21: Granulomatous Diseases

Granulomatous Diseases

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.

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).


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.


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.

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.

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.

Histopathologic features

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.

Granulomas may be absent or poorly formed in people with poor immune responses, especially those infected with HIV.

Diagnosis and laboratory findings

A presumptive diagnosis of active tuberculosis is commonly made on the finding of acid-fast bacilli on microscopic examination of a diagnostic specimen such as a tissue biopsy or a smear of expectorated sputum. Definitive diagnosis requires the isolation and identification of M. tuberculosis from a diagnostic specimen, usually sputum in a patient with productive cough. Specimens are cultured on egg- or agar-based medium and incubated at 37°C under 5% CO2. The organisms grow slowly in culture and 4–8 weeks may be required before growth is detected.

Automated liquid culture systems are faster and show a greater yield than solid media-based systems.

New automated molecular tests such as XpertMTB/RIF which is a nucleic acid amplification test allow rapid diagnosis not only of tuberculosis, but also of multidrug-resistant tuberculosis (MDR-TB).

Due to inconsistent results and high rates of false-negative and false-positive results, serological tests for the diagnosis of active tuberculosis are not recommended.

Screening for latent M. tuberculosis infection can be performed with skin testing with purified protein derivative (PPD). However, the test is of limited value in the diagnosis of active disease because of its low sensitivity and specificity. False-negative reactions are common in immunosuppressed patients and in those with overwhelming tuberculosis. Positive reactions are elicited from individuals who have been infected with M. tuberculosis but do not have active disease and from persons sensitized by non-tuberculous mycobacteria or Bacille Calmette-Guérin (BCG) vaccination.

The gold standard for identifying M. tuberculosis infection is an interferon-γ release assay which measures interferon-γ titers released by T cells in response to stimulation with certain TB-speific antigens, such as ESAT-10 and CFP-10.

Management protocols and prognosis

Because of drug resistance, cure of tuberculosis requires prolonged concomitant administration of at least two agents to which the organism is susceptible. Four major drugs are considered as first-line treatment agents: isoniazid, rifampin (rifampicin), pyrazinamide and ethambutol. Second-line drugs include streptomycin, kanamycin, amikacin, capreomycin, ethionamide, cycloserine, para-aminosalicylic acid and fluoroquinolone antibiotics such as ofloxacin. Second-line agents are used in patients resistant to first-line therapy, because of their lower efficacy and higher toxicity.

Infectious cases should be diagnosed rapidly and appropriately treated until cure. The development of drug-resistant tuberculosis is primarily the result of monotherapy or failure of the healthcare provider to prescribe at least two drugs to which the tubercle bacilli are susceptible. Resistance occurs also if the patient fails to take properly prescribed therapy. Multidrug-resistant tuberculosis (MDR-TB) is a form of tuberculosis that does not respond to the standard drug treatment, i.e. the two main first-line drugs: isoniazid and rifampicin. The term extensive (extreme) drug resistant tuberculosis (XDR-TB) has been used to describe a form of MDR-TB resistant to any fluoroquinolone and one of three injectable aminoglycosides (capreomycin, kanamycin and amikacin).

Strategies for prevention and disease control include BCG vaccination and treatment of persons with latent tuberculosis infection who are at high risk of developing active disease, such as those infected with HIV, close contacts of persons with known or suspected active tuberculosis, persons with medical risk factors associated with reactivation of tuberculosis, medically underserved and low-income populations, alcoholics, injection drug users, persons with abnormal chest radiographs compatible with past tuberculosis, and residents of long-term care facilities. BCG vaccine is recommended for routine use at birth in countries with high tuberculosis prevalence. However, general use of BCG may not be recommended in countries with low risk of transmission due to the wide variation in efficacy of the vaccines available.

Leprosy (Hansen’s Disease)

Leprosy is a chronic granulomatous disease affecting the skin and peripheral nerves caused by Mycobacterium leprae. Impairment of nerve function results in major disabilities which have physical, social and psychological consequences and are the basis of the stigmatization historically associated with the disease. M. leprae is an acid-fast-staining, gram-positive, obligate intracellular bacillus with tropism for macrophages and Schwann cells. The organism grows preferentially in areas of lower temperature, which is why the skin seems to be a target site for infection. M. leprae does not grow in culture media. Animal reservoirs of M. leprae include the nine-banded armadillo (due to its low core body temperature), mice footpads and some non-human primates.

According to the WHO, about 720,000 new cases of leprosy are reported each year, and about two million persons suffer from leprosy-related disabilities. The disease is endemic in several developing tropical countries, including India (which accounts for the majority of reported cases worldwide), Brazil, Myanmar, Madagascar and Mozambique. More than 80% of all new cases are reported in these geographic locations. Moreover, geographic and ethnic differences in disease distribution are noted within each of these countries. In contrast to other mycobacterial infections, leprosy does not seem to be more frequent in patients infected with HIV, and co-infection with HIV and M. leprae does not appear to alter the course of either disease.


The precise mechanism of transmission of leprosy is still unknown. Leprosy is not very contagious and has low infectivity. Leprosy is not spread by touching, and exposure to the microorganism rarely results in clinical disease. Transmission seems to require frequent and prolonged contact with an infected person and there is an eight-fold increased risk of disease development in household contacts. Disease transmission is thought to occur by inhalation of bacilliladen aerosols from lesions in the respiratory tract. The inhaled microorganisms are disseminated by alveolar macrophages to different body organs. Growth occurs mainly in cooler body sites, such as the skin, mucosa and peripheral nerves. The incubation period between exposure to the M. leprae and disease development is very long, and is thought to be between 3 and 5 years, with a range of a few months to 30 years.

Interactions between host genetic factors and the microorganism determine the clinical pattern of the disease. Some genes control the overall susceptibility and resistance of the individual to the disease (innate resistance), while HLA-associated genes influence the ability and the pattern of the immune response mounted against the microorganism (through the function of T lymphocytes and antigen-presenting cells).

Tuberculoid and lepromatous leprosy represent the two main clinical patterns of the disease situated at either end of a spectrum with borderline forms situated along this spectrum. Tuberculoid leprosy is seen in patients who are able to mount a vigorous immune response to the mycobacterium, and is characterized by low bacillary counts (paucibacillary leprosy), few skin lesions and involvement of a small number of nerve trunks. It shows a predominant Th1 cytokine response with high levels of IL-2, IL-12, IFN-γ and TNF-α. Lepromatous leprosy is characterized by a limited cellular immune response, uncontrolled bacillary proliferation within host macrophages (multibacillary leprosy), diffuse skin lesions and extensive involvement of peripheral nerves. In this form, there is a defective Th1 or a dominant Th2 cytokine response. High levels of IL-4, IL-5 and IL-10 are detected in these lesions. Most patients, however, fall into a broad borderline category between these two ends of the spectrum, and are classified as borderline-tuberculoid, mid-borderline (or dimorphous) and borderline-lepromatous. These forms are clinically unstable, and affected patients can experience a shift of the disease toward any end of the spectrum.

Clinical features

Leprosy is twice as common in males as in females, especially after puberty. The age at diagnosis varies between 10 and 20 years. Leprosy can affect the skin, peripheral nerves, eyes and bone. Peripheral nerve lesions can cause numbness and weakness, which results in traumatic injuries to affected organs.

Tuberculoid leprosy, which corresponds to the pauci-bacillary form of the disease, presents initially on the skin as hypopigmented, well-demarcated macules that enlarge slowly and develop elevated margins. The number of lesions is usually limited. Loss of dermal appendages (hair follicles and sweat glands) also is seen, especially in fully developed skin lesions. Nerve involvement occurs early in the course of the disease and sensory, motor and autonomic nerves are affected, with resulting hypoesthesia, muscle weakness and anhidrosis. Involved nerves are enlarged and can be visible clinically. Some patients can present with severe painful neuritis. Sensory loss in the hands and feet often leads to severe trauma and burns. When the facial nerve is affected, patients can experience lagophthalmos (inability to close eyelids completely) and facial paralysis. When the ophthalmic branch of the trigeminal nerve is involved, anesthesia of the cornea and conjunctiva can increase the risk of corneal trauma and ulceration. These ocular lesions can result in blindness.

Lepromatous leprosy, which corresponds to multibacillary form of leprosy, shows extensive, symmetric and bilateral skin lesions. The skin of the face is commonly affected, becoming thickened and corrugated. Earlobes become pendulous and the lateral portions of the eyebrows are lost. Involvement of the nose causes nasal stuffiness and nasal bleeds, while perforation of the nasal septum results in saddlenose deformity. Nerve involvement is less prominent in lepromatous leprosy.

Leprosy reactions are acute inflammatory complications presenting as medical emergencies during the course of the disease. These can occur in untreated patients, but may often represent a complication of therapy.

Oral manifestations

Oral lesions are not common in patients affected by leprosy, nor are they considered pathognomonic of the disease. Their prevalence ranges from 0 to 60% of cases. This may decrease further with recent advances in therapy. Oral lesions seem to be more frequent in the lepromatous form of the disease and include papules, plaques, nodules, nonspecific erosions and ulcerations involving the tongue, buccal mucosa and palate.

A triad of changes affecting the facial bones and termed facies leprosa was described through archaeological studies. It consists of atrophy of the anterior nasal spine, atrophy and recession of the maxillary alveolar process, and endonasal inflammatory changes. The alveolar destruction limited to the maxillary anterior region can result in loosening and loss of teeth in the area. Granulomatous inflammation of the nasal cavity can result in palatal perforation and oronasal communication.

In lepromatous leprosy, M. leprae can infect the dental pulp and cause pulp necrosis. The microorganisms can accumulate within myelinated nerves in the pulp. Infected macrophages can be seen around capillaries. The resulting vascular damage may cause a reddish discoloration of the tooth.

Diagnosis and laboratory findings

The diagnosis of leprosy is based on a positive history of prolonged contact with a known infected person, living in endemic areas of the disease, clinical presentation and laboratory findings. Important diagnostic signs include: (i) hypopigmented or reddish patches with definite loss of sensation, (ii) thickened peripheral nerves, and (iii) acid-fast bacilli on skin smears or biopsy material.

Skin smears obtained to detect the microorganism are highly specific, but not very sensitive, because bacilli may not be identified in tuberculoid leprosy. This test is not used routinely as a diagnostic aid because laboratory services are not readily available. Intradermal injection of heat-killed M. leprae (lepromin test) has no diagnostic utility in individual cases. A positive lepromin test reflects the ability of a person to develop a granulomatous response to the microorganism, but does not indicate infection with, or exposure to M. leprae. Major advances in the laboratory diagnosis of leprosy were made by the development of genetic probes and polymerase chain reaction (PCR) that can identify M. leprae DNA in clinical specimens. These molecular techniques are highly sensitive and specific, but are not currently used in clinical practice, in part due to the complexity of the procedures. The gold standard for the diagnosis of leprosy is a full thickness skin biopsy obtained from the advancing margin of an active lesion.

Jan 12, 2015 | Posted by in Oral and Maxillofacial Radiology | Comments Off on 21: Granulomatous Diseases
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