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Granuloma - Focal collection of inflammatory cells at sites of tissue infection and includes activated macrophages (epithelioid cells), Langhans’ giant cells, and lymphocytes.
Caseation necrosis - Regions in granulomas with eosinophilic, granular, and friable (cheeselike) cellular debris with necrosis
Granulomatous inflammation - A distinctive pattern of chronic inflammatory reaction characterized by focal accumulation of activated macrophages (epithelioid histiocytes)
Granulomatous inflammation is a cell-mediated hypersensitivity-type reaction to persistent and nondegradable microbial agents. Pulmonary infectious granulomatous inflammation is encountered in fungal, mycobacterial, parasitic and bacterial infections (see below).
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Mycobacterium tuberculosis complex: M tuberculosis (common), M bovis (uncommon), and M africanum (rare)
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Mycobacterial infections: Mycobacterium tuberculosis complex and nontuberculous mycobacteria
M tuberculosis complex includes M tuberculosis (common), M bovis (uncommon), and M africanum (rare).
M tuberculosis is a nonmotile, aerobic, intracellular bacterial pathogen measuring. 5-3 µm. Tubercle bacilli cause infection by inhalation route. The factors that determine progression of disease include the number of bacilli inhaled, bacterial virulence, susceptibility of the host, and the immunologic response of the host to the infection. 
In the lung, the initial infection may be contained and walled off by activated macrophages, lymphocytes, and Langerhans giant cells, leading to the formation of granulomatous inflammation.  This mechanism contains the infection but may not eradicate. Initial infections that are not contained may cause either progressive local disease (primary progressive pulmonary tuberculosis), or may disseminate hematogenously to seed other organs such as kidney, CNS, or bones, occasionally causing miliary tuberculosis. Infections initially contained by host defenses (latent tuberculosis) may, at a later time, in the face of immunosuppression, reactivate to cause either progressive local disease or disseminate.
Primary pulmonary tuberculosis results from initial infection with tubercle bacilli. Primary lung focus is localized to subpleural location of upper lobe and superior part of the lower lobes with involvement of hilar and mediastinal lymph nodes (Ghon complex).
Pulmonary lesions progress to tuberculous pneumonia, cavitate, and can shed tubercle bacilli into bloodstream and result in miliary tuberculosis. 
Postprimary (secondary or reactivation) tuberculosis
This is the most common form of tuberculosis in adults. Reactivation of latent M tuberculosis is seen in the subapical posterior lung segments and is likely due to high pO2 concentration and limited lymphatic drainage. Host factors that contribute to reactivation include poor nutrition, substandard (close) living conditions, pulmonary silicosis, cancer, diabetes mellitus, advanced age, corticosteroids; immunosuppressive agents, and HIV infection.
Gross and microscopic pathology
Caseous necrosis is a hallmark of tuberculosis and leads to destruction of mycobacteria, as well as lung parenchyma (see the image below).
Bacterial replication is inhibited within the caseous focus due to low oxygen tension and low PH.  The granulomas of tuberculosis (see the first image below) are necrotizing and non-necrotizing, with involvement of lung parenchyma leading to peribronchial, perivascular, interstitial and alveolar granulomas and occasionally leading to exudative tuberculous granulomatous pneumonia (see the second image below). Stains commonly used to identify the mycobacteria are Ziehl-Neelsen and Fite. The bacilli stain bright red with a beaded pattern on acid fast stains.
These caseous lesions can either transform into fibrocaseous granulomas with dense fibrous capsule or get organized with fibrosis, calcification, and ossification or undergo liquefaction and cavitation. Cavitation occurs when the liquefied areas rupture into an airway and subsequently evacuated. This leads to dissemination of bacilli and development of tuberculous pneumonia. 
Miliary tuberculosis occurs when massive numbers of bacteria are spread hematogenously producing widespread lesions of the same size and age.
Nontuberculous pneumonia occurs in immunocompromised and immunocompetent host. The lesions are characterized by the accumulation of mycobacteria within foamy histiocytes and poorly formed granulomas.
Definitions and terminology used in fungal infections is as follows: 
Capsule - Colorless mucopolysaccharide coat covering the external aspect of the fungus cell
Dematiaceous - Naturally pigmented, usually brown or black
Dimorphic - Growth as hyphae in vitro at 25 º C and as budding yeasts or spherules in infected tissues or in vitro at 37 º C
Endospore - Asexual spore formed within a closed structure such as a spherule
Germ tube - Tubelike structure produced by conidium that eventually develops into a hypha
Hypha - Filament that forms the body of the fungus
Mycelium - Mass of intertwined and branched hyphae
Pseudohypha - Short hyphal-like structures produced by successive yeast buds that elongate that fail to separate
Septate - Hyphae with cross walls
Spherule - Round or spherical structure within which asexual endospores are produced by cytoplasmic cleavage
Sporangium - A closed structure within which asexual spores are produced by cytoplasmic cleavage
Histoplasmosis: Histoplasma capsulatum
Histoplasmosis is a respiratory infection caused by inhalation of airborne infectious conidia of H capsulatum and is endemic in Ohio, Mississippi river valleys, and the Caribbean islands. It is a dimorphic fungus with yeast forms in tissues (37 ºC) and hyphal forms in soil and culture (25 ºC). The yeast forms are thin-walled, spherical-to-oval shaped, 2-5 µm in diameter, and proliferate with narrow-based budding forms. [1, 2]
Primary pulmonary disease: Three forms of pulmonary disease are seen. Acute pulmonary histoplasmosis, chronic progressive form, and disseminated histoplasmosis.
Acute pulmonary histoplasmosis: This is associated with acute fibrinous exudate, lymphohistiocytic infiltrate, and small non-necrotizing and necrotizing granulomas. 
Chronic progressive histoplasmosis
Gross and Microscopic Pathology: The nodules of Histoplasma are well circumscribed, hyalinized, with a laminated yellow cut surface (see the image below). Grossly the nodules are indistinguishable from other granulomatous infections in the lung.
Chronic form is characterized by large granulomas with large central areas of necrosis rimmed by epithelioid histiocytes, lymphocytes, and occasional giant cells; this, in turn, is rimmed by variably thick fibrous capsule. Areas of calcifications within the central necrotic granuloma are frequently present. The microcalcifications may occasionally be mistaken for organisms. Small nonnecrotizing granulomas and organizing pneumonia are seen around the large granuloma and adjacent lung parenchyma.
Over time, these granulomas get hyalinized and calcified. Pulmonary vessels entrapped in the inflammatory process may show nonnecrotizing or necrotizing granulomas as a secondary phenomenon. Histoplasma fungal organisms are identified within the necrotic focus by performing a GMS and or a PAS stain. Yeast forms are not visible on H&E sections. Small oval-shaped yeast forms, 2-5 µm, with narrow based budding, are seen either singly or in clusters within the necrotic center (see the image below). Poorly stained (ghost forms), distorted or fragmented forms are commonly present.
Organisms similar in size such as pneumocystis, leishmania, and cryptococcus need to be differentiated from histoplasma. Depending on the plane of section of the tissue, pneumocystis organisms are either spherical, sickle, or crescent-shaped. Cryptococcal yeast forms are variable in size and shape and range from 2-20 µm and are visible on H&E sections.
Solitary histoplasma nodules may resemble neoplastic nodules radiologically, especially when they lack calcification, are minimally speculated, and seem to be enlarging on sequential chest radiographs.
Widely disseminated form occurs in severely immunocompromised patients. Lesions are seen in lung as well as extra pulmonary sites. Granulomas are typically absent, and the host reaction is predominantly histiocytic, characterized by intracellular multiplication of organisms, and morphologically identified as diffuse histiocytic proliferation packed with numerous intracellular organisms (see the image below).
Granulomatous pneumocystis jiroveci pneumonia
Primary exposure to pneumocystis occurs early in life; organisms remain in the latent form and are reactivated in immunocompromised host.
Four developmental forms are described: Trophozoites, precysts, sporozoites, and mature cysts.  Through cell-wall thickening, the trophozoites develop into precyst, and within precysts, through meiosis and mitosis, sporozoites are formed. Mature cyst contains 8 sporozoites. The cysts are the forms seen in tissue sections and are 5-7 µm and are identified by Gomori methenamine silver stain.
The typical features of pneumocystis pneumonia consist of chronic interstitial inflammation and frothy eosinophilic exudate. The exudate is punctuated by round basophilic dots that correspond to nuclei of sporozoites and trophozoites. Rarely, pneumocystis pneumonia presents as granulomatous inflammation in patients who are marginally immunocompromised.  Granulomas are loose to well-formed and associated with or without necrosis (see the first image below). Pneumocystis cysts are round-to-oval, crescent-shaped, disk-shaped, and boat-shaped organisms that are identified on silver stains. Yeast forms of histoplasma may be mistaken for cysts of pneumocystis and needs to be differentiated (see the second image below).
Morphological Comparison of Histoplasma and Pneueumocystis
Blastomycosis: Blastomyces dermatitidis
Blastomycosis is endemic in the Ohio and Mississippi River valley, around the Great Lakes, and in southeast United States. Infection of the respiratory tract occurs through inhalation of airborne conidia or mycelia and yeast forms develop once deposited in the distal airways.
Blastomyces is a dimorphic fungus with yeast forms in tissues (37 º C) and hyphal forms in culture (25 º C). Yeast forms are 8-15 µm in diameter, spherical, with a thick double-contoured refractile walls. Rarely, giant or macro forms ranging in size from 20-40 µm are seen. 
Primary pulmonary disease: Begins in the lung and remains confined to the lungs.
Acute blastomycosis of the lung is a suppurative infection with infiltration of neutrophils and abscesses. In chronic forms there is a mixed suppurative and granulomatous inflammatory reaction (see the images below). Disseminated forms are rarely seen in immuno-compromised host.Blastomycosis. A) Gross specimen of lung with a large yellow nodule in the upper lobe. B) H&E section of the mass with multiple necrotizing granulomas. C) H&E section high power showing numerous organisms in the lung, including many in giant cells. D) GMS stain demonstrates numerous yeast forms consistent with blastomycosis.A) H&E: large double-contoured yeasts in acute suppurative lung. B) GMS stain: Broad-based budding yeast form of blastomycosis.
Cryptococcosis: Cryptococcus neoformans
Natural habitat is soil mixed with excreta of birds (pigeons). Lung is the portal of entry, and infection is caused by inhalation of aerosolized organisms. Yeast forms are seen in tissues and cultures and are thin-walled, spherical to oval, encapsulated yeasts, varying in size from 2-20 µm, with narrow based budding are typically seen in tissues.
Mild or asymptomatic pulmonary infection is seen with mixed suppurative and granulomatous inflammatory reaction in immunocompetent host. [1, 5] Cerebromeningeal and disseminated forms of cryptococcosis are usually seen in immunocompromised host.
Gross and microscopic pathology
Grossly, the lesions in the lung are firm grayish-white nodules with central necrosis, similar to other granulomatous lesions of the lung. Histologically, the suppurative and granulomatous lesions are characterized by central necrosis with peripheral histiocytic reaction. The yeast forms are visible on H&E-stained sections as lightly eosinophilic, oval to round, thin-walled forms that are surrounded by a clear polysaccharide rich capsule (see the image below).
The capsule stains red with mucicarmine stain. Typically, variation in size and shape of the yeast exists and is best observed on GMS stain. The organisms are seen in the necrotic center as well as within histiocytes and giant cells, ranging in size from 2-20 µm. A study by Wang et al showed that Cryptococcus neoformans can enlarge its size to form titan cells during infection, and its diameter can reach up to 100 μm. 
The cryptococci within the necrotic center may be capsule deficient and may not be positive with mucicarmine stain. Cryptococci may occasionally be confused with histoplasma and Blastomyces. The round shape for cryptococcus versus oval shape for histoplasma, variation in size and shape for cryptococcus versus uniform size for histoplasma and double-contoured refractile wall of Blastomyces helps in the differentiation of cryptococcus from other fungi.
Coccidiomycosis: Coccidioides immitis
Also known as San Joaquin Valley fever, coccidiomycosis is endemic in the southwestern and western United States. It is a dimorphic fungus with yeast forms in tissue (37 º C) and hyphal forms in culture (30 º C). The tissue forms are present in macrophages or giant cells as thick-walled, nonbudding spherules 20-60 µm in diameter filled with endospores.
Gross and microscopic pathology
The pulmonary nodules seen in coccidioides are similar to histoplasmoma and other granulomatous inflammation of the lung. Grossly, these are well-circumscribed firm yellow laminated nodules.
Histologically, the granulomas are necrotizing and non-necrotizing, predominantly necrotizing with large necrotic center that is surrounded in the periphery by epithelioid histiocytes, lymphocytes, and multinucleated giant cells. These granulomas microscopically are similar to histoplasma. Causative organisms are identified within the necrotic field on H&E and silver stain. The coccidioides fungal organisms are one of the largest forms of all the common fungal organisms. The round spherules are 20-60 µm in diameter and contain numerous endospores. On a small biopsy, these endospores can be mistaken for other fungal yeast forms if seen without the large round spherule (see the images below). In such cases, one needs to correlate with microbiological cultures.
Aspergillus fumigatus, Aspergillus flavus, and Aspergillus niger are the most frequent pathogens.
The fungal organisms grow as branched (45ºC) and septate hyphae (5-10 µm) in infected tissues.
Allergic aspergillosis involves the nasal cavity, paranasal sinuses, and lower respiratory tract.
Allergic bronchopulmonary aspergillosis develops as a result of hypersensitivity to aspergillus antigens. Patients present with asthma, pulmonary infiltrates, peripheral eosinophilia, and elevated levels of serum IgE level. Pathologic lesions include mucoid impaction and bronchocentric granulomas.
Obstructive bronchial colonization is seen as a complication of cystic fibrosis, asthma, chronic bronchitis, and bronchiectasis.
Aspergilloma occurs when growth of fungus occurs in preformed cavities such as old tuberculous cavity or other cavitary lung disease or infarction.
Invasive aspergillosis develops in severely immunocompromised patients with invasion of blood vessels leading to pulmonary nodular infarcts (see the first image below) and hematogenous dissemination (see the second image below).
Mucor, Absidia, Rhizopus, and Cunninghamelia
The organisms are abundant in nature, with organisms recovered from bread, fruits, vegetables, soil, and manure. Opportunistic infections are seen in neutropenic and diabetic ketoacidotic patients. Pulmonary zygomycosis occurs following inhalation of the sporangiospores.
Gross and microscopic pathology
Lung is the most common organ involved in disseminated zygomycosis. The hyphae invade through the bronchial wall and into the vascular system and cause hemorrhagic pulmonary infarcts, acute bronchopneumonia, necrosis, and granulomatous inflammation (see the first 3 images below).  The hyphae are randomly distributed in necrotic center, wall of the blood vessels, and in thrombosed vessels. The hyphae are broad, ribbonlike, 10-25 µm in width, nonseptate or with rare septae, often twisted, and with right-angle branching. Although hyphae are seen on H&E, they are better visualized on GMS stain.
The hyphae of mucor needs to be differentiated from aspergillous (see the image below).
Morphological Comparison of Aspergillus and Mucor
The image below demonstrates a morphological comparison of aspergillus and mucor.
Pulmonary dirofilariasis is acquired when humans are bitten by mosquitoes that feed on both humans and dogs.  Infected dogs carrying the microfilaria are ingested by the mosquito and are inoculated into the skin of humans. The worms enter the blood stream and reach the heart and are carried into the pulmonary arterial circulation, where they cause thrombosis, infarction of the lung, and granulomatous reaction (see the image below).
Echinococcosis is caused by larval tape worms of the genus Echinococcus. Three species are known to cause human infection: Echinococcus granulosus, Echinococcus multilocularis, and Echinococcus vogeli. Cystic hydatid disease is caused ingestion of feces of an infected host such as the dog. Dogs acquire infection from feeding of livestock infected with larval forms of echinococcus.
Ingested eggs are hatched in the small intestine; subsequently, the organisms penetrate the wall of the intestine and enter the venous circulation. The liver is the most common site of infection; rarely, lung is infected through hematogenous seeding or through penetration of the diaphragm into the lower lobe of the lung. The cysts (see the images below) are surrounded by a dense fibrous tissue. Cysts occasionally rupture leading to necrotizing granulomatous reaction.
Granulomatous bronchopneumonia can rarely be seen in bacterial infections due to brucella and nocardia.
Histochemistry and Immunohistochemistry
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Ziehl-Neelsen stains and Fite stains are routinely used for acid fast bacilli.
Auramine-Rhodamine stains can also be used for acid fast bacilli; however, this requires a fluorescent microscope.
Gomori methenamine silver (GMS) stains and Periodic acid-Schiff (PAS) are commonly used for identifying fungal organisms. 
Other stains such as Fontana-Masson and Mucicarmine stains are used for Cryptococci.
Polymerase chain reaction (PCR) and other molecular tests are available through reference laboratories for rapid detection and speciation of mycobacteria.
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- Fungal Infections
- Morphological Comparison of Histoplasma and Pneueumocystis
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- Bacterial Infections
- Histochemistry and Immunohistochemistry
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