Introduction

A granuloma is a focal aggregate of immune cells that forms in response to a persistent inflammatory stimulus. It characteristically demonstrates the compact organization of mature macrophages, which may or may not be associated with other inflammatory cell types. Granulomas are evolutionarily ancient structures found throughout both vertebrate and invertebrate species and are likely to have evolved as a protective mechanism to destroy or encapsulate foreign material.[1] They were first identified and described as "tubercules" in the lungs of tuberculosis sufferers as early as 1679. However, at this point, neither the principal cell type (macrophages) nor the causative organism (Mycobacterium tuberculosis) has been discovered.[2]

Causes

Granuloma formation begins with an inflammatory trigger, such as an infectious pathogen or a foreign body. Macrophages are recruited to the site of inflammation and activated as part of the innate immune response. If the recruited and activated macrophage is unable to remove the inflammatory stimulus efficiently, a further immune response may be triggered, orchestrated by dendritic cells and major histocompatibility complex II. Additional macrophages are recruited to the site, and a chronic inflammatory reaction develops. The macrophages form a tight aggregate around the inflammatory stimulus and may become surrounded by a peripheral cuff of lymphocytes. This inflammatory focus is known as a granuloma.[3]

A wide range of stimuli can result in granuloma formation, including infectious and noninfectious triggers. In some cases, such as sarcoidosis, the trigger is yet to be identified. Infectious stimuli include bacteria such as Mycobacteria, parasites such as Schistosomiasis, and fungi such as Aspergillus. Noninfectious triggers include autoimmune disease, neoplasia, and foreign bodies such as sutures.[3]

Anatomical Pathology

The following histological features may appear on the examination of granulomas:

Macrophage Morphology

Macrophages may undergo various changes within the granuloma, resulting in a range of histological appearances. Activated macrophages may undergo transformation, resulting in an "epithelioid" appearance, with flattened cell shape, ovoid nuclei, and membranes that interdigitate with adjacent cells.[4] The fusion of multiple macrophages together produces multinucleated giant cells (Langhans cells). Macrophages in which oxidized lipids have accumulated are known as foam cells.[5]

Necrosis

Necrosis develops in a subset of granulomas as they mature. Granulomas of specific etiologies are more likely to undergo necrosis than others, though the reasons behind this are not well understood.[5] Tubercular and other infectious granulomas frequently become necrotic, whereas those caused by sarcoidosis and Crohn disease generally do not, even when large and mature. Tuberculous granulomas are particularly associated with caseating granulomas, in which the necrotic area exhibits a "cheese-like" macroscopic appearance. Necrosis is generally thought to be a pathological process and is known to be associated with increased morbidity and transmission in tuberculosis.[1]

Fibrosis

Fibrosis is a prominent feature of many granulomas, which is unsurprising given the chronic nature of the lesions. Fibrosis may be adaptive, for example, as a method of sequestering parasitic eggs, but is more often pathological. Fibrosis can lead to widespread loss of tissue function and may lead, for example, to liver failure in schistosomiasis or reduced lung function in tuberculosis.[5]

Clinicopathologic Correlations

Although the presence of a granuloma may be easily confirmable with microscopic evaluation of a biopsy specimen using H&E staining, determining the underlying cause may be more challenging. Histological features of the granuloma may provide clues as to the underlying pathology. The presence of caseating necrosis, for example, is strongly associated with Mycobacteria species. Some pathogens, such as Coccoides species, might be visible microscopically either in a necrotic region or within the macrophages themselves.[3] A foreign body such as suture material may also be easily identifiable in the center of a granuloma.

Mukhopadhyay et al reviewed 131 resected necrotizing pulmonary granulomas, which were unexplained after the initial histological examination.[6] They were able to determine a cause in 60% of these cases with further evaluation, including cultures, fungal serology, and correlation with clinical and radiological findings.

Other approaches that can improve diagnostic sensitivity include special stains and molecular testing. Grocott methenamine silver (GMS) and Ziehl-Neelsen stains are frequently used to evaluate granulomas to identify fungi and Mycobacteria, respectively.[3]

Clinical Significance

The following are important examples of conditions associated with granuloma formation:

Tuberculosis

Worldwide, tuberculosis accounts for the highest proportion of adult deaths from infectious diseases.[7] The causative agent, Mycobacterium tuberculosis, is an obligate aerobe that can exist within macrophages. The bacterium initially enters through the lungs, where it triggers a granulomatous inflammatory response. The granuloma in pulmonary TB is known as a Ghon focus. The infection is usually contained by the granuloma, though latent infection is common. In the case of immunodeficiency, the primary infection may not be contained within the lungs. It may cause widespread disease, or in latent disease, residual bacteria may reactivate and spread to other areas of the body.[3]

Sarcoidosis

Sarcoidosis is a multisystem granulomatous disease characterized by the development of noncaseating epithelioid cell granulomas with no apparent cause. While the suspicion is that an infectious pathogen is a trigger for granuloma formation in sarcoidosis, a causative antigen remains unidentified despite extensive research. As sarcoid granulomas predominantly affect the lungs and intrathoracic lymph nodes, the suspicion is that the trigger is an inhaled pathogen that the host immune system cannot easily remove.[8] Although the lungs are the most frequently affected organ (95% of patients), granulomas may appear throughout the body, particularly in the skin, lymph nodes, eyes, and liver.[9]

Crohn Disease

Crohn disease is a chronic inflammatory disorder affecting the gastrointestinal tract primarily. Nonnecrotic granulomas are one of the histological hallmarks of Crohn disease, though they are not universally present. Their presence may help differentiate Crohn disease from other inflammatory disorders of the bowel, such as ulcerative colitis. The presence of granulomas has also demonstrated an association with a more severe Crohn disease phenotype.[10]

Granulomatosis With Polyangiitis

Granulomatosis with polyangiitis (GPA) (formerly known as Wegener granulomatosis) is a granulomatous autoimmune vasculitis, primarily affecting small to medium-sized vessels in the kidneys and respiratory tract. Though granulomatous inflammation is one of the key features of GPA, according to the American College of Rheumatology, granulomas are not invariably present on biopsy. Secondary pathological features that may be helpful in diagnosis include the presence of multinucleated giant cells, interstitial collagen alteration, and the presence of a polymorphous inflammatory infiltrate.[11]