PATHOLOGY OF

TUBERCULOSIS

Dr. Maha Arafah and Prof. Ammar Rikabi

Department of Pathology
KSU, Riyadh
2017
TUBERCULOSIS
¨ Define tuberculosis.
¨ List the diseases caused by Mycobacteria.
¨ Know the epidemiology of tuberculosis (TB).
¨ List conditions associated with increased risk of Tuberculosis.
¨ List factors predisposing to extension of the infection.
¨ Recognize the morphology of Mycobacteria and its special stain (the Ziehl-
Neelsen) as well as the morphology of granulomas in TB (tubercles).
¨ Know the Pathogenesis of tuberculosis
¨ In regards to Mycobacterial lung infection: Compare and contrast the
following in relation to their gross and histologic lung pathology:
¤ Primary tuberculosis (include a definition of the Ghon complex).
¤ Secondary or reactivation tuberculosis.
¤ Miliary tuberculosis.
¨ List organs other than lung that are commonly affected by tuberculosis.
¨ Know the basis and use of tuberculin skin (Mantoux) test.
¨ List the common clinical presentation of tuberculosis.
¨ List the complication and prognosis of tuberculosis.
Define tuberculosis.

¨ Tuberculosis is a serious chronic pulmonary

and systemic disease caused most often
by M. tuberculosis
List the diseases caused by Mycobacteria

Ø Mycobacterium tuberculosis is the etiologic

agent of Tuberculosis in humans. Humans are
the only reservoir for the bacterium.
Ø

Ø Mycobacterium bovis is the etiologic agent of TB

in cows and rarely in humans. Both cows and
humans can serve as reservoirs. Humans can
also be infected by the consumption of
unpasteurized milk. This route of transmission can
lead to the development of extrapulmonary TB.

Ø M. leprae : causes leprosy

List the diseases caused by Mycobacteria

Others:
Ø M. kansasii, M. avium, M. intracellulare cause atypical
mycobacterial infections in humans esp in AIDS. They cause
respiratory and gastrointestinal symptoms and can involve other
organs too.

Ø M. ulcerans causes buruli ulcers of skin.

Know the epidemiology of tuberculosis

¨ According to the World Health Organization

(WHO), tuberculosis is estimated to affect
more than a billion individuals worldwide, with
8.7 million new cases and 1.4 million deaths
each year
List factors predisposing to extension of the
infection

Flourishes wherever there is

¨ Poverty

¨ crowding

¨ malnutrion

¨ chronic debilitating illness e.g.chronic lung

disease (particularly silicosis), chronic
renal failure etc.
List conditions associated with
increased risk of Tuberculosis.
¨ A disease of the elderly
¨ People with AIDS
¨ Diabetes mellitus
¨ Hodgkin's lymphoma
¨ Alcoholism
¨ Chronic lung disease (particularly silicosis)
¨ Immunosuppression e.g. with glucocorticoids
TB is a Granulomatous disease.
What is Granuloma?
¨ A granuloma is a microscopic aggregation of macrophages that are
transformed into epithelium-like cells surrounded by a collar of
mononuclear leukocytes, principally lymphocytes and occasionally plasma
cells.
¨ Epithelioid cells fuse to form giant cells containing 20 or more nuclei.
¨ The nuclei arranged either peripherally (Langhans-type giant cell) or
haphazardly (foreign body-type giant cell). Both Langhans ("classic TB")
and foreign-body giant cells are common.
¨ These giant cells can be found either at the periphery or the center of the
granuloma.
¨ Fibrous connective tissue often surrounds granulomas (remodeling of
tissue)
¨ In TB Areas within the granuloma can undergo necrosis (caseous
necrosis). Necrosis can lead to calcification
¨ TB granulomas are called tubercles, and if they are caseating in the center,
they are called soft tubercles.
Recognize the morphology of granulomas in TB (tubercles).
 Recognize the morphology of granulomas in TB (tubercles).

Granuloma: the predominant cell type is an activated macrophage with a

modified epithelial-like (epithelioid) appearance. Also seen are lymphocytes,
multinucealted giant cells and occasional plasma cells.
 Recognize the morphology of granulomas in TB (tubercles).

Langhans Giant Cell

Lymphocytic Rim

Caseous Necrosis

Epithelioid Macrophage
 Recognize the morphology of Mycobacteria and its special stain (the Ziehl-Neelsen)

¨ Ziehl-Neelsen
stain is an acid-
fast staining
method to stain M.
tuberculosis. The
Acid-fast bacilli
appear pink in a
contrasting
background.
Pathogenesis of tuberculosis
The steps in M. tuberculosis infection are:
1. Entry into macrophages:
Phagocytosis mediated by several receptors
expressed on the phagocyte, including mannose
binding lectin

2. Replication in macrophages.
M. tuberculosis inhibits maturation of the
phagosome and blocks formation of the
phagolysosome (by inhibiting Ca2+ signals),
allowing the bacterium to replicate within the
vesicle, protected from the microbicidal
mechanisms of lysosomes.
Pathogenesis of primary TB

During the earliest stage of primary tuberculosis (<3

weeks) in the nonsensitized individual, bacteria proliferate
in the pulmonary alveolar macrophages and air spaces,
resulting in bacteremia and seeding of multiple sites.
Despite the bacteremia, most people at this stage are
asymptomatic or have a mild flu-like illness
Pathogenesis of Primary Tuberculosis

3. The TH1 response. About 3 weeks after infection, a T-helper 1

(TH1) response is mounted that activates macrophages, enabling
them to become bactericidal.

Differentiation of TH1 TH1-mediated Macrophages activated

cells depends on IL-12, by IFN-γ differentiate
macrophage
which is produced by into the “epithelioid
antigen-presenting cells activation and killing histiocytes” that
that have encountered of bacteria by aggregate to form
the bacilli produce IFN-γ granulomas
Pathogenesis of tuberculosis
IFN-γ
4. TH1-mediated macrophage activation and killing of
bacteria.
¨ IFN-γ is the critical mediator that enables
macrophages to contain the M. tuberculosis
infection.
How?
I. IFN-γ stimulates maturation of the phagolysosome in
infected macrophages, exposing the bacteria to a lethal
acidic, oxidizing environment.
II. IFN-γ stimulates expression of inducible nitric oxide
synthase, which produces nitric oxide (NO
III. IFN-γ mobilizes antimicrobial peptides (defensins)
against the bacteria
IV. IFN-γ stimulates autophagy, a process that sequesters
and then destroys damaged organelles and intracellular
bacteria such as M. tuberculosis.
Pathogenesis of granuloma

5. Granulomatous inflammation and tissue damage.

Macrophages activated by IFN-γ differentiate into

the “epithelioid histiocytes” that aggregate to form
granulomas; some epithelioid cells may fuse to
form giant cells (langhans gaint cell)

Activated macrophages also secrete TNF and

chemokines, which promote recruitment of more
monocytes
Pathogenesis of tuberculosis
¨ Role of other immune cells: In addition to the
TH1 response, NKT cells that recognize
mycobacterial lipid antigens bound to CD1 on
antigen-presenting cells, or T cells that
express a γδ T-cell receptor, also make IFN-γ.
Pathogenesis of granuloma
¨ Host susceptibility to disease. People with
genetic deficiencies in the IL-12 pathway and
the IFN-γ pathway, including STAT1 a signal
transducer for IFN-γ, are vulnerable to severe
mycobacterial infections.
¨ Polymorphisms in a large number of genes,
including HLA, IFN-γ, IFN-γ receptor, and
TLR2 have been found to be associated with
susceptibility to tuberculosis
 Summary of Pathogensis
¨ Immunity to M. tuberculosis is primarily mediated by TH1
cells, which stimulate macrophages to kill the bacteria

¨ This immune response, while largely effective, comes at

the cost of accompanying tissue destruction

¨ Reactivation of the infection or re-exposure to the bacilli

in a previously sensitized host results in rapid
mobilization of a defensive reaction but also increased
tissue necrosis

¨ loss of T-cell immunity (indicated by tuberculin

negativity in a previously tuberculin-positive individual)
may be an ominous sign that resistance to the organism
has faded
Route of transmission of TB
Route of transmission of TB

¨ M. bovis infections, acquired through drinking

infected milk, usually start in the tonsils or
Peyer's patches.
Pathogenesis of TB:

Infection - Immunity

Infection with M. tuberculosis typically

leads to the development of delayed
hypersensitivity, which can be detected by
the tuberculin (Mantoux) test.
When the bacilli enter the body……

The bacilli have 5 potential fates upon entering the human body:
1. They may be killed by the immune system,

2. They may multiply and cause primary TB,

3. They may become dormant and remain asymptomatic,

4. They may proliferate after a latency period (reactivation disease).

Reactivation TB may occur following either (2) or (3) above.

5. If immunosuppressed ---- Primary Progressive TB or Miliary TB

The clinical course or presentation of TB

¨ The course of TB depends on the age and the immunity of

the patient and the total burden of organism.
¨ Some patients have only an indolent, asymptomatic infection
while in others TB is a destructive disseminated disease.
¨ There is a difference between infection and active TB. Not
everyone who is infected develops clinical symptoms.
1. Primary TB occurs on first exposure to the organism and
can pursue either an indolent or aggressive course (primary
progressive TB).
2. Secondary TB develops long after a primary infection,
mostly as a result of reactivation of a primary infection. It
can also be produced by exposure to exogenous
organisms. Secondary TB is always an active disease.
3. Miliary TB
 PRIMARY TB

¨ Primary TB is a first exposure to tubercle bacilli. The

inhaled organism is deposited in the alveoli.
¨ Ingested by macrophages and they ellicit a type IV delayed
hypersensitivity response
¨ In a immunologically competent person a granulomatous
response in produced. It takes 5-6 days invoke granuloma
formation which are usually formed by 3 to 4 weeks.
¨ In immunocompromised persons, granulomas are poorly
formed.
 PRIMARY TB
¨ The lung lesion of primary TB is known as Ghon focus.
¨ It is commonly found in the sub-pleural area.
¨ It drains into the hilar lymph nodes.
¨ The combination of the Ghon focus and the involved medistinal
or hilar lymph nodes is called as Ghon complex.
¨ Most of the time this Ghon complex heals undergoing shrinkage
fibrous scarring and calcification. It takes 2 to 8 weeks for
healing.
¨ Clinicaly: low grade fever and flu like symptoms
¨ Chest x-ray shows a subpleural midzonal round lesion with hilar
lymph nodes enlargement.
¨ Tuberculin skin test become positive
 PRIMARY TUBERCULOSIS: Ghon
Focus & Ghon complex

Ø Ghon Focus: lung lesion of primary TB, involves upper segments of the lower lobes
or lower segment of the upper lobe.
Ø Ghon complex: combination of a peripheral ghon focus and involved mediastinal
or hilar lymphnode.
Ø Microscopically the classic lesion of TB is a caseous granuloma
Caseating granulomas
 progressive primary
Possible sequalae of
tuberculosis
primary tuberculosis

1. No problems.
2. The disease may advance into
progressive primary tuberculosis
in immunocompromised patients
such as AIDS patients, elderly, and
malnourished children. The
infection progresses and spreads to
other areas of lung, lymph nodes or
other multiple sites.
3. The foci of scarring may harbor a
small number of organisms that
remain viable for years and later if
immune mechanisms wane or fail,
these bacilli may multiply and
cause reactivation of TB
(secondary TB).
SECONDARY TUBERCULOSIS

It is post primary infection in an immunized individual.

The mycobacteria in secondary TB may be either coming from:
1. A reactivation of dormant organisms from old
granulomas (dormant primary lesion).
¤ This is more common.
¤ It may develop even decades after primary infection.
¤ Causes: various conditions including:
n Cancer
n Chemotherapy
n AIDS
n Old age
2. Or
Exogenous re-infection (newly acquired bacilli)
by a high dose of virulent bacilli.
n Seen more in endemic areas.
 Pathologic features of secondary
tuberculosis:

Ø Secondary pulmonary tuberculosis can involve any

organ but the lungs are the most common site.
§ In the lungs it is classically localized to the apex of the upper
lobes of one or both lungs.
§ (M.tuberculosis bacilli love oxygen and prefer to grow where it is
most abundant so it starts at the apical and subapical regions of
the lungs).
§ Appear grossly as sharply circumscribed firm mass with
central cavity surrounded by fibrous wall.
§ The cavitation is loaded with the mycobacteria. It becomes
an important source of infection because the patient now
coughs sputum that contains bacilli.
§ Histologically: epithelioid granulomas with central caseation
and Langhan’s type
Scondary TB lung

Cavitatory tuberculosis with

intracavitary hemorrhage.
Extensive necrosis with
cavitation, usually occurring in
the upper lung lobe .
Complications of TB
§ Scarring: It can heal by fibrosis leaving a residual apical
scar.
§ Calcification (dystrophic)
§ Pleural fibrosis & adhesions
§ Local spread e.g. implantation of bacteria in the larynx
leading to hoarseness or bronchial spread leads to
bronchopneumonia
§ Systemic spread/milary TB, via:
Ø Vein – via left ventricle to whole body
Ø Artery – miliary spread within the lung
 Miliary Tuberculosis:

¨ when bacteria in the lungs enters

the pulmonary venous return to the
heart; the organisms subsequently
disseminate through the systemic
arterial system and the lymphatic
channels
Systemic miliary tuberculosis
¨ It produces multiple small yellow
nodular lesions in several organs.
Almost every organ in the body
may be seeded. Lesions resemble
those in the lung.
¨ In the lungs there multiple lesions
either microscopic or small, visible
(2-mm) foci of yellow-white
consolidation scattered through the
lung parenchyma.
Miliary TB
Ø Millet like – grain.

Ø blood or bronchial spread

 Extrapulmonary tuberculosis
n Lymph nodes/ tuberculous
lymphadenitis : are the most frequent
form of extrapulmonary tuberculosis esp.
in the cervical region
n Liver and spleen
n adrenals
n fallopian tube and endometrium
n Epididymis and prostate
n kidneys
n meninges around the base of the
brain (tuberculous meningitis),
n Bone marrow
n Vertebrae (Pott's disease).
TB adrenal gland TB epididymis
 Renal TB
Tuberculoma

TB Vertebra
(Potts
Spine)
Pott’s disease

Psoas abscess

n Vertebrae (Pott's disease). It

collapses the spine and leads to
paraspinal "cold" abscesses
n in these patients may track along
the tissue planes to present as an
abdominal or pelvic mass
TB Prostate gland TB intestine
 Mantoux) test

The size of induration is measured

48–72 hours later
Prognosis
¨ The prognosis with proper treatment is
generally good if infections are localized to the
lungs, except when they are caused by drug-
resistant strains or occur in aged debilitated, or
immunosuppressed persons, who are at high
risk for developing miliary TB.
 TAKE HOME MESSAGES:
1. Mycobacterium tuberculosis is the causative organism of
tuberculosis (TB) in the lungs and elsewhere.
2. It gains access to the lung by inhalation and causes
pulmonary TB.
3. A granuloma in TB is composed of activated macrophages,
Langhans’ giant cells with surrounding lymphoid cells and
fibroblasts with central caseation necrosis.
¤ Primary tuberculosis is the form of disease that develops in a
previously unexposed, and therefore unsensitized, person.
¤ Secondary (reactivation) tuberculosis arises in previously exposed
individuals when host immune defenses are compromised, and
usually manifests as cavitary lesions in the lung apices.
¤ Both progressive primary tuberculosis and secondary tuberculosis
can result in systemic seeding, causing life-threatening forms such
as miliary tuberculosis and tuberculous meningitis.
4. The outcome depends on the adequacy of the host immune
response and treatment