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Jornal de Pneumologia

Print version ISSN 0102-3586On-line version ISSN 1678-4642

J. Pneumologia vol.29 no.3 São Paulo May/June 2003 



Interstitial granulomatous pulmonary diseases: a diagnostic approach for the general pathologist*



Aloísio S. Felipe da SilvaI; Danieli Cheke da RosaI; Vera Luiza CapelozziII

IResident Physician of Pathological Anatomy.
IIAssociated Professor of the Department of Pathology.





Some kinds of interstitial pneumonia present a histopathological pattern dominated by sarcoid - necrotizing or non-necrotizing - granulomas, which can be divided into two main groups: infectious and non-infectious. The infectious causes include tuberculosis, histoplasmosis, fungi in general, paracoccidioidomycosis, ascaridiasis, echinococcosis and dirophilariosis. The non-infectious causes include histiocytosis-X, hipersensitivity pneumonia, vasculitis, lymphomas, sarcoidosis, and pneumoconioses such as silicosis and berylliosis. The purpose of this review is to provide a practical guideline to enable general pathologists to make the differential diagnosis of granulomatous pulmonary diseases. For this purpose, anatomical-clinical-radiological correlations will be presented and targeted to each diagnosis discussed. Whenever a granulomatous inflammatory process is in progress, the search for infective agents by direct observation, by culture, and by histochemical methods should be mandatory. The histological aspects of infectious granulomas to be analyzed should include their random histo-anatomical location, the type of inflammatory reaction, and necrosis. A panel of complementary reactions (immunohistochemistry and PCR) should identify the infectious agent and, whenever their results and the culture are negative, the possibility of non-infectious granulomatous diseases has to be evaluated. In such cases, the histo-anatomical distribution (bronchocentric, lymphangitic, angiocentric, random), the qualitative characteristics of the lesions (type of necrosis and inflammatory reaction), and the correlation with the X-ray findings will help the diagnosis.

Key words: Granulomatous diseases. Histologic diagnosis. Interstitial pulmonary diseases. Pathology. Granuloma.



Acronyms and abbreviations used in this work
PCR – Polymerase chain reaction
BCG – Bacillus Calmette-Guérin
CHP – Chronic hypersensitivity pneumonia
IgG-Fc –
ANCA – anti-neutrophil cytoplasm auto-antibody
BALT – Bronchial associated lymphoid tissue



Diffuse granulomatous pulmonary diseases form a heterogeneous group of clinical and physiopathological entities.(1-5) However, the formation of granulomas as a common histopathological feature constitutes an important diagnostic element, since it orients the clinical reasoning towards a relatively limited group of etiologies.(6) An accurate diagnosis is based on a correlation between clinical and radiological data and the specific histological, histochemical and microbiological characteristics of each disease.(7-9) Molecular and immunohistochemical methods may be necessary. The path to the final histopathological diagnosis should be systematized, considering both physiopathology and the differential morphological aspects of granulomatous diseases.

Granulomatous inflammation as a pulmonary defense mechanism

The respiratory system is exposed to a variety of potentially harmful agents, many of which are environmental and aggress the organism by inhalation. There are several lines of defense against such agents, covering from the upper airways to the alveolar spaces.

The first line of defense of the respiratory system consists of mechanical factors, such as hair and the coughing reflex, mucociliary transport, and biochemical mucus components such as immunoglobulins and complement. Although unspecific, these mechanisms prevent most of the external agents from reaching the alveolar space. Among the unspecific defense mechanisms of the alveolar space, there are the pulmonary surfactant and the alveolar macrophages.(10) The latter can stimulate the rapid migration of neutrophils into the alveolar lumen, as initial phagocytes.

Once exposed to the antigen, the alveolar macrophage can activate the specific immune response, through antigenic presentation. This response is characterized by cytokine-mediated clonal lymphocyte expansion, migration of lymphocytes, plasmacytes and monocytes into the interstitium and the alveolar space. Effector mechanisms mediated by specific immunoglobulins, effector T-cells, and macrophage activation are also triggered.

The granulomatous inflammatory process is one of the effector mechanisms of the immune response and the last line of pulmonary defense. This response pattern arises as a result of certain aggressive agents or antigens, which could not be eliminated by the previously mentioned mechanisms. The formation of a granuloma is determined by an interaction between macrophages and T- lymphocytes, triggered by antigenic presentation, and mediated by cytokines. The process culminates with the recruiting, proliferation and activation of both cell types, besides fibroblast migration.(11,12)

Although previously exemplified for preferentially inhaled agents, granuloma formation also occurs in a group of diseases in which the immune response plays a crucial role in the clinical and anatomicopathological manifestations, even though their etiological aspects remain poorly elucidated, such as, for example, sarcoidosis.


Granulomatous pulmonary diseases

The granulomatous pulmonary diseases are summarized in Chart 1, divided into two main groups: infectious and non-infectious.



Infectious causes include tuberculosis, histoplasmosis, fungi in general, paracoccidioidomycosis, ascaridiasis, echinococcosis, and dirophilariosis.

Non-infectious causes include histiocytosis-X, hypersensitivity pneumonia, vasculitis, lymphomas, sarcoidosis, and pneumoconioses, such as silicosis and berylliosis.


Initial approach: infectious diseases

Once a granulomatous inflammatory process is detected, the search for infectious agents through direct observation, culture, and histochemical methods is mandatory. Infectious granulomatous diseases are important differential diagnoses, considering their prevalence, clinical-pathological heterogeneity, and the available therapeutic possibilities.

The initial approach usually includes a search for the alcohol-acid-resistant bacillus (Ziehl-Neelsen staining) and mycobacteria detection, and silver-methenamine staining (Grocott staining) to identify fungi.(6,11,12) Nocardia can also be detected by these methods. Actinomyces sp can be identified by Gram staining.(12)

The search for possible infectious agents causing certain histopathological pictures of the granulomatous disease also counts on resources provided by immunohistochemistry and molecular biology. If there is a clinical-radiological suspicion, a search for BCG antigen can be performed for mycobacteria, and for fungus antigens of P. brasiliensis and P. carinii. The BCG antigen has been intensely used by some groups, whereas the use of P. brasiliensis and P. carinii antigens is less common. Many pathologists are particularly critical regarding the first one, and many do not know it, but there are data from the literature attesting to its validity.(13,14) PCR (polymerase chain reaction) can be used in histological pictures suspected of mycobacteriosis, where the infectious agent was not identified by other methods.(13,14) It is estimated that 106 microorganisms per millimeter of tissue are required for Ziehl-Neelsen staining to be positive.(13) A positive PCR result is not considered valid from the diagnostic viewpoint, unless one or more microorganisms can be identified inside the tissue by the Ziehl-Neelsen technique.

If the panel of complementary reactions was unable to identify an infectious agent, the histological and radiological characteristics(9) are fundamental for the clinical management and establishment of diagnostic hypotheses, while waiting for the microbiological culture result.

Tissue culture techniques require from three to six weeks to identify the microorganism.(13,15)

Chart 2 exemplifies the sequence of events in the diagnosis of granulomatous diseases.



Differential histological characteristics: infectious diseases

The histological aspects of infectious granulomas include their random histo-anatomic location and the presence of an inflammatory reaction (Figure 1) and necrosis (Figure 2).





In tuberculosis and pulmonary mycoses, the distribution of granulomas is random, i.e., the pathological process can affect any region of the pulmonary lobes, without any preferential location.(8,12) A random granulomatous process with the presence of both necrosis and inflammation, although not pathognomonic, increases the probability of an infectious disease diagnosis. However, a few comments are necessary.

In immunosuppressed patients, inflammation is frequently discreet or absent (Figure 1). Necrosis is predominant, with only outlines of granulomas, and there may be no giant cells.(12)

Different types of necrosis can suggest the etiological agent. Thus, caseous necrosis is typical for tuberculosis and also for nocardiosis (Figure 2). Suppurative (liquefactive) necrosis is present in mycoses, while dirophilariosis is accompanied by coagulative necrosis. Figures 3 to 5 exemplify the radiological distribution of the lesions in tuberculosis.







If the panel of complementary reactions (histochemistry, immunohistochemistry, and PCR) was unable to identify an infectious agent and the culture results were negative, the possibility of a non-infectious granulomatous disease has to be evaluated. To this effect, the anatomical-clinical-radiological correlation is fundamental.(9)


Differential histological characteristics: non-infectious diseases

Each non-infectious granulomatous pulmonary disease presents distinctive clinical and radiological characteristics, particularly in the classical form. However, these characteristics may present various degrees of overlapping, being even mistaken for possible infectious diseases. In this context, the histopathological test is of fundamental importance to confirm the granulomatous nature, and to rule out a possible infectious cause. Moreover, the etiopathogenic differences are reflected by the histological presentation of each disease, allowing to differentiate them morphologically with a certain degree of accuracy.

The histological characteristics evaluated are the histo-anatomical distribution of granulomas and the presence of necrosis. Charts 3 and 4 summarize the different categories.





Bronchocentric distribution

Diseases with a bronchocentric or inhalation distribution, like chronic hypersensitivity pneumonia and histiocytosis-X, tend to affect the axial region of the pulmonary lobe, being characterized as airway-centered diseases.(8)

Chronic hypersensitivity pneumonia (CHP) is characterized by a chronic interstitial inflammatory process, usually secondary to prolonged exposure to inhaled organic dusts and occupational antigens. CHP can present a distinctive histopathological pattern when all three characteristics are present: 1) interstitial cellular bronchiolocentric pneumonia, 2) non-caseating granulomas, and 3) intraluminal fibrosis or organizing pneumonia (Figure 6).(16,17) The formation of incomplete non-necrotizing granuloma occurs, and can be accompanied by obliterating bronchiolitis in 25% to 50% of the cases, and by obliterating bronchiolitis with organizing pneumonia in 15% to 25%.(18) The radiological presentation can be seen in Figures 7 and 8.







Histiocytosis-X or Langerhans cell histiocytosis is characterized by the clonal expansion of antigen-presenting dendritic cells (Langerhans cells), a kind of histiocytes. There are different forms of clinical presentation: acute disseminated children’s disease (Letterer-Siwe syndrome), chronic multifocal children’s disease (Hand-Schüller-Christian syndrome), indolent localized disease (eosinophilic granuloma), systemic disease with pulmonary involvement, and primary pulmonary Langerhans cell histiocytosis. Pulmonary affection (Figure 9) is characterized by stellate nodules or granulomas, formed by dendritic cells with varying proportions of lymphocytes, plasmacytes, neutrophils e eosinophils.(19-21) The dendritic cells express proteins S100 and CD1a, and can be identified by immunohistochemistry.(20-21) They exhibit a broad and frequently granulous cytoplasm and nuclei with invaginations (Figure 10). Electron microscopy reveals characteristic cytoplasmatic Birbeck granules (Figure 11).(22) Sometimes, they can be accompanied by necrosis. Other characteristics of the Langerhans cells include the presence of C3, receptors for IgG-Fc and Ia antigen (HLA-DR).(22,23) Figure 12 shows the radiological aspect of histiocytosis-X.









Angiocentric distribution

In this group of diseases, the affection is centered in the pulmonary vessels, sometimes in the arteries and veins, sometimes in the capillaries.(8) Wegener’s granulomatosis, microscopic polyangiitis, the Churg-Strauss syndrome, and drug-induced ANCA-associated vasculitis belong to this group. They are characterized by inflammatory vascular affection and by the association with positive titles of the anti-neutrophil cytoplasm auto-antibody (ANCA). Although they are distinct clinical entities, they have several histopathological and etiopathogenic aspects in common.

Wegener’s granulomatosis is characterized by a triad consisting of necrotizing granulomatous inflammation of the upper and lower respiratory tract, focal necrotizing vasculitis of small- and medium-caliber vessels, and renal disease, in the form of focal necrotizing or crescentic glomerulitis.(24) In the pulmonary parenchima, the necrotizing granulomas can flow together, leading to a characterisitic pattern of basophilic geographical necrosis (Figure 13). The formation of neutrophilic micro-abscesses with a variable number of giant cells also occurs. The pulmonary vessel damage occurs as necrotizing vasculites (Figure 14) or granulomatous vasculites of the arterioles and venules, with or without capillaritis (Figure 15). There may be cutaneous damage by leukocytoclastic vasculitis. Figures 16 to 18 present the radiographic aspect of Wegener’s granulomatosis.













Microscopic polyangiitis affects arterioles, venules and capillaries, the lesion being rarer in larger vessels.(25) Necrotizing glomerulitis and pulmonary capillaritis are common. Isolated cutaneous leukocytoclastic vasculitis may occur.

In allergic granulomatosis and angiitis (Churg-Strauss syndrome), the vascular lesions resemble those of microscopic polyangiitis, mainly with necrotizing vasculitis and extravascular granulomas.(26) There is, however, a strong association here with allergic conditions like severe asthma and rhinitis.(27) There is systemic hypereosinophilia, that can be detected in peripheral blood. Severe renal alterations are rare, and there may be fever. In stage 1, diffuse pulmonay infiltration by eosinophils occurs, while in stage 2 vasculitis, necrosis and granulomas are more pronounced (Figure 19).



Lymphangitic distribution

This group of diseases, which includes sarcoidosis and some pulmonary lymphomas, presents granulomas distributed along the pulmonary lymph ways, both on the central axis and along the peripheral lobular interstitium, the septa, and subpleural regions.(8)

Pulmonary lymphomas account for 0.5% of the primary lung tumors.(28) They are classified in ways as variable as systemic lymphomas; however, the most common histological type is the low-degree small lymphocyte lymphoma (Figure 20). This category comprises 50% to 90% of the primary pulmonary lymphomas.(29) They are B-cell neoplasias originated from BALT (bronchial associated lymphoid tissue), which involve, in up to 20% of cases, the bone marrow, and are related to monoclonal serum proteins. Radiologically, they can be diffuse or localized. They affect mainly patients in their sixties, usually asymptomatic; such patients have a long survival.



Angiocentric immunoproliferative lesions (angiocentric lymphomas or lymphomatoid granulomatosis) constitute the second most common group.(30) Figure 21 shows their radiological aspect. Clinically, they affect men in their fifties, presented as bilateral pulmonary nodules, sometimes involving other organs such as the central nervous system and the skin. Histopathologically, they are T-cell or B-cell lymphomas infected by the Epstein-Barr virus, usually of a high degree, which form nodules and perilymphatic infiltrates. Necrosis and polymorphonuclear infiltrates may also develop.



Sarcoidosis is characterized by the presence of non-necrotizing epithelioid granulomas in different organs and systems affecting, in the great majority of cases, the lungs and hilar lymph nodes.(31) Its etiology remains unknown.(32) Histologically, it is characterized by "hard" granulomas, in which the epithelioid cell is the dominant element (Figure 22), distributed within the pulmonary interstitium along the pleura and interlobular septa, and around the vasculo-bronchial axis.(33) Differential diagnosis is made with other granulomatous diseases, such as mycobacterioses(13) and berylliosis,(34) usually being a diagnosis by exclusion. Figure 23 exemplifies the radiological aspect of sarcoidosis.





Nodular diseases

Rheumatoid pulmonary nodule is uncommon in patients with rheumatoid disease, occurring in less than 1% of the cases.(35) Its frequency is higher in men with active articular disease, and involves an increase of the rheumatoid factor. Histologically, it resembles the subcutaneous rheumatoid nodules, which are more common, and are characterized by a central area of fibrinoid necrosis surrounded by a belt of epithelioid macrophages and numerous lymphocytes and plasmacytes, characterizing the palisade granuloma.(36) Its differential diagnosis with infectious diseases or malignant granulomatoses is difficult. Figure 24 shows the radiological aspect of rheumatoid nodule.




Interstitial pneumonia can present a histopathological pattern dominated by sarcoid granulomas, caseating or not, which can be grouped into infectious and non-infectious cases. The infectious causes include tuberculosis, histoplasmosis, fungi in general, paracoccidioidomycosis, ascaridiasis, echinococcosis, and dirophilariosis. The non-infectious causes include histiocytosis-X, hypersensitivity pneumonia, vasculites, lymphomas, sarcoidosis, and pneumoconioses such as silicosis and berylliosis. The histological aspects of infectious granulomas to be analyzed include their random histo-anatomic location, the kind of inflammatory reaction, and necrosis. A panel of complementary reactions (immunohistochemistry and PCR) should identify any infectious agent and, if both their results and the culture are negative, the possibility of a non-infectious granulomatous disease will have to be evaluated. In such cases, the histo-anatomic distribution (bronchocentric, lymphangitic, angiocentric, random), the qualitative characteristics of the lesions (kind of necrosis and inflammatory reaction) and the correlation with X-rays will help in the diagnosis.



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Correspondence to
Vera Luiza Capelozzi
Professora Associada do Departamento de Patologia, Faculdade de Medicina da USP
Av. Dr. Arnaldo, 455, 1º andar, sala 1.143
01246-903 – São Paulo, SP Brazil
Phone: +55 11 3066-7427; fax: +55 11 5096-0761

Received for publication on 11/06/02
Approved, after revision, on 02/21/03.



* Lecture given during the III Annual Course on Interstitial Pulmonary Diseases – March 1 and 2, 2002. Scientific support: Fapesp – Fundação de Amparo à Pesquisa do Estado de São Paulo (São Paulo State Foundation for the Support of Reseach). LIM05-HCFMUSP – Medical Investigation Laboratory – Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. CNPq – Conselho Nacional de Desenvolvimento Científico e Tecnológico (National Council for Scientific and Technological Development).

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