computed tomography (CT) imaging of the lungs. It is typically defined as an area of hazy opacification (x-ray) or increased attenuation (CT) due to air displacement by fluid, airway collapse, fibrosis, or a neoplastic process. When a substance other than air fills an area of the lung it increases that area's density. On both x-ray and CT, this appears more grey or hazy as opposed to the normally dark-appearing lungs. Although it can sometimes be seen in normal lungs, common pathologic causes include infections, interstitial lung disease, and pulmonary edema.
A lung cavity or pulmonary cavity is an abnormal, thick-walled, air-filled space within the lung. Cavities in the lung can be caused by infections, cancer, autoimmune conditions, trauma, congenital defects, or pulmonary embolism. The most common cause of a single lung cavity is lung cancer. Bacterial, mycobacterial, and fungal infections are common causes of lung cavities. Globally, tuberculosis is likely the most common infectious cause of lung cavities. Less commonly, parasitic infections can cause cavities. Viral infections almost never cause cavities. The terms cavity and cyst are frequently used interchangeably; however, a cavity is thick walled, while a cyst is thin walled. The distinction is important because cystic lesions are unlikely to be cancer, while cavitary lesions are often caused by cancer.