Pathology of Granulomatous Pulmonary Diseases

There is significant worldwide variation in the prevalence of pulmonary granulomatous diseases. Mycobacteria are the most common cause of pulmonary granulomas worldwide.⁵  A retrospective review of 500 lung biopsies and resections from 10 institutions in 7 countries⁵  demonstrated that, worldwide, sarcoidosis and infection accounted for 136 of 500 (27%) (range, 12%–36%) and 125 of 500 (25%) (range, 4%–48%) of cases, respectively. Mycobacterial infection was diagnosed in 56 of 300 cases (19%) outside of the US versus 16 of 200 (8%) in the US. Fungal infection was diagnosed in 38 of 200 (19%) of the US cases versus 13 of 300 (4%) in other locations. Pulmonary granulomas in immunosuppressed individuals are almost invariably associated with infection. Distinction between infection and noninfectious etiologies is often the most important role of the pathologist and has the greatest impact on clinical management in most cases. A major problem encountered in the evaluation of granulomas is that a definitive diagnosis cannot be arrived at in a significant percentage of cases^1,4,5,7,8  (Table 1).

A granuloma may be defined as “a compact (organized) collection of mature mononuclear phagocytes (macrophages and/or epithelioid cells) which may or may not be accompanied by accessory features such as necrosis or the infiltration of inflammatory leukocytes.”⁹  Although necrosis and multinucleate giant cells are often present in granulomas, their absence does not disqualify a lesion from being called a granuloma. In some lesions that are recognizable as granulomas, the aggregates of epithelioid cells are not very compact but are loosely arranged. These are referred to as “poorly formed” or “loose” granulomas and are characteristically seen in hypersensitivity pneumonitis (HP), granulomatosis with polyangiitis (GPA), foreign body reactions, lymphocytic interstitial pneumonia, and others.

Initial presentation of persistent and poorly degradable antigens by dendritic cells to T4+ lymphocytes cells results in their transformation to Th1 lymphocytes. This is followed by complex interactions between lymphokines produced by the Th1 lymphocytes and cytokines produced by cells of the mononuclear phagocytic system that result in maturation of monocytes to mature macrophages, which undergo transformation to epithelioid cells resulting in the formation of epithelioid granulomas. Details of current concepts of the immunopathogenesis of epithelioid granulomas in sarcoidosis are well presented by Beijer et al.¹⁰  Compared with macrophages, epithelioid cells have increased secretory and bactericidal capability and reduced phagocytic capability. Epithelioid granulomas may be surrounded by a rim of T8+ suppressor lymphocytes. Granulomas without this lymphocyte rim are referred to as “naked” granulomas. The lymphocytes admixed with epithelioid cells within the granulomas are mostly T4+ lymphocytes. A study using quantitative stereometry determined that in the central part of sarcoid granulomas, lymphocytes outnumber epithelioid cells by a ratio of 2:1 and, therefore, appear to be the predominating cell type¹¹ ; this finding requires confirmation. The function of granulomas as stated by Adams⁹  is they “appear to be the host's response to a high local concentration of a foreign substance which was not destroyed by the acute inflammatory response and which is being contained and destroyed by mononuclear phagocytes in various stages of maturation or activation.”

Multinucleate giant cells, derived from fusion of monocytes, macrophages, and epithelioid cells, rather than by proliferation and nondivision, are present in most granulomas and may assume a variety of appearances. The traditional classification of giant cells as being of Langhans type (peripheral nuclei) and foreign body type (central nuclei) has no diagnostic significance and both types may be present in the same specimen. Giant cells exhibit considerable variation in the location of their nuclei and frequently do not meet the classical criteria for either Langhans or foreign body types.

Whereas epithelioid granulomas are initiated and regulated by the immune system and are a manifestation of Type IV delayed hypersensitivity, the pathogenesis of reactions to particulate foreign materials (ie, foreign body granulomas) probably does not involve the immune system in most cases. In contrast to epithelioid granulomas, foreign body granulomas consist mostly of giant cells and macrophages in varying proportions

Necrosis in granulomas may occur when the granuloma-inciting agent is highly toxic to the macrophages and/or when a vigorous delayed hypersensitivity response is evoked. The term “caseous necrosis,” which refers to the grossly visible, cheese-like appearance, but not to the microscopic appearance, of a necrotic lesion, has proven to be a source of substantial confusion for both pathologists and clinicians. Medlar¹²  stated that:

Although the term “caseous necrosis” has usually been associated with tuberculosis (TB), this type of necrosis may be seen in numerous other conditions, including fungal infections, pulmonary angiitis and granulomatosis, malignant neoplasms, parasitic infections, syphilis, tularemia, typhoid fever, and others. The “caseous” or cheese-like appearance results from incomplete digestion of necrotic tissue. The terms “caseous,” “caseating,” and so on apply only to the gross appearance of some necrotic lesions and have no microscopic counterpart. Therefore, stating that a lesion is a “caseating granuloma” based on its microscopic appearance is inappropriate. Since the modifiers “caseous,” “caseating,” and so on have no diagnostic relevance and may be misleading because of their association with tuberculosis, it is recommended that they not be used in pathology reports to describe microscopic findings. The terms “necrotizing” and “nonnecrotizing” are preferable. Granulomas that exhibit minimal, focal necrosis will be discussed in the section on sarcoidosis.

Epithelioid granulomas may be nonnecrotizing (Figure 1, A) or necrotizing (Figure 1, B); some may exhibit minimal, focal necrosis. Foreign body granulomas are almost always nonnecrotizing. Various subtypes of necrotizing granulomas include palisading, suppurative, necrobiotic, and stellate, suppurative granulomas. Fibrin-ring and spindle-cell granulomas/pseudotumors are unusual types of nonnecrotizing granulomas. Spindle-cell granulomas/pseudotumors, usually caused by Mycobacterium avium complex (MAC) infection in immunocompromised patients, contain multitudes of acid-fast bacilli (AFB). Disease associations of granuloma subtypes are summarized in Table 2. Microscopic descriptions of the granuloma subtypes are summarized in Table 3.

Nonnecrotizing granulomas usually have a noninfectious etiology. However, some infectious diseases may also present with nonnecrotizing granulomas. For example, nonnecrotizing granulomas have been reported to be the only biopsy finding in 14 of 42 cases (33%) of TB.⁸  The most common pulmonary diseases typically presenting with nonnecrotizing granulomas are sarcoidosis, hypersensitivity pneumonitis, chronic beryllium disease, and foreign body granulomas.

Necrotizing granulomas usually have an infectious etiology, most caused by Mycobacteria and fungi. Exceptions include rheumatoid nodules, GPA, and the necrotizing sarcoid granulomatosis (NSG) variant of sarcoidosis. Palisaded necrotizing granulomas in the lungs are almost always rheumatoid nodules but can also be caused by a variety of infections.¹³ 

A variety of inclusions may be present within the giant cells of granulomas. They are nonspecific and are not diagnostic of any disease entity.

Schaumann (conchoidal) bodies, are large (25–200 μm), concentrically lamellated, calcific bodies that are present predominantly within giant cells in the granulomas of up to 50% of cases of sarcoidosis but also occur, and may be prominent, in hypersensitivity pneumonitis, berylliosis, and other granulomatous diseases¹⁴  (Figure 2, A). They are composed of a mucopolysaccharide matrix impregnated with calcium salts and some iron. As the bodies enlarge, cell rupture may occur resulting in their extrusion into the extracellular space. A crystalline component that is colorless, intensely birefringent, and spiculated may be seen frequently, either alone, or in combination with the Schaumann body (Figure 2, A). As many as 70% of Schaumann bodies have crystals associated with them ranging in size from 1 to 20 μm. They stain for iron and calcium salts; the majority are calcium oxalate admixed with calcium carbonate.¹⁵  It is likely that the crystals act as a nidus for the formation of the Schaumann body. Jones Williams¹⁶  reported finding crystalline and conchoidal bodies in 88% of cases of sarcoidosis, 62% of chronic beryllium disease, and 6% of tuberculosis cases.

Crystalline bodies occurring without Schaumann bodies have been reported in 41% of cases of sarcoidosis, 15% of chronic beryllium disease, and 3% of tuberculosis¹⁶  (Figure 2, B). Histochemical analysis of the crystalline inclusions indicates that the majority are composed of calcium oxalate and calcium carbonate.¹⁵ 

Asteroid bodies are visually striking stellate inclusions that are found mostly within the giant cells of foreign body granulomas (Figure 2, C). They may also be present in sarcoidosis and in a variety of other granulomatous diseases, including tuberculosis, leprosy, histoplasmosis, schistosomiasis, and others.¹⁷  They vary from 5 to 30 μm in size and contain as many as 30 or more rays radiating from a central core. Although they may be seen in granuloma-containing tissues in 2% to 9% of patients with sarcoidosis,^14,17  there is a widely held misconception that the presence of asteroid bodies supports or indicates the diagnosis of sarcoidosis. Ultrastructural features of asteroid bodies were reported by Cain and Kraus.¹⁸ 

Slit-like cholesterol inclusions may be seen within the giant cells of granulomas of varied etiology (Figure 2, D). They may be present in as many as 17% of cases of sarcoidosis¹⁴  and occasionally in other granulomatous conditions. Their pathogenesis is uncertain, and they have no diagnostic significance.

Tiny, spindle-shaped bodies, called Hamazaki-Wesenberg bodies (Figure 2, E), with rare exceptions, are located extracellularly and do not present as inclusions in giant cells. They are frequently seen in the granulomatous lymph nodes from patients with sarcoidosis and in nongranulomatous lymph nodes from patients with sarcoidosis and a variety of other disorders.^19,20  They are oval or spindle-shaped and approximately the same diameter as a resting lymphocyte. They appear yellow-brown in sections stained with hematoxylin-eosin (H&E) (Figure 2, E). The yellow-brown pigment has the histochemical characteristics of lipofuscin. They have been reported in 11% to 68% of sarcoid lymph nodes and in 11.5% to 15% of nongranulomatous lymph nodes, which were either normal or involved with various diseases.^14,21  When stained with the Grocott methenamine silver stain they often exhibit an appearance that is similar to yeast-like budding (Figure 2, F) and can easily be mistaken for fungi (budding yeasts). Positive staining with the Ziehl-Neelsen (ZN) stain, and absence of a host response readily facilitate their distinction from fungi. Ultrastructural examination shows that the Hamazaki-Wesenberg bodies are giant, intracellular, and extracellular lysosomes and residual bodies.¹⁴ 

Approximately 25% of pulmonary granulomatous lesions are caused by an infectious agent; Mycobacteria and fungi are the cause of almost all. Cultures and polymerase chain reaction (PCR) are most likely to detect mycobacterial infection, whereas the diagnosis of most pulmonary fungal infections is based on histology.⁵  Nevertheless, AFB and fungal stains should be performed and carefully examined in all cases where the causative agent is not identified on the H&E-stained slides. Culture is the “gold standard” for identification of infectious agents in tissue specimens. However, culture is, unfortunately, not performed in most cases.

A lung biopsy is usually not required to diagnose TB because the diagnosis can typically be made based on exposure history, symptoms, and radiologic findings, ideally supplemented by the finding of AFB in sputum smears.²²  If possible, the presence of Mycobacterium tuberculosis (MTb) should be documented by cultures or PCR. Lung biopsies are usually performed in those individuals presenting radiographically with nodules or masses, which may raise concern about a possible neoplasm.

The usual biopsy finding in TB is necrotizing granulomas (Figure 1, B). However, nonnecrotizing granulomas have been reported to be the only biopsy finding in up to 33% of cases⁸  and may be the only subtype of granuloma identified, particularly in small biopsies with few granulomas. Occasionally, only necrotic tissue is present.

The ZN, Kinyoun acid-fast stain, and fluorochrome staining using auramine O with or without rhodamine are routinely used to identify AFB in tissue; neither can distinguish MTb from nontuberculous Mycobacteria (NTM). Disadvantages of the ZN stain are its low sensitivity ranging from 8.3% to 60% in culture positive cases^12,23,24  and examination is very time-consuming and prone to error. Its specificity for detecting Mycobacteria is high, approaching 100%. In 20 culture-proven mycobacterial infections, Mycobacteria were identified histologically in only 4 using ZN, Fite, and auramine-rhodamine (AR) stains; none of the stains were found to be superior.⁶  AFB are most likely to be detected in areas of necrosis and within giant cells. Jain et al²²  have compiled a list of tips for identifying AFB in necrotizing granulomas. These include staining at least 2 blocks exhibiting necrosis, selecting the blocks with the greatest amount of necrosis, and searching within areas of necrosis where the yield is greatest using a ×40 or oil immersion objective. False-positive AFB stains can result from contamination of water used to prepare the stains with NTM.²⁵  Filtered or distilled water should be used to prepare these stains.

Auramine O or AR fluorescent stains are widely used for identification of AFB. Sensitivity is generally reported to be greater than the ZN stain and time required for examination is shorter. However, whether they are more or less specific than ZN remains controversial. In some laboratories, the AR stain is used for screening and ZN is subsequently performed on AR positives. The requirement for a fluorescent microscope makes this method unavailable for many pathologists. Because of low sensitivity, a negative AFB stain does not exclude mycobacterial infection.

MTb-specific DNA fragments can be identified by PCR. Several studies of the results of PCR performed on formalin-fixed, paraffin-embedded tissue obtained from MTb culture–positive patients reported sensitivity ranging from 58% to 100% (median 89%) and specificity ranging from 92% to 100% (median 97%).^23,26–28  Thus, PCR appears to compare favorably with culture for the diagnosis of tuberculosis. It can also differentiate MTb from NTM. A major advantage of PCR is the relatively short turnaround time compared with culture, which can take up to 12 weeks, and its ability to distinguish between MTb and NTM.

There are a small number of reports of diagnosis of TB in formalin-fixed, paraffin-embedded tissue using immunohistochemistry with an anti-MTP64 antibody.^29,30  This technique does not appear to be in widespread use currently.

Next-generation sequencing can provide whole bacterial genome sequences in a short timeframe (hours-days), at a relatively low cost and, increasingly, without the need for culture.³¹  Although next-generation sequencing can be used to identify MTb in culture isolates and clinical specimens, it cannot currently be used to identify MTb in formalin-fixed, paraffin-embedded tissue.

NTM are an important cause of pulmonary and extrapulmonary infections. The subject of NTM lung disease is well reviewed by Jain et al²²  and El-Zammar and Katzenstein.²  NTM lung disease is mostly caused by MAC, a group of Mycobacteria comprising M intracellulare and M avium that are grouped together because they commonly infect humans simultaneously. Its radiologic features overlap with those of pulmonary TB. The terms “atypical Mycobacteria” and “Mycobacteria other than tuberculosis” have also been used in the past for these organisms. Other NTMs, such as M kansasii, M fortuitum, M chelonae, M abscesus, M gordonae, M xenopi, and others can cause pulmonary disease, but much less frequently than MAC.²²  In this review, the term NTM encompasses all the NTM mentioned above, but especially MAC because they are the most common. There is significant geographic variation in types of NTM associated with pulmonary disease.²  MAC followed by M kansasii is most frequent in the US.²  In immunosuppressed patients, NTM infection commonly presents microscopically as sheets of large, foamy histiocytes laden with innumerable AFB; granulomas are usually absent. NTM pulmonary infections typically occur in immunocompetent patients and are characterized by necrotizing granulomas containing AFB that are indistinguishable from MTb. Necrotizing granulomas have also been reported to occur with NTM infection in immunocompromised patients.³²  NTM are the most common cause of spindle-cell granulomas, a rare type of granuloma containing innumerable AFB; they can also be caused by MTb.

Because NTM are ubiquitous in the environment, especially in soil and water, they are a common contaminant of sputum and, to a lesser extent, of bronchoalveolar lavage specimens and bronchial washings even if tap water is not used. When NTM grow in culture of tissue the question arises as to whether they represent true infection or contamination. Because lung biopsy and resection specimens are considered to be sterile, a positive culture of NTM from these specimens is considered clinically significant. Identification of AFB in granulomas in the tissue from which a positive culture was obtained is a further indication of true infection, because it shows that the microorganisms are in a granuloma.²²  The combination of culture positivity for NTM from lung tissue and the presence of granulomas in that tissue with or without AFB being demonstrated, is considered sufficient to establish the diagnosis of NTM pulmonary disease.^33,34  In cases where AFB are identified in pulmonary granulomas and culture is negative, PCR can be used to distinguish between MTb and NTM.

Granulomas are present in infections caused by many species of fungi, including Histoplasma, Cryptococcus, Blastomyces, Coccidioides, Paracoccidioides, and others. Candida and Aspergillus usually cause acute inflammation but are also capable of inciting granulomas.^35,36  Fungal granulomas are often suppurative. Many fungi are easily seen with routine H&E staining, but fungal morphology is best appreciated with the Grocott methenamine silver stain. Mucicarmine stains the mucinous capsule of Cryptococcus and helps to distinguish it from Blastomyces that is about the same size but has a relatively thick, refractile cell wall and exhibits broad based budding. Nonencapsulated cryptococci are not stained by mucicarmine. In the author's experience, negative fungal stains are rare in fungal infections. However, in granulomatous Pneumocystis infection, the cyst forms of Pneumocystis jiroveci may be rare and difficult to identify; Grocott methenamine silver–stained step sections may be needed. Although the “gold standard” for fungal identification is culture, fungi that present as yeast forms in tissue can usually be identified with a high degree of confidence based on morphologic features, including size, presence, or absence of budding and pseudohyphae, type of budding, presence of endospores, and presence of a refractile cell wall. These include Histoplasma, Candida, Cryptococcus, Blastomyces, Coccidioides, Paracoccidioides, and others. On the other hand, the many types of fungi that present with hyphal forms have overlapping morphology and, with some exceptions, cannot be accurately diagnosed based on morphology alone; culture is required. Because the detailed morphologic and diagnostic features of the numerous pathogenic fungi are beyond the scope of this review, readers are referred to publications that provide detailed coverage of fungal morphology.^3,37 

A variety of nonmycobacterial bacteria may produce granulomatous inflammation, which is usually necrotizing and often suppurative. These include Brucella spp, Actinomyces spp, Francisella tularensis, Bartonella henselae, Nocardia spp Yersnia enterocolitica, Listeria monocytogenes, Burkholderia pseudomallei (melioidosis), Coxiella burnetti, and others^2,38  (Table 2). Although Gram and silver stains may be helpful in some cases, diagnosis is usually based on identification in cultures.

Pulmonary granulomas may be produced by Dirofilaria immitis (dog heartworm), and the ova of Schistosoma spp and Paragonimus westermanii.

Dogs, as well as other mammals, the natural hosts, harbor the adult form of D immitis in their right ventricle where they produce microfilariae that are shed into the bloodstream. Mosquitos, the intermediate hosts, become infected with microfilariae when they bite the natural host. Microfilariae develop into L3 larvae in the mosquito. When humans are bitten by an infected mosquito, the L3 larvae develop into immature adults in subcutaneous tissue and eventually migrate to the right ventricle where they die and are swept into the pulmonary arteries. They then embolize to the lungs where they produce infarcts surrounded by granulomatous inflammation with or without eosinophilia. These lesions most often appear as an incidental finding of a solitary, well-circumscribed lesion on radiologic studies in an asymptomatic patient.²  The immature, dead worms are found within a necrotic blood vessel(s) located in the necrotic tissue (Figure 3), but they are sometimes difficult to find and step sections may be needed. They appear as large, round-to-oval structures averaging 200 μm in diameter. They have a thick (5–25 μm), multilayered cuticle that contains transverse striations. In old lesions the worms may calcify.² 

Ova of Paragonimus spp in lung tissue and ova of Schistosoma spp in pulmonary capillaries elicit a granulomatous reaction. The ova are usually easily seen.

Sarcoidosis is a common disease of unknown etiology with a worldwide distribution. It involves the lungs and intrathoracic lymph nodes in almost all cases. There is evidence of lung involvement even in cases that present radiographically with hilar lymphadenopathy only.³⁹  It is the most common granulomatous disease involving the lungs in areas of the world where the incidence of TB is low. The pathologic features of sarcoidosis have been the subject of several comprehensive reviews.^40–44  It appears to be triggered by a variety of unidentified antigens that can provoke granuloma formation in persons who are genetically predisposed to mount an exaggerated immune response. Extrathoracic involvement occurs in a small percentage of patients and may involve any organ system. An extensive description of sarcoidosis was published in 1999,⁴⁵  but there is not yet a precise definition of this disease.

Pathologists almost always encounter the granulomas of sarcoidosis in bronchial, transbronchial lung, and intrathoracic lymph node biopsy specimens. They are occasionally seen in needle core biopsies of nodular lung lesions. Granulomas have been reported in endobronchial biopsies in 40% to 71% of patients.^46–50  In bronchial biopsies that do not exhibit well-formed granulomas, the only finding may be scattered giant cells with or without Schaumann bodies or extracellular Schaumann bodies alone. Transbronchial lung biopsy is most frequently used to demonstrate granulomas in those suspected to have sarcoidosis. Overall sensitivity ranging from approximately 50% to more than 90% has been reported.^46–50  The yield of granulomas is highest in those patients who have radiographic evidence of lung involvement and is directly proportional to the number of biopsy specimens obtained. Biopsy of peripheral and intrathoracic lymph nodes may also be performed where appropriate. In cases of suspected sarcoidosis in which granulomas are not found using the above-mentioned biopsy procedures, surgical lung biopsies or transbronchial cryobiopsies may be performed. Jacob et al⁵¹  reported a sensitivity of 74% for detecting granulomas in 27 patients with suspected sarcoidosis with transbronchial lung cryobiopsies. Wedge resections or even lobectomies may occasionally be performed in cases presenting with single or multiple nodules that are suspicious for neoplasm.

Nonspecific chronic interstitial inflammation representing the “alveolitis” of sarcoidosis appears to be the precursor of granuloma formation in the lungs; it was reported as a predominant or prominent finding in two-thirds of open lung biopsy specimens.⁵²  It is rarely seen in small bronchial and transbronchial biopsy specimens.

A very characteristic feature of sarcoidosis is the tendency for the granulomas to localize around bronchovascular bundles and fibrous septa (Figure 4). This is referred to as lymphangitic or perilymphatic localization because a lymphatic network is associated with these structures. Because the granulomas are usually localized to the lungs and peribronchial and mediastinal lymph nodes, it is likely that the inciting antigens, although unidentified, are tiny respirable particles that, after entering the lungs, soon enter the pulmonary lymphatics through which they are transported to the lymph nodes. The lymphangitic distribution of granulomas is rarely seen in small, nonsurgical biopsy specimens; it may be evident in cryobiopsies, surgical lung biopsies, and in autopsy lungs. Berylliosis, whose microscopic appearance may closely resemble that of sarcoidosis, and pulmonary lymphomas may also exhibit a lymphangitic localization.

The granulomas of sarcoidosis are usually nonnecrotizing (Figure 1, A). They may be discrete but tend to become confluent. Stains for AFB and fungi should be performed in all cases to evaluate the possibility of infection. Airways and pleura are often involved but pleural effusions occur infrequently. The granulomas are often uniform in appearance and are mostly located in the interstitium but are also occasionally seen within airspaces (Figure 5, A). The epithelioid cells are occasionally spindle shaped. In older cases, the granulomas may exhibit a peripheral rim of hyalinization or fibrosis that tends to become thicker over time. In some longstanding cases the granulomas may be completely replaced by scar tissue, sometimes referred to as “tombstone lesions,” and the only indication of a preexisting granuloma is the oval shape of the scar. Calcification may occur in granulomatous lesions that have undergone extensive fibrosis.

Giant cells, which may contain inclusions, are usually present within the granulomas. Schaumann bodies are the most frequently encountered inclusions; asteroid bodies, crystalline inclusions, and cholesterol crystals may also be found. These inclusions are nonspecific and nondiagnostic and may be seen in granulomas of any etiology. Although Hamazaki-Wesenberg bodies are most frequently seen in granuloma-containing lymph nodes in sarcoidosis, they are rarely seen in the lungs and within granulomas.⁴² 

Granulomatous vasculitis was reported as a predominating or prominent finding in two-thirds of 128 open lung biopsies⁵³  and in 100% of 40 autopsy lungs⁵⁴  (Figure 5, B and C). Venous involvement is more common than arterial involvement; lymphatic vessels are frequently involved. Elastic tissue stains often reveal focal destruction of elastic laminae (Figure 5, C). Fibrinoid necrosis, thrombosis, and aneurysms are not features of the granulomatous vasculitis in sarcoidosis. The vasculitis can usually be identified with routine H&E staining. However, involved blood vessels in areas of confluent granulomas and or fibrosis are often obscured, and elastic tissue stains may aid in their identification.

Although granulomatous pulmonary vasculitis is most often seen in sarcoidosis, it is a nonspecific lesion that is not diagnostic of sarcoidosis. It may be seen in a variety of conditions, including tuberculosis, GPA, the NSG variant of sarcoidosis, berylliosis, foreign body embolization in intravenous drug abusers, schistosomiasis, and seminomas.

Sarcoidosis is an uncommon cause of pulmonary hypertension. A small number of case reports strongly suggest that in some sarcoidosis patients with pulmonary hypertension the cause may be marked narrowing of pulmonary veins secondary to granulomatous vasculitis.^55,56 

Although the granulomas of sarcoidosis have traditionally been considered to be nonnecrotizing, necrosis within granulomas may be seen in 6% to 35% of cases.^{17,40,57–59}  The necrosis is usually focal, involves a small percentage of the granulomas and has variously been described as fibrinoid, granular, eosinophilic granular, and coagulative (Figure 5, D and E). Apoptotic nuclei of epithelioid cells and lymphocytes are often seen adjacent to and within the small foci of necrosis (Figure 5, D) but may also been seen in granulomas without necrosis.⁶⁰  Rare cases of classical sarcoidosis may exhibit larger and even confluent areas of necrosis^42,61  (Figure 5, F). Suppurative necrosis is a rarity in sarcoidosis.

Based on a review of 4 decades of the world's literature, there is strong evidence that the lesion that was described by Liebow⁶²  in 1973, which he called NSG, is a variant of sarcoidosis and is likely equivalent to nodular sarcoidosis.⁶³  The finding of granulomas that are usually confluent, necrosis of varying amounts involving granulomas, and granulomatous vasculitis (Figure 6, A through C) are required for the diagnosis. Because the microscopic features of NSG overlap with those of infectious diseases, especially TB and fungal infections, NSG should not be diagnosed unless reasonable efforts to exclude an infectious etiology, including cultures, are undertaken. NSG is always diagnosed in surgical lung biopsies or resections. It was recommended that the use of NSG as a diagnostic term be discontinued and replaced by “sarcoidosis with an NSG pattern.” It was suggested that “our concept of sarcoidosis should now be expanded to recognize that there is a continuous spectrum of necrosis ranging from minimal to extensive.”⁶³ 

The diagnosis of sarcoidosis requires that other causes of granulomas be reasonably excluded and clinical, radiologic, and laboratory findings should be compatible with sarcoidosis. The diagnosis should be the result of multidisciplinary coordination and never be made by the pathologist based on microscopic findings alone. Sarcoidosis should be diagnosed by the patient's primary care physician or pulmonologist after considering and correlating all the data supplied by the various disciplines. The biopsy report should specify the presence or absence of granulomas and the results of AFB and fungal stains. Terms such as “consistent with” or “suggestive of sarcoidosis” should be avoided because they may be misleading. A study emphasizing this point sought to determine the frequency of positive microbiologic cultures in 92 adult patients with transbronchial biopsy specimens exhibiting nonnecrotizing granulomas and negative histochemical stains for microorganisms.⁶⁴  Positive cultures for Mycobacteria and fungi were obtained in specimens from 10 patients (11%); Mycobacteria were cultured in 9 of 10 and fungus (Histoplasma) in 1 of 10. If cultures had not been performed, all 92 patients would likely have been diagnosed with sarcoidosis.

Berylliosis is a rare occupational lung disease caused by exposure and development of Type IV hypersensitivity to beryllium or beryllium compounds. Those at risk are involved in beryllium extraction and production, metal machining, and working in the computer, aerospace, ceramics, and electronics industries. Although the microscopic appearance has been described as closely mimicking sarcoidosis, including nonnecrotizing granulomas, hilar lymph node involvement, and lymphangitic distribution of granulomas,⁶⁵  there are some differences. Interstitial inflammation and poorly formed granulomas, usually not a feature of sarcoidosis and resembling hypersensitivity pneumonitis, may be helpful in distinguishing berylliosis from sarcoidosis.^66–68  The diagnosis of berylliosis is highly dependent on an occupational history of exposure and can be confirmed by demonstrating the presence of beryllium in tissues and/or body fluids and/or sensitization of lymphocytes to beryllium. Other metallic dusts or fumes including aluminum, titanium, zirconium, and others, may also cause pulmonary granulomas.⁴² 

HP, also known as extrinsic allergic alveolitis, represents an immune-mediated reaction to a variety of inhaled antigens and chemicals. Comprehensive reviews of HP^69,70  report many antigens and chemicals, and their sources, which have been associated with HP. The most common causes of HP are microbial and avian antigens. Farmer's lung, caused by bacterial and fungal antigens, and pigeon breeders/bird fanciers' lung, caused by avian antigens, are the 2 most common forms of HP. Cigarette smoking is reported to be associated with a decreased risk of developing HP as well as reduced severity.⁷¹ 

HP has traditionally been classified as occurring in acute, subacute, and chronic forms, although there are no widely accepted criteria to distinguish these various forms.⁶⁹  In the acute form symptoms arise within hours after exposure, tend to peak in 18 to 24 hours, and then subside if the triggering agent is removed.⁷⁰  Persons with acute HP almost never have a lung biopsy. In the small number of reported cases in which a lung biopsy was performed, the findings are basically those of acute lung injury⁷² ; small granulomas were present in some cases.

Most lung biopsies are obtained from patients with the subacute form of HP (SHP). Although the diagnosis of HP can occasionally be made or suspected on examination of transbronchial lung biopsies, surgical lung biopsies, or cryobiopsies are usually required for diagnosis.

The major histologic findings in SHP are as follows:

1. Chronic interstitial inflammation that appears temporally uniform and is accentuated around small airways (Figure 6, D). Lymphocytes predominate; plasma cells are frequently present, but eosinophils are rare.

2. Bronchiolitis (Figure 6, E) that may or may not be accompanied by peribronchiolar metaplasia, bronchiolectasis, granulomas, and fibrosis of bronchiolar walls.

3. Small, poorly formed (loose) nonnecrotizing granulomas (Figure 6, D and E) and/or individual, scattered giant cells are present in approximately 70% of cases.³⁴  The granulomas are usually located in the interstitium or close to, or within, small airways. Intra-alveolar granulomas and giant cells can also be seen.

4. Schaumann bodies and/or cholesterol crystals may be seen within the cytoplasm of giant cells; they are nonspecific and have no diagnostic value. The finding of individual, extracellular Schaumann bodies is evidence of preexisting granulomas. Other nonspecific inclusions in giant cells may be present with lesser frequency than Schaumann bodies.

5. Foci of organizing pneumonia are frequently present (Figure 6, F).

6. Obliterative bronchiolitis may be present in some cases.

7. Lymphoid follicles may be present in some cases.

8. In a minority of cases, SHP may present as the cellular variant of nonspecific interstitial pneumonia.

9. Small foci of endogenous lipid pneumonia may be present secondary to bronchiolar obstruction.

The triad of interstitial pneumonitis, cellular bronchiolitis, and poorly formed granulomas is seen in 80% of well-documented cases of SHP.⁷³ 

A history of exposure to respirable antigens or chemicals is helpful when correlated with histologic and radiographic findings. However, failure to identify a relevant antigenic exposure is not unusual even when the histologic findings are typical of SHP. The most important differential diagnostic consideration is distinguishing SHP from sarcoidosis (Table 4). Nonspecific interstitial pneumonia might be a diagnostic consideration in those unusual cases of SHP where granulomas or giant cells are not found. However, the interstitial inflammation in nonspecific interstitial pneumonia is usually diffuse and not localized around small airways and there is no small airway inflammation or foci of organizing pneumonia. Lymphocytic interstitial pneumonia is usually characterized by dense interstitial lymphocytic or lymphoplasmacytic infiltrates and nodules, sometimes exhibiting germinal centers, which do not exhibit peribronchiolar localization. Poorly formed granulomas, as seen in many lymphoproliferative disorders, may be present within the lymphocytic infiltrates.

Detailed description of the pathologic findings in chronic hypersensitivity pneumonitis (CHP) are presented in a comprehensive review by Churg et al.⁷⁴  CHP presents as a chronic, fibrosing form of interstitial pneumonia; features of SHP may be present as well. Fibrosis is required for the diagnosis of CHP.⁷⁴  Lung biopsy findings in CHP need to be distinguished from those of a variety of idiopathic interstitial pneumonias, a challenging task requiring multidisciplinary coordination. CHP may have histologic features that overlap with usual interstitial pneumonia, including patchy fibrosis, subpleural/paraseptal localization, fibroblastic foci, and honeycombing.⁷⁴  Separation of usual interstitial pneumonia from CHP is crucial because usual interstitial pneumonia is treated with antifibrotic agents, whereas CHP is treated with immunosuppressive agents.⁷⁴  Those with CHP have a significantly better prognosis after lung transplantation than those with usual interstitial pneumonia, probably because they are less likely to develop bronchiolitis obliterans.⁷⁵  The following histologic findings tend to favor CHP over usual interstitial pneumonia: upper zone, peribronchiolar, and bridging fibrosis; giant cells, granulomas (usually rare), prominent interstitial inflammation, and organizing pneumonia.⁷⁴  Despite the above-mentioned criteria, the diagnosis of CHP is difficult and often controversial.

Hot tub lung is associated with exposure to MAC when present in aerosols from indoor hot tubs/spas as well as swimming pools, showers, humidifiers, and wind instruments.^3,70,76,77  High-resolution computerized tomography findings are usually diffuse centrilobular nodules and/or ground glass opacities. Cavitary nodules have also been reported. It is generally considered to be a form of HP, but because MAC has been cultured from lung tissue⁷⁷  there is uncertainty as to whether it represents an infection, hypersensitivity, or a combination of both.⁷⁰  Biopsy usually shows nonnecrotizing granulomas that may be localized around airways; necrotizing granulomas are sometimes present. Granulomas are present in the lumens of small bronchioles³  as well as in the interstitium and airspaces (Figure 7). The granulomas are usually larger and more well-formed than those seen in nonmycobacterial HP. Organizing pneumonia is often present. AFB stains of granulomas are usually negative but may be positive.³  Lymphangitic distribution of granulomas and granulomatous vasculitis are characteristic features of sarcoidosis that are not seen in hot tub lung. Although it has been stated that the exclusive interstitial location of granulomas in sarcoidosis is a reliable distinguishing feature between sarcoidosis and hot tub lung,³  in the author's experience, airspace granulomas also occur in sarcoidosis (Figure 5, A). Hot tub lung can be suspected, but not diagnosed, based on biopsy findings alone. In addition to histologic findings, definitive diagnosis requires a history of indoor hot tub use or exposure to aerosolized water contaminated with MAC.

GPA, formerly Wegener granulomatosis, is a rare systemic, immune-mediated inflammatory process of undetermined etiology, mostly occurring in adults. The lesions are characterized by necrosis, necrotizing vasculitis, and granulomas that predominantly involve the upper and lower respiratory tract and kidneys. Head and neck involvement are most common followed by lung involvement that might be the only presenting feature; hilar lymph nodes are usually not involved. Radiographic appearance at presentation is usually multiple nodular or mass lesions that frequently exhibit cavitation or, rarely, a solitary nodule with or without cavitation. Diffuse airspace disease seen on computed tomography examination usually reflects hemorrhage from capillaritis.

A surgical biopsy may be required in cases with atypical clinical presentations. The most frequent atypical scenario is the presence of solitary or multiple nodules with or without cavitation or cavitary infiltrates in patients without evidence of multisystem involvement (localized/limited GPA).⁶  GPA limited to lung involvement is common.

The major histologic findings are granulomatous inflammation, necrosis, and vasculitis accompanied by a mixed inflammatory cell infiltrate and variable amounts of fibroblastic proliferation. Organizing pneumonia is a frequent finding and may occasionally be the predominating finding in biopsy specimens. Necrosis appears as microabscesses, large, geographic zones of necrosis (Figure 8, A) that often have a “dirty” appearance due to the presence of neutrophils and necrotic debris and necrosis of collagen. The granulomatous inflammation may consist of scattered single or loose clusters of giant cells, small suppurative granulomas (Figure 8, B), giant cells surrounding microabscesses, foci of geographic necrosis surrounded by palisaded histiocytes, and microgranulomas consisting of small foci of palisaded histiocytes arranged in a cartwheel fashion and surrounding a minute focus of eosinophilic necrosis (Figure 8, C). Granulomatous inflammation is sometimes centered on bronchioles; if it is a prominent finding it may be confused with bronchocentric granulomatosis. Well-formed, compact granulomas as occur in sarcoidosis are rarely seen; if present, a diagnosis other than GPA should be considered.

Vasculitis may involve arteries, veins (Figure 8, D and E), and capillaries (Figure 8, F) and should only be diagnosed in inflamed areas outside of areas of necrosis. Vasculitis may involve the entire vessel wall or involvement may be focal (Figure 8, D). Vasculitis in GPA may be nonnecrotizing or necrotizing. The former, which is characterized by vascular infiltration by lymphocytes and other inflammatory cells, is not considered to be a diagnostic feature of GPA.^2,3  Necrotizing vasculitis, required for the diagnosis of GPA^2,3 ; is characterized by suppurative necrosis, suppurative granulomas, fibrinoid necrosis, or the presence of karyorrhectic neutrophils within the vessel wall^2,3  (Figure 8, D and E). Destruction of elastic laminae is best visualized with an elastic tissue stain. Inflammation may be transmural or involve only the intima. Necrotizing granulomatous vasculitis may be seen occasionally, however, in most cases of GPA the vasculitis is nongranulomatous. Capillary involvement (capillaritis) is characterized by neutrophils, usually exhibiting karyorrhexis, and fibrinoid necrosis within the capillary walls (Figure 8, F). Capillaritis is not a specific finding for GPA but may be the only finding in a biopsy specimen. Patients presenting with capillaritis often have severe hemoptysis.

GPA uncommonly presents with microscopic variants that are characterized by the predominance of a single feature that may make diagnosis difficult. These are the bronchocentric, organizing pneumonia and capillaritis with hemorrhage variants.³ 

Diagnosis of GPA is significantly aided by the serum antineutrophilic cytoplasmic antibody (ANCA) test. The 2 immunofluorescence patterns observed are the cytoplasmic (C-ANCA), the most common, and the perinuclear (P-ANCA) pattern. C-ANCA and P-ANCA are directed against proteinase 3 and myeloperoxidase, respectively. Both may occur in GPA but the C-ANCA pattern is by far the most common, having been reported in 84% to 99% of active, generalized cases and in 60% of localized cases.⁷⁸  There are no significant differences in the lung biopsy findings of those expressing C-ANCA or P-ANCA.^79,80  The P-ANCA pattern is more often seen in microscopic polyangiitis, polyarteritis nodosa, and eosinophilic granulomatosis with polyangiitis.

Before making a diagnosis of GPA it is mandatory to exclude the possibility of infection using AFB and fungal stains and, ideally, cultures. The diagnosis of GPA requires multidisciplinary collaboration and cannot be made or excluded based on the presence of C-ANCA positivity alone. C-ANCA may be negative when involvement is limited to the lungs and there may be false positives.

Eosinophilic granulomatosis with polyangiitis, formerly Churg-Strauss syndrome, is a multisystem disorder mostly affecting adults and belonging to the small-vessel ANCA-associated vasculitides. It is characterized by eosinophil-rich and granulomatous inflammation often involving the respiratory tract, and necrotizing vasculitis, predominantly involving small-sized to medium-sized vessels.⁸¹  It is associated with asthma in 95% of patients and eosinophilia. The lungs are one of the most frequently involved sites. Aside from asthma, patients may present with sinusitis, allergic rhinitis, and nasal polyposis. The diagnosis is based mostly on the following clinical criteria: asthma, eosinophilia, neuropathy, nonfixed pulmonary infiltrates, paranasal sinus abnormalities, and a biopsy containing a blood vessel with extravascular eosinophils.⁸²  P-ANCA is present in approximately 70% of cases.⁸³  Biopsies are usually obtained from extrapulmonary sites, especially skin. In the lungs a combination of eosinophilic pneumonia, granulomatous inflammation, and necrotizing vasculitis is considered pathognomonic, but that combination is present infrequently.^83,84  Granulomas are usually necrotizing and often appear as small groups of palisaded histiocytes surrounding foci of central necrosis. The vasculitis involves arteries and veins and exhibits either granulomatous inflammation with or without prominent giant cells or a nongranulomatous mixed chronic inflammatory cell infiltrate with many eosinophils.²  Fibrinoid necrosis of blood vessel walls in often seen (Figure 8, G). Eosinophilic pneumonia may occur alone or may accompany necrotizing vasculitis, but usually without granulomatous inflammation²  (Figure 8, H).

Pulmonary rheumatoid nodules are rare, representing only 0.2% of cases of pulmonary granulomatous diseases.⁵  The pulmonary nodules are palisaded granulomas with a central area of eosinophilic or basophilic necrosis surrounded by palisaded histiocytes; they are identical in appearance to those encountered in subcutaneous tissue. Most patients also have subcutaneous nodules. The lung nodules are usually multiple and peripheral, subpleural location is common² ; the pleura may also be involved. There may an associated nonnecrotizing vasculitis. The presence of multinucleate giant cells, neutrophils, and eosinophils admixed with the palisaded histiocytes would be unusual and should suggest another diagnosis.²  As with any necrotizing granulomatous condition, the possibility of infection should be excluded with special stains for microorganisms and cultures, if possible. The diagnosis of pulmonary rheumatoid nodule can be made with confidence if an infectious etiology can be reasonably excluded and the patient is known to have rheumatoid disease. If the history is not known or if the patient is known not to have rheumatoid disease, the possibility of rheumatoid nodule can be included in the differential diagnosis that would also include infection, GPA, and others (Table 2).

Bronchocentric granulomatosis (BG) is characterized by necrotizing granulomas that primarily involve and destroy bronchioles. Approximately half of the cases occur in asthmatics with allergic bronchopulmonary fungal disease, mainly aspergillosis, associated with blood and tissue eosinophilia.⁸⁵  In these patients, BG is generally considered to be a manifestation of fungal hypersensitivity.^85,86  Eosinophilic pneumonia and/or mucoid impaction of bronchi, both additional manifestations of allergic bronchopulmonary fungal disease, may also be present. Except in rare cases, fungi are not found in the granulomas. In those cases where fungi are found, they are usually present in the necrotic center where the bronchiolar lumen is located. The etiology of the nonasthmatic cases is varied and, in many cases, unknown; blood and tissue eosinophilia are usually absent.

The necrotizing granulomas are centered on bronchioles (Figure 9) and there is often palisading of histiocytes. There may be partial or complete involvement of the circumference of the bronchiole. The presence of small remnants of bronchiolar epithelium in the center of the granuloma provides good evidence for bronchiolar involvement. If there is no bronchiolar epithelium within the granuloma, location of the granuloma next to a pulmonary artery or arteriole strongly suggests that the granuloma involves a bronchiole. Elastic tissue stains are often helpful in identifying pulmonary arteries and bronchioles that may be obscured by dense inflammation. Pulmonary arterioles may be secondarily inflamed.

The diagnosis of BG can be made with confidence in asthmatic patients with eosinophilia if an infectious etiology has been reasonably excluded. Pathologists should be hesitant to diagnose BG in nonasthmatic patients, even if special stains and cultures for microorganisms are negative, because infection is still possible and other noninfectious conditions may simulate BG. Bronchocentric granulomas may occur in GPA, rheumatoid arthritis, and infections. Tuberculosis and other infections, including MAC, and histoplasmosis, may present with bronchocentric granulomas.⁸⁷  GPA can be distinguished from BG by the presence of necrotizing vasculitis, which is not a feature of BG. Secondary vasculitis, which is nonnecrotizing, may occur in BG. Rheumatoid nodules are usually subpleural but can simultaneously involve other areas of the lung including airways. BG, GPA, and rheumatoid nodules may exhibit peripheral palisading of histiocytes. The pathology report should provide a differential diagnosis that includes BG, infection, and others depending on the patient's medical history.

Foreign bodies can reach the lung parenchyma via aspiration, embolization, and inhalation; they usually incite a nonnecrotizing granulomatous reaction. In contrast to epithelioid granulomas, foreign body granulomas are composed of giant cells and macrophages in varying numbers.

Aspiration occurs in persons who have conditions that impair their gag, cough, and swallowing reflexes. Aspirated foreign materials usually consist of food items, especially vegetable fragments and skeletal muscle. Barium, pill fragments, and other materials may also be aspirated. Most aspirated particles greater than 10 μm in diameter are deposited in the throat and upper airways and cannot penetrate the lower tissues of the respiratory tract. If the individual survives an episode of aspiration, pneumonia follows as a reaction to foreign material, gastric acid, and bacteria originating from the upper aerodigestive tract. Aspiration pneumonia can be diagnosed with certainty only by identifying foreign bodies. It is characterized by acute and organizing inflammation usually accompanied by one or more of the following: abscess formation, suppurative granulomas, and a giant cell reaction. Aspirated vegetable material usually incites a giant cell reaction, whereas skeletal muscle fibers usually do not. Vegetable fragments can be recognized by their latticework arrangement of square or rectangular large cells with thick cell walls composed of cellulose. They are often infiltrated by inflammatory cells and surrounded by giant cells (Figure 10, A). The appearance of aspirated foreign bodies varies significantly depending upon the degree of digestive changes and degenerative changes following aspiration. Skeletal muscle fibers often lose their striations. If little food material was present in the stomach at the time of aspiration, foreign bodies may be difficult or impossible to find. A clue to aspiration in the absence of foreign material and granulomas is the presence of scattered giant cells along with acute and/or organizing pneumonia. This finding, in the proper clinical setting, should encourage a search for foreign material by obtaining deeper sections and/or examination of additional tissue. When the stomach is empty, only gastric juice will be aspirated; this usually results in diffuse alveolar damage.⁸⁸ 

Aspiration pneumonia is most often detected at autopsy but can also be diagnosed in biopsies. It often goes unrecognized by both clinicians and pathologists. In a review of 59 surgical lung specimens exhibiting aspiration pneumonia, aspiration was suspected clinically in only 4 of 45 (9%) of cases in which a clinical impression or differential diagnosis was provided.⁸⁹  In a report of 100 consecutive granulomas in a pulmonary pathology consultation practice, it was determined that aspiration pneumonia was the condition most frequently unrecognized by the referring pathologist.⁴ 

Embolization of foreign bodies to the lungs that incite a granulomatous reaction occurs most frequently as the result of intravenous drug abuse and complications of therapeutic procedures. The landmark publication by Tomashefski and Hirsch in 1980⁹⁰  called attention to pulmonary lesions produced by intravenous injection of solutions prepared from tablets or capsules intended for oral consumption. The most frequently injected medications are opioids and amphetamines. Aside from the active ingredient, pills/tablets contain fillers/excipients that provide bulk, adhesion, and other properties. Although cornstarch and talc were commonly used as fillers in the past, microcrystalline cellulose (a binder) and crospovidone (a disintegrant) are mostly encountered at present. When the fillers enter the lung via the pulmonary arterial circulation, they are trapped in arterioles and capillaries and incite a florid giant cell reaction in and around the vessels and in perivascular parenchyma. Cornstarch granules have a spherical shape and exhibit Maltese cross birefringence. Talc crystals are large and have a sheet-like or plate-like appearance (Figure 10, B) and may exhibit a yellowish tint in H&E-stained sections. Microcrystalline cellulose appears as bundles of long, rod-like crystals (Figure 10, C). The distinction between microcrystalline cellulose and talc in H&E-stained sections may be difficult. This distinction can be made with the modified Russell Movat pentachrome stain that stains microcrystalline cellulose yellow and talc, light blue-green⁹¹  (Figure 10, B). The modified Russell Movat pentachrome stain is technically challenging and may give inconsistent results unless performed by an experienced histotechnologist. Crospovidone fragments stain dark blue with H&E and have a very distinctive, unique, coral-like appearance (Figure 10, D). All the filler materials, except crospovidone, exhibit strong birefringence when examined with polarized light.

Silicone leakage from breast implants may rarely embolize to the lungs. Total parenteral nutrition-associated crystalline precipitates resulting in pulmonary vascular occlusions and alveolar granulomas have been reported.⁹² 

Many types of inhaled particulate matter are capable of inciting pulmonary granulomas. Lung injury associated with inhalation of opioids (usually cocaine or heroin) and amphetamines is usually caused by the talc with which these drugs are mixed. The talc crystals incite a granulomatous reaction that is not perivascular and consists primarily of giant cells; a similar reaction occurs with inhaled crack-cocaine.⁹³  Cocaine users may also develop spontaneous pneumothorax.⁹⁴  The presence of granulomas of undetermined etiology in surgical specimens of lung obtained for treatment of spontaneous pneumothorax, should raise the possibility of cocaine abuse. Inhaled metals that promote granuloma formation include aluminum, barium, beryllium, cobalt copper, gold, rare earths (lanthanides), titanium, and zirconium.⁹⁵  Inhalation of hair spray may incite the formation of granulomas.⁹⁶  A history of exposure is essential for consideration of the diagnosis of inhalation-induced granulomas. The medical literature contains a multitude of case reports of many other materials that, when inhaled, cause pulmonary granulomas.

A variety of drugs are sometimes associated with production of granulomas. The medical literature contains mostly individual case reports as well as few small case series.^97,98  A review of the World Health Organization Pharmacovigilance Database by Cohen Aubart et al⁹⁹  found 59 drugs that produce granulomas that the authors referred to as “drug-induced sarcoidosis.” Overall, 85.5% of these drug reactions were considered “serious” and 3.5% were fatal. Most of the drugs associated with granulomas were tumor necrosis factor-alpha antagonists, interferon, or polyethylene glycol interferon therapeutics and immune checkpoint inhibitors. The authors stated that the clinical/radiologic presentations of “drug-induced sarcoidosis” are usually close to sarcoidosis but there was no specific mention of the presence or absence of lung granulomas. However, because the reactions were said to resemble sarcoidosis, it seems reasonable to assume that there was lung involvement. Of the 59 drugs identified, the 10 most strongly associated with inciting granulomas are interferon-alpha 2a, interferon-alpha 2b, ribavirin, peginterferon-alpha 2a, peginterferon 2b, interferon-alpha, interferon-alpha 1a, pembrolizumab, bosentan, and ipilimumab. Other drugs that have been implicated in causing pulmonary granulomas are the Bacillus Calmette-Guerin vaccine, etanercept, everolimus, sirolimus, fluoxetin, isoniazid, imatinib, mesalamine, mesylate, nivolumab, sulfasalazine, and ustekinumab. The terminology that has been used for these drug reactions includes the terms “sarcoidosis-like reactions” and “drug-induced-sarcoidosis.” In the author's opinion, the term “drug-induced granulomatous disease” seems preferable because sarcoidosis is not yet defined.

Chronic granulomatous disease (CGD) is a diverse group of rare, hereditary diseases characterized by production of defective phagocyte nicotinamide adenine dinucleotide phosphate oxidase by cells of the immune system, thus impairing the ability of neutrophils and macrophages to kill ingested pathogens.¹⁰⁰  Approximately 90% of those with CGD are males who have mutations on the X-linked CYBB gene coding for gp91phox.¹⁰⁰ 

CGD is diagnosed in childhood, usually before age 5; it is rare in adults. Patients with CGD typically experience recurrent bouts of fungal and bacterial infections, most frequently involving the lungs. The histopathologic features of lung biopsy specimens obtained from 20 patients with CGD were described in detail by Moskaluk et al.¹⁰¹  Granulomas were present in all cases. They were suppurative, necrotizing, and nonnecrotizing. Occasional large foci of confluent, geographic necrosis was present surrounded by palisaded histiocytes. Abscess formation was more frequently associated with fungal infections than bacterial infections. In addition to granulomas and abscesses, there was diffuse chronic inflammation with foci of fibrosis. Fungi and bacteria were cultured from 11 of 20 (56%) and 6 of 20 (30%) of specimens, respectively. Aspergillus spp were the most frequently isolated fungi. Pathologists can suspect the diagnosis of CGD based on knowing the patient's age, history of recurrent lung infections, and the histologic findings. However, there are no histologic findings that are diagnostic of CGD.

Combined variable immunodeficiency (CVID), a rare disease, is the most common symptomatic primary antibody deficiency disease.¹⁰²  It occurs in children and adults. Hypogammaglobulinemia leads to recurrent bacterial infections. The lower and upper respiratory tracts are the major sites of infections. Bacterial pneumonia is the most frequent acute infection; viral infections may also occur. Chronic lung disease, including bronchiectasis, chronic obstructive pulmonary disease, and asthma, as well as chronic sinusitis, develops in many patients.¹⁰²  At least 10% to 20% of CVID patients develop interstitial lung disease (ILD) resulting from immune dysregulation.¹⁰³  ILD in these patients includes follicular bronchiolitis, nodular lymphoid hyperplasia, granulomatous lung disease, lymphocytic interstitial pneumonia, nonspecific interstitial pneumonia, and organizing pneumonia. The radiologic and histologic heterogeneity of ILDs in CVID and other types of primary antibody deficiency disease has led to the coining of the umbrella term “GLILD,” granulomatous lymphocytic interstitial lung disease, which encompasses granulomatous disease and all forms of pulmonary lymphoid hyperplasia.¹⁰⁴  The term is said to be applicable to any type of interstitial lymphocytic infiltrate and/or granuloma in the lung of a patient with a primary antibody deficiency disease if other conditions that can produce these findings, including infections, other defined ILDs, and malignant lymphoproliferative diseases, have been excluded.¹⁰⁵  Granulomas are usually nonnecrotizing. After recently studying 34 surgical lung biopsy cases of CVID and 4 of IgA deficiency (IgAD) Larsen et al¹⁰⁶  concluded that “GLILD is neither a specific nor a useful entity and biopsies from CVID and IgAD deficient patients should be diagnosed simply by microscopic pattern(s) observed.” There are no specific histologic findings that enable a diagnosis of CVID.

Pulmonary granulomatous reactions associated with cancer may be encountered in a variety of circumstances. The most common is the occasional presence of granulomas immediately adjacent to any subtype of lung carcinoma and/or in regional draining lymph nodes; they are usually nonnecrotizing epithelioid granulomas or single or multiple giant cells. Their pathogenesis is poorly understood; it is assumed that the inciting agents are tumor antigens. Similar granulomatous reactions have been reported with carcinomas arising in any organ. Brincker¹⁰⁷  reported granulomatous reactions in 165 of 3770 (4.4%) of carcinomas. In heavily keratinized squamous carcinoma, a foreign body giant cell reaction to extruded keratin is sometimes seen. Granulomatous reactions have been reported in 210 of 1551 (13.5%) and 8 of 110 (7.3%) of Hodgkin and non-Hodgkin lymphomas, respectively¹⁰⁸ ; they occur in T-cell lymphomas and B-cell lymphomas. Patients with chronic, active sarcoidosis are at increased risk of developing lymphomas¹⁰⁹ ; this has been referred to as the “sarcoidosis-lymphoma syndrome.”¹⁰⁸  Pulmonary granulomas may be associated with administration of therapeutic agents, such as BCG and interferons, and other drugs used to treat cancer (see section on drug-induced granulomas).

It is well known that a systemic granulomatous condition that may involve the lungs, sometimes referred to as “sarcoidosis,” can develop before, concomitant with, or after a diagnosis of certain solid tumors. These tumors include lymphoma, melanoma, testicular germ cell tumors (especially seminoma), and carcinomas of the cervix, liver, lung, uterus, breast, and head and neck.^110–112  The terminology used for these granulomatous conditions is somewhat confusing and controversial and includes “sarcoidosis,” “sarcoid reaction,” and “sarcoid-like reaction.” Since there is not yet a precise definition of sarcoidosis, it is inappropriate to label these granulomatous reactions as sarcoidosis. Until we know more about these conditions and sarcoidosis, descriptive terminology is preferable (ie, “cancer-related granulomatosis” or “sarcoid-like reaction”).

Granulomas are ubiquitous, occurring in almost every disease category. Although sarcoidosis and mycobacterial infection each account for approximately 25% of pulmonary granulomas worldwide, there is significant geographic variation in their incidence. Pathologic diagnosis is often challenging, and a definitive diagnosis, which can only be achieved by demonstrating an etiologic agent within granulomas or by culture, is not achieved in a substantial percentage of pulmonary granulomas. The presence or absence of necrosis in granulomas are not completely reliable indicators of the presence or absence of infection. Multidisciplinary interaction and coordination in cases where an etiologic agent is not identified microscopically or by culture often helps to establish a diagnosis; its importance cannot be overemphasized.