CHAPTER 2  Ulcerative Conditions 31
erythema should be included in a differential diagnosis.
Aphthous ulcers, herpetic ulcers, erythema multiforme,
pemphigus, pemphigoid, drug eruptions, and streptococcal
infection should be considered. Diagnosis of gonorrhea is
traditionally based on demonstration of the organism with
Gram stain or culture on Thayer-Martin medium. Rapid
identification of N. gonorrhoeae with immunofluorescent
antibody techniques and other laboratory tests may be used
to support clinical impressions.
Treatment
Uncomplicated gonorrhea responds to a single dose of ap-
propriately selected antibiotic. In the West, infections are
susceptible to penicillins and treatment is effective with a
single parenteral dose of 2.0 to 3.5 g of ampicillin. In the
Far East and parts of Africa, up to 50% of cases are resistant
to penicillins and can be managed with a single 500-mg
dose of ciprofloxacin. This regimen is also appropriate for
pharyngeal gonorrhea, for which ampicillin is generally in-
effective. Concerns have been expressed about the develop-
ment of gonococcal resistance to antibiotics. Some strains
already have been reported to be resistant to cephalosporins
and fluoroquinolone, including multidrug-resistant forms.
Thus, fewer treatment options are available.
Tuberculosis
Etiology and Pathogenesis
Tuberculosis infects about one third of the world’s popula-
tion and kills approximately 3 million people per year, mak-
ing it one of the most significant causes of death in the
world. In developed countries, a significant decrease in the
incidence of TB has occurred as the result of improvements
in living conditions, reductions in overcrowding, and anti-
biotic use. However, the 1980s saw a re-emergence of sig-
nificant numbers of cases of TB, many in association with
Non-immune host
Skin test negative
Exposure to
M. tuberculosis
Primary TB
Lung
Arrested TB
Skin test positive
Reactivation
Secondary TB
Lung
Reinfection
• Figure 2-16  ​Pathogenesis of tuberculosis.
HIV infection and acquired immunodeficiency syndrome
(AIDS), in Europe and Africa. In addition, the issue of
multidrug resistance has proved to be a growing problem in
management of the disease.
TB is caused by the aerobic, non–spore-forming bacillus
Mycobacterium tuberculosis (Figure 2-16). The organism
has a thick, waxy coat that does not react with Gram stains
but retains the red dyes (Ziehl-Neelsen and Fite tech-
niques). With these stains, the organisms do not decolor
with acid-alcohol and therefore are also known as acid-fast
bacilli. Two major forms of Mycobacterium are recognized:
M. tuberculosis and M. bovis. M. tuberculosis is an airborne
infection that is transmitted by inhalation of infected drop-
lets. M. bovis is primarily a disease of cows that is transmit-
ted to humans through infected milk, producing intestinal
or tonsillar lesions. Two other closely related forms of
Mycobacterium are recognized: M. avium and M. intracel-
lulare. Both are nonvirulent in healthy individuals but cause
disseminated disease in immunocompromised individuals,
such as those with HIV infection.
M. tuberculosis infection is spread through small air-
borne droplets, which carry the organism to pulmonary air
spaces. Phagocytosis by alveolar macrophages follows, and
the battle between bacterial virulence and host resistance
begins. The pathogenicity of M. tuberculosis is due both to
its ability to resist degradation by macrophages and to the
development of a type IV hypersensitivity reaction. This
latter feature explains the destructiveness of lesions in the
host tissues and the emergence of drug-resistant strains. As
the immune system is sensitized by mycobacterial antigens,
positive tuberculin reactivity develops. The Mantoux and
tine skin tests, which use a tubercle bacillus antigen called
purified protein derivative (PPD), determine whether an
individual is hypersensitive to antigen challenge. A positive
inflammatory skin reaction indicates that the individual’s
Progressive TB
Hematogenous spread
Lymphatic spread
Direct extension
Implantation from sputum
(oral lesions)
32 C H A P T E R 2   Ulcerative Conditions
cell-mediated immune system has been sensitized and signi-
fies previous exposure and subclinical infection. It does not
necessarily imply active disease.
A granulomatous inflammatory response to M. tubercu-
losis follows sensitization. In most cases, the cell-mediated
immune response is able to control the infection, allowing
subsequent arrest of the disease. Inflammatory foci eventu-
ally may undergo dystrophic calcification, but latent organ-
isms in these foci may become reactivated at a later date. In
a small number of cases, the disease may progress through
airborne, hematogenous, or lymphatic spread, so-called
miliary spread.
Oral mucous membranes may become infected through
implantation of organisms found in sputum or, less com-
monly, through hematogenous deposition. Similar seeding
of the oral cavity may follow secondary or reactivated TB.
Clinical Features
Unless the primary infection becomes progressive, an in-
fected patient will probably exhibit no symptoms (Box 2-4;
Figure 2-17). Skin testing and chest radiographs may provide
the only indicators of infection. In reactivated disease,
• BOX 2-4 Tuberculosis
Etiology
Mycobacterium tuberculosis; oral lesions follow lung infections
Risk factors—overcrowding, debilitation, immunosuppression
Important public health disease
Clinical Features
Chronic ulcers, nonhealing and indurated, often multiple
Histopathology
Caseating granulomas (macrophages) with Langerhans giant
cells
Treatment
Prolonged, multidrug therapy required (isoniazid, rifampin,
ethambutol)
• Figure 2-17  ​Tuberculosis of the maxillary alveolar ridge.
low-grade signs and symptoms of fever, night sweats, malaise,
and weight loss may appear. With progression, cough, he-
moptysis, and chest pain (pleural involvement) occur. As
other organs become infected a highly varied clinical picture
appears and is dependent on the organs involved.
Oral manifestations that usually follow implantation of
M. tuberculosis from infected sputum may appear on any
mucosal surface. The tongue and the palate are favored loca-
tions. The typical lesion is an indurated, chronic, nonheal-
ing ulcer that is usually painful. Bony involvement of
the maxilla and mandible may produce tuberculous osteo-
myelitis. This most likely follows hematogenous spread of
the organism. Pharyngeal involvement results in painful
ulcers, which may cause dysphagia, odynophagia, and voice
changes.
Histopathology
The basic microscopic lesion of TB is granulomatous in-
flammation, in which granulomas show central caseous
necrosis (Figure 2-18). In tissues, M. tuberculosis incites a
characteristic macrophage response, in which focal zones of
macrophages become surrounded by lymphocytes and
fibroblasts. The macrophages develop an abundant eosino-
philic cytoplasm, giving them a superficial resemblance to
epithelial cells; for this reason, they are frequently called
epithelioid cells. Fusion of macrophages results in the ap-
pearance of Langerhans giant cells, in which nuclei are dis-
tributed around the periphery of the cytoplasm. As the
granulomas age, central necrosis occurs; this is usually re-
ferred to as caseous necrosis because of the gross cheesy
texture of these zones.
A Ziehl-Neelsen or Fite stain must be used to confirm
the presence of the organism in the granulomas, because
several infectious and noninfectious conditions may pro-
duce a similar granulomatous reaction (Figure 2-19). In the
absence of acid-fast bacilli, other microscopic consider-
ations would include syphilis, cat-scratch disease, tularemia,
histoplasmosis, blastomycosis, coccidioidomycosis, orofa-
cial granulomatosis, sarcoidosis, and some foreign body
reactions, such as those induced by beryllium.
• Figure 2-18  ​Tuberculosis granuloma composed of macrophages
and multinucleated giant cells.

• Figure 2-19  ​Fite stain showing tuberculosis microorganisms (red
rods). (Reproduced with permission from Regezi JA, Sciubba JJ,
Pogrel MA: Atlas of Oral and Maxillofacial Pathology. Philadelphia,
2000, WB Saunders, Fig. 1-31.)
Differential Diagnosis
On the basis of clinical signs and symptoms alone, oral TB
cannot be differentiated from several other conditions. A
chronic indurated ulcer should prompt the clinician to
consider primary syphilis and oral manifestations of deep
fungal diseases. Noninfectious processes that should be
considered clinically are foreign body reaction, sarcoid-
osis, Crohn’s disease, orofacial granulomatosis, squamous
cell carcinoma, and chronic traumatic ulcer. Major aph-
thae might be included, although a history of recurrent
disease should help separate this condition from the oth-
ers. In approximately half of cases, the diagnosis or oral
manifestation of oral tuberculosis has led to a diagnosis of
undiagnosed systemic infection. Rarely, carcinomas may
coexist at the same lesion site.
Treatment
First-line drugs likely to be used for treatment of TB in-
clude isoniazid, rifampin, pyrazinamide, and ethambutol.
Drug combinations are often used in 6-, 9-, or 12-month
treatment regimens, which may be continued for as long
as 2 years. Streptomycin is rarely used for first-line treat-
ment except in multidrug-resistant cases. Oral lesions
would be expected to resolve with treatment of the pa-
tient’s systemic disease. Unfortunately, infection with
multidrug-resistant organisms is a serious clinical problem
that appears to be on the increase. Development and test-
ing of new classes of drugs are necessary to meet the chal-
lenge of resistant organisms.
Patients who convert from a negative to a positive skin
test response may benefit from prophylactic chemotherapy,
typically using isoniazid for 1 year. This decision is depen-
dent on risk factors involved, such as age and immune sta-
tus, and on the opinion of the attending physician.
Bacille Calmette-Guérin (BCG) vaccine is effective in
controlling childhood TB, but it loses efficacy in adulthood.
New vaccines that are under investigation offer hope for
at-risk populations.
CHAPTER 2  Ulcerative Conditions 33
Leprosy
Etiology and Pathogenesis
Leprosy, also known as Hansen’s disease, is a chronic
infectious disease caused by the acid-fast bacilli Mycobacte-
rium leprae and Mycobacterium lepromatosis. Worldwide,
20 million individuals are estimated to be infected. It is the
most common cause of peripheral neuritis in the world.
Because the causative organisms are difficult to grow in cul-
ture, these infections continue to be cultivated in the foot-
pads of mice and in the armadillo, which has a low core
body temperature. Leprosy is only moderately contagious;
transmission of the disease requires frequent direct contact
with an infected individual for a long period, with an incu-
bation period ranging up to 5 years for the tuberculoid form
versus up to 12 years in the lepromatous form of the disease.
Inoculation through the respiratory tract is believed to be a
potential mode of transmission.
Clinical Features
Oral lesions appear in the lepromatous form of the disease in
20% to 60% of cases, as multiple nodules (necrotic and ul-
cerated), with associated slow healing and atrophic scarring.
A clinical spectrum of disease ranges from a limited form
(tuberculoid leprosy) in those with a well-functioning im-
mune system, to a generalized form (lepromatous leprosy) in
individuals with reduced levels of cell-mediated immune re-
activity; immunocompromised individuals have a more seri-
ously damaging course. Generally, skin and peripheral nerves
are affected because the organism grows best in temperatures
less than the core body temperature of 37 degrees C. Cutane-
ous lesions appear as erythematous plaques or nodules, repre-
senting a granulomatous response to the organism. Similar
lesions may occur intraorally or intranasally. In time, severe
maxillofacial deformities may appear, producing the classic
destruction of the anterior nasal spine and anterior maxillary
alveolus, as well as intranasal inflammation and tissue de-
struction called facies leprosa. Damage to peripheral nerves
results in anesthesia, leading to trauma to the extremities and
consequent ulceration, as well as bone resorption.
Histopathology
Microscopically, a granulomatous inflammatory response,
in which macrophages/epithelioid histiocytes and multi-
nucleated giant cells predominate, is usually seen. Infiltra-
tion of nerves by mononuclear inflammatory cells is also
noted. Well-formed granulomas, similar to those present in
the tissue lesions of TB, are typically seen in tuberculoid
leprosy. Poorly formed granulomas with sheets of macro-
phages reflect the pattern more typical of leproid leprosy.
Acid-fast bacilli can be found within macrophages and are
best demonstrated with the Fite stain. Organisms are most
numerous in the lepromatous form of leprosy.
Diagnosis
A history of contact with a known infected patient or of
living in a known endemic area is important for establishing