Review Articles
Pathology of Granulomatous Pulmonary Diseases
Yale Rosen, MD
 Context.—Because granulomas are represented in almost
every disease category, the number of clinically and
pathologically important granulomatous pulmonary dis-
eases is large. Their diagnosis by pathologists is particularly
challenging because of their nonspecificity. A specific
diagnosis can be achieved only when a granuloma-inciting
agent(s) (eg, acid-fast bacilli, fungi, foreign bodies, etc) are
identified microscopically or by culture; this does not
occur in most cases. Furthermore, a specific diagnosis
cannot be reached in a high percentage of cases. Although
sarcoidosis and infectious diseases account for approxi-
mately half of pulmonary granulomatous diseases world-
wide, there is significant geographic variation in their
prevalence.
Objectives.—To present updated information to serve as
a guide to pathologic diagnosis of pulmonary granuloma-
tous diseases, to address some commonly held misconcep-
tions and to stress the importance of multidisciplinary
coordination. Presentation of basic aspects of granulomas
is followed by discussion of specific disease entities, such
T he assessment of granulomatous lung lesions seen in
surgical and autopsy specimens is often challenging.
Many excellent reviews devoted to or addressing differential
diagnosis of pulmonary granulomatous diseases have been
published.1–7 This review presents up-to-date information
on granulomatous lung diseases and is intended to serve as
a practical and useful guide to diagnosis. Initial discussion of
some basic features of granulomas will be followed by
discussion of individual pulmonary granulomatous diseases.
Differential diagnosis, issues that are not widely appreciat-
ed, and some commonly held misconceptions will be
addressed.
Identification of the etiology or disease association of
granulomatous lesions is often difficult because granulomas
are nonspecific lesions whose appearance does not reveal
their etiology or disease association unless the inciting agent
can be identified within the granuloma or by culture.
Although the inciting agent is not identified in most cases,
the morphologic features of some granulomas and associ-
Accepted for publication January 28, 2021.
Published online April 27, 2021.
From the Department of Pathology, SUNY Downstate Health
Sciences University, Brooklyn, New York.
The author has no relevant financial interest in the products or
companies described in this article.
Corresponding author: Yale Rosen, MD, Department of Pathology,
SUNY Downstate Health Sciences University, 450 Clarkson Ave,
Brooklyn, NY 11203 (email: yrosen854@gmail.com).
Arch Pathol Lab Med—Vol 146, February 2022
as tuberculous and nontuberculous Mycobacterial infec-
tions, fungal, bacterial, and parasitic infections, sarcoido-
sis, necrotizing sarcoid granulomatosis, berylliosis,
hypersensitivity pneumonitis, hot tub lung, rheumatoid
nodule, bronchocentric granulomatosis, aspirated, inhaled,
and embolized foreign bodies, drug-induced granulomas,
chronic granulomatous disease, common variable immu-
nodeficiency, and granulomatous lesions associated with
various types of cancer.
Data Sources.—Review of pertinent medical literature
using the PubMed search engine and the author’s practical
experience.
Conclusions.—Although the diagnosis of granulomatous
lung diseases continues to present significant challenges to
pathologists, the information presented in this review can
be helpful in overcoming them. The importance of
multidisciplinary coordination in cases where morphologic
diagnosis is not possible cannot be overstated.
(Arch Pathol Lab Med. 2022;146:233–251; doi: 10.5858/
arpa.2020-0543-RA)
ated lesions may provide diagnostic clues. Correlation of the
pathologic findings with the patient’s medical history,
clinical, radiologic, and laboratory findings is often necessary
to reach a diagnosis. The importance of a multidisciplinary
approach to reaching the diagnosis of granulomatous lesions
in which an inciting agent cannot be identified is empha-
sized.
OVERVIEW OF PULMONARY GRANULOMATOUS
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 immunosup-
pressed 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 cases1,4,5,7,8 (Table 1).
Pathology of Granulomatous Pulmonary Diseases—Rosen 233
 Table 1. Granulomatous Lung Diseases Without Definitive Pathologic Diagnosis
Author(s) Cases, n Cases, % Comment
1
Ulbright and Katzenstein 22/86 26 Solitary necrotizing granulomas
Hutton Klein et al4 27/100 27 100 consecutive granulomatous cases in a pulmonary pathology
consultation practice. A specific diagnosis was favored in 34/100 (34%)
and a differential diagnosis was provided in 39/100 (39%)
Mukhopadhyay et al5 210/500 42 Granulomas of all types
Mukhopadhyay et al7 131/566 23% initially; Necrotizing granulomas. Subsequent comprehensive analysis of the 131
9% after cases following review of medical records, laboratory data including
comprehensive cultures, and radiographic data disclosed the cause of granulomas in an
review additional 79/131 cases (60%), resulting in 52 of the initial 566 cases
(9%) remaining undiagnosed
Woodard et al8 10/59 17 Granulomas of all types

DEFINITION, DEVELOPMENT, AND MORPHOLOGY OF
GRANULOMAS
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 granulo-
mas, 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 character-
istically seen in hypersensitivity pneumonitis (HP), granu-
lomatosis with polyangiitis (GPA), foreign body reactions,
lymphocytic interstitial pneumonia, and others.
Initial presentation of persistent and poorly degradable
antigens by dendritic cells to T4þ 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 trans-
formation to epithelioid cells resulting in the formation of
epithelioid granulomas. Details of current concepts of the
immunopathogenesis of epithelioid granulomas in sarcoid-
osis 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 T8þ
suppressor lymphocytes. Granulomas without this lympho-
cyte rim are referred to as ‘‘naked’’ granulomas. The
lymphocytes admixed with epithelioid cells within the
granulomas are mostly T4þ 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 confirma-
tion. 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 phago-
cytes in various stages of maturation or activation.’’
Multinucleate giant cells, derived from fusion of mono-
cytes, macrophages, and epithelioid cells, rather than by
proliferation and nondivision, are present in most granulo-
mas and may assume a variety of appearances. The
traditional classification of giant cells as being of Langhans
234 Arch Pathol Lab Med—Vol 146, February 2022
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 consid-
erable 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 regu-
lated 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:
The term caseation is applied to the gross character-
istics of the necrotic material commonly seen in
tuberculous infection. This necrotic tissue can easily be
removed from the surrounding living tissue, leaving a
cavity. It has no texture and varies in consistence from
thick pus to a crumbly material not unlike cottage
cheese.
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, malig-
nant 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.
Pathology of Granulomatous Pulmonary Diseases—Rosen
 suppurative granulomas. Fibrin-ring and spindle-cell gran-
ulomas/pseudotumors are unusual types of nonnecrotizing
granulomas. Spindle-cell granulomas/pseudotumors, usual-
ly 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 descrip-
tions 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 etiol-
ogy, most caused by Mycobacteria and fungi. Exceptions
include rheumatoid nodules, GPA, and the necrotizing
sarcoid granulomatosis (NSG) variant of sarcoidosis. Pali-
saded necrotizing granulomas in the lungs are almost
always rheumatoid nodules but can also be caused by a
variety of infections.13

Figure 1. A, Nonnecrotizing epithelioid granuloma in sarcoidosis. B,
Necrotizing epithelioid granuloma in tuberculosis (hematoxylin-eosin,
original magnification 3200 [A and B]).
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,
INCLUSIONS IN GRANULOMAS
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 Bodies
Schaumann (conchoidal) bodies, are large (25–200 lm),
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 frequent-
ly, either alone, or in combination with the Schaumann

Table 2. Granuloma Subtypes and Their Disease Associations

Granuloma Subtype Typical Disease Associations
Nonnecrotizing Sarcoidosis, berylliosis, HP, hot tub lung, CVID, drug reactions, foreign bodies, inhaled metals,
schistosomiasis (ova), paragonimiasis (ova)
Necrotizing TB, NTM, fungal infections, NSG, BG, CGD
Minimal, focal necrosis Sarcoidosis
Suppurative Fungal infections, GPA, CGD, aspiration, EGPA, CVID
Suppurative, stellate Cat scratch disease, lymphogranuloma venereum, tularemia, Yersinia
Palisading Rheumatoid nodule, CGD, GPA, EGPA, BG, infections, including phaeohyphomycosis, NTM,
cat scratch disease, sporotrichosis, cryptococcosis, and coccidioidomycosis
Necrobiotic Most seen postbiopsy of urinary bladder, prostate, and cervix. Associated with electrocautery
Fibrin ring Q fever, EBV, visceral leishmaniasis, toxoplasmosis, Hodgkin lymphoma, typhus, allopurinol
hypersensitivity, CMV, immune checkpoint inhibitors, and others. Seen mostly in liver and
bone marrow. Lung involvement not reported
Spindle cell granuloma/pseudotumor MAC infection, TB, and histoplasmosis (rare). Usually occurs in immunosuppressed persons
Abbreviations: BG, bronchocentric granulomatosis; CGD, chronic granulomatous disease; CMV, cytomegalovirus; CVID, common variable
immunodeficiency; EBV, Epstein-Barr virus; EGPA, eosinophilic granulomatosis with polyangiitis; GPA, granulomatosis with polyangiitis; HP,
hypersensitivity pneumonitis; MAC, Mycobacterium avium complex; NSG, necrotizing sarcoid granulomatosis variant of sarcoidosis; NTM,
nontuberculous mycobacteria; TB, tuberculosis.

Arch Pathol Lab Med—Vol 146, February 2022 Pathology of Granulomatous Pulmonary Diseases—Rosen 235
 Table 3. Microscopic Descriptions of Granuloma Subtypes
Granuloma Subtype Description
Nonnecrotizing Compact, organized collection of epithelioid cells or macrophages with or without giant cells.
Necrosis absent
Necrotizing Necrosis is a prominent feature
Minimal, focal necrosis Minimal foci of necrosis focally distributed; involving a small percentage of granulomas
Suppurative Granuloma with focal necrosis with purulent exudate
Suppurative, stellate Elongated, irregular, often stellate with central suppurative necrosis
Palisading Elongated and compressed histiocytes, aligned parallel to each other and surrounding a central
zone of necrosis
Necrobiotic Collagen necrosis surrounded by palisaded histiocytes. Resembles rheumatoid nodule
Fibrin ring Small, compact collection of macrophages surrounded by a thin ring of fibrin
Spindle cell granuloma/pseudotumor Spindled macrophages simulating a neoplasm. Reported to be CD68 positive

body (Figure 2, A). As many as 70% of Schaumann bodies
have crystals associated with them ranging in size from 1 to
20 lm. 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 crys-
talline and conchoidal bodies in 88% of cases of sarcoidosis,
62% of chronic beryllium disease, and 6% of tuberculosis
cases.
Crystalline Bodies
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
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, schistoso-
miasis, and others.17 They vary from 5 to 30 lm 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
Cholesterol Inclusions
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.
HAMAZAKI-WESENBERG BODIES
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
236 Arch Pathol Lab Med—Vol 146, February 2022
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 hema-
toxylin-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 exam-
ination shows that the Hamazaki-Wesenberg bodies are
giant, intracellular, and extracellular lysosomes and residual
bodies.14
ETIOLOGY AND DISEASE ASSOCIATIONS OF
PULMONARY GRANULOMATOUS DISEASES
Infectious Diseases
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.
Mycobacterial Infections
Tuberculosis.—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 neo-
plasm.
The usual biopsy finding in TB is necrotizing granulomas
(Figure 1, B). However, nonnecrotizing granulomas have
Pathology of Granulomatous Pulmonary Diseases—Rosen
Figure 2. Sarcoidosis. A, Giant cell with Schaumann body. Inset (polarized): calcium oxalate crystals with thin rims of calcification; early
Schaumann body. B, Calcium oxalate and carbonate crystals within giant cells. C, Giant cell containing 2 asteroid bodies. D, Cholesterol granuloma.
E, Hamazaki-Wesenberg bodies (yellow-brown bodies) in a lymph node. Courtesy of Runjan Chetty, MB BCh. F, Grocott methenamine silver stain of
Hamazaki-Wesenberg bodies showing their resemblance to budding yeasts (hematoxylin-eosin, original magnifications 3400 [A, A inset, and E] and
3200 [B through D]); Grocott methenamine silver stain, original magnification 3400 [F]).

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. Occa-
sionally, 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 cases12,23,24 and
Arch Pathol Lab Med—Vol 146, February 2022
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
Pathology of Granulomatous Pulmonary Diseases—Rosen 237
greatest amount of necrosis, and searching within areas of
necrosis where the yield is greatest using a 340 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 fluores-
cent 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 immuno-
histochemistry 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.
Nontuberculous Mycobacterial Infection.—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 simulta-
neously. 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 granulo-
mas have also been reported to occur with NTM infection in
238 Arch Pathol Lab Med—Vol 146, February 2022
immunocompromised patients.32 NTM are the most com-
mon 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 speci-
mens 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.
Fungal Infections.—Granulomas are present in infec-
tions caused by many species of fungi, including Histoplas-
ma, Cryptococcus, Blastomyces, Coccidioides, Paracoccidioides,
and others. Candida and Aspergillus usually cause acute
inflammation but are also capable of inciting granulo-
mas.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 methena-
mine 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 mucicar-
mine. 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 endo-
spores, 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
Nonmycobacterial Bacterial Infections
A variety of nonmycobacterial bacteria may produce
granulomatous inflammation, which is usually necrotizing
and often suppurative. These include Brucella spp, Actino-
myces spp, Francisella tularensis, Bartonella henselae, Nocardia
spp Yersnia enterocolitica, Listeria monocytogenes, Burkholderia
pseudomallei (melioidosis), Coxiella burnetti, and others2,38
Pathology of Granulomatous Pulmonary Diseases—Rosen

Figure 3. Cross sections of 2 immature, adult Dirofilaria immitis
worms in necrotic blood vessels within infarcted lung tissue (hematox-
ylin-eosin, original magnification 3200).
Figure 4. Lymphangitic localization of granulomas around broncho-
vascular bundles in sarcoidosis (hematoxylin-eosin, original magnifica-
tion 340).
(Table 2). Although Gram and silver stains may be helpful in
some cases, diagnosis is usually based on identification in
cultures.
Parasitic Diseases
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 blood-
stream. 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
Arch Pathol Lab Med—Vol 146, February 2022
find and step sections may be needed. They appear as large,
round-to-oval structures averaging 200 lm in diameter.
They have a thick (5–25 lm), 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 granulo-
matous reaction. The ova are usually easily seen.
Diseases of Unknown Etiology/Idiopathy
Sarcoidosis.—Sarcoidosis is a common disease of un-
known 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 geneti-
cally 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 intratho-
racic 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 cryo-
biopsies. 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 lym-
phatic network is associated with these structures. Because
Pathology of Granulomatous Pulmonary Diseases—Rosen 239
Figure 5. Sarcoidosis. A, Airspace granuloma. B, Granulomatous vasculitis. C, Granulomatous vasculitis. Elastic tissue stain showing focal
destruction of elastic tissue. D, Granuloma with numerous apoptotic bodies surrounding a minute focus of necrosis between arrows. E, Granulomas
with multifocal minimal necrosis at arrows. F, Large foci of necrosis in granulomas (hematoxylin-eosin, original magnifications 3100 [A and E] and
3200 [B through D and F]).

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 trans-
ported 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 micro-
scopic appearance may closely resemble that of sarcoidosis,
240 Arch Pathol Lab Med—Vol 146, February 2022
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 appear-
ance and are mostly located in the interstitium but are also
occasionally seen within airspaces (Figure 5, A). The
Pathology of Granulomatous Pulmonary Diseases—Rosen
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 preexist-
ing 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 predominat-
ing 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 intra-
venous drug abusers, schistosomiasis, and seminomas.
Sarcoidosis is an uncommon cause of pulmonary hyper-
tension. A small number of case reports strongly suggest
that in some sarcoidosis patients with pulmonary hyper-
tension 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
necrosis42,61 (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
Arch Pathol Lab Med—Vol 146, February 2022
unless reasonable efforts to exclude an infectious etiology,
including cultures, are undertaken. NSG is always diag-
nosed 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 sarcoid-
osis. 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 transbron-
chial biopsy specimens exhibiting nonnecrotizing granulo-
mas 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.
Hypersensitivity Diseases
Berylliosis.—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 granulo-
mas, 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 distinguish-
ing 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
Hypersensitivity Pneumonitis.—HP, also known as
extrinsic allergic alveolitis, represents an immune-mediated
reaction to a variety of inhaled antigens and chemicals.
Comprehensive reviews of HP69,70 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
Pathology of Granulomatous Pulmonary Diseases—Rosen 241
Figure 6. A through C, Necrotizing sarcoid granulomatosis variant of sarcoidosis. A, Localization of granulomas around bronchovascular bundles.
B, Confluent granulomas with extensive necrosis. C, Granulomatous vasculitis. D through F, Subacute hypersensitivity pneumonitis. D, Diffuse
interstitial inflammation and a poorly formed granuloma. E, Bronchiolitis with poorly formed granulomas. F, Focal organizing pneumonia at arrow
(hematoxylin-eosin, original magnifications 320 [A], 3200 [B, C, and F]), and 340 [D and E]).

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
242 Arch Pathol Lab Med—Vol 146, February 2022
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
Pathology of Granulomatous Pulmonary Diseases—Rosen
 Table 4. Comparative Histologic Features of Sarcoidosis and Subacute Hypersensitivity Pneumonitis
Sarcoidosis
Interstitial inflammation Inconspicuous, if present
Granulomas Well formed, compact, may have
focal, minimal necrosis
Schaumann bodies Frequently present
Other inclusions May be present
Lymphangitic localization of granulomas Yes
Organizing pneumonia No
Nongranulomatous inflammation of small airways Unusual
Granulomatous vasculitis Common in surgical lung biopsies
Pleural granulomas Up to 35%25
Subacute Hypersensitivity Pneumonitis
Always present. Peribronchiolar accentuation
Small, loosely formed, no necrosis. Giant cells
may be present without granulomas
Frequently present
May be present
No
Yes
Yes. Chronic inflammation 6 granulomas
Rare
Not reported

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, bronchiol-
ectasis, 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 granu-
lomas 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 sar-
coidosis (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 peribron-
chiolar localization. Poorly formed granulomas, as seen in
many lymphoproliferative disorders, may be present within
the lymphocytic infiltrates.
Arch Pathol Lab Med—Vol 146, February 2022
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 pneu-
monia.74 Despite the above-mentioned criteria, the diagno-
sis of CHP is difficult and often controversial.
Hot Tub Lung.—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. Cavi-
tary 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 granulo-
mas 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 granuloma-
tous 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).
Pathology of Granulomatous Pulmonary Diseases—Rosen 243

Figure 7. Airspace granuloma and interstitial inflammation in hot tub
lung (hematoxylin-eosin, original magnification 3200). Courtesy of
Sanjay Mukhopadhyay, MD.
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.
Vasculitic Granulomatous Diseases
Granulomatosis With Polyangiitis.—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 pre-
dominantly 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 inflam-
mation, necrosis, and vasculitis accompanied by a mixed
inflammatory cell infiltrate and variable amounts of fibro-
blastic 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 microab-
scesses, foci of geographic necrosis surrounded by palisaded
histiocytes, and microgranulomas consisting of small foci of
palisaded histiocytes arranged in a cartwheel fashion and
244 Arch Pathol Lab Med—Vol 146, February 2022
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 GPA2,3;
is characterized by suppurative necrosis, suppurative gran-
ulomas, fibrinoid necrosis, or the presence of karyorrhectic
neutrophils within the vessel wall2,3 (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 vascu-
litis may be seen occasionally, however, in most cases of
GPA the vasculitis is nongranulomatous. Capillary involve-
ment (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.—Eo-
sinophilic 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.
Pathology of Granulomatous Pulmonary Diseases—Rosen
Figure 8. A through F, Granulomatosis with polyangiitis. A, Extensive geographic necrosis. B, Granuloma with suppurative necrosis. C, Granuloma
with a small focus of central eosinophilic necrosis and focal palisading of peripheral histiocytes. D, Necrotizing vasculitis; partial involvement of the
vessel wall. E, Necrotizing vasculitis. F, Capillaritis with acute inflammation and fibrinoid necrosis of alveolar capillary walls. G and H, Eosinophilic
granulomatosis with polyangiitis. G, Fibrinoid necrosis of a pulmonary blood vessel with surrounding eosinophilic pneumonia. H, Eosinophilic
pneumonia (hematoxylin-eosin, original magnifications 320 [A] and 3200 [B through H]).

Arch Pathol Lab Med—Vol 146, February 2022 Pathology of Granulomatous Pulmonary Diseases—Rosen 245
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, eosino-
philia, neuropathy, nonfixed pulmonary infiltrates, parana-
sal 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, granulo-
matous inflammation, and necrotizing vasculitis is consid-
ered 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 infil-
trate 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).
Autoimmune Granulomas
Rheumatoid Nodule.—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 nonnecrotiz-
ing 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 condi-
tion, 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).
Mixed Allergic and Idiopathic Granulomatous Reactions
Bronchocentric Granulomatosis.—Bronchocentric
granulomatosis (BG) is characterized by necrotizing gran-
ulomas that primarily involve and destroy bronchioles.
Approximately half of the cases occur in asthmatics with
allergic bronchopulmonary fungal disease, mainly aspergil-
losis, 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
246 Arch Pathol Lab Med—Vol 146, February 2022
Figure 9. Bronchocentric granulomatosis, idiopathic (hematoxylin-
eosin, original magnification 3100).
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 circumfer-
ence 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 granulo-
mas.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 Body Reactions
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.
Pathology of Granulomatous Pulmonary Diseases—Rosen
Figure 10. A, Aspirated vegetable fragment with giant cells and acute inflammation. B, Pale blue-green staining talc crystals with dense fibrosis and
giant cell reaction in pleura; postpleurodesis. Movat pentachrome stain. Courtesy of Sanjay Mukhopadhyay, MD. C, Extravascular embolized
microcrystalline cellulose with giant cell reaction in an intravenous drug abuser. D, Embolized crospovidone in an airspace with giant cell reaction in
an intravenous drug abuser (hematoxylin-eosin, original magnifications 3100 [A] and 3200 [C and D]; Movat pentachrome, original magnification
3200 [B]).

Aspiration.—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 lm 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
Arch Pathol Lab Med—Vol 146, February 2022
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 granulo-
mas 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.—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
Pathology of Granulomatous Pulmonary Diseases—Rosen 247
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 gran-
ules 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 techni-
cally challenging and may give inconsistent results unless
performed by an experienced histotechnologist. Crospovi-
done 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
Inhalation.—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 (lantha-
nides), 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.
Drug-Induced 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
248 Arch Pathol Lab Med—Vol 146, February 2022
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, ever-
olimus, sirolimus, fluoxetin, isoniazid, imatinib, mesal-
amine, mesylate, nivolumab, sulfasalazine, and
ustekinumab. The terminology that has been used for these
drug reactions includes the terms ‘‘sarcoidosis-like reac-
tions’’ and ‘‘drug-induced-sarcoidosis.’’ In the author’s
opinion, the term ‘‘drug-induced granulomatous disease’’
seems preferable because sarcoidosis is not yet defined.
Granulomas Associated With a Defective Enzyme
Chronic Granulomatous Disease.—Chronic granulo-
matous 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 suppura-
tive, 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.
Granulomas Associated With Primary Antibody Deficiency
Common Variable Immunodeficiency.—Combined
variable immunodeficiency (CVID), a rare disease, is the
most common symptomatic primary antibody deficiency
disease.102 It occurs in children and adults. Hypogamma-
globulinemia 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 pul-
Pathology of Granulomatous Pulmonary Diseases—Rosen
monary 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 hyper-
plasia, granulomatous lung disease, lymphocytic interstitial
pneumonia, nonspecific interstitial pneumonia, and orga-
nizing pneumonia. The radiologic and histologic heteroge-
neity 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 nonnecro-
tizing. 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.
Granulomas Associated With Cancer
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 carcino-
mas arising in any organ. Brincker107 reported granuloma-
tous 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 lympho-
mas109; 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 termi-
nology used for these granulomatous conditions is some-
what confusing and controversial and includes
‘‘sarcoidosis,’’ ‘‘sarcoid reaction,’’ and ‘‘sarcoid-like reac-
tion.’’ 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
Arch Pathol Lab Med—Vol 146, February 2022
preferable (ie, ‘‘cancer-related granulomatosis’’ or ‘‘sar-
coid-like reaction’’).
CONCLUSIONS
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.
References
1. Ulbright TM, Katzenstein AL. Solitary necrotizing granulomas of the lung:
differentiating features and etiology. Am J Surg Pathol. 1980;4(1):13–28.
2. El-Zammar OA, Katzenstein AL. Pathological diagnosis of granulomatous
lung disease: a review. Histopathology. 2007;50(3):289–310.
3. Mukhopadhyay S, Gal AA. Granulomatous lung disease: an approach to the
differential diagnosis. Arch Pathol Lab Med. 2010;134(5):668–690.
4. Hutton Klein JR, Tazelaar HD, Leslie KO, Colby TV. One hundred
consecutive granulomas in a pulmonary pathology consultation practice. Am J
Surg Pathol. 2010;34(10):1456–1464.
5. Mukhopadhyay S, Farver CF, Vaszar LT, Dempsey OJ, Popper HH, Mani H.
Causes of pulmonary granulomas: a retrospective study of 500 cases from seven
countries. J Clin Pathol. 2012;65(1):51–57.
6. Mukhopadhyay S, Aubry MC. Pulmonary granulomas: differential
diagnosis, histologic features and algorithmic approach. Diagn Histopathol.
2013;19(8):288–297.
7. Mukhopadhyay S, Wilcox BE, Myers JL, Bryant SC, Buckwalter SP,
Wengenack N. Pulmonary necrotizing granulomas of unknown cause: clinical
and pathologic analysis of 131 patients with completely resected nodules. Chest.
2013;144(3):813–824.
8. Woodard BH, Rosenberg SI, Farnham R, Adams DO. Incidence and nature
of primary granulomatous inflammation in surgically removed material. Am J
Surg Pathol. 1982;6(2):119–129.
9. Adams DO. The biology of the granuloma. In: Ioachim HL, ed. Pathology of
Granulomas. New York, NY: Raven; 1983:1–20.
10. Beijer E, Veltkamp M, Meek B, Moller DR. Etiology and immunopatho-
genesis of sarcoidosis: novel insights. Semin Respir Crit Care Med. 2017;38(4):
404–416.
11. Kosjerina Z, Zaric B, Vuckovic D, Lalosevic D, Djenadic G, Murer B. The
sarcoid granuloma: ‘‘epithelioid’’ or ‘‘lymphocytic-epithelioid’’ granuloma?
Multidiscip Respir Med. 2012;7(1):11.
12. Medlar EM. A study of the process of caseation in tuberculosis. Am J
Pathol. 1926;2(4):275–290.
13. Su WP, Kuechle MK, Peters MS, Muller SA. Palisading granulomas caused
by infectious diseases. Am J Dermatopathol. 1992;14(3):211–215
14. Rosen Y, Vuletin JC, Pertschuk LP, Silverstein E. Sarcoidosis from the
pathologist’s vantage point. Pathol Annu 1979;14(Part 1):405–439.
15. Visscher D, Churg A, Katzenstein AL. Significance of crystalline inclusions
in lung granulomas. Mod Pathol. 1988;1(6):415–419.
16. Jones Williams W. The nature and origin of Schaumann bodies. J Pathol
Bacteriol. 1960;79:193–201.
17. Ricker W, Clark M. Sarcoidosis; a clinicopathologic review of 300 cases,
including 22 autopsies. Am J Clin Pathol. 1949;19(8):725–749.
18. Cain H, Kraus B. The ultrastructure and morphogenesis of asteroid bodies
in sarcoidosis and other granulomatous disorders. In: Williams JW, Davies BH
eds. Eighth International Conference on Sarcoidosis and Other Granulomatous
Diseases. Alpha Omega; 1980:30–37.
19. Hamazaki T. Über ein neues, säuerfeste Substanz führendes Spindelkör-
perchen der Menschlischen Lymphdrüsen. Virchows Arch (Pathol Anat). 1938;
301;490–522.
20. Wesenberg W. Uber säurefeste ‘‘Spindelkörper Hamazaki’’ bei Sarkoidose
der Lymphknoten und über doppellichtbrechende Zelleinschlüsse bei Sarkoidose
der Lungen. Arch Klin Exp Dermatol. 1966;227(1):101–107.
21. Doyle WF, Brahman HD, Burgess JH. The nature of yellow-brown bodies
in peritoneal lymph nodes. Arch Pathol. 1973;96(5):320–326.
22. Jain D, Ghosh S, Teixeira L, Mukhopadhyay S. Pathology of pulmonary
tuberculosis and non-tuberculous mycobacterial lung disease: facts, misconcep-
tions, and practical tips for pathologists. Semin Diagn Pathol. 2017;34(6):518–
529.
Pathology of Granulomatous Pulmonary Diseases—Rosen 249
 23. Hillemann D, Galle J, Vollmer E, Richter E. Real-time PCR assay for
improved detection of Mycobacterium tuberculosis complex in paraffin-
embedded tissues. Int J Tuberc Lung Dis. 2006;10(3):340–342.
24. Kommareddi S, Abramowsky CR, Swinehart GL, Hrabak A. Non-
tuberculous mycobacterial infections: comparison of the fluorescent auramine-
O and Ziehl-Neelsen techniques in tissue diagnosis. Hum Pathol. 1984;15(11):
1085–1089.
25. Vaerewijck MJ, Huys G, Palomino JC, Swings J, Portaels F. Mycobacteria in
drinking water distribution systems: ecology and significance for human health.
FEMS Microbiol Rev. 2005;29(5):911–934.
26. Park JS, Kang YA, Kwon SY, et al. Nested PCR in lung tissue for diagnosis of
pulmonary tuberculosis. Eur Respir J. 2010;35(4):851–857.
27. Seo AN, Park HJ, Lee HS, et al. Performance characteristics of nested
polymerase chain reaction vs real-time polymerase chain reaction methods for
detecting mycobacterium tuberculosis complex in paraffin-embedded human
tissues. Am J Clin Pathol. 2014;142(3):384–390.
28. Lee HS, Park KU, Park JO, Chang HE, Song J, Choe G. Rapid, sensitive, and
specific detection of Mycobacterium tuberculosis complex by real-time PCR on
paraffin-embedded human tissues. J Mol Diagn. 2011;13(4):390–394.
29. Kohli R, Punia RS, Kaushik R, Kundu R, Mohan H. Relative value of
immunohistochemistry in detection of mycobacterial antigen in suspected cases
of tuberculosis in tissue sections. Indian J Pathol Microbiol. 2014;57(4):574–578.
30. Purohit MR, Sviland L, Wiker H, Mustafa T. Rapid and specific diagnosis of
extrapulmonary tuberculosis by immunostaining of tissues and aspirates with
anti-MPT64. Appl Immunohistochem Mol Morphol. 2017;25(4):282–288.
31. Jeanes C, O’Grady J. Diagnosing tuberculosis in the 21st century - dawn of
a genomics revolution? Int J Mycobacteriol. 2016;5(4):384–391.
32. Farhi DC, Mason UG III, Horsburgh CR Jr. Pathologic findings in
disseminated Mycobacterium avium-intracellulare infection. A report of 11 cases.
Am J Clin Pathol. 1986;85(1):67–72.
33. Griffith DE, Aksamit T, Brown-Elliott BA, et al.; ATS Mycobacterial
Diseases Subcommittee; American Thoracic Society; Infectious Disease Society
of America. An official ATS/IDSA statement: diagnosis, treatment, and prevention
of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007;
175(4):367–416.
34. Mukhopadhyay S. Role of histology in the diagnosis of infectious causes of
granulomatous lung disease. Curr Opin Pulm Med. 2011;17(3):189–196.
35. Dermawan JKT, Ghosh S, Keating MK, Gopalakrishna KV, Mukhopadhyay
S. Candida pneumonia with severe clinical course, recovery with antifungal
therapy and unusual pathologic findings: a case report. Medicine (Baltimore).
2018;97(2):e9650.
36. Dermawan JK, Ghosh S, Mukhopadhyay S. Expanding the spectrum of
chronic necrotising (semi-invasive) aspergillosis: a series of eight cases presenting
as radiologically solid lung nodules mimicking malignancy. Histopathology.
2020;76(5):685–697
37. Procop GW, Pritt BS. Fungal infections. In: Pritt BS, Mathison BA, Milner
DA, et al., eds. Atlas of Fundamental Infectious Disease Histopathology.
Northfield, Illinois: College of American Pathologists: 2018:91–148.
38. Scheutz AN, Pritt BS. Bacterial infections. In: Pritt BS, Mathison BA, Milner
DA, et al., eds. Atlas of Fundamental Infectious Disease Histopathology.
Northfield, Illinois: College of American Pathologists; 2018:19–90.
39. Rosen Y, Amorosa JK, Moon S, Cohen J, Lyons HA. Occurrence of lung
granulomas in patients with stage I sarcoidosis. AJR Am J Roentgenol. 1977;
129(6):1083–1085.
40. Mitchell DN, Scadding JG, Heard BE, Hinson KF. Sarcoidosis:
histopathological definition and clinical diagnosis. J Clin Pathol. 1977;30(5):
395–408.
41. Sheffield EA. Pathology of sarcoidosis. Clin Chest Med. 1997;18(4):7 41–
54.
42. Rosen Y. Pathology of sarcoidosis. Semin Respir Crit Care Med. 2007;
28(1):36–52.
43. Rossi G, Cavazza A, Colby TV. Pathology of sarcoidosis. Clin Rev Allergy
Immunol. 2015;49(1):36–44.
44. Ma Y, Gal A, Koss M. Reprint of: The pathology of pulmonary sarcoidosis:
update. Semin Diagn Pathol. 2018;35(5):324–333.
45. Statement on sarcoidosis. Joint Statement of the American Thoracic
Society (ATS), the European Respiratory Society (ERS) and the World Association
of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the
ATS Board of Directors and by the ERS Executive Committee, February 1999. Am
J Respir Crit Care Med. 1999;160(2):736–755.
46. Kieszko R, Krawczyk P, Michnar M, Chocholska S, Milanowski J. The yield
of endobronchial biopsy in pulmonary sarcoidosis: connection between
spirometric impairment and lymphocyte subpopulations in bronchoalveolar
lavage fluid. Respiration. 2004;71(1):72–76.
47. Shorr AF, Torrington KG, Hnatiuk OW. Endobronchial biopsy for
sarcoidosis: a prospective study. Chest. 2001;120(1):109–114.
48. Koerner SK, Sakowitz AJ, Appelman RI, Becker NH, Schoenbaum SW.
Transbronchial lung biopsy for the diagnosis of sarcoidosis. N Engl J Med. 1975;
293(6):268–270.
49. Koonitz CH, Joyner LR, Nelson RA. Transbronchial lung biopsy via the
fiberoptic bronchoscope in sarcoidosis. Ann Intern Med. 1976;85(1):64–66.
50. Gilman MJ, Wang KP. Transbronchial lung biopsy in sarcoidosis. An
approach to determine the optimal number of biopsies. Am Rev Respir Dis. 1980;
122(5):721–724.
250 Arch Pathol Lab Med—Vol 146, February 2022
51. Jacob M, Bastos HN, Mota PC, et al. Diagnostic yield and safety of
transbronchial cryobiopsy in sarcoidosis. ERJ Open Res. 2019;5(4):00203–2019.
52. Rosen Y, Athanassiades TJ, Moon S, Lyons HA. Nongranulomatous
interstitial pneumonitis in sarcoidosis. Relationship to development of epithelioid
granulomas. Chest. 1978;74(2):122–125.
53. Rosen Y, Moon S, Huang CT, Lyons HA. Granulomatous pulmonary
angiitis in sarcoidosis. Arch Pathol Lab Med. 1977;101(4):170–174.
54. Takemura T, Matsui Y, Saiki S, Mikami R. Pulmonary vascular involvement
in sarcoidosis: a report of 40 autopsy cases. Hum Pathol.1992;23(11):1216–
1223.
55. Smith LJ, Lawrence JB, Katzenstein AA. Vascular sarcoidosis: a rare cause
of pulmonary hypertension. Am J Med Sci. 1983;285(1):38–44.
56. Crissman JD, Koss M, Carson RP. Pulmonary veno-occlusive disease
secondary to granulomatous venulitis. Am J Surg Pathol.1980;4(1):93–99
57. Longcope WT, Freiman DG. A study of sarcoidosis; based on a combined
investigation of 160 cases including 30 autopsies from The Johns Hopkins
Hospital and Massachusetts General Hospital. Medicine. 1952;31(1):1–132.
58. Thomson AD. The pathology of sarcoidosis. Postgrad Med J. 1958;34(391):
248–253.
59. Carrington CB, Gaensler EA, Mikus JP, Schachter AW, Burke GW, Goff
AM. Structure and function in sarcoidosis. Ann N Y Acad Sci. 1976;278:265–283.
60. Kunitake R, Kuwano K, Miyazaki H, Hagimoto N, Nomoto Y, Hara N.
Apoptosis in the course of granulomatous inflammation in pulmonary sarcoid-
osis. Eur Respir J. 1999;13(6):1329–1337.
61. Strickland-Marmol LB, Fessler RG, Rojiani AM. Necrotizing sarcoid
granulomatosis mimicking an intracranial neoplasm: clinicopathologic features
and review of the literature. Mod Pathol. 2000;13:909–913.
62. Liebow AA. The J. Burns Amberson lecture–pulmonary angiitis and
granulomatosis. Am Rev Respir Dis. 1973;108(1):1–18.
63. Rosen Y. Four decades of necrotizing sarcoid granulomatosis: what do we
know now? Arch Pathol Lab Med. 2015;139(2):252–262.
64. Hsu RM, Connors AF Jr, Tomashefski JF Jr. Histologic, microbiologic, and
clinical correlates of the diagnosis of sarcoidosis by transbronchial biopsy. Arch
Pathol Lab Med. 1996;120(4):364–368
65. Churg AM, Green FHY. Occupational lung disease. In: Churg AM, Myers
JL, Tazelaar HD, Wright JL, eds. Thurlbeck’s Pathology of the Lung. 3rd ed. New
York, NY: Thieme; 2005:769–862.
66. Jones Williams W. Beryllium disease. Postgrad Med J. 1988; 64(753):511–
516.
67. Freiman DG, Hardy HL. Beryllium disease. The relation of pulmonary
pathology to clinical course and prognosis based on a study of 130 cases from the
U.S. beryllium case registry. Hum Pathol. 1970;1(1):25–44.
68. Williams WJ. A histological study of the lungs in 52 cases of chronic
beryllium disease. Br J Ind Med. 1958;15(2):84–91.
69. Spagnolo P, Rossi G, Cavazza A, et al. Hypersensitivity pneumonitis: a
comprehensive review. J Investig Allergol Clin Immunol. 2015;25(4):237–250.
70. Miller R, Allen TC, Barrios RJ, et al. Hypersensitivity pneumonitis a
perspective from members of the Pulmonary Pathology Society. Arch Pathol Lab
Med. 2018;142(1):120–126.
71. Selman M, Buendı́a-Roldán I. Immunopathology, diagnosis, and
management of hypersensitivity pneumonitis. Semin Respir Crit Care Med.
2012;335:543–554.
72. Hariri LP, Mino-Kenudson M, Shea B, et al. Distinct histopathology of
acute onset or abrupt exacerbation of hypersensitivity pneumonitis. Hum Pathol.
2012;43(5):660–668.
73. Coleman A, Colby TV. Histologic diagnosis of extrinsic allergic alveolitis.
Am J Surg Pathol. 1988;12(7):514–518.
74. Churg A, Bilawich A, Wright JL. Pathology of chronic hypersensitivity
pneumonitis. What is it? What are the diagnostic criteria? Why do we care? Arch
Pathol Lab Med. 2018;142(1):109–119.
75. Kern RM, Singer JP, Koth L, et al. Lung transplantation for hypersensitivity
pneumonitis. Chest. 2015; 147(6):1558–1565.
76. Barrios RJ. Hypersensitivity pneumonitis: histopathology. Arch Pathol Lab
Med. 2008;132(2):199–203.
77. Khoor A, Leslie KO, Tazelaar HD, Helmers RA, Colby TV. Diffuse
pulmonary disease caused by nontuberculous mycobacteria in immunocompe-
tent people (hot tub lung). Am J Clin Pathol. 2001;115(5):755–762.
78. Katzenstein ALA. Katzenstein and Askin’s Surgical Pathology of Non-
Neoplastic Lung Disease. 4th ed. Philadelphia, PA: Elsevier; 2006.
79. Gal AA, Salinas FF, Staton GW Jr. The clinical and pathological spectrum
of antineutrophil cytoplasmic autoantibody-related pulmonary disease. A
comparison between perinuclear and cytoplasmic antineutrophil cytoplasmic
autoantibodies. Arch Pathol Lab Med. 1994;118(12):1209–1214.
80. Gaudin PB, Askin FB, Falk RJ, Jennette JC. The pathologic spectrum of
pulmonary lesions in patients with anti-neutrophil cytoplasmic autoantibodies
specific for anti-proteinase 3 and anti-myeloperoxidase. Am J Clin Pathol. 1995;
104(1):7–16.
81. Nguyen Y, Guillevin L. Eosinophilic granulomatosis with polyangiitis
(Churg-Strauss). Semin Respir Crit Care Med. 2018;39(4):471–481.
82. Masi AT, Hunder GG, Lie JT, et al. The American College of Rheumatology
1990 criteria for the classification of Churg-Strauss syndrome (allergic granulo-
matosis and angiitis). Arthritis Rheum. 1990;33(8):1094–1100.
83. Katzenstein AL. Diagnostic features and differential diagnosis of Churg-
Strauss syndrome in the lung. A review. Am J Clin Pathol. 2000;114(5):767–772.
Pathology of Granulomatous Pulmonary Diseases—Rosen
 84. Koss MN, Antonovych T, Hochholzer L. Allergic granulomatosis (Churg-
Strauss syndrome): pulmonary and renal morphologic findings. Am J Surg Pathol.
1981;5(1):21–28.
85. Katzenstein AL, Liebow AA, Friedman PJ. Bronchocentric granulomatosis,
mucoid impaction, and hypersensitivity reactions to fungi. Am Rev Respir Dis.
1975;111(4):497–537.
86. Bosken CH, Myers JL, Greenberger PA, Katzenstein AL. Pathologic features
of allergic bronchopulmonary aspergillosis. Am J Surg Pathol. 1988;12(3):216–
222.
87. Myers JL, Katzenstein AL. Granulomatous infection mimicking broncho-
centric granulomatosis. Am J Surg Pathol. 1986;10(5):317–22.
88. Dail DH. Bronchial and transbronchial diseases. In Dail DH, Hammar SP,
eds. Pulmonary Pathology. 2nd ed. New York, NY: Springer-Verlag; 1994:79–119.
89. Mukhopadhyay S, Katzenstein AL. Pulmonary diseases due to aspiration of
food and other particulate matter: a clinicopathologic study of 59 cases
diagnosed on biopsy or resection specimens. Am J Surg Pathol. 2007;31(5):
752–759.
90. Tomashefski JF Jr, Hirsch CS. The pulmonary vascular lesions of
intravenous drug abuse. Hum Pathol. 1980;11(2):133–145.
91. Sigdel S, Gemind JT, Tomashefski JF Jr. The Movat pentachrome stain as a
means of identifying microcrystalline cellulose among other particulates found in
lung tissue. Arch Pathol Lab Med. 2011;135(2):249–254.
92. McNearney T, Bajaj C, Boyars M, Cottingham J, Haque A. Total parenteral
nutrition associated crystalline precipitates resulting in pulmonary artery
occlusions and alveolar granulomas. Dig Dis Sci. 2003;48(7):1352–1354.
93. Hirche TO, Lambrecht E, Wagner TO. Crack-syndrome: the pulmonary
complications of inhaled cocaine. A review a propos a case report. Pneumologie.
2002;56(11):684–688.
94. Ciriaco P, Rossetti F, Carretta A, et at. Spontaneous pneumothorax in
cocaine users. QJM. 2019;112(7):519–522.
95. Newman LS. Metals that cause sarcoidosis. Semin Respir Infect. 1998;
13(3):212–220.
96. Gebbers JO, Burkhardt A, Tetzner C, Rüdiger HW, von Wichert P. ‘‘Hair-
spray lung.’’ Clinical and morphological findings. Schweiz Med Wochenschr.
1980;110(16):610–615.
97. Larsen BT, Chae JM, Dixit AS, Helmers RA. Methotrexate pneumonitis:
review of the literature and histopathological findings in nine patients. Am J Surg
Pathol. 2019;43(10):1331–1340.
98. Rambhia PH, Reichert B, Scott JF, et al. Immune checkpoint inhibitor-
induced sarcoidosis-like granulomas. Int J Clin Oncol. 2019;24(10):1171–1181.
Arch Pathol Lab Med—Vol 146, February 2022
99. Cohen Aubart F, Lhote R, Amoura A, et al. Drug-induced sarcoidosis: an
overview of the WHO pharmacovigilance database. J Intern Med. 2020;288(3):
356–362.
100. Chiriaco M, Salfa I, Di Matteo G, Rossi P, Finocchi A. Chronic
granulomatous disease: clinical, molecular, and therapeutic aspects. Pediatr
Allergy Immunol. 2016;27(3):242–253.
101. Moskaluk CA, Pogrebniak HW, Pass HI, Gallin JI, Travis WD. Surgical
pathology of the lung in chronic granulomatous disease. Am J Clin Pathol. 1994;
102(5):684–691.
102. Cinetto F, Scarpa R, Rattazzi M, Agostini C. The broad spectrum of lung
diseases in primary antibody deficiencies. Eur Respir Rev. 2018;27(149):180019.
103. Prasse A, Kayser G, Warnatz K. Common variable immunodeficiency-
associated granulomatous and interstitial lung disease. Curr Opin Pulm Med.
2013;19(5):503–509.
104. Park JH, Levinson AI. Granulomatous-lymphocytic interstitial lung disease
(GLILD) in common variable immunodeficiency (CVID). Clin Immunol. 2010;
134(2):97–103.
105. Hurst JR, Verma N, Lowe D, et al. British Lung Foundation/United
Kingdom Primary Immunodeficiency Network consensus statement on the
definition, diagnosis, and management of granulomatous-lymphocytic interstitial
lung disease in common variable immunodeficiency disorders. J Allergy Clin
Immunol Pract. 2017;5(4):938–945
106. Larsen BT, Smith ML, Tazelaar HD, Yi ES, Churg A. GLILD revisited:
pulmonary pathology of common variable and selective iga immunodeficiency.
Am J Surg Pathol. 2020;44(8):1073–1081.
107. Brincker H. Sarcoid reactions in malignant tumours. Cancer Treat Rev.
1986;13(3):147–156.
108. Brincker H. The sarcoidosis-lymphoma syndrome. Br J Cancer 1986;54(3):
467–473.
109. de Charry F, Sadoune K, Sebban C, et al. Association of lymphoma and
granulomatosis: a case series. Rev Med Interne. 2016;37:453–459.
110. Cohen PR, Kurzrock R. Sarcoidosis and malignancy. Clin Dermatol. 2007;
25(3):326–333.
111. Pavic M, Debourdeau P, Vacelet V, Rousset H. Sarcoidosis and sarcoid
reactions in cancer. Rev Med Interne. 2008;29(1):39–45.
112. Butt S, Alzebdeh R, Kable TD, Soubani AO. Non-caseating granulomas in
patients after the diagnosis of cancer: clinical characteristics and outcome.
Sarcoidosis Vasc Diffuse Lung Dis. 2011;28(1):444–449.
Pathology of Granulomatous Pulmonary Diseases—Rosen 251