Moderators: Dr. Dani Zander, Dr. David Hwang and Dr. Osamu Matsubara
Section 4 -
Mimics of Lung Infection
One of the greatest challenges for the pathologist is to classify non-neoplastic lung diseases into
specific disorders. Pattern recognition is the mainstay of histo-pathological diagnosis and it is of
great importance in the evaluation of lung biopsies.
Since the lung responds to injury in a stereotypic fashion, irrespective of etiology, the various
pathological findings can represent several different diagnoses under consideration. Not infrequently,
the lung biopsy shows features that initially suggest an infection, but is subsequently proven to be
some other type of pathological process.
These mimics can be considered within the framework of three general categories: 1) those in which
the pathological findings resemble an infection, 2) those
in which the diagnosis of an infection necessitates a thorough clinicopathological correlation, and 3)
those in which the clinical or pathological presentation suggests an infection, yet the pathological
findings point to another diagnosis (TABLE 1).
A. Pathological Mimics
The pathological mimics of infection have histopathologcial features that overlap with
other disorders. Certain non-infectious disorders associated with a granulomatous inflammatory
infiltrate pose the greatest problems for the pathologist. A large number of entities can cause
necrotizing and non-necrotizing granulomatous inflammation in the absence of infection. In terms of the
former, Wegener's granulomatosis is a systemic vasculitic disorder that causes necrotizing granulomas in
the lung, but also can affect the kidneys and head and neck. The necrotizing granulomas have a
distinctive appearance with peripheral pallisading and central necrosis. These granulomas may somewhat
resemble those seen in tuberculosis and in certain fungal disorders, such as blastomycosis and
coccidioidomycosis. The presence of "tuberculoid-type" granulomas in this setting would be more
worrisome for infection. Often, the broad areas of "geographic necrosis" bear some resemblance to the
"caseous" necrosis seen in certain mycobacterial or fungal infections. The associated vasculitis seen in
WG typically affects medium- to small-sized arteries and should be recognized in areas not associated
with necrosis. This is an important consideration, since in certain infections or in infarction, the
inflammatory cells can involve adjacent blood vessels and mimic a vasculitis.
Sarcoidosis is a non-necrotizing granulomatous disorder that poses considerable diagnostic
problems for the pathologist. Since certain infections may result in both necrotizing and
non-necrotizing granulomas, the pathologist should be concerned that limited samples from transbronchial
or needle biopsies may be misleading. In active sarcoidosis the characteristic well-delineated
granulomas follow a bronchovascular and interstitial distribution. Small foci of fibrinoid, granular, or
eosinophilic necrosis may be present in sarcoidosis; more extensive necrosis with or without vasculitis
may be seen necrotizing sarcoid granulomatosis. Although histochemical stains for acid fast bacilli and
fungi are useful in confirming the presence of an infection, the absence of organisms in these stains
does not exclude this possibility. Certainly, additional correlations with microbiologcal cultures are
needed to confirm or exclude an infectious diagnosis.
Hamazaki-Wesenberg bodies which occur in various granulomatous disorders may mimic fungal organisms.
These distinctive small (1-15μm) round, ovoid, or spindle-shaped yellow-brown structures may be seen
in H&E stain. They stain black with GMS or Fontana stain and red with PAS stain. The location of
these structures in the subcapsular sinus and lack of association with necrosis are key diagnostic
Other non-infectious lung diseases evoke a prominent inflammatory response reminiscent of
that seen in certain infections. Lymphocytic infiltrates are seen in non-infectious lung diseases,
particularly for those disorders involving the airways or interstitum. Neutrophilic infiltrates are
commonly associated with a number of acute infectious processes, but are a prominent feature in certain
pulmonary alveolar hemorrhagic disorders. A neutrophilic capillaritis, which typically occurs in
ANCA-associated disorders and other connective tissue diseases, can be difficult to separate from an
early bronchopneumonia. Various types of pulmonary eosinophilic disorders can occur in the absence of
infection, and consideration of certain fungal and parasitic disorders is always warranted.
Hyperplastic alveolar lining cells that occur in the setting of acute lung injury such as
in diffuse alveolar damage can resemble the changes seen in viral infections. The presence of many
enlarged hob-nail shaped cells with clumped nuclear chromatin, eosinophilic nucleoli, and the absence of
nuclear / cytoplasmic inclusions suggests a reactive process. However, since there can be some
morphological overlap with viral infections, judicious use of immunohistochemical stains may be necessary
in some cases.
B. Clinicopathological Mimics
Several disorders affecting the lungs show features that warrant a careful
clinicopathological correlation to exclude an infection. In many of these disorders, the pathological
findings are variable and overlap with other entities in the differential diagnosis. For example, lung
biopsies from patients with acute interstitial pneumonia or with connective tissue disorders, such as
systemic lupus erythematosus, may show diffuse alveolar damage. Special stains and correlation with
microbiological cultures and serological tests are needed to exclude an infection or autoimmune
process. Another example would be in the setting of pulmonary drug toxicity. A large number of drugs
may cause direct and indirect injury and exhibit a wide spectrum of histopathological changes. It is
only through careful correlation and exclusion of other disorders that this diagnosis can be
C. Radiological / Clinical Mimics
In various clinical settings under which an infection is thought to be the main diagnosis,
another pathological process is evident in the lung biopsy. These are the disorders in which there is
considerable clinical overlap, yet the distinctive and often characteristic histopathological features
make it relatively easy for the pathologist to render these diagnoses. Even as our radiologist
colleagues become more confident in their ability to arrive at a specific diagnoses, it is not that
uncommon for the pathologist to "surprise the clinician and radiologist" with an unsuspected diagnosis.
a multicentric bronchioloalveolar carcinoma or lymphangitic metastases may show radiographic
resemblance to an infectious pneumonia. Several of the other disorders listed in TABLE 1 have unique
pathological features which would exclude the possibility of infection.
Lung biopsies are preformed in the hopes of achieving useful information that would lead to
appropriate clinical management. The separation of infectious lung diseases from its mimics may be
straight-forward or more complex, necessitating clinicopathological correlation. As novel therapeutic
modalities are implemented,
there certainly will be many opportunities and challenges for the pathologist.
Mimics of Infection
1. Pathological mimics|
Asthma / chronic bronchitis
Chronic hypersensitivity pneumonitis
Eosinophil-associated lung disease
Pneumocyte hyperplasia in acute lung injury
2. Clinicopathological mimics|
Acute interstitial pneumonia
Connective tissue disorders: systemic lupus erythematosus
Bronchiolitis obliterans organizing pneumonia
Thromoembolic lung disease
3. Radiological / Clinical Mimics|
Lymphoproliferative disorders & lymphoma
Rejection in lung and heart-lung transplantation
Obliterative bronchiolitis in bone marrow transplant patients
Pulmonary alveolar proteinosis
DAD / Pulmonary edema
Acute & chronic aspiration pneumonia
Lipoid pneumonia (exogenous / endogenous)
- Intravascular foreign body
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