Granulomatous Diseases

Adel Kauzman and lona Leong

Granulomatous diseases are a heterogeneous group of disorders that are characterized by a specific pattern of chronic inflammation called granulomatous inflammation, in which granulomas are formed. Granulomas usually develop as a result of a cell-mediated hypersensitivity reaction to a non-degradable antigen. The clinical significance of a histological finding of granulomatous inflammation is that this type of inflammation is associated with a relatively limited number of conditions.

A granuloma is a focal aggregate of inflammatory cells, composed predominantly of epithelioid macrophages, which may be surrounded by a rim of lymphocytes and/or plasma cells. Epithelioid macrophages resemble epithelial cells, having abundant pale pink cytoplasm, vesicular and oval nuclei and indistinct cell borders (Figure 1). Some activated macrophages may fuse to form multinucleated giant cells which may be located within the center or periphery of the granuloma (Figure 2). In Langhans type giant cells the nuclei are arranged in the periphery, often in the shape of a horseshoe. The nuclei of foreign body type giant cells are arranged haphazardly in the cytoplasm. Some granulomas may show central areas of necrosis. Caseous necrosis, in which the dead tissue is soft and dry and resembles cheese, is classically associated with tuberculosis. Long-standing granulomas may be surrounded by a rim of fibrous connective tissue and fibroblasts.

Figure 1 Photomicrograph of a granulomatous inflammatory reaction showing multiple granulomas surrounded by lymphocytes. Each granuloma is composed predominantly of epithelioid macrophages and multinucleated giant cells. Epithelioid macrophages show abundant pale pink cytoplasm, vesicular and oval nuclei and indistinct cell borders. (Hematoxylin and eosin, original magnification 200x)

Figure 2 Photomicrograph showing a multinucleated giant cell in the center of a granuloma. The nuclei of the giant cell are arranged in the periphery of the cytoplasm. (Hematoxylin and eosin, original magnification 250x)

Granulomas can be classified as immune or foreign body type. Foreign body type granulomas develop in response to inert endogenous or exogenous foreign material (Table 1). Immune-mediated granulomatous inflammation represents a form of delayed type (cell-mediated) hypersensitivity reaction and may be secondary to specific types of bacterial, fungal and parasitic infections. Immune granulomas are mostly seen with mycobacterial and fungal infections because the infectious organisms typically have antigens which are poorly degraded by macrophages. Antigen exposure initiates a cell-mediated immune response, resulting in activated CD4⁺ T lymphocytes of the Th1 type which secrete cytokines such as interleukin (IL)-2, IL-12, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α. The cytokines stimulate activation of macrophages to form granulomas. Some immune-mediated granulomatous diseases are of unknown etiology (Table 1).

Table 1

Granulomatous diseases that may affect the oral tissues

Tuberculosis

Tuberculosis is a common worldwide infection caused by bacteria belonging to the Mycobacterium tuberculosis complex. Although tuberculosis usually affects the lungs, it may also involve other organs in up to one-third of cases. Initial infection, also known as primary infection, is followed by a long latency period characterized by absence of symptoms in most individuals. Latent infection progresses to active disease in a minority of individuals, due to reactivation or exogenous re-infection with a second strain of M. tuberculosis. Therefore infection must be distinguished from active disease. Active tuberculosis caused by drugsusceptible strains is curable if properly treated, but may be fatal within 5 years in more than half the cases if untreated.

The M. tuberculosis complex includes M. tuberculosis, the most frequent and important agent of human disease. M. bovis is transmitted by unpasteurized milk and is the cause of a small percentage of cases in developing countries. M. tuberculosis is an aerobic, non-spore-forming, rod-shaped bacterium. The organism is classified as an acid-fast bacillus because the high mycolic acid and lipid content in the cell wall prevents decolorization by acid alcohol with acid-fast stains such as the commonly used Ziehl-Neelsen stain.

Tuberculosis is a disease of poverty associated with overcrowding and undernutrition. Other risk factors for tuberculosis include human immunodeficiency virus (HIV) infection, diabetes, smoking, excessive alcohol consumption, end-stage renal failure, and therapy with tumor necrosis factor antagonists and corticosteroids.

Based on World Health Organization (WHO) estimates, approximately two billion people or one-third of the world’s total population were infected with M. tuberculosis in 2010, with 1.4 million deaths caused by tuberculosis yearly. Tuberculosis occurs world-wide, but the majority of cases occur in low-income countries and in countries with emerging economies. The developing countries of Africa and Asia have the highest prevalence of tuberculosis, with the most cases occurring in India, China, South Africa, Indonesia and Pakistan. Tuberculosis is uncommon in North America and Europe, where it occurs predominantly in HIV-infected persons, immigrants from high-prevalence countries, disadvantaged and marginalized populations. Although intense efforts at disease control have resulted in stabilization or decreasing incidence of tuberculosis in most countries, there has been a rapid increase in Africa related to the spread of the HIV epidemic.

Pathogenesis

The disease is usually transmitted by the airborne spread of droplet nuclei produced by patients with infectious pulmonary tuberculosis. Droplets aerosolized by coughing, sneezing or speaking are inhaled. Thus transmission of infection is enhanced by crowded conditions in poorly ventilated rooms and prolonged, close contact with patients with active tuberculosis. Inhaled bacilli reaching the alveoli are ingested by non-specifically activated alveolar macrophages, which may contain the bacillary multiplication or be killed by the multiplying bacilli. Chemotactic factors released by lysed macrophages attract non-activated monocytes from the bloodstream to the site. These initial stages of infection are usually asymptomatic.

Specific immunity develops about 2–4 weeks after infection. Large numbers of activated macrophages accumulate at the site of the primary lesion, forming granulomas or tubercles. Granuloma formation is mediated by cytokines released by alveolar macrophages, including TNF-α. This delayed-type hypersensitivity reaction to bacillary antigens destroys macrophages and causes necrosis in the center of the tubercles. The necrotic material resembles soft cheese, hence the designation ‘caseous necrosis’. Its low oxygen tension and low pH inhibit growth of M. tuberculosis. Viable organisms may however remain dormant within the macrophages or in the necrotic material for years or even throughout the patient’s lifetime. Some tubercles in the lung parenchyma and hilar lymph nodes may heal by fibrosis and calcification, while others undergo further evolution.

Clinical features

Tuberculosis is classified as pulmonary or extrapulmonary. Pulmonary tuberculosis can be primary or secondary. Primary pulmonary disease results from an initial infection with M. tuberculosis in previously unexposed individuals and is usually asymptomatic. The lesion is usually peripheral and localized to the middle and lower lung zones and is accompanied by hilar or paratracheal lymphadenopathy. In most cases, the lesion heals spontaneously and may later be evident as a small calcified nodule (Ghon lesion) (Figure 3). Approximately 5–10% of patients progress directly from initial infection to active disease, usually because of an existing state of immunosuppression. This is especially seen in children and in persons with impaired immunity, such as those with malnutrition or HIV infection. The initial lesion enlarges, cavitates, invades and destroys bronchial walls and blood vessels. Large numbers of bacilli spread into the airways and the environment through expectorated sputum. Patients may develop pleural effusion and progressive primary tuberculosis. Hematogeneous dissemination may result in fatal miliary tuberculosis (Figure 4) or tuberculous meningitis.

Figure 3 Gross appearance of Ghon lesion in the lung of a patient with a history of healed primary pulmonary tuberculosis. It presents as a calcified spherical mass

Figure 4 Gross appearance of miliary tuberculosis in the lung

Secondary pulmonary tuberculosis, also known as post-primary disease, is usually due to endogenous reactivation of latent infection. Triggers for reactivation include immunosuppression, especially AIDS, malnutrition and vitamin D deficiency. The disease usually occurs in the apical and posterior segments of the upper lung lobes, where the high oxygen tension favors mycobacterial growth. The extent of lung involvement varies greatly, from small infiltrates to extensive cavitatory disease. Massive involvement of the lungs, with coalescence of lesions, produces tuberculous pneumonia. The result may be death, spontaneous remission or chronic disease with a progressively debilitating course (‘consumption’). Individuals with chronic disease continue to discharge tubercle bacilli into the environment. Symptoms and signs are often non-specific and insidious early in the course of secondary pulmonary tuberculosis, consisting mainly of fever, night sweats, weight loss, anorexia, general malaise and weakness. Cough eventually develops in most individuals, often initially non-productive and subsequently accompanied by the production of purulent sputum. The sputum may be blood-streaked due to blood vessel involvement.

Virtually any organ system may be affected by extrapulmonary tuberculosis, but the most commonly involved sites are the lymph nodes, pleura, genitourinary tract, bones and joints, meninges, peritoneum, pericardium, and the head and neck region. In the head and neck, tuberculosis can involve the larynx, middle ear, nasal cavity, nasopharynx, oral cavity, parotid gland, esophagus and spine. As a result of hematogeneous dissemination in HIV-infected individuals, extrapulmonary tuberculosis is seen more commonly nowadays than in the past.

Lymph node tuberculosis (tuberculous lymphadenitis) is the most common form of extrapulmonary tuberculosis and is especially common in HIV-infected persons. It usually presents as painless swelling of the lymph nodes, most commonly at cervical and supraclavicular sites (scrofula). Lymph nodes are usually discrete in early disease but may develop caseous necrosis and form fistulas through the overlying skin draining caseous material. Involved nodes may radiographically appear calcified (Figure 5). Pulmonary tuberculosis is unusual in patients with scrofula.

Figure 5 Panoramic radiograph of a patient with a history of tuberculosis showing calcified cervical and submandibular lymph nodes

Oral manifestations

The most common manifestation of tuberculosis in the oral cavity is a chronic painless ulcer. Less frequently tuberculous lesions present as nodular, granular or rarely firm leukoplakic areas. Most oral lesions represent secondary infection from the initial pulmonary lesions, either from hematogeneous spread or from exposure to infected sputum. Secondary oral lesions usually occur on the tongue, palate and lip.

Primary oral tuberculosis without pulmonary involvement is rare. It usually involves the gingiva, mucobuccal fold and areas of inflammation adjacent to teeth or in extraction sites. Primary oral lesions are frequently accompanied by enlarged regional lymph nodes. Tuberculous osteomyelitis has been reported in the jaws and appears as ill-defined areas of radiolucency.

Affected tissues show multiple granulomas called tubercles which consist of aggregates of epithelioid histiocytes, lymphocytes and Langhans multinucleated giant cells (Figure 1). The tubercles often show central caseous necrosis (Figure 6). Special stains such as Ziehl-Neelsen or other acid-fast stains are required to demonstrate the bacteria (Figure 7). Because of the relative scarcity of bacilli within tissue, organisms may not be successfully demonstrated in all cases, and a negative result therefore does not completely eliminate the possibility of tuberculosis.