2nd Semester Compendium of Systemic Pathology

Simona Gurzu loan Jung
COMPENDIUM OF
SYSTEMIC PATHOLOGY
2012
Contents
INTRODUCTION................................................................................................. 13
PATHOLOGY OF THE CARDIOVASCULAR SYSTEM.................. : ........... 15
PATHOLOGY OF THE HEART................................................................... 16
Diseases of the pericardium........................................................................ 16
Vascular disorders................................................................................. 16
Pneumopericardium.............................................................................. 17
Pericarditis............................................................................................ 17
Pericardia! tumors................................................................................. 18
Pathology of the myocardium...................................................................... 20
Ische1nic heart disease.......................................................................... 20
Angina ..................................................................................... 20
Chronic ischemic heart disease............................................... 21
Sudden ischemic cardiac death................................................ 22
Myocardial infarction .............................................................. 22
Cardiac hypertrophy............................................................................. 29
Cardiac dilatation ................................................................................. 30
Cardiomyopathies................................................................................ 30
Myocarditis.......................................................................................... 34
Pathology of the endocardium .................................................................... 36
Endocarditis......................................................................................... 36
Valvulopathies..................................................................................... 41
Heart failure................................................................................................ 42
Heart tuniors..... .. ........................................................................................ 44
Pathology of cardiovascular interventions and surge,y............................. 45
Congenital heart diseases............................................................................ 47
VASCULAR PATHOLOGY................................................................................ 52
Diseases of the arteries................................................................................ 53
Aging................................................................................................... 53
Arteriosclerosis................................................................................... 53
Hypertension....................................................................................... 59
Aneurysm............................................................................................ 62
Aortic dissection .................................................................................. 64
Arteritis................................................................................................ 65
Raynaud's disease and Raynaud's phenomenon................................. 70
Pathology of the veins................................................................................. 71
Varicose veins...................................................................................... 71
Phlebothrombosis................................................................................ 72
Thrombophlebitis................................................................................ 74
Diseases of the lymphatics........................................................................... 75
Diseases of the capillaries............................................................................ 75
Tumors of the blood vessels........................................................................... 76
Benign tumors....................................................................................... 76
Malignant tumors................................................................................. 77
Pseudotumoral vascular lesions........................................................... 78
PATHOLOGY OF THE RESPIRATORY SYSTEM ....................................... 79
PATHOLOGY OF THE AIRWAYS............................................................... 80
Pathology of the nose, middle ear and paransal sinuses............................. 80
Vascular disorders................................................................................. 80
Rhinitis................................................................................................. 80
Otitis..................................................................................................... 81
Sinusitis................................................................................................ 82
Specific inflammations of the nose, middle ear and paransal sinuses.. 82
Tumors of the nose and paransal sinuses .............................................. 83
Diseases of the larynx................................................................................... 84
Congenital malformations.................................................................... 84
Laryngeal stenosis................................................................................ 84
Vascular disorders................................................................................ 84
Laryngitis............................................................................................. 84
Tumors of the larynx............................................................................ 85
Pathology of the trachea and bronchi .......................................................... 88
Stenosis of the trachea and bronchi...................................................... 88
Tracheitis.............................................................................................. 88
Tumors of the trachea........................................................................... 89
Bronchitis, bronchiolitis....................................................................... 89
Chronic obstructive pulmonary diseases.............................................. 91
Chronic bronchitis................................................................ 91
Bronchial asthma................................................................. 92
Bronchiectasis...................................................................... 93
PATHOLOGY OF THE LUNG......................................................................... 95
Congenital disorders................................................................................... 96
Vascular disorders ....................................................................................... 96
Disorders of air content............................................................................... 99
Pulmonary emphysema........................................................................ 99
Atelectasis.......................................................................................... I 03
Respiratory distress syndrome ................................................................... 104
Hyaline membrane disease.................................................................. 104
Adult respiratory distress syndrome.................................................... 104
l
Non-specific pulmonary inf ammations....................................................... 106
Lobar pneumonia.............................................................................. 106
Bronchopneumonia........................................................................... 107
Interstitial pneumonia....................................................................... 109
Pulmonary fibrosis............................................................................ 111
Purulent inflammations of the lung................................................... 111
Illicit drug use................................................................................... 112
Specific pulmonary inflammations............................................................... 112
Pulmonary tuberculosis..................................................................... 112
Other specific pulmonary inflammations.......................................... 115
Lung twnors................................................................................................. 115
Benign tu1nors................................................................................... 115
Malignant tumors.............................................................................. 115
Prognostic factors of primary lung carcinomas................................ 120
Predictive factors of primary lung carcinomas................................. 120
Lung metastases................................................................................ 120
Pathology of the pleura............................................................................... 122
Vascular disorders............................................................................. 122
Pneumothorax................................................................................... 122
Pleuritis............................................................................................. 123
Pleural tumors................................................................................... 123
PATHOLOGY OF THE GASTROINTESTINAL TRACT........................... 125
PATHOLOGY OF THE ORAL CAVITY.................................................... 126
Congenital malfoi-mations of the mouth...................................................... 126
Jriflammations of the mouth......................................................................... 126
Tumors of the oral cavity............................................................................. 128
Premalignant lesions......................................................................... 128
Benign tumors................................................................................... 128
Pseudotumors.................................................................................... 129
PATHOLOGY OF THE PHARYNX............................................................ 130
Pharyngitis.................................................................................................. 130
Tuniors of the pharynx................................................................................. l 31
PATHOLOGY OF THE TONSILS............................................................... 131
PATHOLOGY OF THE SALIVARY GLANDS.......................................... 133
Sialadenitis.................................................................................................. 13 3
Salivary gland tuniors.................................................................................. 134
PATHOLOGY OF THE ESOPHAGUS........................................................ 136
Congenital malformations............................................................................ 136
Diverticula and stenosis............................................................................... 137
Esophageal varices.................................................................................. 137
Mallory-Weiss tear.................................................................................. 137
Esophagitis.........................................................................._. ................... 139
Baretts esophagus................................................................................... 139
Tumors of the esophagus and esophagogastric junction........................ 140
Premalignant lesions......................................................................... 140
Benign tumors................................................................................... 140
PATHOLOGY OF THE STOMACH........................................................... 141
Congenital pyloric stenosis......................................................................... 141
Acute dilatation of the stomach.................................................................. 141
Gastritis..............................:....................................................................... 1 42
Hyperplasia of the gastric mucosa............................................................. 1 43
Gastroduodenal ulcerations....................................................................... 144
Acute gastroduodenal erosions......................................................... 144
Acute peptic ulcer............................................................................. 1 44
Chronic peptic ulcer.......................................................................... 1 45
Tumors of the stomach................................................................................ 1 47
Benign tumors................................................................................... 147
Premalignant disorders...................................................................... 148
Malignant tumors of the stomach...................................................... 149
Gastric carcinoma............................................................... 149
Malignant gastric lymphoma.............................................. 153
Malignant gastrointestinal stromal tumors......................... 1 53
Neuroendocrine neoplasms of the stomach........................ 153
Secondary tumors of the stomach....................................... 1 55
Gastric pseudotumors.......................................................... 155
PATHOLOGY OF THE INTESTINES AND THE APPENDIX................. 1 56
Congenital and acquired disorders of the intestinal lumen....................... 156
Vascular disorders..................................................................................... 158
Ma/absorption syndromes.......................................................................... 1 58
Inflammations of the small and large intestine.......................................... 161
Acute enterocolitis............................................................................ 161
Chronic non-specific enterocolitis.................................................... 162
Ischemic enterocolitis......................................................... 162
Indeterminate enterocolitis................................................. 1 62
Crohn's disease ................................................................... 1 62
Ulcerative colitis................................................................. 163
Specific enterocolitis........................................................................ 164
Appendicitis.............................................................................................. 166
Other nontumor lesions of the rectum and anal canal............................... 167
Tumors of the small intestine...................................................................... 168
Benign tumors................................................................................... 168
Colorectal tumors....................................................................................... 170
Benign tumors................................................................................... 170
Colorectal carcinoma.......................................................... 171
PATHOLOGY OF THE PERITONEAL CAVITY...................................... 175
Vascular disorders.................................................................................... 175
Peritonitis .................................................................................................. 175
Peritoneal tun1ors...................................................................................... 176
HERNIAS...................................................................................................... 178
INTESTINAL OBSTRUCTION................................................................... 180
PATHOLOGY OF THE LIVER, GALLBLADDER AND PANCREAS...... 182
PATHOLOGY OF THE LIVER................................................................... 183
Congenital malformations....................................................................... 183
Vascular disorders................................................................................... 183
Metabolic disorders................................................................................. 184
Hepatic necrosis....................................................................................... 185
Inflammations of the liver......................................................................... 186
Hepatitis............................................................................................ 187
Liver abscesses................................................................................. 189
Hepatic cirrhosis............................................................................... 190
Alcoholic liver injury........................................................................ 194
Tumors of the liver..................................................................................... 197
Pseudotumors.................................................................................... 197
Benign tumors................................................................................... 198
Malignant tumors............................................................................... 198
PATHOLOGY OF THE GALLBLADDER AND BILIARY TREE........... 201
Cholelithiasis ............................................................................................ 201
Cholecystitis and cholangitis .................................................................... 202
Tumors of the gallbladder and biliary tree............................................... 205
PATHOLOGY OF THE PANCREAS.......................................................... 206
Regressive processes and malformations ................................................ 206
Pancreatitis............................................................................................... 206
Pancreatic tumors..................................................................................... 208
Tumors of the exocrine pancreas....................................................... 208
Tumors of the endocrine pancreas..................................................... 209
Diabetes mellitus...................................................................................... 211
PATHOLOGY OF THE KIDNEY AND URINARY TRACT....................... 213
PATHOLOGY OF THE KIDNEY............................................................... 214
Glon1erular diseases................................................................................ 214
Glomerulonephritis with nephritic syndrome................................... 214
Glomerulonephritis with nephrotic syndrome.................................. 216
Chronic glomerulonephritis............................... ............................... 218
Secondary glomerulonephritis................................................. ......... 21 8
Glomerulopathy................................................................................ 220
Tubular disorders.................................................................................... 220
Acute hypoxic tubular necrosis........................................................ 220
Toxic and infectious tubular necrosis............................................... 221
Obstructive tubular lesions............................................................... 221
Other tubular disorders..................................................................... 222
Interstitial nephritis................................................................................ 223
Infective interstitial nephritis........................................................... 223
Non-infective interstitial nephritis................................................... 224
Renal tuberculosis.................................................................................. 224
Vascular disorders of the kidney............................................................ 226
Arterial and arteriolar damages........................................................ 226
Lesions produced by microthrombosis............................................ 227
Thrombotic microangiopathy........................................................... 227
Renal sinus lipomatosis........................................................................... 227
Uren1ia..................................................................................................... 229
Renal tuniors............................................................................................ 230
Kidney malformations and cysts.............................................................. 231
PATHOLOGY OF THE URINARY TRACT.............................................. 233
Dilatation of the urinary tract.................................................................. 233
Urinary calculi......................................................................................... 233
Inflammation ofthe urinary tract............................................................ 233
Tumors of the urinary tract...................................................................... 234
PATHOLOGY OF THE FEMALE GENITAL SYSTEM, PREGNANCY
AND BREAST..................................................................................................... 236
PATHOLOGY OF THE FEMALE GENITAL SYSTEM............................ 237
Pathology of the ovary............................................................................ 237
Nontumor lesions.............................................................................. 237
Ovarian inflammations...................................................................... 237
Non-neoplastic cysts......................................................................... 238
Ovarian tumors................................................................................... 23 8
Epithelial tumors.......................................:......................... 239
Ovarian sex-cord/stromal tumors........................................ 243
Genn cell tumors................................................................. 244
Pathology of the fallopian tubes............................................................. 245
Tubal (ectopic) pregnancy................................................................ 245
Salpingitis......................................................................................... 245
Non-neoplatic cysts.......................................................................... 246
Tumors of the fallopian tubes........................................................... 246
Pathology of the uterine cervix............................................................... 247
Cervicits........................................................................................... 247
HPV related epithelial lesions.......................................................... 247
Tumors of the uterine cervix............................................................ 248
Pathology of the uterine corpus.............................................................. 250
Endometrial atrophy......................................................................... 250
Endometrial hyperplasia................................................................... 250
Endometritis...................................................................................... 250
Endometriosis................................................................................... 251
Tumors of the uterine corpus............................................................ 251
Congenital uterine abnormalities...................................................... 253
Pathology of the vagina.......................................................................... 254
Vaginal inflammations..................................................................... 254
Tumors of the vagina........................................................................ 254
Pathology of the vulva............................................................................ 255
Inflammations.................................................................................. 255
Tumors ............................................................................................ 255
Pathology of pregnancy.......................................................................... 256
Spontaneous abortion...................................................................... 256
Ectopic pregnancy........................................................................... 256
Toxemia in pregnancy..................................................................... 256
Pathology of the placenta................................................................ 257
Gestational trophoblastic lesions..................................................... 258
Complications during delivery........................................................ 259
Pathology of the breast.......................................................................... 260
Malformations................................................................................. 260
Inflammations.................................................................................. 260
Fibrocystic breast changes............................................................... 261
Benign epithelial proliferation......................................................... 261
Breast tumors ................... ........................... ..... ... ............................ 262
PATHOLOGY OF THE MALE GENITAL TRACT..................................... 266
PATHOLOGY OF THE TESTIS AND EPIDIDYMIS................................... 267
Congenital and other nontumor lesions.................................................. 267
Inflammations......................................................................................... 268
Testicular and epididymal tumors.......................................................... 268
PATHOLOGY OF THE SPERMATIC CORD AND SEMINAL VESICLES..271
PATHOLOGY OF THE PROSTATE GLAND............................................... 271
Prostatitis............................................................................................... 27 1
Benign prostatic hyperplasia................................................................. 272
Prostatic carcinoma............................................................................... 272
PATHOLOGY OF THE PENIS....................................................................... 275
PATHOLOGY OF THE SCROTUM............................................................... 275
PATHOLOGY OF THE NERVOUS SYSTEM............................................... 277
PATHOLOGY OF THE DURA MATER....................................................... 278
PATHOLOGY OF THE LEPTOMENINGES................................................ 279
Vascular disorders.................................................................................. 279
Meningitis............................................................................................... 280
PATHOLOGY OF THE CEREBRAL VENTRICLES................................... 282
PATHOLOGY OF THE BRAIN PARENCHYMA........................................ 284
Vascular disorders.................................................................................. 284
Inflammations of the brain and spinal cord............................................ 287
Non-purulent infl ammations............................................................. 287
Polioencephalitis, poliomyelitis.......................................... 287
Leucoencephalitis, leucomyelitis........................................ 288
Persistent viral encephalitis................................................. 288
Prion encephalopathies........................................................ 289
Purulent inflammation....................................................................... 289
Specific inflammations...................................................................... 290
Cerebral atrophy...................................................................................... 290
Degenerative cerebral diseases............................................................... 290
Brain tun1ors............................................................................................ 292
PATHOLOGY OF THE LOCOMOTOR SYSTEM ....................................... 295
BONE PATHOLOGY................................................................................... 296
Skeletal deformities................................................................................. 296
Aseptic bone necrosis.............................................................................. 296
Osteoporosis............................................................................................ 297
Congenital disorders of osteogenesis...................................................... 297
Acquired metabolic bone diseases ........................................................... 298
Inflammations.......................................................................................... 299
Bone tumors............................................................................................. 301
JOINT PATHOLOGY................................................................................... 303
Arthrosis................................................................................................. 303
Arthritis................................................................................................... 303
Other joint lesions................................................................................... 304
PATHOLOGY OF SKELETAL MUSCLE................................................... 305
Muscle atrophy....................................................................................... 305
Systemic niyopathies............................................................................... 305
Myositis................................................................................................... 305
BLOOD AND BONE MARROW PATHOLOGY........................................... 306
ERYTHROCYTE PATHOLOGY................................................................ 307
Polycythemia........................ ........................................................ .......... 308
Anemia ................................................................................................... 308
PATHOLOGY OF LEUKOCYTES............................................................. 3 1 1
Leukemias............................................................................................... 3 11
Acute leukemia................................................................................. 311
Chronic myeloid leukemia................................................................ 312
Chronic lymphocytic leukemia ......................................................... 312
BONE MARROW PATHOLOGY............................................................... 313
DISORDERS OF BLOOD COAGULATION AND HEMOSTASIS.......... 313
SPLEEN PATHOLOGY............................................................................... 314
PATHOLOGY OF THE ENDOCRINE SYSTEM .......................................... 315
PATHOLOGY OF THE PITUITARY GLAND........................................... 31 6
ADRENAL GLANDS DISORDERS............................................................ 316
PATHOLOGY OF THYROID GLAND....................................................... 318
REFERENCES.................................................................................................... 320
PATHOLOGY OF THE
CARDIOVASCULAR SYSTEM
15
I. PATHOLOGY OF THE HEART
Diseases of the pericardium

Pathology of the myocardium
Ischemic heart disease
Hypertrophy and dilatation
Cardiomyopathies
Myocarditis
Pathology of the endocardium
Endocarditis
Valvulopathies
Heart failure
Tumors of the heart
Pathology of cardiovascular interventions and surgery
Congenital heart diseases
DISEASES OF THE PERICARDIUM
Vascular disorders
Hydropericardium (pericardia/ effusion)

Definition: accumulation of a clear serous fluid (transudate) within the pericardia!
cavity (usually less than 1000 ml)
Causes: heart failure (increased hydrostatic pressure)
hypoalbuminemia (decreased colloid osmotic pressure)
Consequences: dilatation of the pericardia! sac; if the fluid accumulation is too fast
or a large quantity of fluid is involved it may cause cardiac tamponade
Pathomechanism of cardiac tamponade: the increased pressure around the heart
reduces venous return and the blo�d pressure in both atria increases. On one hand,
the increased pressure in the right atrium leads to increasing of central venous
pressure, jugular veins distension and liver congestion. On the other hand, the
increased pressure in the left atrium leads to pulmonary hypertension, dyspnea and
cyanosis. Other direct consequence of fluid accumulation in the pericardia! sac is
impairment of myocardial dilatation. As a result of all these disorders, the cardiac
output falls because of systemic hypotension which, untreated, can lead to death.
16
Hemopericardium
Definition: accumulation of blood in the pericardia) cavity
Causes: cardiac or aortic root rupture, anticoagulant therapy, etc.
Consequences: cardiac tamponade (200-300 ml can lead to death)
Clinical features: hypotension, low blood pressure during inspiration (pulsus
paradoxus)
Subepicardial petechiae
Definition: tiny multiple hemorrhages (1-2 mm in diameter) on the pericardium
Causes: asphyxia, shock, septicemia, intoxication, blood disorders, etc.
Pneumopericardium
Definition: accumulation of a air or gases in the pericardia! cavity

Causes: chest trauma (fractured ribs), lung and pleura injuries, gas-producing
bacteria (e.g. Clostridium)
Consequences: without clinical impact; very rarely, cardiac tamponade
Pericarditis
Primary pericarditis is a very rare condition. It is usually associated with the

inflammation of the neighbouring tissues or can be a manifestation of a generalized
disease.
Clinical features: fever, tachycardia, chest pain, pulsus paradoxus
on auscultation: pericardia) friction rub
Classification:
• according to etiology
- infective pericarditis: viruses (Coxsackie virus, poliovirus), fungi, bacteria
(Staphylococcus aureus, Haemophilus influenzae, Streptococcus, Koch's bacillus)
- aseptic (non-infective) pericarditis: rheumatic fever (part of pancarditis), uremia
(associated with pleuritis and enterocolitis), systemic lupus erythematosus,
hypersensitivity (drugs, allergy)
- pericarditis followed to myocardial infarction, idiopathic pericarditis
• according to pathogenesis
- perifocal pericarditis (associated with pleuritis, myocarditis, peritonitis, etc.)
- systemic-related pericarditis: septicemia, uremia (renal failure)
- pericarditis following radiation, trauma (very rarely)
• according to chronology
- acute pericarditis - most of the cases
- chronic pericarditis: tuberculosis, viral infections, rheumatoid arthritis, etc.
17
• according to the type of the iriflammatory exudate
- serous pericarditis: rheumatic fever, systemic lupus erythematosus
tuberculosis, viral infections
- fibrinous pericarditis (villous membrane with characteristic 'bread and butter
appearance') is the most common type of non-infective pericarditis which can be
related to rheumatic fever, uremia or cardiac surgery; sometimes, it can be the
result of viral infection or perifocal inflammation (pleuritis) but acute myocardial
infarction (first week after infarction) and tumor metastasis can also be involved
- purulent pericarditis: perifocal inflammations, septicopyaemia
- necrotizing pericarditis: perifocal inflammations (pleuritis or mediastinitis)
- hemorrhagic pericarditis: tuberculosis, tumor metastases, etc.
- tuberculous pericarditis: associated with either a serous/fibrinous exudate or
caseous necrosis; it can be the result of systemic spread or direct extension via the
infected pleura
• particular types of pericarditis
- Dressler's syndrome - it usually occurs after acute myocardial infarction or
cardiac surgery; the outcome is favourable with steroid therapy
Evolution and consequences of pericarditis

- acute pericarditis:
- absorption of the inflammatory exudate (serous pericarditis)
- lysis of the fibrinous membrane (fibrinous inflammation)
- death (purulent, necrotizing or hemorrhagic pericarditis)
- connective tissue organization can lead to the formation of fibrous
(connective) adhesions of the pericardia) layers which can be complicated
with dystrophic calcification
- chronic pericarditis: fibrosis, adhesions, scarring
- 'chronic constrictive pericarditis' represents the encasement of the heart with a
thick fibrous tissue; the cava vein can be narrowed, the diastolic filling is affected;
generalized congestive heart failure may occur due to direct mechanical
obstruction; treatment: surgical excision of the fibrous tissue
Pericardial tumors
- primary tumors: malignant mesothelioma - very rarely

- secondary tumors: metastases originating from lung, breast, kidney, liver or
esophageal cancers may be associated with hemorrhagic pericarditis
18
Fig. 1. Fibrinous inflammations in a patient with uremia:
A. Pericarditis; B. Pleuritis; C. Colitis
Fig. 2. Lesions of the pericardium:

A. Petechiae; B. Hydropericardium; C. Metastases from a lung carcinoma
19
PATHOLOGY OF THE MYOCARDIUM
ISCHEMIC HEART DISEASE
Clinical syndromes: - angina

- chronic ischemic heart disease
- sudden death
- myocardial infarction
- heart failure
Etiopathogenesis: ischemic heart disease occurs as a result of low or complete
obstruction of blood flow into the myocardium. The main causes are:
• injuries to the coronary arteries
- coronarosclerosis
- abnormal vasomotor tone, vasculitis, emboli
- necrosis in the medial layer of the coronary arteries (during pregnancy)
- congenital malformations - Bland-White-Garland syndrome (the left coronary
artery arises from the pulmonary artery - infants die during the first days after
birth)
• lesions of the myocardium
- hypertrophy, myocarditis, connective tissue disorders, amyloidosis, metastases
• conduction system abnormalities
- arrhythmias: atrial extrasystole, paroxysmal supraventricular tachycardia,
atrial/ventricular fibrillation
• lesions of the endocardium
- endocarditis, valvulopathies
• metabolic disorders
- hypoglycemia, thyroid lesions, increased levels of catecholamines
• other causes
- hypoxia, shock, severe anemia, carbone monoxide intoxication, lung disorders
Angina
Definition: severe episodes of retrostemal chest pain caused by temporary

ischemia. It usually radiates to the arms, neck and jaw. The pain is the result of
prolonged hypoxia. The myocytes use anaerobic metabolism and produce toxic
metabolites (e.g. lactic acid) and bradykinin, important mediators of pain.
Morphological features: coronarosclerosis, myocardosclerosis
20
Stable angina
Definition: short painful episodes relieved with rest and/or drugs.
Risk factors: coronarosclerosis, myocardial hypertrophy
Precipitating factors: increased cardiac work (physical effort, heavy meals,
emotional stress, exposure to cold, etc.) or sudden decrease of blood pressure
Unstable or crescendo angina
- not related to cardiac work and its onset cannot be easily predicted
- can be determined by: sudden luminal thrombosis, abnormal coronary vasomotor
tone, ulcerated atheromatous plaques
- prolonged episodes, characteristic, severe or rapidly progressive angina-like pain
- complications: sudden death, myocardial infarction
Variant or also called Printzmetal's angina
- painful recurrent episodes which are not associated with coronary lesions
- can be produced by a coronary spasm and can appear during rest
Chronic ischemic heart disease

(Myocardosclerosis)
It is the most frequent syndrome of ischemic heart disease which usually affects
elderly people. Hypertension and myocardial hypertrophy are important
background factors. Myocardosclerosis is related to prolonged coronarosclerosis
which is associated with gradual narrowing of the coronary artery lumen (in more
than two coronary arteries the diameter of the lumen is narrowed with more than
75%)
Pathogenesis: the gradual onset of coronarosclerosis leads to prolonged hypoxia
which can cause the gradual replacement of cardiac muscle fibers with fibrous
tissue (myocardosclerosis) and the atrophy of the myocardium. The valves are
frequently involved (fibrous thickening, calcification, stenosis, incompetence).
These lesions can determine heart failure followed by chronic systemic and
pulmonary congestion.
Clinical features:
- asymptomatic in early stages
- signs of progressive heart failure (congestion of the pulmonary and systemic
circulation) which may be accelerated by opportunistic infections
- arrhythmias: atrial fibrillation, atrioventricular node block, etc.
- associated disorders: angina and myocardial infarction.
21
Sudden ischemic cardiac death
(Sudden arrhythmic death syndrome - SADS)
It is the most dramatic syndrome of ischemic heart disease. The main death causing
mechanism is ventricular fibrillation. Sudden cardiac death can be the consequence
of acute lesions of the coronary arteries (rupture of an atherosclerotic plaque,
thrombi in the left main coronary trunk, which is labelled as the 'artery of sudden
death' or 'widowmaker artery') or some chronic lesions can lead to decompensated
heart failure (ventricular hypertrophy, myocardosclerosis, progressive
coron'1fosclerosis).
Myocardial infarction
Definition: acute myocardial infarction is the coagulative necrosis of the

myocardium (white, pale or anemic infarct) which occurs as a result of sudden
obstruction of a coronary artery or sudden reduction of the coronary blood supply
Etiology:
- progressive coronarosclerosis with the obstruction of the arterial lumen
- ulceration of an atheromatous plaque - acute coronary thrombosis
- congenital malformations of the coronary arteries, aortic dissection, vasculitis
- coronary artery embolism
Risk factors:
- hypertension, hyperlipemia, diabetes mellitus, obesity (the deadly quartet)
- emotional stress, the use of tobacco, ingestion of cocaine/sympathomimetic drugs
Clinical features: severe retrostemal chest pain radiating to the arms and neck
which can persist for several hours and may be associated with nausea, vomiting,
sweating, weakness; 15% of the cases are painless
Classification of myocardial infarction:
• according to the affected area
- regional infarction - considering the distribution of the coronary artery
- paradoxical infarction - does not consider the distribution of the coronary artery
• according to the affected branch of the coronary artery
1. infarction of the left ventricle (95% of the cases)
- anterior or antero-septal infarction (40% of the cases): the anterior descending
branch of the left coronary artery is obstructed
- posterior or posteroseptal infarction: the right coronary artery is obstructed
- lateral infarction: the circumflex branch of the left coronary artery is obstructed
2. infarction of the right ventricle/atrium - very rare, usually associated with the
infarction of the left ventricle
22
• according to the extension into the myocardial wall
- transmural infarction - full necrosis of the entire thickness of the wall
- intramural infarction - expanded necrosis which does not involve the entire
thickness of the wall
- subendocardial infarction - the inner half or one-third of the wall is affected;
ventricular hypertrophy is a risk factor but the necrosis of this area can also occur
in the absence of coronary artery lesions (e.g. shock - sudden hypotension)
- miliary necrosis (irifarct-like lesions) - multiple minute necrosis in the
subendocardial layer and papillary muscles due to severe hypoxia
Clinicopathological features:
- infarction can be diagnosed based on serum enzyme levels and ECG
characteristics (ST - segment elevation and inversion of T wave) during the first
hours; in subendocardial infarction ECG may have normal aspect
- irreversible death of myocytes occurs after 20 minutes - 3 hours
- microscopic lesions are observed after 6-8 hours
- macroscopic lesions appear after 1 5 hours
- scarring (fibrosis) begins after 2-3 weeks
- maximum friability (softness, necrosis) appears during the first 1 0 days; it is
called 'myomalacia cordis' (malakos, Gr. = soft)
- pathological Q waves can be observed on ECG after scarring
The process of healing:

- posterior infarction presents the best outcome
- independently by localization, scarring rate is 1 mm/ 1 0 days
- thrombolysis should be performed in the first two-three hours, before myocytes
are irreversible damaged; if it is performed after the above mentioned period of
time, hemorrhages and expanded area of myocardial necrosis can be associated
(reperfusion injury) with it because during prolonged hypoxia xanthine
dehydrogenase is transformed into xanthine-oxidase; in case of late reperfusion, in
the presence of the oxygen, the xanthine-oxidase can be transformed into another
superoxide which is reponsible for reperfusion injuries.
23
Time M icroscopy Macroscopy ECG Serum
-,�
Q
0-2 h no changes no changes elevated serum
troponin and
myoglobin levels,
Ieukocytosis
4-6 h swollen
myocardial fibers
hypereosinophilia
minimal
changes JV\_ elevated serum
CKMB
(myocardial
creatine kinase)
level
24 h-3 days lack of nuclei hyperemia elevated serum

(karyopyknosis) of the GOT and LDH
neutrophils and
myocardium
followed by --- (Iacto-
� dehidrogenasis)
hyperemia in the a pale- levels
narrow rim yellow area
surrounded
by a
hyperemic
narrow rim
3 - 1 0 days neutrophils in the pale area, decreased serum
infarcted area high enzymes level
¼
surrounded by friability - �
granulation tissue myomalacia
cordis
weeks-months the infarcted area white

is replaced by fibrous area
connective tissue ( scar tissue) �
(scarring)
�
Table 1 . Clinicopathological features of myocardial infarction according to the

period of time the period of time after the onset of the myocardial infarction
24
Complications:
I. Sudden cardiac death
- 20% of the patients die in first 24-48 hours due to ventricular fibrillation
- thrombolysis reduces mortality
- mortality rate depends on the size of infarct and associated diseases
2. Arrhythmias (90% of the cases)
- atrioventricular node block, tachycardia
- ventricular fibrillation - - - ►. death
3. Heart failure
- affects 60% of the patients with expanded necrosis
- occurs when more than 20% of the ventricular myocardium is infarcted
4. Cardiogenic shock ( l 0-15% of the cases)
- occurs when more than 40% of the ventricular myocardium is infarcted
5. Ventricular rupture (5-1 0% of the cases)
- usually appears in the 7th -10th days after infarction (myomalacia cordis)
- patients with small but transmural infarction are more predisposed
- causes of death are hemopericardium and cardiac tamponade
6. Thromboembolism (15-20% ofthe cases)
- tipically the consequence of intraventricular thrombus formation and can lead to
embolism in brain, kidneys, intestines, lower limbs, etc.
- sometimes, due to longer bed rest and venous stasis, patients can present
thrombophlebitis which can lead to pulmonary thromboembolism
7. Ventricular aneurysm (10-35% of the cases)
- ventricular dilatation which appears after the formation of a myocardial scar
- can lead to thrombogenesis or ventricular failure
- can be the treated with the surgical excision of the aneurysm
8. Progressive infarction (recurrent irifarction)
- due to further occlusion of one of the coronary arterial branches other new
infarctions can appear and the risk of complications increases
- clinical features: persistent pain
9. Other complications:
- mitral incompetence, pericarditis, angina pectoris (ischemia in non-necrotic areas)
I 0. Dressler 's syndrome
- autoimmune inflammatory response of the body to necrosis, characterized by:
fever, chest pain, increased erythrocyte sedimentation rate, leukocytosis,
pericarditis and hydrothorax
Causes of death: arrhythmias

heart failure, cardiogenic shock, cardiac tamponade
thromboembolism
25
circumflex artery
right coronary artery
left anterior descending artery
Normal blood supply depending on the coronary artery
J
left anterior descending artery I I circumflex artery 1 1 right coronary artery
antero-septal infarction lateral infarction postero-septal infarction
Fig. 3. Localization of myocardial infarction depends on the obstructed artery

(RV=right ventricle; LV=left ventricle)
26
Posterolateral infarction Anteroseptal infarction
Progressively expanding infarction Posterior infarction
Subendocardial infarction Intramural infarction
Fig. 4. Myocardial infarction

(P=posterior; L =lateral; A=anterior; S=septum)
27
Fig. 5. Morphological aspects in the healing process of myocardial infarction. First
hours - hyperaemic area (A) with hypereosinophilic fibers, without nuclei (B);
First days - pale area surrounded by a hyperaemic narrow rim (C); in picture D, the
hypereosinophilic infarcted area (1) can be compared with the normal myocardium
with nuclei (3); the narrow rim is composed of neutrophils and dilated capillaries
(2); First weeks/months: a white scarring tissue (E) replaces myocardial fibers (F)
28
CARDIAC HYPERTROPHY
Definition: the increase of myocardial fibers m volume as a compensatory

mechanism to increased cardiac workload
Etiology: the increase of intracardiac blood volume and/or blood pressure; the
ventricles are more affected than the atria.
• left ventricular hypertrophy
- cardiac causes: aortic stenosis, aortic incompetence, mitral incompetence
congenital malformations (explained later in this book)
- extracardiac causes: hypertension, atherosclerosis, congenital malformations (e.g.
stenosis of aortic isthmus), thyrotoxicosis, severe anemia (increasing in the
metabolic rate leads to increasing of the cardiac work and peripheral blood flow)
• right ventricular hypertrophy
- cardiac causes: aortic, mitral and tricuspid valvulopathies
congenital malformations
- extracardiac causes (chronic car pulmonale): chronic diseases of the respiratory
tract (pulmonary emphysema, bronchial asthma, bronchiectasis, pulmonary
fibrosis, pneumoconioses), thoracic deformities (pleural callus, scoliosis, Pott's
disease), pulmonary artery diseases - recurrent embolism, primary pulmonary
hypertension
Morphology of cardiac hypertrophy:

• concentric hypertrophy
- hypertrophy of the ventricular wall, without dilatation of the cavity
- in the left ventricle the thickness is larger than 15 mm, in the right ventricle larger
than 6 mm
• eccentric hypertrophy
- hypertrophy of the ventricular wall and dilatation of the cavity
Consequences of cardiac hypertrophy: chronic ischemia, myocardosclerosis,

functional mitral incompetence, arrhythmias, heart failure
Clinical features: angina, dyspnea, syncopal attacks, hypertension, arrhythmias.
29
CARDIAC DILATATION
Definition: the enlargement of heart cavities as a compensatory mechanism to

increasing blood volume and/or pressure. The dilatation can or cannot be
associated with cardiac hypertrophy.
Classification:
• tonogenic dilatation: the contractility of the myocardial fibers is preserved
• myogen dilatation: irreversible decrease of the contractility of the
myocardial fibers leads to heart failure and generalized congestion
Etiology:
• acute cardiac dilatation can be caused by pulmonary embolism,
myocardial infarction or physical effort (tonogenic and reversible dilatation)
• chronic cardiac dilatation can be tonogenic or a myogen irreversible
dilatation which can be associated with valvulopathies, cardiomyopathies, severe
myocarditis, myocardosclerosis, etc.
CARDIOMYOPATHIES
Definition: diseases of the cardiac muscles unrelated to ischemic heart diseases,

valvulopathies, hypertension or rheumatic fever. The etiology is frequently
unknown, genetic influences can play an important role in their pathogenesis
(primary cardiomyopathies). Secondary cardiomyopathies are related to other
extracardiac diseases.
Primary cardiomyopathies
Dilated (congestive) cardiomyopathy

- the most common type of primary cardiomyopathies
- a familial disease which occurs especially in young males
- genetic causes: myotonic dystrophy, Duchenne dystrophy, gene mutations of the
mitochondrial respiratory chain or dystrophin gene which controls
the activity of cytoskeletal proteins
- morphology: dilatation of the four cardiac chambers and ventricular hypertrophy
the weight of the heart can be above 500-1000 grams (bovine heart)
- evolution: the systolic function is affected, mural thrombi are often observed
myocardial fibrosis, thromboembolism, heart failure, sudden death
- treatment: cardiac transplant
30
Hypertrophic cardiomyopathy
- a rare familial disease which can occur in both young males and females
- etiology: frequent gene mutations of the myocyte contractile proteins filament;
it can also be present in athletes
- morphology: disproportionate thickening of the interventricular septum, close to
the aortic outflow tract (asymmetrical left ventricular hypertrophy)
without cavity dilatation; the weight of the heart can be 500-1200
grams (bovine heart)
- evolution: both systolic and diastolic functions are restricted
mitral valve incompetence, arrhythmias, heart failure
sudden death (30% of the cases)
- treatment: drugs, surgical valve replacement or cardiac transplant
Restrictive cardiomyopathy
- an idiopathic fibrosis of the endocardium and underlying myocardium which
leads to the increase of rigidity and abnormal diastolic relaxation (restriction of the
ventricular filling, d�crease of cardiac output)
Classification:
• endomyocardialfibrosis: fibrosis of the endocardium, underlying
myocardium, papillary muscles, chordae tendineae
• endomyocardial fibroelastosis is a very rare disease in infants and young
children which consists of the thickenning of the left atrial and ventricular
endocardium (proliferation of elastic fibers)
Arrhythmogenic right ventricular cardiomyopathy

- a rare familial disease which occurs in young persons
- a progressive loss of right ventricular myocytes associated with fibrosis,
inflammation and fatty change
- genetic causes: gene mutations of cell adhesion proteins (e.g. desmoplakin)
- associated disorders: woolly hair, peripheral hyperkeratosis.
31
Secondary cardiomyopathies
Toxic cardiomyopathies
- alcohol - dilated cardiomyopathy which affects 20% of alcoholics
- the toxic effect is associated with deficiency of vitamin B I
- cocaine - dilated cardiomyopathy associated with coronary artery constriction,
cardiac ischemia and arrhythmias (increased release of cathecolamines)
- heavy metals (lead, cobalt, arsenic, etc.)
Iatrogenic (doctor-induced) cardiomyopathies

- cytotoxic drugs (chemotherapeuthic substances as doxorubicin, steroids)
- radiotherapy (mediastinal tumors) ---t restrictive cardiomyopathy
Dysmetabolic cardiomyopathies
- protein metabolism: severe hypoproteinemia (cirrhosis, glomerulonephritis)
amyloidosis (restrictive cardiomyopathy)
- carbohydrate metabolism: glycogenosis (Pompe disease)
- lipid metabolism: hypoxia, anemia (fatty change - tigered effect)
infections, toxins (diffuse fatty change)
- pigment accumulation: lipofuscin (cardiac brown atrophy - elderly, cachexia)
hemosiderin (hemochromatosis)
- ionic metabolism : hypokalemia ---t edema, fibrosis, focal myocardial necrosis
hyperkalemia ---t arrhythmias, cardiac stop ! ! !
Other related disease:

- endocrine diseases: hyperthyroidism, hypoparathyroidism, acromegaly
- autoautoimmune diseases: systemic lupus erythematosus, systemic scleroderma,
etc.
- pregnancy-related and postpartum (puerperal) cardiomyopathies appear in the
last months of pregnancy or within 6 months after childbirth, can be totally
reversible or can recur during subsequent pregnancy
- viral infections: acute dilated cardiomyopathy (myocarditis)
32
Fig. 6. Concentric and eccentric left ventricular hypertrophy (LV). The right
ventricle (RV) is normal in the left image and hypertrophic in the right
Fig. 7. Normal sized heart, 350 g (A) and dilated cardiomyopathy, 1000 g (B-D)
33
MYOCARDITIS
The inflammation of the myocardium is rare. Myocarditis is usually an acute

process with total recovery but sometimes it can progress to dilated
cardiomyopathy, heart failure or sudden death in both children and adults.
Clinical features: asymptomatic or flu-like symptoms, retrosternal pain, fever,

dysproportion between pulse rate and temperature, arrhythmias, etc.
Diagnosis is based on myocardial biopsy which reveals inflammatory infiltrate

within the myocardium and necrosis of myocytes.
Etiology:
• infective myocarditis
- viruses: Coxsackie A and B, Echoviruses, Epstein Barr Virus (EBV)
Varicella Zoster, Cytomegalovirus (CMV), Herpes Simplex
Influenza A and B, Echovirus, Measles, Respiratory Syncytial Virus
Polio virus, Hepatitis A virus, etc.
- bacteria: Streptococcus pyogenes, Staphylococcus aureus, Meningococcus
Leptospira, Corynebacterium diphteriae, Mycobacterium tuberculosis
Treponema pallidum, Borrelia burgdorferi (Lyme disease), etc.
- protozoa - Trypanosoma cruzi (Chagas disease), Toxoplasma gondii
- parasites - Trichinella spiralis
- fungi - Aspergillus, Candida albicans, Cryptococcus
• non-irifective myocarditis
- physical agents - ionising radiations
- toxic drugs - chemotherapic agents (Fluorouracil), Arsenic, Phenothiazine
- hypersensitivity reactions to drugs - Penicillin, Methyldopa, Streptomycin, etc.
- autoautoimmune diseases - rheumatic fever, systemic lupus erythematosus, etc.
- cardiac transplant rejection
- idiopathic (Fiedler 's) myocarditis
Morphology:
• interstitial myocarditis
- causes: hypersensitivity reactions, viral infections, drugs
- morphology: cardiac dilatation, interstitial inflammatory infiltrate (lymphocytes
and plasma cells) and edema, minimal myocytes injuries
- evolution : healing with complete recovery or myocardosclerosis
heart failure is a very rare complication
34
• alterative myocarditis
- causes: septicemia, bacterial or protozoa infections, Trichinella spiralis,
hypersensitivity reactions, etc.
- morphology: cardiac dilatation, focal areas of myocyte necrosis, edema, minimal
inflammatory infiltrate
- evolution: healing with myocardial fibrosis, heart block or heart failure
• Fiedler 's (idiopathic) myocarditis
- morphology: granulomas with giant cells formation and inflammatory infiltrate
(lymphocytes, plasma cells, eosinophils); it is usually associated with focal fibrosis
in the left ventricle wall
- evolution: healing with myocardial fibrosis, heart failure or sudden cardiac death
• purulent myocarditis
- causes: Streptococcus pyogenes, Staphylococcus aureus, fungi
septicemia, pyaemia
infective emboli in coronary arteries, infective endocarditis
- morphology: myocardial abcesses, focal myocyte necrosis
- evolution: healing with fibrosis or
pericardia! empyema due to perforation or
heart failure
• granulomatous myocarditis
a) Rheumatic fever
- ussualy associated with endocarditis and pericarditis (pancarditis)
- microscopic view : ,:\schoff bodies (Anitschkow cells and Aschoff giant cells)
- complications: acute phases - heart failure
chronic phases - myocardosclerosis, arrhythmias
b) Rheumatoid arthritis
- an autoautoimmune disease associated with myocarditis in 50% of the cases
- microscopic view: fibrinoid necrosis of the arterial wall surrounded by
inflammatory cells (lymphocytes, plasma cells) and focal necrosis ofmyocytes
c) Tuberculosis
- tubercles may be observed during milliary tuberculosis or tuberculous pericarditis
d) Sarcoidosis
- associated with the sarcoidosis of the lung, bone, skin and other organs
e) Syphilis
- myocarditis is very rarely observed in third phase of syphilis.
35
Fig. 8. Microscopic aspects of myocarditis
PATHOLOGY OF THE ENDOCARDIUM
ENDOCARDITIS
Definition: the inflammation of the endocardial layer of the heart. The term is
usually reserved for heart valves inflammation but the mural endocardium of the
atrium or ventricle and the chordae tendinaea may also be affected
Classification:
- according to etiology: infective and non-infective endocarditis
- according to evolution: acute, subacute, chronic and recurrent endocarditis
- according to morphology: simple, ulcerative and vegetative endocarditis
Localization:
- mitral valve - 40% of the cases
- mitral + aortic valves - 40% of the cases
- aortic valve - 15% of the cases
- tricuspid + pulmonary valves - 5% of the cases
36
Non-infective endocarditis
(Rheumatic valvular disease)
Definition: endocarditis which occurs during rheumatic fever as a immune reaction

of the body to Lancefield group A Streptococcus pyogenes
Clinical features: fever, tachycardia, flitting arthralgia, elevated erythrocytes
sedimentation rate, anemia, leukocytosis, elevated streptococcal antibodies titre
(anti-streptolysin O or ASLO titre)
Localization: mitral + aortic valves - 50% of the cases
mitral valve - 35% of the cases
all valves - 15% of the cases
Simple endocarditis
- occurs in acute phases of rheumatic fever
- macroscopic view: diffuse valvular edema, mild thickening of the cusps
without thrombi
- microscopic view : mild inflammatory infiltrate
- consequences: mild valvular fibrosis
Simple vegetative endor:arditis

- macroscopic view: ori the closure lines of valve cusps and the chordae tendineae,
small thrombotic vegetations which can be easily removed in early stages; in
;hronic endocarditis, the valves are vascularized and the thrombi present
connective organization
- microscopic view: thrombotic vegetations composed of platelets, leukocytes,
fibrin, without bacteria (aseptic thrombi! ! !); Aschoff bodies can be observed m
cardiac valves
, - consequences: fibrous thickening and calcification of the cusps
commissural fusion, valvular stenosis and/or incompetence
heart failure
superinfection (infective endocarditis)
Recurrent vegetative non-infective endocarditis

- occurs during recurrent attacks of streptococcal infections
- consequences: chronic rheumatic valve disease
valvular fibrosis, valvular deformities.
37
Infective endocarditis
Definition: colonization of heart valves by microorganisms

Morphology: valvular ulceration and infective thrombi (vegetations) which contain
the causal agent
Risk factors: bacteraemia, septicemia, pyaemia, pneumonia, urinary infections,
gastritis, entero-colitis, cholecystitis, poor dental hygiene, teeth infections,
intravenous drug administration, surgery procedures (dental treatment, cystoscopy,
urethral catheterization, etc.)
Predisposing conditions: rheumatic fever, aortic stenosis, floppy mitral valve,
congenital defects (patent ductus arteriosus, coarctation of aorta), valve prostheses,
intracardiac catheters, pacemakers, immunodeficiencies (cytotoxic drugs, elderly)
Clinical features: fever, tachycardia, cardiac murmur, mild anemia, raised
erythrocytes sedimentation rate, leukocytosis, positive blood culture, hematuria,
Schottmtiller' s triad (valvulopathy + splenomegaly + focal glomerulonephritis)
Prognostic factors: pre-existing valve disease, degree of the valve damage, causal
agent virulence, patient' s immune status
Acute (malignant) infective endocarditis

- elevated bacterial virulence can affect the normal valves, usually mitral and aortic
Etiology: Streptococcus pyogenes, Staphylococcus aureus (intravenous drug users),
enterococci (Streptococcus faecalis), fungi, etc.
- macroscopic view : large vegetation on the cusps and parietal endocardium
valvular rupture and necrosis
- microscopic view : fibrin, neutrophils and the infective agent into vegetations
- consequences: healing with calcifications and valve deformities
without treatment it may be fatal (acute septicemia, heart failure)
Subacute infective endocarditis

- low virulence bacteria affect the previously damaged heart valves
- characterized by insidious onset
Etiology: Streptococcus viridans (periodontal infections, aggressive chewing),
Staphylococcus epidermidis (venous catheters, pacemakers), fungi (intravenous
drugs, immunosuppression - Candida, Aspergillus)
- macroscopic view: large friable vegetations and ulcerations on the contact surface
of the cusps, rupture of the cusps and the chordae, infection of the underlying
myocardium
- microscopic view : platelets, leukocytes, fibrin and the infective microorganisms
into vegetations (infective thrombi! ! !)
- evolution: prolonged endocarditis, subacute sepsis
38
Complications of infective endocarditis:
- valvular lesions (stenosis and incompetence), progressive heart failure
- myocarditis (Bracht-Wachter nodes)
- septic embolism - infarction and abscesses in brain, myocardium, spleen, kidney
- petechiae on skin, mucosa, retina
- splinter hemorrhages under the nails, clubbing
- toxemia - fever, weight loss, splenomegaly
- immune reactions - Lohlein's glomerulonephritis
- Osier's nodes in the subcutaneous tissues of the fingers (immune arteritis)
- death (heart failure, embolism, renal failure).
Particular types of endocarditis
Libman-Sacks endocarditis
- occurs during systemic lupus erythematosus
- the mitral, aortic and tricuspid valves and the atrial endocardium are involved
- morphology: non-infective small platelets-rich vegetations (under 2 mm)
valvular fibrinoid necrosis
- evolution: healing with fibrosis and valvular deformities
Marantic, terminal or cachectic endocarditis

- occurs in patients with cachexia, tuberculosis and immunosuppressive diseases
- morphology: small thrombi on the mitral and aortic valves
- differential diagnosis: DIC (Disseminated Intravascular Coagulability)
Rheumatoid arthritis - related endocarditis

- the aortic valve is affected in patients with spondylarthritis ankylopoietica
(Bechterew's disease)
Loffler 's (idiopathic) endocarditis

- the atrial and ventricular endocardial layers is affected, this can lead to heart
failure
- associated diseases: eosinophilic pneumonia, allergy
Syphilis - related endocarditis

- the aortic valve can be affected in the third stage of the disease
39
Fig. 9. Paiticular aspects of the endocarditis. In aseptic types, vegetations on the
endocardial layer (A,B). Infective thrombi are associated with infective
endocarditis (C) and atrial endocardium is involved in lupus erythematosus (D)
Fig. 1 0. Consequences of endocarditis

A.- mitral stenosis; B. mitral stenosis and incompetence
40
VALVULOPATHIES (VALVULAR HEART DISEASES)
Definition: congenital or acquired abnormalities of the cardiac valves

Risk factors: rheumatic endocarditis, infective endocarditis
atherosclerosis, syphilis, Marfan's syndrome - aortic valve lesions
intravenous drug misuse - tricuspid valve lesions
congenital malformations
carcinoid syndrome - tricuspid and pulmonary valve lesions
Types of valvulopathies
- valvular stenosis - reduction of the diameter of the valvular orifice
- valvular incompetence - the valve cannot close properly
- combined valvulopathies
Compensatory mechanisms: ventricular and atrial hypertrophy and dilatation
Clinical features:
- ejection systolic murmur - mitral incompetence
- ejection systolic murmur - aortic stenosis
- diastolic murmur, 'water-hammer' pulse - mitral stenosis, aortic incompetence
Valvular stenosis
- only an organic valvulopathy
- causes: valvular fibrosis and deformities, commissural fusion
- consequences: the pressure load increases in the previous chamber, which
becomes dilated and hypertrophic, and decreases in the post-stenosis chamber
which has normal size or is atrophic
Valvular incompetence (insufficiency)

- can be an organic or functional incompetence
- causes: valvular fibrosis and deformities (organic valvulopathy)
cardiac dilatation - valvular ring dilatation (functional incompetence)
- consequences: retrograde blood flow in the previous chamber leads to its
dilatation and hypertrophy; at the same time, the blood flow increases in the post
valvulopathy chamber which becomes dilated and hypertrophic; finally, it leads to
heart failure
Combined valvulopathies
- the consequences depend on the predominant type of the valvulopathy (stenosis
or incompetence)
41
Mitra/ stenosis
- early stages: hypertrophy and dilatation of the left atrium
the left ventricle has normal size
- late stages: congestion in pulmonary circulation, hypertrophy and dilatation of the
right heart, functional tricuspid incompetence and atrophy of the left ventricle
- complications: atrial fibrillation, thrombi in the left atrium (thromboembolism)
endocarditis, heart failure.
Mitra/ incompetence
- early stages: hypertrophy and dilatation of both left atrium and left ventricle
- late stages: congestion in pulmonary circulation, hypertrophy and dilatation of the
right heart, functional tricuspid incompetence
Aortic stenosis, aortic incompetence
- early stages: hypertrophy and dilatation of the left ventricle
- late stages: hypertrophy and dilatation of the left atrium, functional mitral
incompetence, congestion in pulmonary circulation, hypertrophy and dilatation of
the right heart, functional tricuspid incompetence
- complications: hypertrophy and dilatation of all four-cavities of the heart (cor
bovinum), arrhythmias, angina, syncope, sudden death
Tricuspid valvulopathy, pulmonary valvulopathy
- hypertrophy and dilatation of the right ventricle and right atrium
- congestion in systemic circulation
HEART FAILURE
Definition:incapacity of the ventricular muscles to maintain an adequate circulation
required by the body
Etiology:
- decreased myocardial contraction: myocardial infarction, myocardosclerosis
cardiomyopathies, myocarditis
- inefficient pumping action : arrhythmias
- decreased myocardial relaxation : hemopericardium
- increased work load: valvulopathies
pulmonary or systemic hypertension, pulmonary embolism
- increased blood volume: valvular incompetences
- increased cardiac output : severe anemia, thyrotoxicosis
Compensatory mechanisms:
- tachycardia (sympathetic nervous supply), increased pumping rate, ventricular
dilatation and hypertrophy. In heart failure the compensatory mechanisms are
inadequate to maintain cardiac output.
42
Consequences:
- low output heart failure = inability of the heart to pump normally during exercise
and/or at rest, which leads to underperfusion (arterial underfilling), increased
hydrosatic pressure and edema, activation of the renin-angiotensin system and
renal vasoconstriction; it is usually a consequence of ischemic heart diseases,
valvulopathies, myocarditis or hypertension
- high output heart failure occurs when the heart failure complicates a pre-existing
state in which the output before failure was increased (severe anemia,
hyperthyroidism, etc.); in these conditions, although the output is higher than
normal, it is not enough for what the body requires
- systolic failure = reduced ejection fraction
- diastolic failure = impaired ventricular diastolic filling
- decreased arterial blood flow -+ generalized ischemia
- impaired venous return -+ generalized venous congestion
- metabolic disorders
- sudden death
Clinical features:
- acute heart failure: fatigue, shortness of breath, pulmonary edema
- chronic heart failure: dyspnea (dyspnea), ankle edema, pulmonary edema,
renal, liver and pulmonary failure, skeletal muscle disorders
NYHA staging: I. asymptomatic heart failure

II. clinical symptoms during significant efforts
III. clinical symptoms during light exercises
IV. clinical symptoms during rest
Causes of death: progressive pump failure, arrhythmias, renal failure
Left ventricular failure

Causes: ischemic heart diseases (myocardial infarction, myocardosclerosis), mitral
and am1ic valvulopathies, myocarditis, cardiomyopathies, congenital cardiac
malformations, increased cardiac output (anemia, thyrotoxicosis), increased work
load (systemic hypertension)
Consequences: in acute stages, acute pulmonary edema and anoxic
encephalopathy; in chronic heart failure, pulmonary congestion, pulmonary
fibrosis, functional mitral incompetence, right ventricular failure, renal failure.
Clinical features: dyspnea or orthopnea
cough (pulmonary hypertension and edema)
43
Right ventricular failure (congestive heart failure)
Causes:
- lung diseases: pulmonary embolism (acute failure)
chronic obstructive pulmonary diseases (e.g. emphysema, chronic
bronchitis, pulmonary fibrosis) - chronic cor pulmonale
- cardiac diseases: valvulopathies, myocarditis, cardiomyopathies
congenital cardiac malformations, left ventricular failure
Consequences: generalized systemic congestion
Clinical features: dyspnea, ankle edema, hepato-splenomegaly
serosal effusions (hydrothorax, ascites).
HEART TUMORS
Primary tumors
Cardiac myxoma is a rare benign tumor which usually occurs in adults, in the left
atrium, as a friable polypoid mass under 10 cm in diameter. It may simulate mitral
stenosis. Differential diagnosis is made with a connective organized thrombus with
myxoid transformation.
Rhabdomyoma is a rare benign tumor which usually occurs in the ventricular
myocardium, in childhood. It can be associated with brain tuberous sclerosis
(Boumeville' s syndrome). Patients can present arrhythmias.
Fibromas, hemangiomas, lymphangiomas and lipomas are very rare benign tumors.
Secondary metastatic tumors
Cardiac metastases are more frequent than primary tumors. Both direct and
systemic (hematogenous) spread can lead to cardiac metastases which are located
in both the myocardium and the pericardium and can be associated with
hemorrhagic pericarditis. The following tumors can present cardiac metastases:
carcinomas (lung, breast, kidney, liver, esophagus, etc.), pleural malignant
mesothelioma, melanomas, lymphomas, angiosarcomas, etc.
44
PATHOLOGY OF CARDIOVASCULAR
INTERVENTIONS AND SURGERY
Coronary artery bypass grafts

- venous bypass grafts using leg veins - luminal stenosis, thrombotic occlusion
- arterial transformation - atheroma
- arterial grafts using internal mammary or radial arteries - long-term survival
Coronary artery angioplasty

- complications: restenosis, arterial rupture and/or dissection
thrombosis, atheroembolism
Prosthetic heart valves

- biological valves (pig/cow/human valves): deformities, calcification, thrombosis
- mechanical valves
• thrombi, thromboembolism, infective endocarditis
• mechanical failure - venous obstruction when a thrombus breaks away
• aortic valve stenosis - -.► stenosis of the origins of the coronary arteries - -.►
- -.► myocardial ischemia
Pacemaker implantation
- infections, thrombosis, perforations of the cardiac walls
Dacron implantation
- thrombosis, embolism
Stone heart syndrome

- failure of myocardial relaxation following cardiac surgery
Cardiac transplant
- acute/chronic graft rejection, immunosupression, infections
- malignant tumors (lymphoma, hepatocellular carcinoma).
45
Fig. 11. A. Myocardium rhabdomyoma; B. Multifocal hepatocellular carcinoma
developed in the liver after heart transplantation
Integral valve prosthesis
""';i,:.,:· �:, •'

::i- - •' . ·, . ,,
Stent implantation in the femoral artery and aortic perforation produced by guidewire
Fig. 12. Cardiovascular lesions during cardiovascular interventions and surgery
46
CONGENITAL HEART DISEASES
Definition: cardiac malformations which usually occur in the first two months after
conception when major cardiovascular structures develop.
Etiology:
• chromosomal abnormalities:
- Down syndrome (Trisomy 21)
- Turner syndrome (missing or incomplete X chromosome)
• environmental factors
- maternal TORCH syndrome - Toxoplasma gondii, Other infections (Syphylis,
Coxsackie B, etc.), Rubella, Cytomegalovirus, Hepatitis virus
- chronic maternal alcoholism and/or avitaminosis
- maternal drug abuse: Contergan/thalidomide (historically a highly teratogenic
sedative drug)
- other maternal diseases: insulin-dependent diabetes, phenylketonuria, etc.
- ionizing radiations
• idiopathic diseases
Clinicopathological features:
- poor feeding, impaired growth
- respiratory disorders, pulmonary hypertension, cyanosis, clubbing
- infective endocarditis, heart failure
Clinicopathological classification of congenital heart diseases
- in most congenital heart diseases there is a communication between the right and
left heart chambers (shunt) which in some cases can cause cyanosis
• cyanotic congenital heart diseases (right to left shunt)
- truncus arteriosus
- transposition of the great arteries
- Fallofs Tetralogy
- Eisenmenger's complex
• acyanotic congenital heart diseases (left to right shunt)
- atrial/ventricular septa! defects
- patent ductus arteriosus
47
Single anatomical abnormalities
Heart size and position defects

- acardius = parasitic twin with lack of heart; survival is not possible
- hypoplastic heart syndrome or hypoplastic ventricle
- dextrocardia = dextroposition of the heart
Atrial septa/ defect (ASD)

- it is either asymptomatic (left to right shunt) or, in adult life, pulmonary
hypertension and right heart failure occur; when the pulmonary pressure exceeds
the aortic pressure (reversed process into right-to-left shunt, Eisenmenger's
complex), patients become cyanotic and can develop paradoxical embolism
Consequences of ASD: left ventricular hypertrophy

right atrial dilatation
pulmonary hypertension
Morphological classification of ASD:

- absence of.the atrial septum - common (or single) atrium and two ventricles
- ostium secundum - large atrial septal defect in the central part of the foramen
ovale; the most common type of ASD
- ostium primum - small atrial septal defect in the lower part of the foramen ovale;
the second most common type of ASD
- patent foramen ovale - a variant of ostium secundum, a small asymptomatic
defect in the upper part of the foramen ovale
- sinus venosus defect - defect located near the entrance of the superior cava vein
- Lutembacher 's disease - ASD + mitral stenosis
Ventricular septa[ defect (VSD):

- communication between ventricles usually associated with left-to-right shunt,
which can lead to pulmonary hypertension in adult life
Morphological classification of VSD:

- single ventricle - two atria and single ventricular chamber
- membranous defect (Roger 's disease) - large defect of the membranous septum
- defects of the muscular septum - single or multifocal defects (' Swiss-cheese' septum)
- atrioventricular septa/ defect - bilocular heart (e.g. Down syndrome)
48
Defects of the arterial trunk
• truncus arteriosus (common arterial trunk)
- refers to the persistence of common arterial trunk which fails to divide into the
pulmonary trunk and aorta; abnormal shunt of blood is present between the aorta
and pulmonary artery and the two ventricles communicate with each other
- consequences: congestive heart failure, pulmonary hypertension in childhood,
cyanotic patches in the nail beds
• transposition ofthe great vessels (arteries)
- the aorta is supplied by the right ventricle and the pulmonary artery by the left
ventricle; this malformation is compatible with life only if communication between
the systemic and pulmonary circulation is ensured by either the ventricular/atrial
septa! defect or the persistence of the ductus arteriosus
• aortic stenosis
- usually associates with ventricular and atrial septa! defect
• pulmonary stenosis
- it is associate with ventricular septa! defect and right ventricular hypertrophy
Defects of the aorta

• patent (open, persistent) ductus arteriosus
- ductus arteriosus (Botallo duct) connects the distal aortic arch with the left
pulmonary artery in the fetus; in normal conditions, it closes in the first two months
of life; in case of malformations, it can persist after the first year of life and the
blood can be forced from the aorta into the pulmonary circulation
- consequences: pulmonary hypertension, right ventricle hypertrophy, heart failure,
infective endocarditis (Streptococcus viridans), etc.
• coarctation (stenosis) ofthe aorta
- a severe stenosis of the aorta extending from the origin of the left subclavian
artery to the orifice of the ductus arteriosus, which is usually fatal in infancy, or
- a fibrotic segment distal to the ductus arteriosus (e.g. Turner syndrome)
- consequences: collateral circulation (alternative pathways from the carotid,
subclavian, intercostal arteries or internal thoracic branches), aortic aneurysm,
aortic dissection, aortitis
- clinical features:
- differences between pulse rates in the legs (poor) and arms (strong)
- hypertension in the upper limbs associated with headache and dizziness
- hypotension in the lower limbs associated with their weakness, pallor, coldness
- 'notching' in chest X-ray = erosion of ribs caused by dilated intercostal arteries
- causes of death: congestive heart failure, brain hemorrhage
aortic dissection, endocarditis
49
Abnormalities of the coronary arteries
- coronary malformations may be either asymptomatic or can lead to sudden death
or cardiac injuries; Bland-White-Garland syndrome is a malformation in which the
left coronary artery arises from the pulmonary artery, which may result in
myocardial infarction
Fig. 13. Single anatomical congenital cardiac malfonnations:

A. Atrial septal defect; B,C. Ventricular septal defects
Fig. 14. Compared to the normal heart (A), in truncus arteriosus the common
arterial trunk comprises a ventricular septa! defect (B,C).
PA = pulmonary artery; Ao = aorta
50
Fig. 1 5. Patent ductus arteriosus. The arrows show the pathway between the aorta
and pulmonary artery. PA = pulmonary artery; Ao = aorta
Artera subclavia
rtera thoracica interna
Arteriae intcrcostalcs
Fig. 16. Diagrammatic representation of coarctation of the ao1ta
51
Multiple anatomical defects
Fallot's tetralogy
- components: stenosis of the pulmonary artery
right ventricular hypertrophy
large ventricular septa] defect
aorta overriding the septa] defect
- consequences: both venous blood from the right ventricle and oxygenated blood
from the left ventricle are pumped into the aorta; evolution depends on the size of
the pulmonary stenosis
- clinical features: cyanosis, polycythemia, dyspnea and characteristic squatting
position ('knee-chest' position)
Eisenmenger 's complex:

- components: right ventricular hypertrophy
ventricular septa! defect
aorta overriding the septa) defect
- cyanosis occurs in late childhood or in adulthood
II. VASCULAR PATHOLOGY

Diseases of the arteries
Arteriosclerosis
Hypertension
Aneurysms
Arteritis (Vasculitis)
Diseases of the veins
Varicose veins
Phlebothrombosis
Thrombophlebitis
Diseases of the lymphatics
Diseases of the capillaries
Tumors of the blood vessels
52
DISEASES OF THE ARTERIES
AGING
Macroscopic view: increased arterial rigidity, arterial dilatation

Microscopic view: fibrosis and thickening of the intimal layer; the smooth muscle
and elastic fibers of the media are replaced by collagen fibers
Clinical features: prominent temporal artery in elderly people, increased pulse
pressure, unfolding of the thoracic aorta on chest X-ray (arterial dilatation).
ARTERIOSCLEROSIS
(Hardening of the arteries)
Definition: a group of arterial disorders which present fibrous thickenning and the
loss of elasticity of the arterial wall.
Classification of arteriosclerosis
Atherosclerosis
- sclerosis of large and medium-sized (larger than 2 mm) arteries (explained later)
Monckeberg 's arteriosclerosis (medial calcific sclerosis)
- it is a particular type of arteriosclerosis characterized by the idiopathic formation
of calcium deposits in the media of medium-sized muscular arteries of the lower
limbs (femoral and tibial arteries), unrelated to atherosclerosis! ! !
- elderly males are more affected
- macroscopic view: increased arterial rigidity without significant narrowing but
with increased risk of thrombogenesis; on cross section: ring-like calcifications; the
arterial wall becomes similar to that of the trachea
Arteriolosclerosis
- sclerosis of the small arteries (less than 2 mm in diameter) and arterioles
- the retina and the kidneys are most commonly affected
- etiology: systemic hypertension, diabetes mellitus
iatrogenic arteriolosclerosis (radiations, transplant)
- consequences: vessel wall thickenning, luminal narrowing, ischemia
nephrosclerosis, retinal degeneration.
53
Atherosclerosis
Definition: a complex arterial lesion of the large and medium-sized arteries (larger
than 2 mm in diameter) which consists in accumulating lipoproteins, cholesterol
and other substances in the arterial intima associated with the proliferation of
myofibroblasts and Iuminal narrowing (athere, Gr. = porridge, gruel; scleroso, Gr.
= hardening). This long-time process usually results in the degeneration of the
intima and its replacement by fibrous tissues, proteoglycans and calcium salts.
The morphology of atherosclerosis (atherosclerotic plaques)

Depending on the morphological aspects, the following lesions are described:
1. Fatty streaks and fatty patches
- early atheromatous lesions which affect young people, they can replace or can be
transformed into other types of atherosclerotique plaques
- macroscopic view: small, flat, yellow patches or streaks on the intima
- microscopic view: accumulation of lipid-laden macrophages and myocytes in the
intima (migrated from the media into the intima); lipid deposition in the
macrophages (foam cells, lipid-laden macrophages) and in the extracellular space
2. Fibrous plaques
- macroscopic view : yellow-white, hard, raised plaques in the arterial intima
- microscopic view: accumulation of proteoglycans and proliferation of collagen
fibers and myocytes resulting in disorganized internal elastic lamina
3. Hyaline plaques
- either fibrous plaques transformed in hyaline or connective organization of a
thrombus
- macroscopic view: white, hard, raised plaques in the intima
- microscopic view : hyaline (glass-like substance) and cholesterol crystals
4. Atheroma
- necrotic transformation of fatty patches or fibrous plaques
- increased risk of thrombogenesis
- macroscopic view : yellow, soft, raised plaques in the intima, wich have a central
cavity with a friable yellow porridge-like substance, covered by the endothelium
- microscopic view: lipid-laden macrophages, extracellular accumulation of
cholesterol and lipoproteins, cellular debris, degeneration of the media (atrophy)
5. Complicated plaques
• ulcerated atheroma
- the ulceration of the overlying endothelium can lead to thrombosis
(atherothrombosis) and infarction in some organs (myocardium, brain, kidney, etc.)
• calcified plaques
- hard plaques that appear as result of extensive dystrophic calcification
54
Fibrous plaque
� �
Hyaline plaque Atheroma
� Calcified pla�
� Ulcerated atheroma
Thrombi
Fig. 1 7. Sequence of events leading to atherosclerosis
.- monocytes
lipid-laden macrophages
INTIMA
MEDIA
Fig. 1 8. Schematic representation of the components of atherosclerotic plaques
55
Fig. 19. Schematic representation of the atheromatous plaque. A. Accumulation of
a yelow porridge-like substance and lipid-laden macrophages in intima; B. Intimal
enlargement and compression of the media; C. Ulcerated atheroma
ulcerated
atheromas atheromas
Fig. 20. Atherosclerotic lesions
56
Clinicopathological syndromes
Atherosclerosis involves systemic arteries larger than 2 mm in diameter, arterial
branching points and bifurcations being more affected (turbulent blood flow).
According to the affected branches, the following lesions can be observed:
1. Aortic (central) atherosclerosis

- the abdominal segments are more affected than the thoracic segment of the aorta
- dilatation of the aorta, aneurysms (localized dilatation), left ventricle hypertrophy
thrombogenesis, etc.
2. Atherosclerosis of the peripheral arteries

• coronary arteries (coronarosclerosis, coronary heart disease)
a) stenosis - if in more than 50% of the lumen can lead to chronic ischemia which
is more prominent during physical effort (stable angina) or is unrelated to exercise
(unstable angina); resulting in myocardosclerosis which can cause arrhythmias
b) complete occlusion: sudden death, myocardial infarction, heart failure
• carotid and cerebral arteries - the vertebral and intracerebral arteries of the
circle of Willis and its branches are more involved, leading to: cerebral infarction,
repeated ischemic attacks, multi-infarct dementia
• mesenteric arteries - intestinal infarction or chronic ischemia associated
with abdominal claudication (painful digestion - "abdominal angina")
• renal arteries - nephrosclerosis, renovascular hypertension
• pancreatic artery - diabetes mellitus
• iliac, femoral and popliteal arteries - intermittent claudication (exercise
induced ischemia and pain of the muscles), toe gangrene, Raynaud's syndrome
3. Atherosclerosis of the pulmonary artery

- the result of pulmonary hypertension, umelated to aortic atherosclerosis.
Complications of atherosclerosis
1. Arterial narrowing -+ ischemia, fibrosis, collateral circulation
2. Atrophy: renal atrophy after long-term renal artery stenosis, brain atrophy
3. Aneurysm - occurs due to a damage of the media; the. aorta and cerebral arteries
are the most affected areas; aneurysms larger than 5 cm in diameter present high
risk of rupture
4. Rupture (ulceration) of atherosclerotic plaques -+ thrombosis
5. Atheroembolism -+ infarction in the myocardium, brain, kidney, etc.
6. Gangrene of the lower limbs
7. Death - may be the consequence of acute arterial obstruction (e.g. coronary
arteries) caused by a thrombus or atherosclerotic plaque.
57
Pathogenesis of atherosclerosis
Cholesterol and other insoluble lipids are lipoproteins. Their hydrophobic centre is
surrounded by a a hydrophilic layer (phospholipids and apolipoproteins which bind
to cell receptors). According to their density, circulating lipoproteins can be
classified as: VLDL (very low-density lipoproteins), LDL (low-density
lipoproteins) and HDL (high density lipoproteins). LDL carries 70% of blood
cholesterol and binds the liver receptors, the liver being the main organ for
cholesterol metabolism. Atherosclerosis is a process that usually begins with a
lesion of the intima. Functional disorders of the endothelial cells determines an
increased expression of cell adhesion molecules, high permeability for LDL and
increased thrombogenicity. Subsequently lipids and inflammatory cells migrate
from blood to intima, followed by proliferation of intimal myofibroblasts. These
disorders can result the formation of atherosclerotic plaques.
Etiology and riskfactors of atherosclerosis (A TS)

Atherosclerosis is a complex and multifactorial disease caused by:
I. Endogenous factors
- hereditary: LDL receptor deficiency, familial xanthomatosis, etc.
- age and gender: males above the age of 40 years and postmenopausal females
2. Environmental factors
- cigarette smoking - dose-related atherosclerosis; disorders of the coagulation
system (elevated serum fibrinogen level and platelet stickiness), damaged
endothelial cells
- diet: saturated fats, cholesterol-rich diet
- sedentary life style, stress, low socio-economic status
3. Other factors
- hyperlipemia, obesity: increased levels of LDL, lipoproteins, plasma fibrinogen
and factor VII and low levels ofHDL, lipid infiltration
- hypertension: increased hemodynamic stress at bifurcations, lipids precipitation
- diabetes mellitus: insulin resistance, hypertension, hyperlipemia and obesity
- alcohol consumption - more than 50 mg daily; unelucidated mechanism
- oral contraceptives: the blood pressure and lipid level are increased
- inflammations: Chlamydia pneumoniae, Cytomegalovirus, etc.
- hypothyroidism
- thrombogenic theory: the incorporation of small thrombi into the intima induces
myofibroblast migration from the media into the intima.
Protective actions against atherosclerosis: diet (polyunsaturated fats, fish oil, fruit,
fibers, vegetables), regular exercise, weight reduction, smoking cessation, blood
pressure control, aspirin consumption (inhibition of platelet aggregation).
58
HYPERTENSION
(Systemic arterial hypertension)
Definition: long-term, persistent, raised pressure in the systemic arterial network; a

neurovegetative disease and a common cause of cardiovascular diseases and
atherosclerosis.
Definition of the World Health Organization: sustained resting blood pressure,
higher than 160/95 mm Hg.
Clinical classification
• borderline hypertension - values between 140/90 and 1 60/95
• mild hypertension - diastolic pressure between 95-1 04 mm Hg
• moderate hypertension - diastolic pressure between I 05-114 mm Hg
• severe hypertension - diastolic pressure > 1 14 mm Hg
Etiology
• primary (essential) hypertension - 95% of the cases
- genetic predisposition
- environmental factors: stress, diet, alcohol consumption, lack of exercise
• secondary hypertension - 5% of the cases
- renal disorders: renal artery stenosis, chronic glomerulonephritis/pyelonephritis,
diabetes mellitus, polycystic kidney (activation of renin-angiotensin system)
- cardio-vascular disorders: coarctation of the aorta, aortic valve incompetence,
atherosclerosis (increased diastolic pressure due to loss of distensibility of arteries),
arteriolosclerosis (increased systolic pressure due to increased resistance)
- endocrine diseases: Cushing' s syndrome (excessive amounts of corticosteroids),
Conn's syndrome (excessive amounts of aldosterone), phaeochromocytoma
(excessive amounts of cathecolamines), congenital adrenal hyperplasia, primary
aldosteronism
- other disorders: pre-eclampsia, metabolic syndromes, tumors of the adrenal
glands, drug consumption (steroid therapy, oral contraceptives, etc.)
Benign hypertension
Definition: very slow rise of the systolic hypertension, with diastolic values less
than 120 mm Hg, which affects elderly persons, has long-term evolution and leads
to gradual injuries of the heart, brain, kidneys and small a1teries
• lesions of the cardiovascular system
- increased cardiac work load and vascular resistance - concentric left ventricular
hypertrophy
- coronarosclerosis - myocardosclerosis and ischemic heart diseases
- arteriolosclerosis (arteriolar hyalinosis)
59
• brain lesions
- arteriosclerosis and Charcot-Buchard aneurysms of the cerebral arteries
• renal lesions
- hyalinosis of the afferent arterioles
- atrophic kidneys, granular surface (benign nephrosclerosis, arteriolosclerosis)
Complications of benign hypertension:
- ischemic heart diseases, arrhythmias, heart failure
- myocardial infarction, sudden death
- arterial aneurysms, aortic dissection
- brain hemorrhages (rupture of the cerebral aneurysms)
- renal failure (very rarely)
Malignant hypertension
Definition: rapid severe evolution of hypertension characterized by dyastolic
pressure higher than 1 20 mm Hg. Untreated, it can lead to death within months. It
can be a primary malignant hypertension, a transformation of the benign type
(accelerated hypertension) or, more frequently, affects young adults and is
secondary to renal disorders. Unlike benign hypertension, the main pathological
features of the malignant type are the severe damages of the arterioles.
• arterial lesions
- fibrinoid necrosis and microaneurysms of cerebral arteries
- fibrinoid necrosis of the afferent glomerular arterioles and glomerulonecrosis
• cardiac lesions
- left ventricle hypertrophy, patchy myocardial necrosis, acute heart failure
• brain lesions
- hemorrhages, edema, encephalopathy
• renal lesions
- fibrinoid necrosis of the afferent arterioles, malignant nephrosclerosis
- uremia, death
Complications of malignant hypertension:
- heart failure
- cerebral hemorrhages, cerebral infarction
- renal failure (uremia, proteinuria, hematuria)
- encephalopathy (focal necrosis, altered consciousness, transient paralyses)
- retinal changes: bilateral flame-shaped hemorrhages
papilloedema
blurred vision.
60
Fig. 21 . Systemic effects of benign hypertension: concentric left hypertrophy (top)
and benign nephrosclerosis (bottom)
61
ANEURYSM
Definition: abnormally localized blood-filed dilatation of a blood vessel caused by

a disease or weakness of the vessel wall (aneurynein, Gr. = to dilate)
The true aneurysm
Definition: localized arterial dilatation, which involves all layers of the arterial wall
(intima, media and adventitia). The aorta and cerebral arteries are especially
involved, but aneurysms of the iliac, femoral, popliteal and carotid arteries can also
occur. The mesenteric artery aneurysm is very rare.
Causes:
- congenital weakness of the arterial wall: single or multiple small round
aneurysms of the medium-sized brain arteries at or near the circle of Willis (berry
aneurysms)
- acquired lesions:
atherosclerosis: abdominal aorta, iliac, popliteal and cerebral arteries
hypertension: cerebral arteries
infective arteritis: aorta, cerebral and mesenteric arteries
syphilis - thoracic aorta
Morphology:
- fusiform aneurysm: symmetrical stretching of the whole circumference
- saccular aneurysm: asymmetrical stretching of a segment of the circumference
- elongated or serpinginous aneurysm: splenic artery
A 1
Fig. 22. Aneurysms. A. Diagrammatic representation of morphological types:

I - fusiform, 2 - saccular, 3 - serpinginous; B,C. Aortic saccular aneurysm with
trombus formation; D. Serpingious aneurysm
62
Particular types:
- Rassmussen aneurysm: associated with tuberculous caverne or chronic gastric
ulcer - the necrotic areas produce erosion and weakness of the arterial wall
- Charcot-Buchard microaneurysms: multiple microaneurysms of the cerebral small
arteries (branches of middle cerebral artery), in hypertensive patients
Complications:
- expanding aneurysm, the compression of the neighbouring organs (trachea,
bronchia, heart, lung, esophagus), bones (vertebral, sternal or rib erosions) or
nerves (e.g. recurrent laryngeal nerve paralysis)
- thrombogenesis - - - ► thromboembolism
- rupture: subarachnoid/intracranial hemorrhages, hemothorax, hemoperitoneum
tracheal hemorrhages (asphyxia), esophageal bleeding (hematemesis)
- infective (mycotic) aneurysms - - - ► septic embolism
Clinical features:
- aneurysms of the abdominal aorta or iliac arteries:
pulsatile abdominal mass, abdominal pain, leg ischemia
- aneurysms of the thoracic aorta: chest pain and pressure, dyspnea, dysphagia
- aneurysms of the cerebral arteries: headache, cerebral hypertension.
False aneurysm
Definition: a blood-filled space formed around a blood vessel that produces

localized dilatation
Causes: arterial trauma - false saccular aneurysm
arteriovenous aneurysm - lesions of the adjacent vessels
Pathomechanism: traumatic lesions of the arterial wall leading to the fonnation of
a hematoma - - - ► connective organization of the external segment of hematoma,
which produces a fibrous cap; after liquefaction and lysis, a cavity is formed inside
of it; finally, a localized bulge keeps the continuity with the arterial wall
U·'
J.,
blood iittlrr1nwralrs
, ·1/ Ht,,malo"'
�
i
u
· ;, ,,,, /a!"""
1
ff
>
Fig. 23. Diagrammatic representation of arteriovenous (left)
and false aneurysm (right)
63
AORTIC DISSECTION
(DISSECTING ANEURYSM)
Definition: the presence of blood inside the arterial wall due to intimal rupture
Pathogenesis: transverse rupture of the intima - - .► accumulation of blood in the
media - - .► dissection of the arterial wall
Morphology:
• diffuse dissection - characeristically begins in the arch of the aorta or in the
ascending aorta; blood can dissect the aortic wall and can split it into inner and
outer layer, developing a false lumen
• localized dissection - it is usually an intramural hematoma which produces
segmental dissection, especially in the abdominal aorta
Predisposing causes:
• diffuse dissection
- medial degeneration: Marfan' s syndrome, Ehlers-Danlos syndrome
- Erdheim cystic medial necrosis - idiopathic disease characterized by mucoid
degeneration of the medial elastic lamellae
• localized dissection
- atherosclerosis, hypertension, surgical interventions
Clinical features:
- acute chest or back pain, loss of peripheral pulse, shock
Complications:
- arterial rupture - - .► hemorrhages (hemopericardium, hemothorax, retroperitoneal
hematoma), aortic valve incompetence, shock, death
- double-barrel aorta - the blood can flow back in the arterial lumen.
Fig. 24. Aortic dissection, with blood accumulation in the media
64
ARTERITIS
I mmune arteritis
Immune necrotizing arteritis: Polyarteritis Nodosa (PAN)
Churg-Strauss syndrome
Wegener's granulomatosis
Cogan' s syndrome
Giant cell arteritis: Giant cell temporal arteritis

Takayasu's disease
Hypersensitive arteritis (see 'General Pathology ')

Serum sickness
Drug-related arteritis
Collagen vascular diseases
Henoch-Schonlein purpura,
Systemic lupus erythematosus
Rheumatic fever
Rheumatoid arthritis
Kawasaki's disease
Thromboangiitis obliterans (Winiwarter-Buerger' s disease)
Arteritis associated with other disorders
Infectious arteritis
65
Immune necrotizing arteritis
Definition: immune complexe deposits inside the arterial wall associated with
fibrinoid necrosis
Polyarteritis nodosa (PAN)

Definition: necrotizing arteritis of small and medium-sized arteries in adults
Etiology: hepatitis B and C viruses, drug-related or
formation of antigen-antibody complexes with unknown origin
Localization: brain, kidney, heart and gut (most common)
liver, stomach, skin, skeletal muscles, peripheral nerves - rarely
the pulmonary arteries are not affected! ! !
Macroscopic view: small nodules around the affected vessels accompanied by
small hemorrhages and/or small infarction
Microscopic view:
- in early stages, fibrinoid necrosis of the arterial wall, neutrophils, lymphocytes
and plasma cells in the intima, media and adventitia
- in late phases, the fibrosis of the arterial wall narrows or produces complete
obstruction of the vascular lumen
Complications
- acute stages: occlusive thrombosis - infarction; rupture - hemorrhage
- chronic inflammation: aneurysm; narrowing of the arterial lumen - ischemia
Clinical features
- ischemic heart disease (angina, infarction, heart failure)
- renal ischemia or renal failure
- brain infarction
- intestinal ischemia - abdominal angina, hemorrhages, perforation, infarction
- peripheral neuropathies
Diagnosis: arteriography, biopsies
Churg-Strauss syndrome (Eosinophilic granulomatous vasculitis)

- similar to polyarteritis nodosa but the small pulmonary arteries are also affected;
bronchial asthma can be associated with it
- microscopic view : eosinophils in the arterial wall, peri-vascular granulomas and
fibrosis of the arterial wall
Cogan 's syndrome

- the morphology of this syndrome is similar to that of polyarteritis nodosa but
keratitis and deafness are also associated features
66
Wegener's granulomatosis (granulomatous arteritis)
- immune necrotizing arteritis which occurs especially in the upper respiratory tract
but also affects the lungs, kidneys (glomerulonephritis) and skin
- granulomas are usually larger than in other types of immune necrotizing arteritis
- clinical features: respiratory disorders (destructive lesions of the nasal mucosa)
skin rashes, polyarthritis, polyneuritis, renal failure
Giant cell arteritis
Definition: immune arteritis characterized by inflammatory infiltrate into the

arterial wall with the fonnation of giant cells
Giant cell temporal arteritis (Cranial arteritis, Horton 's disease)

- unknown etiology
- most commonly in elderly people
- usually affects the following arteries:
cranial arteries and branching of the carotid artery (temporal artery)
retinal arteries, aortic arch (rarely)
Microscopic view: accumulation of lymphocytes, macrophages and multinucleated
giant cells in the arterial wall, with the degeneration of the medial layer; in late
stages, fibrosis of the arterial wall
Clinical features, complications
- no symptoms or headache, facial pain, the superficial temporal artery becomes
tender, hard and pulseless; vision impairment, blindness (retinal or ophtalmic
arteries) and cerebral infarction may be also associated
Diagnosis: temporal artery biopsy
Takayasu 's disease (,,pulsless disease'?

- in young females, the aortic arch and its primary branches and sometimes renal
arteries are affected
Morphology
- inflammatory infiltrate and giant cells in the medial layer of the aortic arch
- narrowing or occlusion of the subclavian and carotid arteries
- weak or lack of radial pulse, ischemia of the superior limbs, thrombosis
- neurological disorders
- myocardial ischemia (coronary arteries)
- renal ischemia and secondary hypertension (renal arteries)
67
Kawasaki' s disease (Mucocutaneous lymph node syndrome)
It is rare in Europe; the children from Asia are more affected

Localization: coronary arteries, skin, lymph nodes and mucosae
Clinical features: skin rashes, fever, generalized lymphadenopathy, arthritis,
conjunctivitis, stomatitis (oral mucosa)
Pathogenesis: circulating anti-endothelial antibodies, viral etiology
Microscopic view: necrotizing arteritis
Evolution, complications: spontaneous healing, aneurysms, thrombosis, myocardial
infarction, death (2% of the cases)
Thromboangiitis obliterans (Winiwarter-Buerger' s disease)
Definition: segmental arteritis, which starts in the medium-size muscular arteries of

the lower limbs, in heavy cigarette-smoking men but in late stages, the arms,
visceral arteries (brain, coronary arteries, lungs), nerves and veins are also affected
Macroscopic view: arterial and venous thrombosis; in late stages, leg gangrene
Microscopic view
- early stages: swollen intima
lymphocytes and plasma cells in the arterial wall
arterial thrombotic obstruction
- chronic stages: organization and recanalisation of thrombi
fibrous thickening of the arterial wall, venous thrombi
- nerve lesions due to inflammatory infiltrate
- legs: migrant thrombophlebitis, pain (intermittent claudication - multiple nerve
root involvement); in late stages, ischemia, chronic ulceration of the toes, feet or
fingers, gangrene, myocardial and/or brain infarction.
Arteritis associated with other disorders
Paraneoplastic arteritis - associated with lymphomas, chronic lymphocytic

leukemia and more rarely with carcinomas
Transplant-related arteritis - inflammatory infiltrate in the arterial wall in acute

rejection, arterial fibrosis and fibrinoid necrosis in chronic rejection
68
Infectious arteritis
Non-specific infectious arteritis

- infective embolism - arteritis
- meningococcal septicemia - inflammation of the skin capillaries - skin
purpura
Syphilis-related arteritis
- the thoracic aorta can be affected in the third stage of syphilis
- macroscopic view: fibrosis of the inti ma - smooth irregular grey-white areas on
the surface of the intima (tree-bark appearance)
- microscopic view: inflammation and degeneration of the media
- complications: aneurysm of the thoracic aorta - pulsatile thoracic mass
ischemic heart disease
endocarditis of the aortic valve - aortic incompetence
Fig. 25. Tree-bark appearance of the syphilitic aortitis and aneurysm
69
RAYNAUD' S DISEASE AND RAYNAUD' S PHENOMENON
Definition: functional disorders of the small arteries and arterioles of the upper
extremities, characterized by prolonged vasoconstriction
Raynaud's disease
- the mechanism of vasoconstriction is unknown
- appears in young women as intermittent symmetrical ischemia of the hand and
the fingers during exposure to cold or stress; the tip of the nose, ears and toes can
also be affected
- clinical features: pale extremities, without consequences
sometimes, trophic skin changes, ulceration, gangrene
Raynaud's phenomenon
- similar symptoms are secondary to some diseases:
✓ collagen diseases: Systemic Lupus Erythematosus
scleroderma
dermatomyositis
✓ arteriosclerosis
✓ thromboangiitis obliterans
✓ hemolytic anemia
✓ primary pulmonary hypertension
✓ allergies - drugs: ergotamine, a-adrenergic blockers
polyvinyl chloride monomer
✓ tumors
✓ trauma (vibrating power tools).
70
PATHOLOGY OF THE VEINS
VARICOSE VEINS
Definition: dilated, tortuous and elongated veins (varicosities or varices). The varix
in veins is analogus to aneurysm in arteries.
Etiopathogenesis
• chronic venous congestion
- varicosities of the legs
high pressure in the peripheral veins, incompetence of valves
predisposing factors: prolonged standing, obesity, pregnancy, tumors
- hemorrhoids: high pressure in the pelvic and abdominal veins
predisposing factors: constipation, obesity, pregnancy, cirrhosis
- varicocele = varicosity of the pampiniform venous plexus (spermatic cord)
- periprostatic and uterovaginal varicosities with phleboliths formation
- esophageal varices, caput medusae (umbilical veins)
portal hypertension in hepatic cirrhosis
• weakness of the venous wall
- congenital factors: familial predisposition (weak venous wall)
- acquired factors: inflammations, toxins
• individual predisposition
- women, elderly people (decreasing muscular activity)
• vein compression
- obesity, tumors (e.g. ovarian tumors)
Morphology of the varix

- dilated and irregular veins, sometimes visibly prominent below the skin
- microscopic view of the venous wall: fibrosis, degeneration of the elastic fibers in
the intima, focal calcification (phlebosclerosis)
Evolution, complications
- lower limb edema, trophic changes, fatigue and pain in the legs
- ulceration: ankle or varicose ulcer (immobility, diabetes mellitus)
- rupture - hemorrhages, death (esophageal varices)
- thrombosis - thromboembolism
- rectal bleeding, rectal prolapse, pain (hemorrhoids).
71
PHLEBOTHROMBOSIS (VENOUS THROMBOSIS)
(phlebos, Gr. = vein)
Predisposing factors
- venous congestion (slow blood flow)
- varicosities of the legs and pelvic veins
- immobility (severe heart failure, post-surgery, leg fractures, long flights)
- trauma, surgery, endothelial damage
- drugs (contraceptive pills, estrogen therapy, steroids, digitalis drugs),
- intravenous cannulation
- old age, malignancies (pancreas, colon, lung tumors)
- obesity, cachexia
- pregnancy, puerperium
- familial trombophilia, hypercoagulability (e.g. polycythemia)
- hepatic cirrhosis ---+ thrombosis of the portal vein (pylephlebothrombosis)
- dehydrated infants - dural sinus thrombosis
Complications
- deep leg vein thrombi - thromboembolism ---+ popliteal, femoral, iliac veins
---+ inferior cava vein - right heart ---+ pulmonary artery (pulmonary embolism)
72
Fig. 26. Varicose veins: hemorrhoids (left) and esophageal varices (right)
Fig. 27. Thrombosis of the iliac vein (left) associated with

pulmonary embolism (right), in a patient with deep vein thrombosis
Fig. 28. Complications of varicose veins: leg gangrene (left) and ankle ulcer (right)
73
THROMBOPHLEBITIS
Definition: venous inflammation associated with thrombosis
Localization and etiology

- hemorrhoidal plexus, veins of the lower limbs (e.g. varices)
- iliac, femoral and inferior cava veins
- uterine and ovarian veins: post-infective abortion, puerperal infections
- venous sinuses of the dura mater: following purulent meningitis
- cavernous sinus of dura mater: after purulent inflammations of superior lips
- jugular veins: following tonsillitis (tonsillar abscess)
- portal vein (pylephlebitis): following infections of the abdominal organs
- umbilical veins: after puerperal infections
Particular types
• thrombophlebitis of the superficial veins of the legs
- clinical features: pain, hyperemia, hardening of the walls of veins
- complications: thromboembolism (very rarely)
• deep vein thrombophlebitis
- the iliac, femoral and ankle veins are more affected
- clinical features:
acute phases: pain, swelling, dilatation of the superficial veins
chronic phlebitis: skin pigmentation (hemosiderin deposition)
edema, ankle ulcer, tissue hardening
- complications: thromboembolism
• migratory thrombophlebitis (thrombophlebitis migrans)
- superficial migrant (flitting) venous thrombophlebitis, anywhere in the body, in
previously healthy veins, frequently related to pancreatic cancer (Trousseau sign)
and thromboangiitis obliterans
• phlegmasia alba do/ens (painful white leg or 'milk leg ')
- primary ilio-femoral phlebothrombosis in pregnant women, prior to or following
childbirth
- the collateral circulation try to compensate ischemia and the leg becomes pale
• phlegmatia cerulea do/ens (painful blue leg)
- the same lesion but the collateral circulation is incompetent; the leg is cyanotic
• chronic phlebitis of the intrahepatic veins (Budd-Chiari syndrome)
- a disease with unknown cause, associated with severe hepatic congestion, portal
hypertension and ascites.
74
DISEASES OF THE LYMPHATICS
Lymphedema
• congenital edema (Milroy 's disease)
- gross and diffuse dilatation of the lymphatic channels in the legs
• acquired secondary edema
- blockage of lymphatic drainage: lymph node metastases, surgical removal or
irradiation of lymph nodes (breast cancer), obesity (compression), filariasis
Lymphangitis
• acute lymphangitis
- recurrent skin infections (streptococcal lymphangitis)
- infections of soft tissues or organs associated with reactive lymphadenitis
• chronic lymphangitis
- Filaria bancrofti, obesity, tumors -----* obstruction of the lymphatic drainage
• tuberculous lymphangitis
- during primary tuberculosis
Carcinomatosis of the lymph vessels
. - tumor cell proliferation in lymph vessels, during metastases
Clinicalfeatures:
- enlarged limb (edema) ± enlarged scrotum (filariasis, elephantiasis)
- red skin (streptococcal lymphangitis)
-' peau d' orange' around a breast cancer (tumor cells produce the blockage of the
lymphatic vessels in the skin)
- hyperkeratosis: filariasis, obesity (dermal fibrosis)
DISEASES OF THE CAPILLARIES

Diabetic microangiopathy
Morphology: accumulation of basement membrane-like material in capillaries
proliferation of endothelial cells
thickening of the capillary walls, microaneurysms, thrombosis
Localization: eye (retina), kidney (Kimmelstiel-Wilson glomerulosclerosis)
skin, skeletal muscles, nerves
Clinical syndromes:
- nephropathy: glomerulosclerosis -----* microalbuminuria
- retinopathy: retinal ischemia and thrombosis of the capillaries -----* blindness
-peripheral neuropathy -----* gangrene.
75
TUMORS OF THE BLOOD VESSELS
BENIGN TUMORS
Hemangiomas
- solitary or multiple tumors located in the skin or different organs
- macroscopic view: no capsule, ill-defined tumors
- they are rather hamartomatous lesions (developmental disorders), not true tumors
• capillary hemangioma (nevusflammeus, vascular nevus)
- macroscopic view: red patches
- microscopic view: small capillaries
- localization: skin, bone, gut, muscles
- they can be present at birth and can spontaneously recur
• juvenile capillary hemangioma (strawberry nevus' of infancy)
- microscopic view: small capillaries + endothelial cell proliferation
- localization: skin (trunk, limbs)
• cavernous hemangioma
- localization: skin, liver, soft tissues, muscles, brain
- macroscopic view : blue, raised, poorly-defined tumor
- microscopic view : large, dilated vascular channels with venous blood
- complications: thrombosis
consumption coagulopathy (Kassabach-Merrit syndrome)
• arteriovenous hemangioma
- microscopic view: proliferation of arterial and venous blood vessels
- localization: meninge, skin (head, legs)
• glomangioma (glomus tumor)
- arises from the modified smooth muscle cells of the Masson's glomus body
(arterio-venous anastomoses in the skin of the fingers)
- macroscopic view: small painful tumors in the fingers or under the nails
- microscopic view: vascular channels separated by glomus cells
• benign hemangiopericytoma
- localization: peripheral soft tissues, retroperitoneum, eye, skin
organs (lung, liver, uterus)
- microscopic view: vascular channels + proliferation of the pericytes
76
Lymphangiomas
- rare tumors, most of them are hamartomatous lesions
• capillary lymphangioma
- microscopic view: small lymphatic channels
- localization: skin, small intestine (mucosa)
• cavernous lymphangioma
- microscopic view: large lymphatic channels
- localization: retroperitoneum, mesenterium, lips, tongue
• cystic lymphangioma
- microscopic view: cystic dilated lymph vessels
- localization: neck (congenital cystic hygroma), mesenterium
MALIGNANT TUMORS
Hemangioendothelioma
- an intermediate grade between hemangiomas and angiosarcomas
- localization: skin, liver, spleen, lung
Angiosarcoma
- localization: liver, spleen, skin, breast, soft tissues
- macroscopic view: red or brown hemorrhagic nodules
- microscopic view: interconnecting vascular channels lined by pleomorphic
atypical endothelial cells
- prognosis: aggressive tumor, highly invasive behaviour
Malignant hemangiopericytoma
- malignant variant of the benign hemangiopericytoma
Lymphangiosarcoma
- malignant variant of lymphangioma
Kaposi's sarcoma
- originally described in elderly men as a tumor with long-term evolution
- the original name was "idiopathic hemorrhagic sarcoma" (Kaposi, 1862)
- nowadays it is most commonly associated with AIDS
- infections with Human Herpes Virus type 8, HIV infection, immunosupression
Macroscopic view
- early stages: red-purple macules, papules, plaques and nodules in skin
- late stages: involvement of lymph nodes and organs: lung, stomach, gut
Microscopic view
- in early stages, proliferation of small vessels covered by atypical endothelial
cells; among them, extravasated erythrocytes
- in late stages: sarcomatous proliferation and vascular channels.
77
PSEUDOTUMORAL VASCULAR LESIONS
Angiomatosis (Telangiectasis)
- congenital or acquired lesions which appear as solitary or multiple clusters of
localized vascular dilatations (telangiectasis)
• Osler-Weber-Rendu disease (Heredita,y hemorrhagic telangiectasia)
- macroscopic view: multiple small telangiectasis of the skin, mucosae, organs
- clinical features: repeated nose bleeding (epistaxis), gastrorrhagia, etc.
• Rippel-Lindau disease
- angiomatosis of the cerebellum or brain stem and retina
• Sturge-Weber syndrome
- angiomatosis which involves the meninges and skin of the face
Pyogenic granuloma
- etiology: repeated trauma or localized infections
- localization: skin and mucous membranes (oral mucosa, nasal cavity)
- macroscopic view: red fungating or ulcerated mass
- microscopic view: granulation tissue
Fig. 29. Cavernous hemangioma of the liver (top), capillary hemangioma of the
skin (bottom left) and pyogenic granuloma (bottom right)
78
PATHOLOGY OF THE
RESPIRATORY SYSTEM
79
I. PATHOLOGY OF THE AIRWAYS
Pathology of the nose, middle ear and paranasal sinuses

Diseases of the larynx
Pathology of the trachea and bronchi
Chronic obstructive broncho-pulmonary diseases
Chronic bronchitis
Bronchial asthma
Bronchiectasis
Pulmonary emphysema
PATHOLOGY OF THE NOSE, MIDDLE EAR AND

PARANASAL SINUSES
VASCULAR DISORDERS
Hyperemia of the nasal mucosa
Etiology: inflammations, inhaled toxic substances
Epistaxis
Definition: hemorrhage from the nasal cavity
Etiology: inflammations, hypertension, trauma
endometriosis, tumors
pyogenic granuloma, angiomatosis, coagulation disorders
RHINITIS
Definition: inflammation of the nasal mucosa
Acute rhinitis
Clinical features: rhinorrhea, nasal obstruction, sneezing
• acute catarrhal rhinitis
- etiology: viruses, common cold, bacteria, inhalation of toxic substances
- morphology: narrowing of the nasal cavity (swollen nasal mucosa)
- complications: sinusitis, rhinopharyngitis, pharyngotonsillitis
• acute necrotizing rhinitis
- etiology: osteomedullary insufficiency, acute leukemia
80
• acute fibrinous rhinitis
- etiology: diphtheria - in infants
• allergic rhinitis
a) seasonal allergic rhinitis (hay fever)
- type I hypersensitivity
- occurs especially during pollen seasons: spring, summer, early autumn
- clinical features: itchy eyes, watery rhinorrhea, sneezing
- morphology: mucosa! edema, mucus secretion, eosinophilic infiltrate
b) perennial allergic rhinitis (non-seasonal allergy)
- unrelated to any of the seasons, being triggered by several allergens: food, flour,
house dust (Dermatophagoides pteronyssinus), animal allergens, etc.
Chronic rhinitis
- etiology: repeated acute rhinitis, dust inhalation
superimposed bacterial infections
- predisposing factors: deviated nasal septum, chronic sinusitis
• hyperplastic polyp (chronic hyperplastic rhinitis)
- macroscopic view : focal mucosa) protrusion (3-4 mm in diameter), swelling or
ulceration of the covering epithelium
- microscopic view: swollen mucosa, goblet cells and glandular hyperplasia
inflammatory infiltrate, Russel bodies
- complications: blockage of the sinus drainage duct ------, sinusitis
• chronic atrophic rhinitis
- macroscopic view : atrophy of the nasal mucosa
- microscopic view: glandular atrophy and squamous metaplasia
- chronic infection with Klebsiella Ozenae is rare and can occur in women
suffering from iron deficiency anemia and is characterized by a foul smelling nasal
exudate
OTITIS
Definition: acute (serous, purulent) or chronic inflammation of the middle ear

Precursor lesions: rhinitis, sinusitis, pharyngitis, etc.
Complications:
- eardrum perforation, mastoiditis, meningitis, brain abscesses
- cholesteatoma is a granulomatous lesion covered by a squamous epithelium,
composed of cell debris and cholesterol crystals; located in the middle ear can
occur in case of chronic otitis
81
SINUSITIS
Definition:inflammation of the maxillary, frontal, ethmoidal or sphenoidal sinuses
• acute sinusitis:
- serous or purulent inflammation (empyema), which occurs due to the direct
spread from rhinitis or periodontitis (maxillary sinusitis)
• chronic sinusitis
- etiology: acute sinusitis, fungal infections (Mucormycosis)
- risk factor: deviated nasal septum
- microscopic view : can be purulent (empyema), can lead to the formation of
hyperplastic polyps or have cystic appearance; the normal ciliated columnar
epithelium can be replaced by squamous epithelium (squamous metaplasia)
• Kartagener 's syndrome
- etiology: congenital disease characterized by defective ciliary function
- components: rhinosinusitis + bronchiectasis + situs inversus
Complications ofsinusitis
- blockage of the sinus drainage pathways - sinus empyema, brain abscesses,
meningitis, osteomyelitis
- systemic spread - thrombophlebitis of the venous sinuses of the dura mater
- chronic sinusitis can be a predisposing factor for autoimmune diseases (rheumatic
fever, collagen vascular diseases, etc.)
SPECIFIC INFLAMMATIONS OF THE NOSE, MIDDLE EAR AND

PARANASAL SINUSES
• tuberculous rhinitis - very rarely

• syphilis: tertiary stage - gumma; congenital syphilis - saddle nose
• rhinoscleroma: a granulomatous inflammation caused by Klebsiella
rhinoscleromatis, characterized by scarring and deformed nasal turbinates
• fungal infections: Aspergillosis, candidiasis (sinusit�s)
• rhinosporidiosis: infection with Rhinosporidium seeberi, transmitted from
cattle, horses, to humans, can lead to the formation of granulomatous nasal polyps
• Wegener s granulomatosis: necrotizing granulomatous arteritis which
involves the nasal cavity, paranasal sinuses, larynx, trachea and lungs, and,
sometimes, the kidneys; clinical features: nasal congestion, septal perforation,
narrowing of the nasal cavity, renal failure.
82
TUMORS OF THE NOSE AND PARANASAL SINUSES
Benign tumors
Sinonasal papilloma
- infection with Human Papilloma Virus (HPV), usually a predisposing factor in
male patients
- can recur and can present malignant transformations
- morphology: exophytic (fungating) tumor covered by squamous or transitional
epithelium (Schneiderian papilloma)
- inverted papilloma - a particular type of tumor which grows inward
Angiofibroma
- a highly vascularized tumor which contain androgen receptors
- usually occurs in adolescent males
Other tumors
- hemangioma, adenoma, glioma, fibroma, chondroma, etc.
Malignant tumors
Squamous cell carcinoma

- the most common malignant tumor of the nasal mucosa and sinuses
- cervical lymph node metastases with unfavourable prognosis
Adenocarcinoma
- occurs most commonly in the nasal cavity and ethmoidal sinus
- risk factors: wood and nickel workers
- spread: cervical lymph node metastases
Other tumors:
- adenoid cystic carcinoma, malignant melanoma
- non-Hodgkin lymphoma, plasmacytoma, sarcomas
- neuroblastoma.
83
DISEASES OF THE LARYNX
Congenital malformations
Subglottic stenosis, laryngeal cyst, laryngeal atresia, etc.
Laryngeal stenosis
Etiology: compression - lymphadenopathies, tumors, thyroid goiter

obstruction - foreign bodies (e.g. food)
stricture - edema, inflammations, tumors
VASCULAR DISORDERS
Laryngeal edema
- etiology: allergens, Quincke (angioneurotic) edema, tumors
severe heart or renal failure, trauma (e.g. improper intubation)
- morphology: swollen epiglottis and aryepiglottic folds
- complications: laryngeal obstruction --+ asphyxia
Reinke 's edema
- vocal cord edema (Reinke' s space), usually as a result of chronic laryngitis
- morphology: swollen vocal cords
INFLAMMATIONS (LARYNGITIS)
Acute catarrhal laryngitis

- etiology: viruses, allergies, inhalation of toxic substances
- acute epiglottitis is a particular type of acute catarrhal laryngitis -caused by
Haemophilus influenzae while the swollen epiglottis can produce airway
obstruction
Acute pseudomembranous laryngitis (diphtheric croup)
- etiology: Corynebacterium diphteriae, inhalation of toxic substances
- macroscopic view: a false membrane covers the epiglottis and vocal cords
- microscopic view of the false membrane: fibrin and neutrophils
- clinical features: inspiratory stridor
Acute necrotizing laryngitis
- etiology: osteomedullary insufficiency, acute leukemia ·
84
Complications of acute laryngitis
- propagation of inflammation ---+ tracheobronchitis, pneumonia
- chronic laryngitis
- laryngeal stenosis
Chronic laryngitis
- occurs as result of chronic inhalation of different substances (e.g. tobacco
smoking, asbestos) but can also be the consequence of repeated acute laryngitis,
allergies, physical factors, irradiation, etc.
- complications: leukoplakia (white dysplastic patches, precancerous lesion)
Specific inflammations
- tuberculosis: ulcerations or chronic inflammatory polyps, usually associated with
lung tuberculosis
- fungal infections (Candida)
- sarcoidosis, leprosy, etc.
TUMORS OF THE LARYNX

Benign tumors
Papilloma
- a single protruded tumor covered by squamous epithelium (adult papilloma)
Papillomatosis
- multiple and recurrent papillomas can occur in children infected with Human
Papilloma Virus (HPV) types 6 and 11 (juvenile laryngeal papillomatosis)
- clinical features: hoarseness, weak cry, stridor
- localization: laryngeal vocal cords
- morphology: small papillary tumors covered by squamous epithelium
- evolution: they can regress or recur but malignant transformation is very rare
Other tumors: fibroma, hemangioma, lipoma, chondroma, etc.
85
Malignant tumors
Carcinomas
- risk factors: smoking, alcohol consumption, inhalation of dusts or toxins
Human Papilloma Virus (HPV)
- clinical features: hoarseness, pain, stridor, dyspnea, dysphagia, hemoptysis
- spread: cervical lymph nodes
- macroscopic view: flat (white plaque), infiltrative, polypoid or ulcerated tumor
- microscopic view: the most common type is squamous cell carcinoma
adenocarcinoma is rare
- localization:
• supraglottic carcinoma (30-35% of the cases)
- located above the vocal cords, on the epiglottis, aryepiglottic folds or piriform
sinuses, presents unfavourable prognosis because the loose surrounding tissues
allow direct and cervical lymph node spread
• glottic carcinoma (60-65% of the cases)
- involves the vocal cords and presents the best prognosis of all because the vocal
cords do not comprise lymphatic vessels and clinical symptoms occur in early
stages (altered voice)
• subglottic carcinoma
- located below the vocal cords, it is very rare, but presents the worst prognosis
Other rarely malignant tumors: lymphomas, sarcomas.
Pseudotumors
Laryngeal polyp (singer ·s node)

- occurs in singers, on the vocal cords
- macroscopic view : small nodes (few millimeters in diameter) on the vocal cords
- microscopic view: squamous epithelium overlying fibrin-rich and myxoid stroma
- clinical features: altered voice, progressive hoarseness
86
Fig. 30. Laryngeal lesions: A. Acute epiglottitis; B. Food bolus obstruction;
C. Diphtheric croup; D. Acute inflammatory ulcers;
E. Laryngeal papillomatosis;
F. Glottic carcinoma (fungating mass on the right), in a 67-year old smoker
87
PATHOLOGY OF THE TRACHEA AND BRONCHI
STENOSIS OF THE TRACHEA AND BRONCHI
Causes: compression: lymphadenopathy, lung or mediastinal tumors

thyroid goiter, aortic aneurysm
obstruction: aspiration of foreign bodies, milk, vomiting fluid
strictures: edema, inflammations, post-intubation scarring, tumors
Evolution of bronchial stenosis:
- compression, strictures - pulmonary emphysema
- complete obstruction - lung atelectasis
Fig. 31. Consequences of bronchial stenosis: I . Minimal stricture: no

consequences; 2. Severe stricture: emphysema; 3. Obstruction: atelectasis
TRACHEITIS
Usually associated with laryngitis and/or bronchitis.
Acute tracheobronchitis
- catarrhal:viruses, toxic substances, allergens
- purulent: bacterial infections
- pseudomembranous (diphtheric croup): diphtheria
- hemorrhagic: staphylococcal infections
- necrotizing: associated with laryngeal carcinoma or acute leukemia
- necrotizing - ulcerative: post-intubation
Chronic tracheobronchitis
- etiology: smoking, polluted air, occupational diseases
88
TUMORS OF THE TRACHEA
They are very rare.

• benign tumors: papilloma, chondroma
• malignant tumors: carcinoma
BRONCHITIS, BRONCHIOLITIS
Acute bronchitis
Definition: acute inflammation of the large and medium-sized bronchi
Clinical features: dyspnea, tachypnea, purulent sputum, cough
Etiology: air pollutants (smoking, sulphur dioxide, chlorine), viruses, bacteria; they
are usually related to laryngotracheitis and can also be:
• catarrhal
• muco-purulent
• hemorrhagic
• necrotizing
• fibrinous
- healing
- prolonged infection - chronic bronchitis
- obstruction of the small bronchi - focal atelectasis of the lung
- bronchopneumonia
- necrotizing bronchitis - lung gangrene
- diphtheric croup - asphyxia
Bronchiolitis
Definition: inflammation of the distal bronchioles, most commonly in children and
elderly patients, associated with dyspnea, tachypnea, sputum
Etiology: viruses, bacteria, inhaled irritants, associated with asthma or idiopathic
• purulent bronchiolitis
- a common bacterial infection of childhood
- evolution: complete healing or can produce secondary pneumonia
• bronchiolitis obliterans
- causes: viruses, inhaled toxic substances, rejection after lung transplantation
collagen vascular diseases
- microscopic view : luminal obstruction and focal atelectasis caused by connective
tissue organization and fibrosis of the exudate.
89
Fig. 32. Purulent bronchiolitis
Fig. 33. Purulent, ulcerative and fibrinous laryngotracheitis
Fig. 34. Peritracheal chondroma
90
CHRONIC OBSTRUCTIVE PULMONARY DISEASES
(COPD)
Pulmonary diseases can be either restrictive or obstructive.
Restrictive pulmonary diseases are acute or chronic disorders associated with

decreased lung expansion and reduced total lung capacity
Causes: - chest wall disorders: obesity, kyphoscoliosis, pleural callus
- interstitial and infiltrative lung lesions
- Acute Respiratory Distress Syndrome (ARDS)
- pneumoconioses, pulmonary fibrosis, etc.
Chronic obstructive pulmonary diseases are respiratory disorders associated with

lung diseases which produce airflow and/or expiratory flow obstruction
Causes: - chronic bronchitis
- bronchial asthma
- bronchiectasis
- pulmonary emphysema (explained later in this book)
Predisposing factors: tobacco smoking, dust inhalation,
recurrent bronchial inflammations, alpha- I antitrypsin deficiency
Consequences:
- progressive respiratory failure - hypoxia - chronic cor pulmonale (CCP)
- hyperventilation - hypocapnia
Clinical features: dyspnea, cough, productive sputum, hemoptysis
cyanosis, finger clubbing, cachexia
Causes of death: respiratory or heart failure, bronchopneumonia, lung cancer
Chronic bronchitis
Definition of the Medical Research Council: ,,chronic or recurrent increase in the

volume of bronchial secretions, sufficient to cause expectoration on most days for a
minimum of three months of the year, for not less than two successive years, which
cannot be attributed to other cardiac or pulmonary diseases"
Etiology: smoking, air pollution (smog-laden cities), repeated acute bronchitis
Macroscopic view: narrowing of the airways, mucus secretion
Microscopic view:
- early stages: mucous gland hypertrophy - mucus hypersecretion
chronic inflammatory infiltrate
- late stages: mucosa) atrophy, squamous metaplasia
91
Classification:
• simple chronic bronchitis
- mucopurulent inflammation with productive cough, no airflow obstruction
• chronic asthmatic bronchitis (intrinsic or non-atopic asthma)
- bronchitis + intermittent bronchospasm + wheezing
Consequences: - bronchiectasis, repeated pneumonia, pulmonary fibrosis
- pulmonary emphysema
- chronic cor pulmonale.
Bronchial asthma
Definition: episodic attacks of reversible small airways obstructions produced by

bronchospasm + inflammation + mucus hypersecretion + edema
Etiology:
• atopic or extrinsic asthma
- environmental allergens: pollen, dusts, chemical substances
- congenital hypersensitivity, usually starts in childhood
� familial aggregation of atopic disorders: atopic eczema, hay fever
• non-atopic or intrinsic asthma
- not related to exogenous allergens or history of atopy and usually occurs in
middle-aged patients with chronic bronchitis
• occupational asthma
- produced by a substance which is inhaled at work for a longer period of time
• drug-induced asthma (e.g. aspirin)
• allergic bronchopulmonary aspergillosis (Aspergillus fumigatus)
Pathogenesis:
• atopic asthma
- type I hypersensitivity (anaphylactic) reaction IgE-mediated (see General
Pathology); releasing of histamine, leukotrienes, anaphylatoxins, etc. produces
hyperacute inflammation of the bronchial mucosa associated with
bronchoconstriction and mucus hypersecretion
• occupational asthma, allergic bronchopulmonary aspergillosis
- type I and type III hypersensitivity reactions
• non-atopic or intrinsic asthma
- airways infections - endogenous antigens - bronchoconstriction (inspiratory
stridor); sometimes the mechanism is unknown, the attacks may be produced by
stress, exercise, exposure to cold, etc.
92
Clinical features:
- wheezing, tachypnea, dyspnea, cough, chest tightness
• asthma attacks = short and recurrent episodes of expiratory dyspnea
• status asthmaticus = persistent dyspnea that lasts for more hours or days
Macroscopic view of the lungs and airways during asthma attacks:

- bronchi: wall edema, mucus hypersecretion, mucus plugs
- overdistended lungs (acute emphysema)
Microscopic view:
• acute phase (asthma attack)
- bronchi: inflammatory infiltrate: eosinophils, mast cells, lymphocytes
hyperemia and edema of the mucosa
mucus hypersecretion, obstruction of the small bronchi
- lungs: bronchial obstruction (mucus) --+ focal atelectasis
bronchial stenosis --+ acute emphysema
• chronic phase
- hypertrophy and chronic inflammation of the bronchial mucosa, thickening of the
bronchial walls
Complications:
- bronchiectasis, pulmonary emphysema, chronic cor pulmonale
- prolonged status asthmaticus can lead to death
- the prognosis of intrinsic asthma in comparison with the extrinsic type is more
unfavourable
Bronchiectasis
Definition: abnormal and irreversible dilatation of medium-sized and small bronchi

associated with muco-purulent chronic bronchitis.
Etiology:
• congenital bronchiectasis - cystic fibrosis (mucoviscidosis)
• acquired bronchiectasis in children
- measles, adenoviruses, whooping cough, immunodeficiencies
• acquired bronchiectasis in adults
- weakness of the bronchial wall: chronic bronchitis, tuberculosis, dust inhalation
- increased bronchial pressure: winds, asthma attacks, tumor, strictures
- fibrosis of lung parenchyma: radiotherapy (lung, mediastinal or breast cancer)
93
Morphology:
- dilated bronchi, muco-purulent exudate, inflammatory infiltrate in bronchial walls
• diffuse bronchiectasis
- diffuse dilatation of the bronchi, especially in the lower lobes
- microscopic view: inflammation and frequent squamous metaplasia
• localized bronchiectasis
- cylindrical, saccular or fusiform dilatation of the medium-sized bronchi
- it usually occurs in elderly people or is related to focal lung scarring
Consequences:
- pneumonia, lung abscesses, necrotizing bronchitis
- pulmonary fibrosis, chronic cor pulmonale
- prolonged toxemia � cachexia
- systemic metastatic abscesses - especially in the brain
- systemic amyloidosis
Clinical features:
- cough, dyspnea, foul-smelling breath and sputum, finger clubbing
Fig. 35. Chronic pulmonary diseases: Broncqiectasis (left) and chronic

pulmonary congestion associated with cor pulmonale, in a patient with chronic
bronchitis (right)
94
II. PATHOLOGY OF THE LUNG
Congenital disorders
Vascular disorders
Lung hyperemia
Pulmonary congestion : acute pulmonary edema and chronic congestion
Embolism, Disseminated Intravascular Coagulation
Lung infarction
Lung hemorrhage
Pulmonary hypertension
Arteritis
Disorders of air content
Pulmonary emphysema
Atelectasis
Acute respiratory distress syndrome (ARDS)
Non-specific pulmonary inflammmations
Pneumonia: lobar pneumonia, bronchopneumonia, interstitial pneumonia
Purulent inflammations: lung abscess, bronchiectasis, lung gangrene
Pneumoconiosis (see General Pathology)
Illicit drug use
Specific pulmonary inflamrnmations
Tuberculosis
Sarcoidosis, Mycoses, etc.
Lung tumors
Pathology of the pleura
95
CONGENITAL DISORDERS
Lung hypoplasia
- underdeveloped lung
Polycystic lung
- congenital cystic adenomatoid malformation which can lead to congenital lobar
emphysema
- localized cysts can be surgically removed
Kartagener 's syndrome

- situs inversus + bronchiectasis + rhinosinusitis
- congenital disease characterized by defective cilliary function
Cysticfibrosis
- mutations in the Cystic Fibrosis gene located on chromosome 7 lead to the
dysfunction of chloride ion channels in cell membranes and the exocrine secretions
present hyperviscosity (dehydrated mucus)
- the lungs, pancreas and gut are more affected
- pulmonary lesions: bronchiolitis, bronchlectasis, recurrent bronchopneumonia
- complications: emphysema, pneumothorax
al-Antitrypsin deficiency
- the dificiency of this serine protease inhibitor leads to pulmonary emphysema
VASCULAR DISORDERS
Lung hyperemia
- causes: inflammations, irradiation, inhaled toxic substances
Pulmonary congestion
• acute pulmonary edema
- etiology: increased venous hydrostatic pressure, acute left ventricular failure,
decreased colloid osmotic pressure (rare), pulmonary capillary lesions, obstruction
of the lymph channels, inhaled toxic substances, pneumonia, parenteral
hyperhydration (infusions), ARDS, etc.
96
II. PATHOLOGY OF THE LUNG
Congenital disorders
Vascular disorders
Lung hyperemia
Pulmonary congestion: acute pulmonary edema and chronic congestion
Embolism, Disseminated Jntravascular Coagulation
Lung infarction
Lung hemorrhage
Arteritis
Disorders of air content
Pulmonary emphysema
Atelectasis
Acute respiratory distress syndrome (ARDS)
Non-specific pulmonary inflammmations
Pneumonia: lobar pneumonia, bronchopneumonia, interstitial pneumonia
Purulent inflammations: lung abscess, bronchiectasis, lung gangrene
Illicit drug use
Specific pulmonary inflammmations
Tuberculosis
Sarcoidosis, Mycoses, etc.
Lung tumors
Pathology of the pleura
95
• chronic pulmonary congestion (brown induration of the lung)
- etiology: chronic left ventricular failure
mitral stenosis or incompetence
- clinical features: dyspnea, cough, clubbing fingers (chronic hypoxia)
on auscultation: crackles (air bubbling and fluid)
- complications: superinfection, pulmonary fibrosis, chronic cor pulmonale
Embolism
- the pulmonary emboli are usually thromboemboli but bone marrow can also
embolise following resuscitation; other rare emboli: fat, amniotic fluid
- risk factors for thromboembolism: thrombophlebitis (lower extremities, pelvic
venous plexus), immobilization, pregnancy, pancreatic carcinoma, heart failure,
drugs (e.g. oral contraceptives)
- clinical features: chest pain, dyspnea, hemoptysis, confusion
- complications:
acute thromboembolism of the pulmonary artery � infarction or sudden death
recurrent small thromboemboli � chronic pulmonary congestion
pulmonary hypertension
Disseminated Intravascular Coagulation (DIC)

- etiology: shock, fat/amniotic fluid embolism, surgery, tumors, etc.
- morphology: disseminated microthrombosis, focal alveolar hemorrhages
Lung infarction
- hemorrhagic (red) infarction which can occur subsequent to thromboembolism in
patients with chronic pulmonary congestion
Lung hemorrhage
- causes: inflammations, DIC, trauma, anticoagulant therapy, Goodpasture's
syndrome (an autoimmune disease characterized by lung hemorrhages and rapidly
progressive glomerulonephritis)
- morphology: atherosclerotic plaques in the intima of the pulmonary artery
chronic cor pulmonale
• primary pulmonary hypertension
- a rare familial disease with unknown cause which occurs especially in young
males, without preexisting conditions
- can be related to drug consumption or toxins but gene mutations can also be
causative factors
97
• secondary pulmonary hypertension
- occurs secondary to one of the following diseases:
- chronic obstructive pulmonary diseases (COPD)
- aortic and mitral valvulopathies (chronic pulmonary congestion)
- recurrent small thromboemboli in the small branches of the pulmonary artery
- congenital cardiac malfonnations with left-to-right shunt
- chronic hypoxemia - high altitude
- Pickwick's syndrome (obesity � dyspnea)
- kyphoscoliosis
Arteritis
- Wegener's granulomatosis and Churg-Strauss syndrome (see Arteritis)
Fig. 36. Congenital lung malformations: hypoplasia of the right lung (left) and
polycystic lung (right)
Fig. 37. Pulmonary vascular disorders. Left: red thromboemboli and bone marrow
embolism; Right: Red triangular-shaped infarction
98
DISORDERS OF AIR CONTENT
Emphysema = the air content in the lungs increases
Dystelectasis = the air content in the lungs decreases
Atelectasis = the absence of air in alveolar spaces
PULMONARY EMPHYSEMA
Definition: overdistension of the lungs due to the dilatation of the air spaces
Types of emphysema: acute emphysema
vicariant emphysema
senile emphysema
chronic obstructive emphysema
interstitial emphysema
Acute emphysema
- definition: acute and reversible overdistension of the lungs, without the

destruction of the alveolar septa
- causes: asphyxia, asthma attacks, respiratory dysfunctions
- morphology: pale and overdistended lungs, dilated alveolar spaces
Vicariant (compensatory) emphysema
- acute or chronic dilated spaces around atelectatic areas (e.g. emphysema of the
upper lobes, around post-tuberculosis scars)
Senile emphysema
- dilatation of alveolar spaces due to senile involution

- not a real emphysema and does not lead to chronic cor pulmonale
- macroscopic view: small spongy-like lungs, emphysematous thorax
Chronic obstructive emphysema
- lung enlargement due to the permanent dilatation of the air spaces, distal to the
terminal bronchiole, associated with the destruction of the alveolar walls
- this emphysema is a type of chronic obstructive pulmonary diseases (COPD)
Etiology
- chronic inflammation of the small airways (e.g. chronic bronchitis)
- genetic causes: a-1 antitripsin deficiency
99
exogenous agents:
chronic bronchitis
inflammatory exudate: expiration disorders

neutrophils and lymphocytes
i
t neutrophil elastase alveolar overdistension
J '--.... destruction of the alveolar septa /
inactivation of antiproteases
t
endogenous agents: a-1 antitrypsin deficiency lung emphysema
Fig. 38. Schematic representation of the etiopathogenesis of pulmonary

emphysema
Types of cltronic empltysema

• centriacinar (centrilobular) emphysema
- enlargement of the air spaces that surround the respiratory bronchioles, without
lesions on the distal alveoli
- it is common in smokers, coal-dust workers and patients with chronic bronchitis
- it occurs especially in the upper lobes
• panacinar (panlobular) emphysema (pan, Gr. = whole)
- diffuse dilatation of the entire lung acinus, from the respiratory bronchiole to the
terminal alveoli and alveolar fusion; does not refer to the whole lung
- in patients with a-1 antitripsin deficiency or COPD both upper and lower
pulmonary lobes can be involved
• paraseptal (distal acinar) emphysema
- the airspaces are affected in the periphery of pulmonary lobules, usually near the
interlobular septa; the proximal part of the acinus is normal
- the emphysematous area can be surrounded by fibrotic areas
• irregular emphysema
- the acini are irregularly affected
• bullous emphysema
- a particular form of emphysema characterized by emphysematous spaces larger
than 1 cm, usually towards the periphery of the upper lobes
- complications: rupture - pneumothorax
100
f'
r:: _,
.., e_j
normal centrilobular panlobular paraseptal irreg�lar
aspect emphysema emphysema emphysema emphysema
Fig. 39. Types of chronic lung emphysema
Morphology of chronic emphysema

- macroscopic view: overdistended pale lungs, with spongy aspect on cut-section
(dilated, aerated spaces); usually associated with chronic bronchitis
- microscopic view: large vesicular spaces, thin and broken alveolar septa,
stretched capillaries; pulmonary artery shows proliferation of smooth muscle
fibers, fibrosis and atherosclerosis
Fig. 40. Chronic lung emphysema with spongy aspect on cut-section (B) and
formation of bullous spaces (C). The cut-surface is similar to a sea sponge (A)
101
Clinicalfeatures in chronic emphysema
- dyspnea, cough
- finger clubbing and confusion due to hypoxia
- emphysematous (dilated) thorax due to the use of accessory respiratory muscles
and increased lung volume
Evolution and consequences ofchronic emphysema
- chronic hypoxia
- pulmonary hypertension - chronic cor pulmonale
- atrophy of lung parenchyma - respiratory failure
- rupture of bullae - pneumothorax
Interstitial emphysema
- a particular type of pulmonary emphysema characterized by penetration of air

into the pulmonary interstiti um
Causes: trauma - rupture of an airway, rupture of an emphysematous bulla
persistent cough or severe coughing
iatrogenic causes (high pressure during artificial respiration)
Morphology:
- the dissection of lung interstitium by the accumulation of air bubbles in the
alveolar septa
Consequences:
- the air can spread to the mediastinum or subcutis (spongy crepitus on palpation)
- pneumothorax.
Fig. 41. Pulmonary interstitial emphysema in childhood (left) and adulthood (right)
due to high pressure during artificial respiration
102
ATELECTASIS
Definition: the absence of air in alveolar spaces

• neonatal atelectasis
= incomplete lung expansion
• acquired atelectasis
= collapse of previously inflated lung, with airless parenchymatous areas
Etiology and pathogenesis
• resorption atelectasis
- total obstruction of one of the bronchi or bronchiole - intraalveolar air
resorption and decreased blood flow in the affected areas
- causes: bronchopulmonary tumors, mucus plugs, bronchial asthma, bronchitis
• compression atelectasis
- causes: hydrothorax, hemothorax, pleural tumors
diaphragmatic elevation - peritonitis, subdiaphragmatic abscess, etc.
• contraction atelectasis
- pneumothorax (decreased lung expansion or lung collapse)
Morphology
- the affected areas are heavy, fleshy and cyanotic
- without air into alveolar spaces
Evolution and complications
- reversible process or it can be associated with pneumonia or lung abscesses.
,,<.. -. .
,: \ compression
� atelectasis
/ contraction
I: atelectasis
Fig. 42. Schematic representation of atelectasis depending on pathogenesis
103
RESPIRATORY DISTRESS SYNDROME
An acute restrictive lung disease associated with lung dystelectasis. Two types
recognized: 1. Infant or neonatal and 2. Adult Respiratory Distress Syndrome
HYALINE MEMBRANE DISEASE

(INFANT/NEONATAL RESPIRATORY DISTRESS SYNDROME)
- distelectatic lung which usually occurs in preterm babies weighing under 1 500 g
- predisposing factors: cesarean birth, maternal diabetes, etc.
- high concentration of ventilatory oxygen may accelerate the evolution
Clinical features
- cyanosis, respiratory disorders
Pathogenesis
- surfactant deficiency in immature lungs - terminal airways collapse -
pulmonary congestion - increased capillary permeability - plasma extravasation
- protein precipitation - formation of hyaline membranes
Macroscopic view: heavy dystelectatic lungs
Microscopic view: dystelectasis, immature alveoli lined by a protein-rich exudate
(hyaline membranes)
Evolution and consequences
- death or healing with sequels: obliterative bronchiolitis, pulmonary fibrosis.
ADULT RESPIRATORY DISTRESS SYNDROME (ARDS)
Synonyms: diffuse alveolar damage (DAD), shock lung

acute alveolar injury, acute lung injury
Clinical features: severe dyspnea, tachypnea, cyanosis
Etiology
- respiratory causes: lung infections, toxin inhalation, oxygen therapy
gastric aspiration
- non-respiratory causes: shock and DIC (sepsis, trauma, burns, pancreatitis, etc.)
- narcotic abuse (heroin, methadone), radiations
Pathogenesis
- destruction of surfactants or diffuse damage to the alveolar capillary walls -
dystelectasis, lung hemorrhages, hyaline membranes, respiratory failure
Macroscopic view
- early phases: heavy dystelectatic lungs - blue, hemorrhagic and edematous lungs
- late phases (organizing stage): solid fleshy grey lungs (fibrosis)
104
Microscopic view
- early phases: mature alveoli lined by a protein-rich exudate (hyaline membranes),
interstitial lung edema, microthrombi in the pulmonary vessels (DIC)
- late phases: connective organization of the protein-rich exudate
fibrosis and thickening of the alveolar septa
Evolution and consequences: no response to oxygen therapy ----* death or healing
with sequels: pulmonary fibrosis and pulmonary hypertension.
Fig. 43. Respiratory distress syndrome: heavy dystelectatic lungs (gross images),
with hyaline membranes lining the alveoli
105
NON-SPECIFIC PULMONARY INFLAMMMATIONS
Lobar pneumonia
Bronchopneumonia
Interstitial pneumonia
Pulmonaryfibrosis
Purulent iriflammations: abscess, gangrene, bronchiectasia
Illicit drug use
LOBAR PNEUMONIA
Definition: bacterial infection of the lung which is sharply confined to one or two
pulmonary lobes; usually occurs in 20-50 years old, previously healthy adults and
it is uncommon in children, elderly people or immunosupressed patients
Etiology: Streptococcus pneumoniae (90%), Klebsiella pneumoniae
Haemophilus lnfluenzae, etc.
Localization: lower lobes except for Klebsiella infection which affects the upper
lobes in alcoholics, diabetics or elderly people
Clinical features: sudden onset, high fever, tachypnea, cough, purulent brown
sputum, chest pain, confusion (hypoxia)
Evolution of lobar pneumonia
Time Pathological Macroscopic view of the Microscopic view - On

phase affected lobe type of intraalveolar auscultation
exudate
first Congestion enlarged, heavy, air + serum crackles
day (Pre-hepatisation) hyperemic and edematous +neutroohils
2th -3th
Red hepatisation firm, dry, fleshy red and hemorrhagic exudate wheezes
days airless, resembling fresh + neutrophils
liver
4•• -s•• Grey hepatisation solid and grey-brown fibrin+ neutrophils wheezes
davs
6th -7th
Yellow friable and yellow neutrophils wheezes
days heoatisation
s••- 10•• Resolution reintlated and enlarged air+neutrophils crackles
davs
Table 2. Clinicopathological features of lobar pneumonia according to

changes in time
106
Complications of lobar pneumonia
• pulmonary complications:
- camification (connective organization of exudate)
- abscess, gangrene
- fibrinous pleuritis
• extra-pulmonary complications:
- lymphadenitis (lung hilus, mediastinum)
- perifocal fibrinous pericarditis
- septicemia, pyaemia, metabolic disorders of several organs
- heart failure.
BRONCHOPNEUMONIA
Definition: acute focal lung inflammation which affects the bronchi, bronchioles
and the surrounding alveoli; it can occur in all ages but it is more frequent in
children, elderly people and immunosupressed patients; it is a multifocal and
bilateral pneumonia
Macroscopic view:
- multiple foci of consolidation throughout the lungs alternating with areas of
normal parenchyma in the lungs (,,spotted lung")
- the most commonly involved sites are the bilateral lower lobes and the
paravertebral areas
- according to the size of inflamed areas, bronchopneumonia can be disseminated
(small focal areas) or confluent (confluence of the affected areas)
Microscopic view
- serous, fibrinous, purulent or hemorrhagic exudate in the alveoli
- the inflammatory exudate can also be observed in the septa and bronchioles
Complications
- lung abscess, pulmonary fibrosis, pleuritis, thoracic empyema, pericarditis
- septicemia, death
Clinical features: cough, fever, dyspnea, confusion (hypoxia)
I
I
(S::j
Fig. 44. Bronchopneumonia (left) and lobar pneumonia (right)
107
Particular types of bronchopneumonia
Bronchopneumonia with Haemophilus injluenzae

- hospitalized and immunosupressed patients are more affected
- can lead to septic shock
Bronclwpneumonia with Pseudomonas aeruginosa
- usually occurs in hospitalized patients with tracheostomia or artificial respiration
- morphology: hemorrhagic or necrotizing areas ± lung abscesses
Bronchopneumonia with Staphylococcus aureus
- can be either a hemorrhagic pneumonia which affects children or
- purulent inflammation with lung abscesses and thoracic empyema
Bronchopneumonia with Legionella pneumophila (Legionnaires' disease)
- affects previously healthy elderly people
- predisposing factors: contaminated shower or cooling systems
- clinical features: headache, myalgia, chest pain, confusion
nausea, vomiting, diarrhea, abdominal pain, tachypnea, cough
Broncltopneumonia with Chlamydia
- Chlamydia psittaci - transmission from infected birds (psittacosis)
- Chlamydia trachomatis - maternal oculogenital infection ---+ neonatal pneumonia
Pneumonia with Klebsiella pneumoniae
- usually occurs in smokers and alcoholics but can also be related to diabetes or
malignancy
- morphology: pneumonia with abscesses in the upper lobes
- clinical features: fever (40 ° C), purulent/hemorrhagic sputum, confusion (hypoxia)
- differential diagnosis: lung tuberculosis, lung tumors
Aspiration pneumonia
- gastric aspiration or inhalation of food from the pharynx
Lipid pneumonia
- inhaled oils (paraffin, oily nose drops)
Hypostatic pneumonia
- long-term immobilization or post-surgery
Eosinopltilic pneumonia
- can be related to allergens (e.g. farmer's lung)
108
INTERSTITIAL PNEUMONIA
Definition: inflammation of the alveolar septa

Macroscopic view: dystelectatic lung
Microscopic view: alveolar septa thickened by infiltration with mononuclear cells;
the alveoli do not contain inflammatory exudate
Complications: bacterial superinfection - bronchopneumonia
death
Acute non-specific interstitial pneunwnia
- usually affects previously healthy people
- etiology: SARS (Severe Acute Respiratory Syndrome)
Influenza viruses (e.g. H l N l)
Respiratory Syncytial Virus (children)
Mycoplasma pneumoniae
- evolution: spontaneous remission
- clinical features: productive cough, dyspnea, tachypnea
Interstitial pneumonia caused by immunosuprcssion
- etiology: Cytomegalovirus, Herpes Virus, Pneumocytis carinii or jiroveci
- common in HIV-infected patients (opportunistic infection) and preterm newborns
- microscopic view: infiltration of the alveolar septa with lymphocytes and plasma
cells; in the alveolar spaces, a minute granular eosinophilic material
Hypersensitivity pneumonitis (Extrinsic Allergic Alveolitis)
- the Farmer's lung is the classic form of this interstitial pneumonia (inhalation of
allergens)
- clinical features: cough, dyspnea, fever and rhinorrhea occur at 4-8 hours
subsequent to exposition to allergens
- can be either acute or chronic disease, which can lead to pulmonary fibrosis
Chronic interstitial pneumonia
- etiology: viruses, dusts, radiation, cytotoxic drugs (chemotherapy) or idiopathic
- clinical features: long-lasting dry cough, dyspnea, finger clubbing, cyanosis
- evolution and complications: pulmonary fibrosis, pulmonary emphysema, chronic
cor pulmonale, risk factors for lung carcinomas.
109
Fig. 45. Lobar pneumonia: red hepatisation of the lower lobe (A) and grey
hepatisation of the upper lobe (B) which corresponds to a pulmonary opacity in the
right lung (C), in a 54-year old male infected with Klebsiella pneumoniae
Fig. 46. Hemorrhagic pneumonia with Staphylococcus Aureus in childhood
Fig. 47. Comparative aspect of bronchopneumonia, with inflammatory exudate in

the alveoli and hyperemic septa (left) and interstitial pneumonia, with mononuclear
infiltrate in the alveolar septa and air in the alveoli (right)
110
PULMONARY FIBROSIS
- a restnctJve pulmonary disease which usually occurs as a consequence of
pneumonia, pneumoconioses or chronic pulmonary congestion but may also be
related to smoking, sarcoidosis, radiation, drug toxicity (nitrofurantoin,
cyclophosphamide) or connective tissue disorders (e.g. systemic scleroderma)
Morphology: small dry lungs, thick alveolar septa
Complications: pulmonary hypertension
chronic cor pulmonale
risk for developing lung carcinoma
• idiopathic pulmonary fibrosis
- a progressive chronic pulmonary fibrosis with unknown cause which occurs
especially in elderly males and is accompanied by progressive dyspnea, dry cough,
fatigue, weight loss and finger clubbing
- macroscopic view: dry lungs with honeycomb aspect on cut-section, especially in
the lower lobes.
PURULENT INFLAMMATIONS OF THE LUNG

Lung abscess
Etiology:
- pneumonia with Staphylococcus Aureus, E. Coli, Klebsiella, anaerobes, etc.
- superinfection of pulmonary infarction or lung tumors
- bronchial obstruction (tumors, foreign bodies), bronchiectasis
- aspiration of gastric content, inhalation of infected material from the pharynx
- septic emboli (multiple metastatic abscesses)
Morphology: solitary or multiple, acute or chronic pus-filled cavities
Differential diagnosis: lung tumors, tuberculosis
Evolution and complications: healing with fibrosis
bronchial elimination - lung cavities
vascular erosion - hemoptysis, lung hemorrhages
thoracic empyema
pericarditis
· systemic spread - septicemia
amyloidosis (chronic abscess).
Lung gangrene
- the necrosis of the lung parenchyma may be associated with anaerobic infections
- morphology: a localized cavity with gangrenous tissue in lung parenchyma
- unfavourable prognosis
Bronchiectasis
- purulent inflammation of the bronchi (see 'CPOD').
111
ILLICIT DRUG USE
- both inhaled and intravenous injected drugs can lead to lung injuries
- consequences depend on the individual's immunity, quantity and routes of
administration but also associated substances (tobacco, alcohol, etc.)
- the following lesions can be associated with drug use:
• inhaled drugs:
- smoking (marihuana, cocaine, tobacco) - chronic bronchitis
- nasal inhalation (cocaine, heroin) - aspiration pneumonia, foreign body
granulomas, pulmonary hypertension, pyothorax
- heroin overdose - pulmonary hemorrhagic edema
- cocaine - alveolar hemorrhages
- methylphenidate - pulmonary emphysema
• injected drugs:
- infective endocarditis of the right heart - septic pulmonary emboli
- pulmonary hypertension
• other lung lesions:
- interstitial pneumonia
- lung infarction
- asthma exacerbation
- chronic obstructive pulmonary diseases
SPECIFIC PULMONARY INFLAMMMATIONS
PULMONARY TUBERCULOSIS
Primary tuberculosis
- the first contact of previously uninfected host with the Koch bacillus (primary
infection) leads to the formation of Ranke-Ghon's primary complex: Ghon's focus
in middle pulmonary area, tuberculous lymphangitis and tuberculous lymphadenitis
-· in patients with preserved immunity minimal systemic dissemination of the bacilli
leads to the formation of tuberculous dormant foci in different organs - in the lung,
the dormant foci are located in the apex (Simon's foci)
- complications: primary phtisis, miliary tuberculosis, Landouzy septicemia,
tuberculous lymphadenitis, etc. (see 'General Pathology')
112
Secondary (post-primary) tuberculosis
Early lesions
- in adults, the decreased immunity can lead to the reactivation of the old
tuberculous dormant Simon's foci or reinfection with Koch bacillus from an
external source
- the name of the apical reactivated Simon's foci is Aschoff-Puhl nodes and can be
detected in the apex of the lung as consolidated nodes
- the bronchogenic spread from the lung apex to lower lobes leads to the formation
of Assman 's subclavicular infiltrate
Evolution and complications:

• in patients with preserved immunity
- productive or proliferative acinous and acinonodular tubercles, with minimal
caseous necrosis
- healing with fibrosis and calcification of the tubercles from the upper lobes
• in patients with anergy (immunocompromised patients)
- bronchogenic spread - multiple pulmonary foci, larger in the upper lobes,
smaller in the lower lobes; the areas with caseous necrosis can be enlarged
(caseous pneumonia) and caseum can be eliminated through the bronchi leading to
the formation of cavities (caverns), first in the pulmonary apex, in later stages in
the middle and lower lobes; sometimes expanded necrotic areas are associated with
the destruction of the lung parenchyma (secondary phtisis); it can be accompanied
by pleuritis and pericarditis
- hematogenous spread: occurs more rarely than in case of primary tuberculosis but
can also lead to miliary tuberculosis or can be associated with renal tuberculosis,
bone tuberculosis (Pott's disease) and also tuberculous meningitis
- erosion into a branch of the pulmonary artery produced by caseous necrosis can
be associated with hemoptysis (pulmonary bleeding), sometimes fatal
- erosion through pleura - bronchopleural fistula, thoracic tuberculous empyema
- erosion into bronchia determines tuberculous bronchopneumonia
• other complications:
- lung lesions: fibrosis, bronchiectasis, · emphysema, atelectasis, hemorrhage ,
abscess, gangrene, aspergillosis (see later)
- pleural lesions: serous, fibrinous, caseous or hemorrhagic pleuritis
- systemic lesions: generalized amyloidosis, anemia, cor pulmonale
metabolic disorders (liver, myocardium)
113
Clinicalfeatures
- asymptomatic patients or
- fatigue, anorexia, weight loss, cough, fever, night sweats
The differential diagnosis of lung tuberculosis
- lung tumors, aspergillosis, bronchopneumonia, lobar pneumonia, Wegener
granulomatosis, silicotic nodules, other Mycobacterial infections (e.g.
Mycobacterium leprae, Mycobacterium avium).
Fig. 48. Complication of secondary tuberculosis:

A. Lung caverns; B. Phtysis of the upper lobe; C. Tuberculous meningoencephalitis
Fig. 49. Miliary tuberculosis. The lung (B) and the kidney (C) display several
1-2 mm white granulomas, similary to milia seeds (A)
1 14
OTHER SPECIFIC PULMONARY INFLAMMATIONS
Sarcoidosis - tuberculous-like granulomas - pulmonary fibrosis

Echinococcosis (hydatid cyst)
Fungal infections
- Aspergillus, Candida
- criptococcosis, histoplasmosis (from bird infections)
• lung aspergillosis
- can occur in immunosupressed patients or Aspergillus can colonize preexisting
lung lesions or cavities (cystic fibrosis, tuberculosis, sarcoidosis, lung infarction)
- macroscopic view: a well-defined red-brown tumor-like cavity or granulomas,
usually in the upper lobe (aspergilloma)
- microscopic view: fungal hyphae and granulomas in lung parenchyma
- Rx features: round well-defined tumor-like opacity in the upper lobe
- differential diagnosis: pneumonia with Klebsiella, tuberculosis
lung tumors, lung infarction
- clinical features: hemoptysis, symptoms related to allergy
Immune arteritis
- Wegener granulomatosis, Churg-Strauss syndrome (see Arteritis).
LUNG TUMORS
BENIGN TUMORS
Usually located in the bronchi and are rarely in the lung parenchyma. Bronchial
adenomas and hamartomatous chondroma are the most common benign tumors
which are usually incidentally observed at radiographic images as well-defined
small nodules; no malignant transformation
MALIGNANT TUMORS
Carcinomas (SCLC, N-SCLC)

Sarcomas (fibrosarcoma, angiosarcoma)
Lymphomas
Pneumoblastoma (see 'General Pathology')
Lung metastases
115
Sarcomas, lymphomas and pneumoblastoma are rare and are not discussed in this
chapter.
1. Bronchopulmonary carcinoma
Lung cancer is in the first place, the most frequent malignant neoplasm worldwide.
Most patients are active smokers. It is usually diagnosed in late stages and patients
die due to their disease
Risk factors
- tobacco smoking (benzopyrene)
- occupational exposure to carcinogens: asbestos, radon or other inhaled dusts
- air pollution
- chest radiation
- chronic bronchitis, bronchiectasis, pulmonary fibrosis
- gene mutations (2.4 fold increased risk in individuals with affected first degree
relatives)
Diagnosis
- involves the following steps: anamnesis, percution, auscultation, Rx, CT-scan,
biopsy; surgical removal or radio/chemotherapy are not allowed prior to biopsy
- sometimes peripheral tumors can be incidentally diagnosed on radiography as a
solitary node within lung parenchyma
- a tumor located in the upper pulmonary lobes should be differentiated by lung
tuberculosis, pneumonia with Klebsiella and lung aspergyllosis
Macroscopic view
• central tumors
- originate from the large bronchi and are located in the hilum or perihilar areas
- the prognosis is unfavourable due to the difficulty of surgical excision in case of
hilar involvement
- complications: bronchial obstruction, atelectasis, bronchiectasis
pneumonia, lung abscesses
• peribronchial tumors
- are located in the hilum and grow along the bronchi toward the periphe1y
• peripheral tumors
- arise from the small bronchi and bronchioles, being located in the peripheral areas
- the prognosis is more favourable due to the possibility of surgical excision
- complications: pleural invasion, hemorrhagic pleuritis/pericarditis, invasion of the
chest wall (chest pain)
116
• Pancoast-Tobias (apical) tumors
- peripheral tumors located in the lung apex
- produce the compression of the superior cava vein (edema and cyanosis of the
face and upper limbs), brachia! plexus and the cervical sympathetic chain causing
brachialgia, muscular atrophy in the shoulder and arm and Claude-Bernard
Horner's syndrome (unilateral enophtalmos, palpebral ptosis, myosis)
• bronchopneumonia-like tumors
- are focal lung tumors, which reproduce a bronchopneumonic pattern
- differential diagnosis: miliary tuberculosis, bronchopneumonia
• intrabronchial tumors
- polyp-like intrabronchial tumors
Microscopic types of tlte broncltopulmonary carcinomas

• small cell lung carcinomas (SCLCs) - 15% of lung tumors
- described later with the group of neuroendocrine tumors
• non-small cell lung carcinomas (N-SCLCs) - 80% of lung tumors
- their growth and spread are less important than in case of SCLCs
- depends on the histological type of differentiation the N-SCLCs can be:
a) squamous cell carcinoma - 30% ofN-SCLCs
- usually a central tumor, strongly related to smoking, the squamous metaplasia
being the main precursor lesion
- usually can be diagnosed in early phases due to early obstructive symptoms
- its incidence decreased in the last years
- macroscopic view : friable central yellow-gray tumor mass which can cavitate and
usually produce direct extension in the hilary lymph nodes
- microscopic view: squamous differentiation with varying degree of keratinization
- except direct invasion of the hilary lymph nodes, they tend to metastasize later
than other N-SCLCs
- clinical features: respiratory disorders, hypercalcemia (secretion of PTH-related
hormone), compression of the mediastinal structures (dysphagia, hoarsness,
diaphragmatic paralysis, hydropericardium)
b) adenocarcinoma - 35% of lung tumors
- most commonly in females and non-smokers, with increasing incidence in the last
decades
- macroscopic view: peripheral gray-white, well-defined single lesions or
multifocal tumors which can invade the pleura (pleural thickening) and the chest
wall; expanded areas of necrosis can occur in tumors larger than 5-6 cm in
diameter
- microscopic view: atypical glands with or without mucus secretion; these tumors
can be well, moderately or poorly differentiated (see 'General Pathology')
117
c) bronchioloalveolar carcinoma - 4% of N-SCLCs
- a subtype of adenocarcinoma
- a rare tumor which usually occurs in non-smokers
- macroscopic view: bronchopneumonia-like or bilateral multinodular appearance
but solitary mass without necrosis can also be observed
- microscopic view: the tumor cells proliferate along the alveolar septa, without
invasion (adenocarcinoma in situ) or minimal invasion of lung stroma (minimally
invasive adenocarcinoma); the correct histological diagnosis can be performed only
on lobectomy not on biopsy specimens
- the prognosis seems to be more favourable than in classic adenocarcinoma but the
diagnosis is usually established in advanced stages
d) large cell carcinoma - 10% of lung tumors
- an undifferentiated carcinoma which con sists of large atypical epithelial cell
sheets, without evidence of squamous or glandular differentiation
- they are usually peripheral tumors with unfavourable prognosis, which occur in
smokers
• neuroendocrine lung tumors - 20% of lung tumors
- those lung tumors which are capable of producing hormones are comprised in this
group and may be associated with paraneoplastic syndromes
- immunohistochemically, the tumor cells express neuroendocrine markers: CD56,
Synaptophysine, Chromogranin
- they can be low-grade (typical carcinoid), intermediate grade (atypical carcinoid)
or high-grade tumors (small cell lung carcinoma and large cell lung neuroendocrine
carcinoma)
a) small cell lung carcinoma (SCLC) - 15% of lung tumors
- they are usually central tumors with aggressive behaviour, 20% of the patients
present metastases when diagnosed
- macroscopic view: rapidly growing central tumors with expanded necrosis, lymph
node involvement and/or bronchial compression or obstruction
- microscopic view : small cells sheets with scant cytoplasm and hyperchromatic
nuclei with absent or inconspicious nucleoli; necrotic areas are expanded; the
tumor cells can be round-shaped or elongated, resembling oat grains (,,oat cells")
and are smaller in size than three small lymphocytes in diameter
- clinical features: stridor, hemoptysis, hoarsness, vocal cord paralysis
paraneoplastic syndromes: Cushing's syndrome (secretion of ACTH)
diabetes insipidus (secretion of ADH)
- staging system: limited-stage disease (tumor confined to one hemithorax and
ipsilateral supraclavicular lymph nodes) and extensive-stage disease (metastases in
bones, bone marrow, brain, liver, etc.)
118
b) carcinoid tumors - 1-2% of lung tumors
- usually not related to smoking
- macroscopic view: central, peripheral or multiple yellow tumors which are
usually intrabronchial
- microscopic view : nests or pseudorosettes composed of polygonal to fusiform
shape cells with pale cytoplasm; these tumors can be typical or low-grade and
atypical or high-grade carcinoid
- clinical features: can be associated with MEN l syndrome (multiple endocrine
neoplasia in parathyroid gland, -pancreas, duodenum, pituitary gland and lung)
- the survival rate depends on tumor grade; the 5-year survival rate is about 90% in
typical carcinoid and 60% in atypical carcinoid cases
c) large cell neuroendocrine tumor - 3% of lung tumors
- a variant of large cell carcinoma
- the tumor cells express neuroendocrine markers, but paraneoplastic syndromes
are uncommon
- poor survival compared to the classical variant, similar to SCLC
Metastatic behaviour of broncltopulmonary carcinomas

- direct spread: pleura, pericardium, chest wall and other mediastinal structures
- lymphatic metastases: mediastinal, cervical, axillary, supra- and subclavicular,
retroperitoneal lymph nodes, etc.
- systemic metastases: bones, brain, liver, adrenal glands and other organs.
""
hemoptysis
brain
bone
Fig. 50. Consequences and metastatic behaviour of the lung carcinoma
119
Prognostic factors of primary lung carcinomas
- tumor prognosis depends on:

a) tumor location
- better prognosis for peripheral tumors which can be surgically removed,
compared to central and bronchopneumonia-like tumors
b) microscopic type
- low-grade tumors, best prognosis: typical carcinoid (90-98% 5-year survival rate)
- intermediate grade tumors: squamous cell carcinoma
adenocarcinoma (70% 5-year survival rate)
atypical carcinoid (60% 5-year survival rate)
- high-grade tumors, worst prognosis: small cell carcinoma (9-25% 5-year survival)
large cell carcinoma
c) tumor stage (pTNM)
- tumor size (pTl s; 3 cm; pT2 3-5 cm; pT3 > 7 cm)
- lymph node metastases
- distant metastases
- in case of SCLCs the extensive stage predict poor prognosis
Predictive factors of primary lung carcinomas
- treatment depends on the tumor stage and type (SCLC or N-SCLC)

- SCLCs and large cell carcinomas benefit from associated chemoradiotherapy; in
case of SCLCs better results are obtained in the localized stage
- in advanced stages of NSLCs gene expression profiling is mandatory for targeted
(individualized) therapy; depends on the type of mutations, following new drugs
can be prescribes: EGFR mutations: Gefitinib or Erlotinib (anti-EGFR antibodies)
K-ras mutations: Tipifamib
BRAF mutations: Sorfenib
EMLH/ALK-1 fusion: ALK-1 inhibitors
2. Lung metastases (Secondary lung tumors)
- the lung is one of the most common organs involved in metastatic process
because it receives the entire cardiac output; the lymphatic spread can also lead to
the involvement of the pulmonary lymphatic vessels (diffuse pulmonary
carcinomatous lymphangitis)
- morphology: multiple tumors throughout the lung parenchyma
120
Fig. 51. Lung peripheral tumors - on the left, a well-defined expanded carcinoma
which communicates with a bronchi and on the right, an apical carcinoma
Fig. 52. On the left, note the aspect of lung metastases in a young patient with
seminoma; the lung cut surface displays multiple small nodules throughout the
lung parenchyma. On the right, the central white tumor mass is a bone metastases
located in the ribs, which was sampled from a patient with lung carcinoma; the
arrow indicates the rich angiogenic network formation surrounding the tumor
121
PATHOLOGY OF THE PLEURA
VASCULAR DISORDERS
Petechiae ofthe pleura

- minute and multiple hemorrhages (1-2 mm in diameter) on the pleural surface
- causes: asphyxia, shock, septicemia, blood disorders
anticoagulant drugs, intoxication
Hydrothorax (Pleural effusion)
- accumulation of a clear serous fluid in the pleural space (>500 ml)
- causes: heart failure, hypoalbuminemia,
Meigs syndrome (ovarian tumor+ascites+hydrothorax)
- consequences: compression atelectasis, depressed diaphragm
Hemothorax
- accumulation of blood in the pleural space
- causes: lung infarction, trauma, rupture of the aortic aneurysm, coagulation
disorders , anticoagulant drugs
- consequences: compression atelectasis, post-hemorrhagic anemia
Chylothorax
- accumulation of lymphatic fluid in the pleural space
- causes: rupture or obstruction of the thoracic duct (trauma, mediastinal tumors)
- consequences: compression atelectasis
PNEUMOTHORAX
Definition: accumulation of air in the pleural cavity

Causes:
- rupture of the bullous emphysema, interstitial emphysema
- trauma, penetrating wound (e.g. stab wound)
- spontaneous pneumothorax can occur in elderly patients with emphysema
- in young patients, pneumothorax is usually associated with trauma may also be
the consequence of excessive cannabis smoking
Consequences: contraction atelectasis
Clinical features:shortness of breath, acute chest pain
Tension pneumothorax is a particular type of pneumothorax in which a valve-like
mechanism allows air to accumulate in the pleural space during inspiration but the
air cannot exit during expiration
122
INFLAMMATIONS (PLEURITIS)
Types of pleuritis
- serous/fibrinous pleuritis - pneumonia, uremia, connective tissue disorders
-purulentpleuritis (pyothorax, empyema) - lung abscesses, lung tumors, trauma
- hemorrhagic pleuritis - pulmonary tuberculosis, metastases, lung tumors
- necrotizing pleuritis- lung gangrene, necrotizing mediastinitis
- healing - - - ►. pleural adhesions
- connective organization of the exudate - - - ►. hyaline plaques (pleural callus)
- encapsulation of the purulent exudate
PLEURAL TUMORS
Benign tumors
- very rare: benign mesothelioma, solitary fibrous tumor, etc.
Malignant mesothelioma
- macroscopic view: diffuse-infiltrative tumor which encase the entire lung or

focally coalescent nodules on the pleural surface
- microscopic view: epithelial-adenoid or sarcomatoid pattern
- risk factors: exposure to asbestos
- lymph node and distant metastases are common
- unfavourable prognosis (one year survival)
- clinical features: presents silent growth and can be accompanied by dyspnea,
hydrothorax and chest pain; thoracoscopy can facilitate the subcutaneous formation
of tumor nodules
Secondary tumors (metastases)
- direct spread from lung cancer

- lymphatic spread form stomach, esophagus or breast carcinomas
- hematogenous dissemination from: malignant melanomas, lymphomas, sarcomas,
carcinomas
123
Fig. 53. Hydrothorax. Accumulation of a clear serous fluid in the
left hemithorax (left) associated with compression atelectasis (right)
Fig. 54. Pleural inflammations. A-B: Fibrinous pleuritis with

winding aspect of the fibrinous membrane; C: Purulent pleuritis;
D: Pleural callus
124
PATHOLOGY OF THE
GASTROINTESTINAL TRACT
125
PATHOLOGY
OF THE GASTROINTESTINAL TRACT
Pathology of the oral cavity, pharynx, tonsils and salivary glands

Pathology of the esophagus
Pathology of the stomach
Pathology of the intestines and the appendix
Pathology of the peritoneal cavity
PATHOLOGY OF THE ORAL CAVITY, PHARYNX,

TONSILS AND SALIVARY GLANDS
PATHOLOGY OF THE ORAL CAVITY
Congenital malformations of the mouth
Hare-lip (cleft lip, cheiloschisis)

= congenital cleft of the upper lip (cheilos, Gr. = lip)
Cleftjaw (gnathoschisis)
= congenital cleft of the alveolar process of the jaw (gnathos, Gr. = jaw)
Cleft palate (palatoschisis)
= congenital cleft of the palate (roof of the mouth)
Inflammations of the mouth
Etiology
- physical injuries, smoking, alcohol, hot or spicy food
- viruses (e.g. Herpes Simplex Virus), bacteria, Candida albicans, etc.
Denominations
- cheilitis = infl ammation of the lips
- angular cheilitis = inflammation of the labial comissure
- glossitis = inflammation of the tongue
- gingivitis = inflammation of the gingiva (gums)
- stomatits = inflammation of the oral mucosa
126
Acute inflammations of the mouth
• catarrhal inflammations
- hyperemia and swelling of the oral mucosa ( e.g. spicy food)
• acute (catarrhal) glossitis
- sore and tender tongue, during fever, especially in childhood
• serous (vesicular) inflammations
- vesicles and ulcers on the lips/oral mucosa caused by Herpes or Coxsackie
viruses (herpetic stomatitis, herpangina) but also by measles virus (Koplik's spots)
or chickenpox (Varicella)
• fibrinous inflammations
- aphthous stomatitis (aphthous ulcer) = recurrent painful ulcers covered by fibrin
membranes, produced by viruses, repeated trauma or food allergies but they can
also be related to autoimmune diseases
• purulent inflammations
- dental abscess (localized inflammation), dental phlegmon (diffuse inflammation)
- Ludwig's phlegmon of the floor of the mouth (Ludwig's angina) - it is usually
associated with dental streptococcal infections
• necrotizing stomatitis or gingivostomatitis
- bacterial or anaerobic infections or
- during acute leukemias or associated with bone marrow failure
Chronic inflammations of the mouth

• chronic glossitis
- it is usually associated with pernicious anemia (Hunter's glossitis), iron or
vitamin B deficiencies but other disorders can also be involved in its etiology
- macroscopic view: atrophic tongue (the prominent papillae of the dorsum of the
tongue are replaced by flat mucosa) and red tongue margins
• chronic cheilitis, chronic stomatitis
- etiology: tobacco smoking, drugs, immunodeficiencies, etc.
Specific inflammations of the mouth

• oral candidiasis
- it is an opportunistic infection caused by Candida albicans which mainly occurs
in children and elderly, after antibiotic treatment, chemotherapy, in vitamins or
mineral deficiencies (iron deficiency anemia) and also in HIV-infected patients
- macroscopic view: white easily detachable plaques on the oral mucosa
- microscopic view : candidal hyphae and inflammatory infiltrate
• tuberculosis, syphilis (rarely).
127
Tumors of the oral cavity (Oral cancer)
1. Premalignant lesions
• leukoplakia (white plaque)

- etiology: HPV, chronic inflammations, smoking, alcohol, poor dental hygiene
- macroscopic view: white undetachable hyperkeratotic plaques on the oral
mucosa; sometimes, they becomes exophytic (protruded) multifocal lesions
- microscopic view: mucosa! keratinisation ± dysplasia
• erythroplakia
- morphology: red dysplastic patches on the oral mucosa
- both leukoplakia and erythroplakia are mainly localized in the floor of the mouth
or ventral and lateral tongue but any part of the oral mucosa can be involved.
• dysplasia (squamous intraepithelial neoplasia)
- it can occur with or independently by the leuokoplakia or erythroplakia
- mild, moderate or severe (high grade dysplasia or carcinoma in situ)
• epithelial atrophy
- in patients with iron deficiency anemia, the mucosa of the tongue can become
atrophic but few cases present malignant transformation
2. Benign tumors
• squamous cell papilloma (HPV)

• hemangioma
• fibroma
• Lipoma
• granular cell tumor
- benign tumor of the soft tissues wich mainly involves the tongue
- microscopic view : proliferation of large granular cells, which are modified
Schwam1 cells, between the muscle cells of the tongue
- differential diagnosis: squamous cell carcinoma of the tongue
• odontogenic tumors
- adamantinoma or ameloblastoma - it arises from remnants of the enamel organ
and is localized around the teeth ar can involve the inferior jaw leading to bone
destruction; sometimes, can have malignant behaviour
- odontoma - dental hamartoma
- other dental tumors: odontogenic cyst, odontogenic keratocyst, etc.
128
3. Malignant tumors
• carcinomas
- risk factors: Human papillomavirus (HPV) infection (usually type 16), tobacco
smoking, alcohol, tobacco chewing, repeated trauma, leukoplakia, exposure to the
ultraviolet light (lips), etc.
- macroscopic view : in most of the cases, non-healing ulcerated nodule with
raised edges; more rarely, prominent fungating tumors or red patches
- localization: lower lip, floor of the mouth, tongue and soft palate are affected, in
that order of frequency; more rarely, it is located on the gingiva or oral mucosa
- microscopic view : squamous cell carcinomas (>90% of the cases)
- evolution: carcinomas of the lower lips - good prognosis (>90% five-year survival
rate); carcinomas of the mouth and tongue - early lymphatic spread to
submandibular or other deeper cervical lymph nodes and poor prognosis (15%
five-year survival rate)
- prognostic factors: tumor size and nodal status (lymph node metastases)
• other malignant tumors
- melanomas, sarcomas, lymphomas, etc.
4. Pseudotumors
• gingival epulis (oulon, Gr. = gingiva)

- a localized tumor-like swelling on the gingiva, as a result of chronic irritation
- microscopic view : giant cells (osteoclast-like cells) or fibrosis
• giant cell granuloma (giant cell tumor)
- it is localized in the jaw and is composed of fibrous tisuue and osteoclasts
• pyogenic granuloma
- a localized protruted mass composed of granulation tissue, usually after trauma
• papillary hyperplasia
- a papillary mas on the palate of patients with inadequate prostheses or with poor
dental hygiene
129
PATHOLOGY OF THE PHARYNX
Pharyngitis
Acute pharyngitis
• catarrhal pharyngitis (sore throat)
- etiology: common cold
viruses (influenza, measles, Coxsackie, Herpes, EBY, etc.)
Streptococcus hemolytic - in childhhod can lead to rheumatic
fever and/or glomerulonephritis
• purulent pha,yngitis
- bacterial superinfection (e.g. Streptococcus pyogenes)
• ulcero-necrotizing pharyngitis
- acute leukemia, agranulocytosis (deficiency of the neutrophils), bone marrow
failure, etc.
- Plaut-Vincent's angina is a severe ulcerative inflammation caused by Borelia
vincentii or anaerobic bacilli which involves the gums, tonsils and surrounding
tissues
• pseudomembranous (diphtheric) pharyngitis
- caused by Corynebacterium diphteriae
- the soft palate and tonsils are more affected
Chronic pharyngitis
- predisposing factors: smoking, dusts, toxic substances, etc.
- complications: pharyngeal leukoplakia .- malignant transformation
Specific pharyngitis: tuberculosis, candidiasis, etc.
130
Tumors of the pharynx
1. Benign tumors
Nasopharyngeal angiofibroma, papilloma (see General Pathology)
2. Malignant tumors
Carcinomas:
- risk factors: EBY or HPV infections, smoking, chronic pharyngitis
• nasopharyngeal carcinoma (EBY-related)
• squamous cell carcinoma (in hypopharynx, in smokers or HPV-related)
• transitional cell carcinoma - after transitional metaplasia
Non-Hodgkin lymphomas
3. Pseudotumors
Pharyngeal (nasal) polyp

- hyperplasia of the pharyngeal tonsil (lymphoid tissue of the nasopharynx), during
chronic inflammations, can lead to obstruction of the nasal turbinates
PATHOLOGY OF THE TONSILS

Acute tonsillitis
• purulent tonsillitis
- swollen, red tonsils, with pus in the tonsillary crypts, during bacterial infections
• ulcero-necrotic tonsillitis
- can be leukemia-related or it is associated with Plaut-Vincent's infection
Evolution, complications of acute tonsillitis: healing, abscess, parapharyngeal
phlegmon, Ludwig's phlegmon, septicemia (rarely)
Chronic tonsillitis
- etiology: chronic bacterial infection (e.g. Streptococcus)
- morphology: dilated crypts, lymphoid hyperplasia or atrophy
Complications of streptococcal tonsillitis: both acute and chronic forms can lead
to rheumatic fever and glomerulonephritis (immune mechanisms)
Tumors
- lymphoepithelial carcinoma, squamous cell carcinoma
- non-Hodgkin lymphomas
- metastasesfrom lung carcinomas (rarely)
13 1
Fig. 55. Lesions of the pharynx and the mouth: A. Necrotizing tonsillitis,
pharyngitis and laryngitis in a child with leukemia; B. Tonsillar hyperplasia in
chronic tonsillitis; C. Ulcerated carcinoma of the hypopharynx
132
PATHOLOGY OF THE SALIVARY GLANDS
Sialolithiasis
= stone formation in the ducts of the submandibular glands or, less often, in the
parotid ducts, can lead to chronic inflammation and glandular atrophy
Sialocele (mucocele) (kele, Gr. = swelling)
= enlargement of the salivary glands due to excessive secretion of mucus and cysts
formation, during inflammations
- the sublingual gland (ranula) and minor salivary glands are more affected
Inflammations (Sialadenitis)
Acute sialadenitis
• mumps (parotitis epidemica)
- the most common viral inflammation of the major salivary glands
- the parotid and submandibular glands are more affected in childhood
- morphology: enlarged glands, with interstitial mononuclear infiltrate
- complications: orchitis, pancreatitis, aseptic meningitis
• purulent parotitis
- infection with pyogenic cocci in immunosupressed patients
- complications: septicemia
Chronic sialadenitis
- chronic inflammation of the parotid or submandibular glands is rare but can lead
to glandular fibrosis
Specific sialadenitis:
- sarcoidosis: chronic sialadenitis + irido-cyclitis
- tuberculosis, actinomycosis, etc.
Sjogren 's syndrome
- an autoimmune exocrinopathy which involves the salivary and lacrimal glands
and can lead to their atrophy
• sicca syndrome or primary Sjogren 's syndrome
- dryness of the mouth (xerostomia) and eyes (xerophtalmia) without organ
involvement
• secondary Sjogren 's syndrome
- xerostomia + xerophtalmia + rheumatoid arthritis
Diagnosis: biopsy of the salivary glands (focal lymphocytic infiltration)
Complications: malignant transformation: B-cell lymphoma of the parotid glands
133
Salivary gland tumors
Tumors of the major and minor salivary glands are rare, representing 5% of head
and neck tumors. More than 70% are benign tumors, mainly located in the parotid
gland.
1. Benign tumors
• pleomorphic adenoma
- the most common benign salivary gland tumors
- microscopic view : epithelial and mesenchymal components (fibrous, myxoid and
chondroid tissues)
- it can recur or can present transformation in carcinoma ex pleomorphic adenoma
• monomorphic adenoma
- microscopic view: epithelial component, with scanty fibrous septa
• Warthin 's tumor (adenolymphoma)
- occurs mainly in the parotid gland of elderly males
- microscopic view: cystic spaces lined by two layers of columnar epithelial cells
and a dense lymphoid stroma
2. Malignant tumors
• low-grade carcinomas
low-grade adenocarcinoma, basal cell adenocarcinoma, acinic cell carcinoma,
clear cell adenocarcinoma, epithelial-myoepithelial carcinoma, cystadenocarcinoma
• high-grade carcinomas
- salivary duct carcinoma, squamous cell carcinoma, adenosquamous carcinoma,
oncocytic carcinoma, sebaceous carcinoma, undifferentiated carcinomas
• other carcinomas
a) mucoepidermoid carcinoma - it is the most common malignant salivary gland
tumor which mainly occurs in the parotid gland (50%)
- low- or high-grade, depending on the amount of mucinous areas and the nuclei
pleomorphism
b) adenoid cystic carcinoma - it is the most common malignant tumor of minor
salivary glands but also occurs in the major salivary glands
- prognostic factors: location (better in major salivary glands), grade of
differentiation (proportion between glandular and solid areas)
c) mixed tumors: carcinoma ex pleomorphic adenoma - usually low-grade
primary malignant mixed tumor - poor prognosis
134
Fig. 56. Salivary gland tumors: A. Warthin's tumor; B. Pleomorphic adenoma;
C. Acinic cell carcinoma; D. Squamous cell carcinoma;
E-F. Mucoepidermoid carcinoma: low-grade (E) and high-grade (F)
135
PATHOLOGY OF THE ESOPHAGUS
CONGENITAL MALFORMATIONS
Atresia
- congenital failure of a part of the esophageal lumen
- both tracheo-esophageal fistula and aspiration pneumonia can be associated
Fig. 57. Schematic representation of esophageal atresia, with (left) and without
tracheo-esophageal fistula (right)
Acltalasia (achalasis, Gr. = failure to relax)

- failure of relaxation of the lower esophageal sphincter (functional narrowing)
- clinical features: dysphagia, regurgitation of undigested food
aspiration pneumonia
- macroscopic view: inflammation and ulceration of the mucosa of the lower
esophagus and dilatation of the proximal esophagus above the narrowed area
- microscopic view: lack of ganglion cells in the myenteric plexus of the lower
esophagus
Hiatal hernia
- congenital or acquired weakness of the diaphragmatic muscle which can be
related to: long-time high abdominal pressure in prolonged physical effort, obesity,
loss of diafragmatic muscular tone in senile involution, etc.
- morphology: the proximal stomach is pulled into mediastinum, above the
diaphragmatic hiatus, usually in the left thoracic cavity
- clinical features: retrostemal burning pain due to gastroduodenal reflux
136
DIVERTICULA AND STENOSIS
Diverticula
Definition: abnormal outpouchings of the esophageal wall
• pulsion (Zenker) diverticulum
- it occurs due to increased intraesophageal pressure or can be achalasia-related
- localization: upper segment of the esophagus
• traction diverticulum
- esophageal pulling from an external factor: paraesophageal scar, mediastinal
tumors, enlargement and fibrosis of the mediastinal lymph nodes, etc.
- localization: middle esophageal segment
- complications: inflammation (diverticulitis), superinfection
perforation - mediastinitis
compression of the mediastinal structures
Stenosis
- etiology: compression: mediastinal tumors, aortic aneurysm, thyroid goitre
strictures: esophageal tumors, chronic esophagitis
scar fibrosis after ingestion of corrosive substances.
obstruction : foreign objects.
ESOPHAGEAL VARICES
Definition: localized dilatations of the esophageal veins, most commonly in the

lower segment
Etiology: portal hypertension caused mainly by hepatic cirrhosis
Complications: rupture of the veins - hematemesis (blood vomiting)
- hemorrhagic shock, death.
MALLORY-WEISS TEAR (MALLORY-WEISS SYNDROME)
- multiple elongated ulcerations in the lower esophagus and cardia, due to repeated
retching or vomiting
- evolution: hematemesis, healing within about 10 days.
137
Zenker diverticulum , ' �
v
•
Achalasia
,;
ri
paraesophageal
iatal hernia
� �
r--r· I
� -.
,,.,
I >I
I "•'
---
Fig. 58. Schematic representation of esophageal deformities
Fig. 59. Circulatory esophageal disorders: esophageal varices

(A,B) and Mallory-Weiss syndrome (C)
138
INFLAMMATIONS (ESOPHAGITIS)
Acute and chronic esophagitis

- etiology: hot/spicy food, alcohol, bacteria, drugs, corrosive substances, etc.
- predisposing factors: leukemias, lymphomas, AIDS, diabetes mellitus, etc.
- endoscopy: hyperemic swollen mucosa
leukoplakia - in chronic esophagitis
- clinical features: retrosternal burning pain and heartburns (central chest pains)
due to reflux of gastroduodenal content, dysphagia
Reflux esophagitis (GORD = Gastroesophageal reflux disease)
- it is related to reflux of the gastro-duodenal content (chemical irritation)
- etiology: high abdominal pressure (obesity, pregnancy, physical effort), disorders
of the lower esophageal sphincter (achalasia, hiatal hernia, etc.), chronic gastritis
- microscopic view: in chronic reflux, increased cell desquamation and hyperplasia
of the basal cells
- evolution and complications healing or mucosal ulcerations, fibrous strictures
Barrett's esophagus (see below)
- clinical features: regurgitations, heartburns, hematemesis
Specific esophagitis
- Candida, Crohn's disease (see 'Enteritis'), systemic scleroderma, tuberculosis
BARRETT' S ESOPHAGUS
Definition: a change in the esophageal mucosa of any length that can be recognized
at endoscopy in the lower third of esophagus and is confirmed to have intestinal
metaplasia by biopsy
Etiology: long-time reflux of the gastroduodenal contents
Macroscopic view: the normal silver-grey mucosa of the lower third esophagus
becomes pink
Microscopic view: the normal lining squamous epithelium of the esophageal
mucosa is replaced by columnar or glandular epithelium, intestinalized type (with
goblet cells) or stomach-type (metaplastic non-goblet columnar lined esophagus);
dysplasia can also be associated
Evolution, complications:
• ulceration
• transformation in adenocarcinoma
- especially in cases with intestinal metaplasia and/or high grade dysplasia
Treatment: long-term follow-up, repeated biopsies, laser electrocoagulation,
radiofrequency ablation and esophagectomy in case of malignant transformation
139
TUMORS OF THE ESOPHAGUS AND
ESOPHAGOGASTRIC JUNCTION
1. Premalignant lesions
- achalasia, high grade dysplasia, leukoplakia, Barrett's esophagus
2. Benign tumors
- they represent 5% of all esophageal tumors

-papilloma (HPV-related), leiomyoma, lipoma, hemagioma, fibroma, etc.
3. Malignant tumors
Carcinoma
Risk factors: intake of tannic acid from strong tea or sorghum wheat,
alcohol or opium consumption, smoking, lack of dietary riboflafin
ingestion of corrosives, thermal injury
obesity, chronic gastrointestinal reflux, Barrett's esophagus
Localization: at the level of physiological esophageal narrowing, in the following
order of frequency: I . over the cardia; 2. tracheal bifurcation and
3. pharyngo-esophageal borderline (cricoid cartilage)
Clinical features: weight loss, dysphagia, hematemesis
Macroscopic view: ulcerated, polypoid (exophytic) or infiltrative tumor
Microscopic types:
a) squamous cell carcinoma
- usually related to the environmental agents
- localization: mainly in the middle esophagus
- spread: direct spread to mediastinum, lower esophagus and stomach
metastases in the mediastinal and/or supraclavicular lymph nodes
- poor prognosis
b) adenocarcinoma and adenosquamous carcinoma
- they are most commonly associated with Barrett's esophagus
- localization: mainly in the lower esophagus and esophagogastric junction
- spread: in the lymph nodes located on the lesser curvature of the stomach
liver metastases
- poor prognosis.
Complications: esophageal stenosis, eso-tracheal fistula � aspiration pneumonia
mediastinitis, pleuritis, necrotizing pericarditis
Other malignant tumors: sarcomas, malignant melanoma, etc.
140
Fig. 60. Esophageal carcinomas: ulcerated tumor (left) and
infiltrative cancer with eso-mediastinal fistula (middle and right)
PATHOLOGY OF THE STOMACH
CONGENITAL PYLORIC STENOSIS
- definition : congenital hypertrophy of the circular muscle of the pyloric sphincter

- clinical features: projectile vomiting
- treatment: surgical thinning of the sphincter wall.
ACUTE DILATATION OF THE STOMACH
- it can be a congenital or acquired disorder (e.g. post-surgical interventions)
141
INFLAMMATIONS (GASTRITIS)
Acute gastritis
• catarrhal gastritis
- etiology: alimentary excesses, alcohol, toxic substances, bacterial toxins, etc.
- macroscopic view : swollen red mucosa
- microscopic view: dilated capillaries, neutrophils and edema in mucosal layer
• hemorrhagic or erosive gastritis
- etiology: aspirin, non-steroid anti-inflammatory drugs (NSAIDs), stress, etc.
- macroscopic view: multiple small erosive hemorrhages
- microscopic view: multifocal loss of the superficial mucosa! epithelium without
progression beyond the muscularis mucosae
• pseudomembranous gastritis
- can be uremia-related, being associated with pseudomembranous colitis and
fibrinous pleuritis/pericarditis
• necrotizing gastritis
- etiology: corrosive agents
Chronic gastritis
Etiology: Helicobacter pylori
bile and duodenal juice reflux
chemical substances, alcohol, drugs
autoimmunity
Microscopical classification
• superficial chronic gastritis
- chronic inflammatory infiltrate (lymphocytes, plasma cells) in the foveolar layer
of the gastric mucosa
• diffuse chronic gastritis:
- chronic inflammatory infiltrate in both foveolar and glandular layers of the gastric
mucosa, sometimes associated with focal atrophy of the glandular layer
- infection with Helicobacter pylori is characterized by presence of lymphoid
follicles with germinal centers in the gastric mucosa
- gastritis produced by chemical injuries are characterized by foveolar hyperplasia
and minimal inflammatory infiltrate
• atrophic chronic gastritis
- few glands in the glandular layer of the mucosa, the foveolar layer being normal
- intestinal metaplasia (goblet cells within the lining glandular epithelium) and
dysplasia can be associated
142
Etiopathogenic classification of chronic gastritis
Chronic 1:astritis tvoe A Chronic f!astritis tvoe B

Etiology autoimmune-associated gastritis Helicobacter pylori (80%)
(5% of the cases) or chemical injuries
( 1 0% of the cases)
Localization fundus and gastric body antrum and pylorus ±
gastric body
Associated hypochlorhydria hypergastrinemia hyperchlorhydria
features serum autoantobodies to gastric (hyperacidity)
parietal cells and intrinsic factor normal gastrinemia
glandular atrophy
pernicious anemia ( 1 0% of the cases)
other autoimmune disorders
Table 3. Particularities of chronic gastritis depend on clinicopathological features
Evolution and complications of chronic gastritis

- atrophic gastritis, intestinal metaplasia and glandular dysplasia are premalignant
disorders .- transformation in adenocarcinoma
- Helicobacter pylori-related gastritis .- MALT-oma
- gastritis localized in antrum .- gastro-duodenal ulcer
HYPERPLASIA OF THE GASTRIC MUCOSA
• foveolar hyperplasia
- etiology: hypochlorhydria, hypergastrinemia, chemical (reflux) gastritis
- diffuse or focal hyperplasia (hyperplastic polyps)
- Menetrier's disease = diffuse and severe idiopathic hyperplasia
- macroscopic view: thickening of the gastric folds
- microscopic view: thickening of the mucosa! foveolar layer
• glandular hyperplasia
- etiology: hypergastrinemia, pancreatic tumors (gastrinoma)
- Zollinger-Ellison syndrome = glandular hyperplasia + hyperplastic polyps +
hyperchlorhydria + peptic ulcers, in patients with gastrinoma
143
Fig. 61. Gastric disorders: A. Uremia-related acute pseudomembranous gastritis;
B. Erosive gastritis; C. Hyperplasia of the gastric mucosa, with thickening of the
gastric folds
GASTRODUODENAL ULCERATIONS
Definition: breaches in the gastric or duodenal wall as a result of acid and pepsin
attacks
Acute gastroduodenal erosions
Definition: multiple small hemorrhagic ulcerations (2-3 mm) which involve the
gastric/duodenal mucosa, without extension beyond the muscularis mucosae
Etiology: shock, septicemia, stress, drugs, surgical interventions (laparatomy)
disorders of Central Nervous System
Evolution: hemorrhages (hematemesis), healing.
Acute peptic ulcer (,,Stress-related ulcer")
Definition: multiple hemorrhagic ulcerations which involve the mucosa, muscularis

mucosae and submucosa
Etiology: acute gastritis, hyperacidity, stress, etc.; Curling's ulcer is a particular
form which occurs during severe burns or major trauma; Cushing's ulcer is usually
associated with stroke or other lesions of the Central Nervous System
Localization: antrum, pylorus or proximal duodenum; Zollinger-Ellison syndrome
is characterized by ulcers of the antrum and duodenum which occur in patients
with pancreatic gastrinoma
Microscopic view: necrosis, hemorrhages and inflammatory infiltrate in mucosa
and submucosa, without granulation tissue
Evolution: hemorrhages (hematemesis), healing.
144
Chronic peptic ulcer
Definition: well-defined single or double chronic ulcerations which extend beyond

the muscularis propria
Etiology
- hyperacidity, gastritis, duodeno-gastric reflux, Helicobacter pylori
- drugs, alcohol, smoking, stress, genetic factors, autoimmune disorders
Pathogenesis
- imbalance between acid production and the defence mechanisms of the mucosa
Localization of the chronic peptic ulcer

1. the first part of the duodenum (65-70% of the cases)
2. antrum, pylorus, lesser curvature of the stomach (20% of the cases)
3. distal esophagus (esophagogastric reflux, Barrett's esophagus)
4. jejunum ( after gastroenterostomy)
Macroscopic view
- single well-defined, round/oval-shape ulcerations, 1 -2 cm in diameter (rarely > 4-
5 cm - giant ulcers), with non-elevated smooth edges, smooth and clear base
- the surrounding mucosa] folds radiate from the ulcer in a spoke-like (sunrays)
fashion
- more rare (1 0% of the cases), second ulcer can be found on the opposite side of
the duodenum ('kissing-ulcers')
Microscopic view
- the active chronic ulcer presents four layers which reflect the steps of healing:
1 . inflammatory exudate (on the luminal surface)
2. fibrinoid necrosis
3. granulation tissue
4. fibrous scar (in the base of the ulcer)
1 . healing with fibrous scar and spoke-like radiation of the surrounding folds
2. erosion of the vessels from the ulcer base - hemorrhages - hematemesis
('coffee ground' vomit) and melena ('coffee ground' stools) - posthemorrhagic
anemia
3. perforation - peritonitis, subphrenic abscess
4. penetration of adjacent organs (liver, pancreas, etc.)
5. fibrous strictures: pyloric/duodenal stenosis
hour-glass deformity of the stomach
6. malignant transformation: in 1 -2 % of the cases, only for gastric ulcer, not for
duodenal ulcer
145
Erosions Acute ulcer Chronic ulcer Penetrant ulcer
Fig. 62. Schematic representation of gastroduodenal ulcerations

(M = mucosa; SM = submucosa; Mp = muscularis propria; S = serosa)
Fig. 63. Gastroduodenal ulcerations: A. Acute multiple hemorrhagic

'stress-related ulcers'; B,C. Chronic gastric ulcers; D. ' Kissing chronic ulcers' ;
E . Perforating chronic ulcer
146
TUMORS OF THE STOMACH
1. Benign tumors
Polyps (polypoid adenomas)

- macroscopic view: pedunculated (stalked) or sessile (without stalk) tumors
- microscopic view: adenomatoid, villous or adeno-villous polyps
- gastric polpys are rare but can present dysplasia and malignant transformation
- fundic gland polyps are most commonly in patients treated with proton pump
inhibitors
Polyposis syndromes
- several gastrointestinal polyps which are usually familial syndromes associated
with genetic mutations
- patients with polyposis should benefit by genetic screening to exclude the other
cancers which can be associated (see Table 4)
- malignization is rare in stomach but quite frequent in the colo-rectal segments
• Peutz-Jeghers syndrome
- mutations in the gene STK11 (LKB1) from chromosome 19
- gastrointestinal polyposis + mucocutaneous melanotic pigmentations (lips, oral
mucosa, perioral, on the palms)
- low potential for malignancy
• Familial adenomatous polyposis (FAP)
- mutations in the gene APC (Adenomatous Polyposis Coli) from chromosome 5
- thousands of gastrointestinal polyps with high risk for malignization in colon
- both sexes can be affected, usually under 40 years
• Gardner syndrome
- F AP + osteomas of the skull + soft tissue tumors
- the risk for malignant transformation is higher than in F AP
• Cronkhite-Canada syndrome
- non-inherited polyposis, no gene mutations, unknown cause
- gastrointestinal polyposis + nail atrophy ± skin pigmentation and alopecia
• · Cowden 's syndrome
- mutations in the gene PTEN (Phosphatase and tensin homolog)
- gastrointestinal polyposis + benign tumors on the skin
• Juvenile polyposis syndrome
- mutations in the gene SMAD4, BMPRl A
- more than 50-100 polyps through the gastrointestinal tract
- 1 0-20% of the cases can present malignant transformation
147
Hereditary polyposis syndrome Mali�nant associated-tumors
Peutz-Jeghers syndrome Colon cancer
Ovarian cancer
Cervical cancer
Breast cancer
Pancreatic cancer
Juvenile volvvosis svndrome Colon cancer
Familial adenomatous polyposis Colon cancer
Brain tumors
Table 4. Hereditary polyposis syndromes and associated cancers
Benign gastrointestinal stromal tumors (GISTs)

- mesenchymal tumors originating from the interstitial cells of Cajal (the
pacemaker cells of the gut) which, in normal conditions, play an important role in
the gastrointestinal peristaltis
- 95% of GISTs present c-KIT mutations and are immunohistochemically marked
by the CD I 17 (c-KlT) antibody
- macroscopic view : solitary or multiple well-defined tumors, usually with
fungating aspect
- endoscopy: the tumors protrude into the lumen and can have a central deep crater
- microscopic view : the tumor cells can present epitheloid, spindle-shape or neural
differentiation and are characterized by low mitotic activity and no necrosis
Other benign tumors
• lipoma
• leiomyoma
• xanthoma
2. Premalignant disorders of the stomach
• atrophic gastritis
• chronic gastritis with intestinal metaplasia
• high-grade dysplasia (gastric intraepithelial neoplasia)
• gastro-enteroanastomosis
• partial or total surgical resection of the stomach (gastrectomy)
• chronic gastric ulcer (0.5-2% of the cases - malignant transformation)
• polypoid adenomas
• Barrett 's esophagus - tumors of the esophagogastric junction
148
3. Malignant tumors of the stomach
• carcinomas (90-95% of the cases)

• malignant lymphomas (4% of the cases)
• malignant gastrointestinal stromal tumors (GIST) - 2% of the cases
• neuroendocrine neoplasms
3.1. Gastric carcinoma
Risk/actors: dietary nitrates (smoked food, water, chili peppers)

Helicobacter Pylori, achlorhydria
the premalignant disorders (see the previous page)
EBV infections
Localization: antrum and pylorus - 45-50% of the cases
lesser curvature - 25-30%
proximal stomach - 1 0-25%
diffuse carcinomas - 15%
greater curvature - 2%
Classification upon the depth of invasion into the stomach wall (pT stage)
• early gastric cancer - the mucosa and submucosa are involved (pTl stage)
• advanced gastric cancer - extension into or beyond the muscularis
Macroscopic view:
• early gastric cancer
- type I: polypoid tumor
- type II: a. minimal protrusion (slightly raised plaques)
b. flat tumor
c. superficially depressed tumor
- type III: excavated (ulcerated) tumor
• advanced gastric cancer
- type I: polypoid (fungating, exophytic) tumor
- type II: ulcerated tumor - central necrosis, elevated margins, infiltration of the
surrounding tissue and no sp(')kelike radiation of the mucosa) folds, compared to
the chronic peptic ulcer which has non-elevated margins and spokelike radiation of
the surrounding folds
- type III: ulcero-infiltrative tumor
- type IV: diffusely infiltrating tumor - thickening of the entire gastric wall
('leather-bottle stomach' or 'linitis plastica')
- type II and III are most common, type IV has the worst prognosis
149
pTla - invasion of the mucosa pTl b - invasion of the submucosa
pT4a - invasion of the serosa pT4b - direct spread in other organs
Fig. 64. Gastric carcinoma staging upon the depth of infiltration (pT stage)
I I
II �
llb
I�
Fig. 65. Macroscopic types of gastric carcinoma according to

the rules of the Japanese Gastric Cancer Association:
early gastric cancer (left) and advanced gastric cancer (right)
150
Histological classification ofgastric carcinomas
• Lauren 's classification
- intestinal type of gastric carcinoma
- diffuse type of gastric carcinoma
- other types
• WHO (World Health Organization) classification
- intestinal adenocarcinoma
- diffuse adenocarcinoma
- mucinous adenocarcinoma
- signet-ring cell carcinoma
- adenosquamous carcinoma
- squamous carcinoma (proximal stomach)
- undifferentiated carcinoma
- other types
I. Intestinal type adenocarcinoma

- gland forming carcinoma which occurs mainly in elderly persons
- depends on the histological grade of differentiation and the capacity of mucus
secretion, intestinal type adenocarcinoma can be:
• well, moderately or poorly differentiated adenocarcinoma (no mucus)
• mucinous adenocarcinoma (>50% of atypical glands present
intraglandular or extracellular accumulation of mucus)
2. Diffuse type adenocarcinoma
- usually corresponds to the diffusely infiltrating macroscopical type
- diffuse infiltration of the gastric wall, no glands
- the younger people are affected (mean age 48), the prognosis is unfavourable
• signet-ring cell carcinoma
- mucus-producing tumor in which the mucus is intracellularly located, in the
cytoplasma of the tumor cells, and the nuclei are pushed to the periphery C signet
ring cells')
• schirrhous (fibrous) carcinoma
- a scar-like tumor ('linitis plastica') which infiltrates the entire gastric wall
· - the stomach becomes rigid and immobile ('leather bottle stomach')
• hereditary diffuse gastric cancer
- familial cancer with mutations in the E-cadherine gene (CDH l )
- signet-ring cell carcinoma in early stages and linitis plastica in late stages
- increased risk for lobular breast cancer and colorectal cancer
151
Spread ofgastric carcinoma
• direct spread:
- omentum, transverse colon, pancreas, liver, spleen, abdominal wall, etc.
• lymph node metastases:
- perigastric, abdominal, retroperitoneal, mediastinal nodes
- left supraclavicular nodes (Virchow's nodes; Troisier's sign)
- a subcutaneous node in the periumbilical region (sister Mary Joseph nodule)
• systemic metastases:
- liver (especially for intestinal type adenocarcinoma), lungs, bones, etc.
• peritoneal dissemination:
- peritoneal carcinomatosis or malignant ascites (especially for diffuse carcinoma)
- ovarian metastases (Krukenberg's twnor) - both ovaries are typically involved
Prognosticfactorsfor gastric carcinomas

• good prognosis
- early gastric cancer - 5-year survival rate is about 90%
- lack of lymph node or systemic metastases
- intestinal type of gastric carcinomas (well/moderately differentiated)
• poor prognosis
- peritoneal carcinomatosis, Krukenberg tumor
- advanced gastric cancer, especially diffuse type
- signet-ring cell or schirrhous carcinomas
- poorly-differentiated adenocarcinoma with significant anaplasia
- lymph node or systemic metastases
- invasion of the resection margins
- angiolymphatic/perineural invasion
Predictivefactorsfor gastric carcinomas

- patients with HER-2 mutations confirmed with in situ hybridization can benefit
by treatment with Herceptine
Clinicalfeatures
- asymptomatic patients or
- weight loss
- abdominal pain
- anorexia
- vomiting
- altered bowel habits
- anemia.
152
3.2. Malignant gastric lymphoma
- 20-40% of the lymphomas of the gastrointestinal tract are located in stomach

- most of them are non-Hodgkin B-cell lymphomas arising in the mucosa-
associated lymphoid tissue (MALT-omas or marginal zone lymphomas)
- their epidemiology seems to be related to Helicobacter pylori infection due to
association of an active chronic inflammatory reaction with increase of the
lymphocytes number; this is the reason why 50% of the low grade gastric
lymphomas can regress after antibiotic treatment for H. pylori
- macroscopic view: they are usually ill-defined ulcerated tumors
- microscopic view: small- or medium-sized lymphocytes with plasma cell
differentiation which infiltrate the glandular layer of the gastric mucosa; in high
grade lymphomas larger blast-like cells can be observed
- prognosis: it depends on the tumor grade (low- or high grade) and stage; better
prognosis than in advanced gastric adenocarcinomas - 5-year survival rate is about
50%, lower in high-grade large B cell lymphoma
- clinicalfeatures: no symptoms or dyspepsia, anorexia, weight loss, etc.
3.3. Malignant gastrointestinal stromal tumors (GIST)
- they are the malignant variant of benign GIST (45% of the GISTs)
- macroscopic view: similarity with the benign GIST ± necrosis
- microscopic view: same features as in benign GISTs+necrosis+atypical mitoses
- tumors larger than 5 cm with more than 5 mitoses per I O high power view
microscopic fields and necrosis usually present malignant behaviour
- the therapy with Imatinib inhibits c-KIT mutations
- clinical features: anemia, anorexia, weight loss, hemorrhages, etc.
3.4. Neuroendocrine neoplasms of the stomach
- occur from the ECL (enterochromafine-like) cells in the oxyntic mucosa, being
more commonly located in the proximal and middle part of the stomach
- classification according to WHO (World Health Organization)
• neuroendocrine tumor (NET} - Grade I (carcinoid) and Grade 2
• neuroendocrine carcinoma (NEC) - large and small cell NEC
- tumors < I cm, without angiolymphatic invasion, without invasion beyond
submucosa, which present < 2 mitoses/I O high power fields, have good prognosis
- high-grade neuroendocrine tumors (NEC) can be aggressive presenting
metastases in lymph nodes, liver, bones, skin, lungs, etc.
153
GIST - fungating aspect Gastric villous polyp Fungating gastric
with central deep crater with malignization carcinoma
Ulcerated Infiltrating signet-ring cell carcinoma

gastric carcinoma with ovarian metastases (Krukenberg' s tumor)
Gastric lymphoma with infiltrating aspect Gastric B-cell lymphoma - the tumor cells
in a 23 year-old female are marked in brown with CD20
Fig. 66. Malignant tumors of the stomach
154
3.5. Secondary tumors of the stomach
- metastasis originating from: breast/lung/genitourinary cancer

esophageal/hepatobiliary/pancreatic cancer
malignant melanomas
4. Gastric pseudotumors
Hyperplastic and inflammatory polyps (non-neoplastic polyps)

Definition: glandular hyperplasia which occurs during chronic gastritis, without
clinical significance
Macroscopic view: multiple polypoid-like lesions
Microscopic view: increased number of glands, without dysplasia
Incidence: more than 75% of the gastric polyps are hyperplastic, only 25% being
polypoid adenomas
Bezoar
Definition: deposits of undigestible materials either in stomach or intestines
('badzher', arabic = antidote), mainly in patients with psychiatric disorders
(trichophagia, trichotillomania), most frequent in women
Classification based on composition:
• trichobezoar (hairball) = ingested hair, food and mucus located in stomach
• Rapunzel syndrome = gastric trichobezoar with a long tail in the duodenum
• phytobezoar = vegetable matter
• dyospyrobezoar = persimmon vegetal fibers
• pharmacobezoar = drugs
• lactobezoar = milk products
Differential diagnosis: gastric tumors (e.g. gastric mature teratomas)
Fig. 67. Gastric pseudotumors: Left - hyperplastic polyps;

Right - 'J-shape' trichobezoar (hairball) and pieces of wool-blanket in the stomach
of a 1 8 year-old female with psychiatric disorders
155
PATHOLOGY OF THE INTESTINES AND THE
APPENDIX
Congenital and acquired disorders of the intestinal lumen

Vascular disorders
Malabsorption syndromes
Inflammations of the small and large intestines
Appendicitis
Other non-tumoral lesions of the rectum and anal canal
Tumors of the small intestine
Colorectal tumors
CONGENITAL AND ACQUIRED DISORDERS OF THE

INTESTINAL LUMEN
Heterotopia
- presence of the pancreatic tissue or gastric mucosa within the intestinal wall
- no clinical importance but sometimes can lead to malignant transformation
Atresia
- congenital failure of a part of the intestinal lumen (e.g. rectal atresia, anal atresia)
- duodenal atresia may be associated with Down's syndrome
Stenosis
- congenital narrowing of the intestinal lumen
Malrotation
- abnormal embryologic rotation of the gut can produce twisting of the intestines
- complications: intestinal obstruction
Meconium ileus
- obstruction of the small intestine in newborns, mainly related to cystic fibrosis or
imperforate anus (anal atresia)
- complications: intestinal perforation, volvulus, death
156
Intestinal diverticulosis (diverticular disease)
Definition: congenital or acquired single or multiple outpouchings (diverticula) in
the intestinal wall
Complications: diverticulitis (inflammation of diverticula)
perforation --+ peritonitis
Clinical features: asymptomatic or
diarrhea, steatorrhea, weight loss, abdominal pain
Classification:
• congenital Meckel's diverticulum
- pathogenesis: incomplete regression of the omphaloenteric duct
- morphology: congenital localized dilatation of the ileum which can associate
gastric or pancreatic ectopia
- complications: inflammation, perforation
peptic ulcer
adenocarcinoma
• congenital diverticulosis of tlte sigmoid colon
multiple sigmoidian diverticula can be associated with polycystic kidney m
patients with Marfan or Ehlers-Danlos syndromes
• acquired diverticula
- multiple colonic diverticula (Graser's disease), usually associated with intestinal
inflammations or constipation
- they are false diverticula, consisting of mucosa! herniation through the muscle
layer due to weakness of the intestinal wall
Hirschsprung's disease (intestinal aganglionosis, congenital megacolon)

- pathogenesis: congenital lack of ganglion cells in the intestinal myenteric plexus,
mainly in the distal colon and rectum, which can associate RET gene mutations
- macroscopic view: intestinal dilatation proximal to the aganglionic segment
- microscopic view: lack of the ganglion cells in the intestinal wall
- clinical features: chronic constipation
- complications: intestinal obstruction and/or inflammations
Acquired megacolon
- pathogenesis: dilatation of the intestinal lumen, without destruction of the
myenteric ganglion cells
- etiology: intestinal chronic infl ammations (e.g. Chagas disease - Trypanosoma)
intestinal obstruction : chronic constipation, tumors
functional disorders of the intestines.
157
VASCULAR DISORDERS
Intestinal infarction (acute ischemia)

Etiology:
- arterial obstruction: atherosclerosis, thrombosis, emboli, incarcerated hernia
- inadequate blood supply: hypotensive shock
Morphology: red (hemorrhagic) infarction characterized by hemorrhagic necrosis
of mucosa and the other intestinal layers
- bacterial superinfection
- without surgical excision - paralytic ileus
perforation, peritonitis (acute abdomen) and
death.
Chronic ischemia
Etiology: arterial narrowing: atherosclerosis, systemic arteritis
Morphology: ischemic enterocolitis - the splenic flexure of the transverse colon
(watershed area) is more affected
Clinical features:
- mesenteric angina (Orthner's disease) = post-prandial abdominal pain
- bloody diarrhea
Hemorrhoids (see Pathology of veins).
MALABSORPTION SYNDROMES
Definition: intestinal improper absorption of nutrients

Etiology:
• primary intestinal diseases: coeliac disease, tropical sprue (see next page)
• secondary intestinal disorders:
- cystic fibrosis (inadequate digestion)
- surgical resection of the intestine
- Whipple 's disease - a rare infection with Tropheryma whippelii which can affect
the gut, lymph nodes, heart valves, lung, central nervous system, etc; clinical
features: malabsorption, arthritis, skin pigmentations, lymphadenopathy; it can be
treated with antibiotics which cross the blood-brain barrier but untreated, it can be
fatal
- inflammations: parasites, bacteria, Crohn's disease (see Enterocolitis)
- environmental factors: drugs, radiation
- altered intestinal flora due to bowel stasis: ,,blind loop syndrome"
- diverticulosis
- lymphatic obstruction: intestinal tuberculosis
158
• disorders of pancreas, liver, stomach, endocrine glands, etc.
- pancreatitis
- obstruction of the biliary channels
- gastrectomy
- endocrine disorders: hypothyroidism, carcinoid syndrome, etc.
Coeliac disease (gluten-sensitive enteropathy)

Definition: an autoimmune disease characterized by decreased absorptive capacity
of the enterocytes and their inability to bind the toxic gluten peptides (glutenin,
gliadin, etc.); it is diagnosed usually during childhood but can also occur in adults
Macroscopic view: flat mucosa, most frequent in duodenum and jejunum
Microscopic view: villous atrophy, crypt elongation (hyperplasia) and lymphocytic
infiltrate in the intestinal mucosa
- reversible process after removal of gluten from the diet or
- malabsorption of sugar, fatty acids, amino acids, monoglycerides, water and
electrolytes - metabolic disorders
- decreasing of the intestinal honnone production (pancreosimin, secretin,
cholecystokinin) - gallstones formation (cholelitiasis)
- development of the enteropathy-associated T-cell lymphoma
Clinical features:
- sensitivity to dietary gluten from cereals products: wheat, rye, barley
- infants: diarrhea, steatorrhea, failure to thrive
- childhood: diarrhea, steatorrhea, pale stools, growth retardation, anemia
- adults: anemia, weight loss, altered bowel habit
- malabsorption syndrome: diarrhea, steatorrhoea, weight loss, fatigue
- associated disorders: diabetes, autoimmune thyroiditis, herpetifonn dermatitis,
splenic atrophy, etc.
Diagnosis: clinical features + biopsy + elevated serum anti-endomysial and anti
tissue transglutaminase antibodies levels
Tropical sprue
- usually occurs in the tropics and subtropical regions but is rare in Africa
- etiology: bacterial infection or unknown cause
- clinicopathological features are similar to coeliac disease but the prognosis is
better and it is not associated with gluten sensivity
- clinical features: diarrhea, weight loss
megaloblastic anemia (folate/vitamin B 1 2 deficiency)
- evolution: remission after treatment with antibiotics and folic acid
159
Pancreatic heterotopic tissue Meckel' s Acquired
in the ilea! muscularis diverticulum diverticulum
Thrombosis of the mesenteric artery and intestinal infarction
Fig. 68. Congenital and acquired disorders of the intestine
Fig. 69. Schematic representation of celiac disease, with villous atrophy (right)
compared to the normal intestinal villi and crypts (left)
160
INFLAMMATIONS OF THE SMALL AND LARGE INTESTINES
Enteritis = inflammation of the small intestine (duodenitis, jejunitis, ileitis)

Colitis = inflammation of the large intestine (colon)
Proctitis = infl ammation of the rectum
Enterocolitis = infl ammation of the small and large intestines
Acute enterocolitis
Catarrhal enterocolitis
- etiology: Escherichia coli, parvoviruses, rotaviruses, Vibrio cholerae, etc.
- morphology: swollen hyperemic intestinal mucosa with neutrophils infiltrate
Catarrhal-hemorrhagic enterocolitis
- etiology: alimentary toxiinfections or
opportunistic infections in immunosupressed patients
E. coli, Staphylococcus aureus, Cytomegalovirus, etc.
- morphology: hemorrhages and neutrophils in the intestinal wall
Pseudomembranous (fibrinous) enterocolitis
• uremia-associated enterocolitis
• antibiotic-associated colitis
- etiology: Clostridium difficile infection in patients who received antibiotherapy
without probiotic protection
• bacillary dysentery
- etiology: Shigella fl exneri/dysenteriae
- localization: usually in the distal colon
• salmonella infections (salmonellosis)
- etiology: Salmonella typhi (typhoid fever), Salmonella enterica, etc.
- sources of infections: water, food (e.g. eggs)
- morphology: round-oval-shaped longitudinal ulcerations in the mucosa, covered
by fibrin membranes; ulcerations and necrosis of the Peyer's patches
- evolution: healing without scarr
Purulent enterocolitis
- very rarely (e.g. Entamoeba histolytica - -.► amoebic dysentery)
Hemorrhagic-necrotizing enterocolitis (intestinal gangrene)
- it can occur in preterm infants leading to dehydration and death
Clinical features of acute enterocolitis

- wathery diarrhea or blood/mucus in the stools, periumbilical/abdominal cramps,
vomiting, fever, headache, etc.
161
Chronic non-specific enterocolitis
('Inflammatory bowel diseases', I BO)
Ischemic enterocolitis
Etiology: atherosclerosis, diabetes, arteritis, radiotherapy, etc.
Localization: mostly in the small intestine and splenic flexure of the colon
Morphology: hemorrhagic mucosa
thinning of the intestinal wall, intestinal dilatation
Indeterminate enterocolitis
Etiology: unknown cause or associated with chronic bacterial/parasitary infections,
immunosupression, drugs, malabsorption syndromes, radiotherapy, etc.
Morphology: mononuclear infiltrate in the intestinal wall, hypertrophy
(hyperplastic polyps) or atrophy of the intestinal mucosa
Crohn 's disease (terminal ileitis)

Definition: non-infective, idiopathic, chronic, relapsing, inflammatory bowel
disease which mainly occurs in adults, in their second decade of life
Localization: commonly in terminal ileum and colon (anal canal, rarely in the
rectum) but any part of the gastrointestinal tract from the mouth to the anus can be
affected
Macroscopic view:
I . patchy deep ulcerations in the swollen mucosa (cobblestone pattern), sharply
demarcated, alternates with normal areas (skip lesions)
2. thickening (fibrosis) of the whole intestinal wall and intestinal strictures
3.fistulae (e.g. enteroenteric, enterocutaneous)
4. lymphadenopathies
Microscopic view
I . deep ulcerations in mucosa and submucosa
2. inflammatory infiltrate, predominantly composed of lymphocytes, in all layers of
the intestine (transmural inflammation) associated with fibrosis
2. lymphoid follicles and non-caseating tuberculous-like granulomas
- intestinal bleeding, malabsorption
- intestinal strictures/obstruction, perforation
- fibrous adhesions of the intestinal wall
- fistulae in the surrounding structures: peritoneum, urinary bladder, vagina, skin
- intraabdominal abscesses
- medium risk for malignant transformation
Clinical features: abdominal pain, malabsorption syndrome, weight loss, etc.
162
Ulcerative colitis
Definition: non-infective, idiopathic, chronic, relapsing, inflammatory bowel
disease which should be differentiated from Crohn's disease
Localization: it primary occurs in rectum (proctitis) but can present proximal
extension (extensive colitis); sometimes, ilea! inflammation can occur (' backwash
ileitis '); the anal canal is usually not involved
Macroscopic view:
1. early stages: swollen mucosa and supe,fzcial ulcerations, which can be
confluent, no deeper than submucosa
2. late stages: granular and thinned mucosa, pseudopolyps
3. severe forms: enlarged ulcerations, intestinal dilatation (toxic megacolon)
4. the mucosa! lesions are continous, no skip areas, no fistulae
Microscopic view:
1. inflammatory infiltrate and superficial ulcerations, confined to the mucosa
2. pseudopolyps
3. cryptic abscesses (cryptitis)
4. the other intestinal layers - normal structure, no inflammation
5. no granulomas, no transmural inflammation
Evolution, local complications:
- loss of blood, fluid and electrolytes ----+ anemia, metabolic disorders
- toxic dilatation, perforation ----+ peritonitis
- high risk for malignant transformation (adenocarcinomas) in long-standing
extensive colitis: 1 5% of the cases after 1 0 years
50% of the cases after 20 years since the diagnosis
Systemic complications - immune disorders:
- skin: pigmentation, erythema nodosum, pyoderma gangrenosum
- joints: arthritis, ank.')'losing spondylitis
- liver: sclerosing cholangitis, cholangiocarcinoma
- eye: uveitis, iritis, conjunctivitis
Clinical features: weight loss, bloody diarrhea, anemia, malabsorption syndrome.
163
Ulcerative colitis
inflammation
of mucosa
and submucosa
Crohn's disease
transmural
inflammation
Fig. 70. Schematic representation of the morphological differences between

ulcerative colitis and Crohn's disease
Specific enterocolitis
Tuberculosis
Localization: commonly in the distal ileum
Etiology: lung tuberculosis (ingestion of infected sputum), drinking infected milk
Morphology: caseous mucosal ulcerations, along the lymph vessels (transverse
ulcers, perpendicular on the intestinal axes) and mesenteric adenopathy
Evolution and complications: intestinal strictures, perforation
malabsorption (lymphatic obstruction)
A ctinomycosis
Etiology: Actinomyces israelii
Localization: commonly in appendix and caecum
Complications: enterocutaneous fistulae with discharging creamy pus.
164
Fig. 71. Acute and chronic enterocolitis: A. Pseudomembranous uremia-related
enteritis; B. Bacillary fibrinous dysentery; C. Typhoid fever with longitudinal
ulcerations corresponding to Peyer's patches; D. Transversal ulcerations in a
patient with intestinal tuberculosis
Fig. 72. Ulcerative colitis with superficial ulcerations, thinned mucosa and
pseudopolyps (left), with malignant transformation (right); the arrow shows an
infiltrative carcinoma marked with blue dye (right)
165
APPENDICITIS
Acute appendicitis
Etiology: bacterial infection

luminal obstruction : faecoliths (faeces), food, seeds
Enterobius vermicularis, etc.
Morphological classification:
• catarrhal appendicitis
- swollen mucosa with neutrophilic infiltrate
- evolution: healing or transformation to phlegmonous appendicitis
• phlegmonous appendicitis
- neutrophils in all layers of the appendicular wall, pus into the lumen
• necrotizing (gangrenous) appendicitis
- etiology: primary gangrene with Clostridium difficile or
superinfection of the other types
- morphology: thrombosis of the intramural blood vessels, gangrene
- healing with/without fibrosis and/or adhesions (catarrhal appendicitis)
- transformation to chronic appendicitis
- periappendicitis and periapendicular abscess
- perforation -----, peritonitis
- systemic spread -----, thrombophlebitis, pylephlebitis, hepatic abscesses
- septicemia
Clinicalfeatures: pain (periumbilical or in the right iliac fosa)
nausea, vomiting, fever.
Chronic appendicitis
Morphology: a) fibrosis of the appendicular wall with/without fibrous obstruction

of the lumen or b) atrophy of the appendicular wall
Evolution
- acutization __, acute appendicitis
- obstruction of the neck of the appendix __, mucocele
- superinfection __, appendicular empyema.
166
OTHER NONTUMOR LESIONS OF THE RECTUM AND ANAL
CANAL
Proctitis
- inflammation of the rectum
- etiology: Candida albicans or sexually transmitted diseases (e.g. gonococcal
proctitis) - anal intercourse or genito-anal spread
- morphology: catarrhal and ulcerative proctitis are the most common types
Lymphogranuloma venereum
- etiology: Chlamydia (venerian disease)
- pathogenesis: spread from the genital organs via lymphatic vessels
- morphology: proctitis+lymphadenopathy
- complications: rectal strictures
Rectalprolapse
- etiology: it occurs especially in females or children due to weakening of the rectal
ligaments and muscles (advanced age, constipation, chidbirth, trichuriasis, cystic
fibrosis, etc.)
- morphology: protrusion of a part of the rectum into the anal canal
Hemorrhoids (see ' Pathology of veins')
Analfissures
- etiology: hemorrhoids or constipation
- morphology: a break in the skin of the anal canal
Ana/fistula
- etiology: surgical intervention, inflammations
- morphology: a communication between the perianal skin and the anal canal
Pilonidal sinus or cyst (pilonidal = nest of hair - pilus, Lat.=hair; nidus, Lat.=nest)
- etiology: hair which has penetrated deep under the skin, in the intergluteal cleft
- morphology: painful sacrococcygeal small channels with purulent drainage,
which can contain hair or cellular debris.
167
TUMORS OF THE SMALL INTESTINE
1. Benign tumors
Epithelial tumors
• polypoid adenomas (polyps)
- similarity with the gastric polyps (see 'Twnors of the stomach')
• polyposis
- gastrointestinal polyposis syndromes (see 'Tumors of the stomach')
- Peutz-Jeghers syndrome is the most common polyposis of the small intestine
Non-epithelial tumors
- benign GISTs - similarity with the gastric benign GISTs
- other benign tumors: hemangioma, fibroma, leiomyoma, lipoma, etc.
2. Malignant tumors
Lymphomas
- they are relatively rare but are the most common malignant tumors of the small
intestine
- macroscopic view: multiple polypoid masses, round-shaped, usually well defined,
with a deep central crater
- microscopic view: most of them are large B-cell lymphomas but coeliac disease
can lead to enteropathy-associated T-cell lymphomas
- complications: intestinal obstruction, small hemorrhages
Malignant GISTs
- similarity with the gastric malignant GISTs (see 'Tumors of the stomach')
Carcinoma
- rarely occurs in the small intestine, 50% of them arising in Vater's papilla
Neuroendocrine neoplasms
- single or multiple tumors, low- or high grade, most of them presenting lymph
node and/or liver metastases at the time of diagnosis
- classification according to WHO (World Health Organization)
• neuroendocrine tumor (NET) - Grade 1 (carcinoid) and Grade 2
• neuroendocrine carcinoma (NEC) - large and small cell NEC
- clinical features: most of them are serotonine-producing tumors and can be
associated with the carcinoid syndrome: diarrhea, borborygmi (bowel sounds),
cyanotic flushing, pulmonary or tricuspid stenosis, asthma-like attacks, etc.
- the gastrin-producing carcinoid tumors (gastrinoma) can associate Zollinger
Ellison syndrome (gastric hyperplastic polyps + hyperchlorhydria + peptic ulcers)
168
Fig. 73. Tumors of the small intestine: A. Pedunculated polyps; B. Sessile
adenomatous polyps; C. Sessile villous polyps; D. Lymphoma - the arrows indicate
two round well-defined nodules with deep central craters
169
COLORECTAL TUMORS
1 . Benign tumors
Adenomas
• polypoid adenomas (adenomatous polyps)
- similarity with the gastric polyps (see 'Tumors of the stomach')
• flat adenoma
- small non-elevated adenoma which can present malignant transformation
• polyposis syndromes
- most of them are congenital (familial) disorders which have been presented in the
chapter 'Tumors of the stomach' : Familial adenomatous polyposis (FAP), Gardner
syndrome, Cronkhite-Canada syndrome, Cowden 's syndrome, etc.
- Turco! syndrome is a familial polyposis characterized by colorectal polyps and
brain tumors (astrocytoma, glioblastomas, etc.), in patients with mutations in the
genes APC (Adenomatous Polyposis Coli) and MMR (Mismatch repair genes)
Other benign tumors
• lipoma
• leiomyoma
2. Premalignant disorders
• villous, tubulo-villous adenoma and polypoid adenoma

• flat adenoma
• polyposis
• inflammatory bowel disease: ulcerative colitis, Crohn 's disease
3. Malignant tumors
• carcinoma (90-95% of the cases)

• malignant gastrointestinal stromal tumors (GIST)
• malignant lymphomas
• neuroendocrine neoplasms
• malignant melanoma (anal canal)
170
Colorectal carcinoma
Colorectal carcinoma (CRC) is the third cause of cancer death in both males and
females worldwide. It is one of the cancers which has a strong genetic base.
Predisposing/actors:
• the premalignant disorders (see the previous page)
• congenital or acquired gene mutations
- K-ras, BRAF, p53, FAP, EGFR, c-myc genes
- MMR (DNA Mismatch repair) genes: MLH I , MSH2, PMS2, MSH6
• dietary factors: low-fiber/high-fat diet
• HPV infections (carcinomas of the anal canal)
Carcinogenesis:
• 'de nova ' (primary malignant tumors) - 70-80% of the cases
- no premalignant lesions with/without gene mutations
• malignant transformation of the adenomatous polyps
- the genes APC, K-ras, c-myc and p53 are usually involved
• malignant transformation of non-polypoidflat adenoma
• ulcerative colitis
- steps of malignization: dysplastic polyps � adenocarcinomas
• hyperplastic polyps with dysplasia - more rarely
• microsatel!ite instability (MSJ)
- alterations of the length of simple repetitive genomic sequences
normal epithelium
! }1.<PC
increasing of the cell proliferation
! 1(-ras, c-myc
adenoma with low-grade dysplasia
! p53
adenoma with high-grade dysplasia
! c-er6<J3-2, !E-caalierin
carcinoma
! nm23 ana1p21, p31 aefetions
metastases
Fig. 74. Diagrammatic representation of the classical adenoma-carcinoma sequence

and the genes which can present mutations during colorectal carcinogenesis
171
Localization
- rectum - 40% of the cases
- sigmoid colon - 25%
- caecum, ascending, transverse and descending colon - 30%
- anal canal - 1-2% of the cases
- synchronous tumors (e.g. caecum+rectum) - 1-2% of the cases
Macroscopic view
- polypoid (fungating) tumors: more frequent in the proximal colon
can lead to intestinal stenosis
- ulcerated tumors: most commonly in the distal colon and rectum
- ulcero-infiltrative tumors
- infiltrative tumors
WHO (World Health Organization) histological classification

- adenocarcinoma - well, moderately or poorly differentiated
- mucinous adenocarcinoma
- signet-ring cell carcinoma
- adenosquamous carcinoma
- squamous carcinoma (mainly in the anal canal)
- other types
Patlwgenetic classification of colorectal carcinomas

• sporadic colorectal carcinomas - 90% of the cases
- 'de novo' carcinomas or malignant polyps without genetic predisposition
- acquired mutations in the genes MMR, K-ras and p53 can be involved
- some of them can present microsatellite instability (MSI carcinomas)
• familial colorectal carcinomas - 2-3%
-polyposis-related cancer
- malignant transformation of the benign familial polyposis
- hereditary non-polyposis cancer (HNPCC) or Lynch syndrome - 2-3%
- familial syndrome characterized by mutations in the MMR genes (MLH I ,
MSH2, MSH6, PMS2) and microsatellite instability (MSI)
- they usually affect young patients around 45 year-old
- most of them are adenocarcinomas located on the right colon
- associated cancers: endometrial cancer, ovarian cancer, soft tissue tumors
172
Spread of colorectal carcinoma
• direct spread:
- uterus, ovaries, urethers, urinary bladder, liver, spleen, etc.
• lymph node metastases:
- adjacent to the colon: pericolic, perirectal lymph nodes
- along the vascular arcades of the marginal arteries and main colic arteries:
ileocolic, right colic, middle colic, left colic, inferior mesenteric (hemorrhoidal),
internal iliac arteries, etc.
- along the major vessels: periaortic lymph nodes
• systemic metastases:
- liver, lungs, bones, etc.
• peritoneal dissemination:
- peritoneal carcinomatosis
Staging systems usedfor colorectal carcinoma

• pTNM staging based on: depth of intramural invasion (pT)
number of lymph nodes with metastases (N)
distant metastases (pM)
• Dukes-MAC staging
- Dukes A - invasion in mucosa and submucosa, no lymph node metastases -pTl N0
- Dukes B1 - invasion in muscularis, no lymph node metastases -pT2N0
- Dukes B2 - invasion in subserosa or serosa, no lymph node metastases -pT3/4N0
- Dukes B3 - direct invasion in other organs, no lymph node metastases-pT4N0
- Dukes Cl/C2/C3 - similar with B l/B2/B3 + lymph node metastases
- Dukes D - peritoneal metastases - M1
Prognosticfactorsfor colorectal carcinomas

• good prognosis
- early stages
- lack of lymph node or systemic metastases
- lack of angiolymphatic invasion
- adenocarcinomas with microsatellite instability (MSI cases)
• poor prognosis
- advanced colorectal cancer
- signet-ring cell carcinomas
- poorly-differentiated adenocarcinoma with significant anaplasia
- lymph node or systemic metastases
- invasion of the resection margins
- angiolymphatic/perineural invasion
173
Predictivefactors for colorectal carcinomas
- patients with EGFR mutations, without K-ras mutations, can benefit from
treatment with anti-EGFR antibodies (Panitumumab, Cetuximab, etc.)
- patients with adenocarcinomas with microsatellite instability (MSI) do not
respond to treatment with 5-Fluorouracil
- metastatic cases benefit from antiangiogenic therapy (Bevacizumab)
Complications: intestinal hemorrhages, ileus (intestinal obstruction)

intestinal perforation --* stercoral (faecal) peritonitis
anemia - bloody stools or occult bleeding
Clinical features: asymptomatic patients or weight loss, abdominal pain, altered

bowel habits, bloody stools, anemia, etc.
Fig. 75. Colorectal tumors: A. GIST; B. Malignant polyp; C. Polypoid tumor with
lymph node metastases; D. Infiltrative carcinoma with invasion of serosa
174
PATHOLOGY OF THE PERITONEAL CAVITY
VASCULAR DISORDERS
Ascites
Definition: accumulation of clear serous fluid (transudate) in the peritoneal cavity
Etiology:
- increased hydrostatic pressure: right heart failure
- decreased colloid osmotic pressure: hypoalbuminemia - hepatic cirrhosis
- renal failure
- Meigs syndrome (ovarian tumor + ascites + hydrothorax)
Chylous ascites
Definition: accumulation of lymphatic fluid in the peritoneal cavity
Etiology: abdominal surgery, trauma, radiotherapy
carcinoid syndrome, carcinomatosis
congenital abnormalities of lymphatics (in children)
- atresia of the lymphatics (Milroy syndrome)
- 'leaky lymphatics'
Hemoperitoneum
Definition: accumulation of blood in the peritoneal cavity
Etiology: rupture of the fallopian tubes (ectopic pregnancy)
abdominal trauma, organ rupture (e.g. spleen, liver)
coagulation disorders
rupture of aortic aneurysm
iatrogen-related: post-surgery, anticoagulant therapy.
INFLAMMATIONS (PERITONITIS)
Acute peritonitis
Classification upon the type of inflammatory exudate

• septical peritonitis
- sero-fibrinous, fibrino-purulent, hemorrhagic or necrotizing (stercoral) peritonitis
- etiology: inflammations of the abdominal organs - appendicitis, colecystitis,
- salpingitis, pancreatitis, etc.
perforation of an abdominal organ - stomach, intestine, etc.
abdominal trauma, post-surgery
rarely: systemic/lymphatic spread - pleuritis, pericarditis, septicemia
• aseptic peritonitis
- etiology: uremia, accumulation of bile, etc.
175
Classification upon the extension
• localized peritonitis
- periapendicular, subphrenic and peridiverticular abscesses
- pelviperitonitis (Douglas-abscess)
• diffuse (generalized) peritonitis
- both visceral and parietal peritoneum are affected
Evolution, complications ofperitonitis
- healing with adhesions
- paralytic ileus
- septic shock - death
- encapsulated collection of pus (abscess).
Chronic peritonitis
- a rare lesion which can be caused by accumulation of talcum, foreign bodies

(after surgery) or infections with parasites but can also be associated with long
term peritoneal dyalisis
Specific peritonitis - Tuberculosis
Pathogenesis: direct spread from the abdominal organs (e.g. fallopian tubes) or
systemic spread, in immunodepressed patients
Morphology: sero-fibrinous or caseating peritonitis + ascites
PERITONEAL TUMORS
Primary tumors
• mesothelioma - benign or malignant
- morphology: white plaques in the peritoneal cavity
• liposarcoma
• other tumors
Peritoneal metastases
• peritoneal carcinomatosis
- it mainly occurs in ovarian, gastric and intestinal malignant tumors (direct spread)
- it is usually associated with ascites or hemorrhagic peritonitis
• peritoneal pseudomyxomatosis (pseudomyxoma peritonei)
- mucinous peritoneal implants which originate from ovarian borderline tumor
(peritoneal implants) or are associated with ovarian carcinomas, appendicitis or
appendicular tumors.
176
Fig. 76. Disorders of peritoneal cavity. A. Fibrinous tuberculous peritonitis with
adhesions; B. Fibrinous peritonitis in a patient with septicemia. Note the fibrinous
membrane on the intestinal surface; C-D. Peritoneal carcinomatosis in a Hiv
infected patient with ovarian carcinoma. Note the replacing of normal yelow
omentum (C) and mesenterium (D) by white tumor deposits
177
HERNIAS
Definition: congenital or acquired protrusion of a serosa-lined sac of peritoneum,
through a weakness or defect of the peritoneal cavity
• physiological weaknesses: the inguinal and femoral canals and umbilicus
• pathological weaknesses: surgical scar, congenital defficiences
Components of the hernia: hernial neck
hernial sac
contents of hernial sac (intestines, omentum, etc.)
External herniation
Inguinal hernia - most commonly in males, it represents herniation of intestinal

loops, omentum and, rarely, large bowel, into the inguinal canal and/or scrotum
• indirect hernia - herniation through lateral fovea inguinalis
• direct hernia - herniation through medial fovea inguinalis
Femoral hernia - most commonly in females, it represents herniation of intestines
into the femoral canal
Umbilical hernia - herniation of intestines through the umbilicus
Post-surgery and post-trauma hernias - herniation through surgical scars
Internal herniation
Hiatal hernia (see 'Congenital malformations of esophaus')

Diaphragmatic hernia
- congenital malformation which occurs in newborns
- complications: the intestines and spleen can herniate into the thoracic cavity
leading to compression of the lungs --+ respiratory failure --+ death
Other types of internal herniation: protrusion of intestines in bursa omentalis.
Complications of hernias
1. pressure at the hernial neck --+ decreasing of the arterial blood flow and venous
drainage of the organs from the hernial sac --+ incarceration or strangulation ileus
(career, Lat. = prison)
2. intestinal infarction (gangrene)
3. peritonitis.
178
Fig. 77. Hernias.
A. Acquired umbilical hernia in an obese patient; B. Congenital umbilical hernia
with intestinal gangrene, inside the hernial sac; C-O. Congenital diaphragmatic
hernias. Note the presence of intestines in the thoracic cavity
179
INTESTINAL OBSTRUCTION (ILEUS)
Definition: mechanical or functional blockage of the small intestine or colon that

prevents food and fluid from passing through
Mechanical ileus
Ileus without vascular disorders

• strictures: intestinal tumors, scars
• external compression: tumors, etc.
• obstruction: foreign bodies, parasites, gallstone, etc.
Ileus with impairment of the arterial bloodflow and venous drainage

• hernial incarceration (see 'Hernia')
• volvulus
- abnormal twisting of one intestinal loop and the mesenterium
- consequence: intestinal gangrene, acute abdomen
• intussusception (invagination)
- one intestinal segment, constricted by a wave of peristalsis can be telescoped
(invaginated) into the distal segment of bowel (e.g. ileocecal invagination)
Functional ileus
Paralytic ileus: peritonitis-related, post-surgery

Vascular ileus: after bowel infarction
Spasm-associated ileus: neuropathies
Evolution, complications of the ileus
- intestinal stasis, peritonitis, intestinal infarction (e.g. strangulation)

- septicemia, death
Clinical features of the ileus
- colicky abdominal pain, abdominal distension

- lack of bowel movement and/or flatulence
- acute abdomen
- vomiting.
180
incarcerated hernia inva ination volvulus
Fig. 78. Schematic representation of different types of ileus
Fig. 79. Mechanical ileus. A. Obstruction with Ascaris lumbricoides;

B. Obstruction with a foreign body (surgical material); C. Ileocecal
invagination
181
PATHOLOGY OF THE
LIVER, GALLBLADDER AND PANCREAS
182
PATHOLOGY OF THE LIVER
Vascular disorders
Metabolic disorders
Hepatic necrosis
Hepatitis
Liver abscesses
Hepatic cirrhosis
Alcoholic liver injury
Tumors of the liver
CONGENITAL MALFORMATIONS
Polycystic disease
- several cysts filled with clear serous fluid in the liver, kidney and other organs
(see 'Malformations of the kidney')
Biliary atresia
- congenital failure of the common bile duct or of a part of the intra- or extrahepatic
bile ducts
- risk factors: maternal infections
- complications: cholestasis, hyperbilirubinemia, jaundice, hepatocellular failure,
death
VASCULAR DISORDERS
Venous congestion
Etiology: systemic congestion (heart failure, shock, valvular heart diseases, etc.)
Morphology:
- acute congestion - dilatation of the central veins of the hepatic lobules
- chronic congestion - dilatation of the central veins and sinusoids (nutmeg liver)
- persistent congestion - liver fibrosis (cardiac cirrhosis) and/or regeneration
Portal hypertension
Etiology:
• prehepatic (presinusoidal) disorders
- portal vein thrombosis: tumor emboli, septicemia (pylephlebitis), etc.
- portal vein fibrosis: sarcoidosis, schistosomiasis, cirrhosis, etc.
183
• hepatic (sinusoidal) disorders
- hepatic cirrhosis
• posthepatic (postsinusoidal) disorders
- Budd-Chiari syndrome: idiopathic thrombosis of the hepatic vein
Evolution, complications: splenomegaly, collateral circulation, encephalopathy
Clinicalfeatures:
- abdominal pain, ascites, splenomegaly, jaundice
- hemorrhages
- hyperbilirubinemia, elevated serum transaminases (ALT, AST) levels
Other vascular disorders
Liver infarction
- obstruction of the hepatic artery - ischemic infarction
- obstruction of one of the portal vein branches - Zahn infarction
Pylephlebothrombosis (Portal vein thrombosis)
- etiology: inflammations of the abdominal organs (e.g. appendicitis)
cirrhosis, tumors, hypercoagulability
Subcapsular hemorrhage
- etiology: trauma, coagulation disorders
METABOLIC DISORDERS
Dystrophies (see 'General Pathology')

- disorders of protein metabolism (e.g. Mallory bodies or 'alcoholic hyaline')
- disorders oflipid metabolism ('fatty change')
- amyloidosis (secondary systemic amyloidosis)
- hemochromatosis, hemosiderosis
- glycogenoses, lipoidoses
- a-1 antitrypsin deficiency
Other lesions
• Wilson 's disease (hepatolenticular degeneration)
- disorders of copper metabolism due to mutations in the ATP7B gene
- clinicopathological features: accumulation of copper in the liver, brain (basal
ganglia) and cornea (Kayser-Fleischer rings) and low serum ceruloplasmin level
- complications: hepatitis, cirrhosis
• Metabolic syndrome
- obesity + diabetes mellitus + hypertension + hyperlipemia
184
HEPATIC NECROSIS
Necrosis of individual hepatocytes
- etiology: acute hepatitis, septicemia, leukemic liver infiltration, etc.

- morphology: coagulative necrosis of isolated hepatocytes throughout the hepatic
lobules, without relationship to lobular architecture
- evolution: healing with liver regeneration
'Piecemeal' necrosis (focal, interface or spotty necrosis)
- etiology: chronic hepatitis

- morphology: focal necrosis of hepatocytes at the periphery of the lobules or of the
interface between the periportal parenchyma and inflammed portal spaces
- evolution : healing with liver regeneration or fibrosis
Zonal necrosis
• centrilobular necrosis
- etiology: hypoxia, acute congestion, shock, drugs (e.g. paracetamol)
- morphology: necrosis of the hepatocytes located around the centrilobular vein
- evolution: healing with complete regeneration
• peripheral (periportal) necrosis
- etiology: intoxication, drugs, phosphorus poisoning, etc.
- morphology: necrosis of the hepatocytes located at the periphery of the lobules
- evolution: healing with complete regeneration or perilobular fibrosis
• bridging necrosis
- etiology: toxic or viral hepatitis
- morphology: expanded hepatocytic necrosis which may connect the adjacent
lobules
- evolution: healing with fibrosis or can lead to hepatic cirrhosis
Diffuse necrosis
- etiology: severe hepatitis, intoxications (e.g. mushrooms, ergot, LSD)

congenital disorders (e.g. maternal infections - syphilis, hepatitis, etc.)
- morphology: necrosis of the entire lobules or of most of the liver parenchyma
- evolution: death or can lead to the postnecrotic cirrhosis of the liver
185
Fig. 80. Hepatic necrosis. A. Schematic representation of the morphological types;
B. Diffuse necrosis in a two month old infant, as a consequence of maternal
hepatitis; C. Centrilobular necrosis; D. ' Piecemeal necrosis'
INFLAMMATIONS OF THE LIVER

Non-specific inflammations
• acute and chronic viral hepatitis
• liver abscesses
• secondary (satellite) hepatitis
Disorders of the gastrointestinal tract and/or biliary channels
Rheumatic diseases, collagen diseases
Leptospirosis
Viral infections: EBV, CMV, Herpes viruses
• intrahepatic cholangitis (primary autoimmune disease)
Specific inflammations: sarcoidosis, tuberculosis, brucellosis, syphilis, etc.
186
HEPATITIS
Acute viral hepatitis
Etiology
- hepatitis viruses - RNA viruses: A, C, D, E (HAV, HCV, HDV, HEV)
- DNA viruses: B (HBV)
Routes of transmission
- fecal-oral route - infectious hepatitis: HAV and HEV
- parenteral (blood, medical instruments) or venereal transmission: HBV, HCV
Macroscopic view
- hepatomegaly, with normal liver consistency and round soft edges
- shrunken liver presenting necroses and hemorrhages (severe forms)
Microscopic view
- swollen dystrophic hepatocytes
- apoptotic necrosis of individual hepatocytes (Councilman bodies)
- lymphocytic infiltrate in the portal spaces and hepatic parenchyma
- bridging necrosis - in severe forms of acute viral hepatitis (HBV, HCV)
Clinicopathological classification
• classical hepatitis: icterus (jaundice), hyperbilirubinemia
elevated serum transaminases (ALT, AST) level
abdominal discomfort, liver tenderness
anorexia, fever, nausea, etc.
• anicteric hepatitis: without jaundice (HAV)
• recurrent hepatitis: fluctuating jaundice during the recovery phase
• prolonged hepatitis
• fulminant (malignant, severe) hepatitis: extensive, diffuse hepatic necrosis
• giant cell hepatitis: in newborns and infants
Evolution and complications
- healing with complete regeneration (HAV, HEV)
- transformation into chronic hepatitis (HBV, HCV, HDV-coinfection)
- diffuse hepatic necrosis - in severe (fulminant) forms of hepatitis
- can be associated with glomerulonephritis and polyarteritis nodosa (HBV).
187
Chronic hepatitis
Definiton: inflammation of the liver that persists for more than 6 months and can
increase in severity; in case of viral hepatitis, the patients can become chronic
carriers
Etiology
- hepatitis viruses: HBV, HCV, HOV (coinfection)
- toxic hepatitis: drugs (iatrogenic hepatitis, illicit drugs)
- metabolic diseases (see the previous pages)
- autoimmune hepatitis (e.g. associated with Systemic Lupus Erythematosus)
- idiopathic hepatitis
Classification
• chronic persistent (mild) hepatitis
Microscopic view: inflammatory infiltrate in the portal spaces, without penetration
across the limiting membrane of the lobules; the lobular architecture remains intact
Evolution: healing with regeneration or
progressive inflammation and fibrosis (rare)
• chronic aggressive hepatitis
Microscopic view: inflammatory infiltrate in the portal spaces
piecemeal and bridging necrosis
peri- and intralobular fibrosis
Evolution, complications: cirrhosis, hepatocellular carcinoma or death
Healing (90-95%)
---------------
nic pe�nt hepatitis
--------------- /
Acute _ _ _ Chronic /
_
hepatiti s hepatitis
�
C h ronic ag ressive hepatitis
He
::::i�:��
✓Cir °sis eath
<.,__.,_
a
t /
Acute fulm i nant

hepati ti s Heal i ng ( rare)
Fig. 81 . Evolutive phases of acute and chronic hepatitis
188
LIVER ABSCESSES
Definition: localized cavities, filled with pus and cellular debris, in liver
parenchyma
Etiopatlwgenetic classification
• cholangitic abscesses
- etiology: ascending infections
- pathogenesis: enteritis or cholecystitis ------, cholangitis ------, liver abscesses
- morphology: multiple abscesses throughout liver parenchyma
• pylephlebitic abscesses
- etiology: pylephlebitis (see 'Liver vascular disorders')
- morphology: solitary or multiple abscesses, mostly in the right lobe of the liver
• metastatic abscesses
- etiology: septicemia or septicopyaemia
- morphology: several abscesses in the liver and other organs
• lymphogenic abscesses
- etiology: pyothorax, cholecystitis, nephritis, etc.
- pathogenesis: lymphatic spread
• other types
- post-traumatic abscesses, superinfection of the liver cysts, etc.
- healing with fibrosis or connective encapsulation of the pus
- perforation ------, peritonitis or subphrenic abscess
- systemic spread ------, septicopyaemia ------, death.
Fig. 82. Metastatic abscesses of the liver
189
HEPATIC CIRRHOSIS
(kirrhos, Gr.= yellowish)
Definition: chronic diffuse fibrous inflammation of the liver characterized by

irreversible damage of the liver architecture
Morphology
• regenerative nodules of hepatocytes
• fibrous septa
• piecemeal and bridging necrosis
Etiological classification
• atrophic cirrhosis (Laennec's cirrhosis)
• postnecrotic cirrhosis
• biliary cirrhosis
• autoimmune cirrhosis (e.g. Systemic Lupus Erythematosus)
• cirrhosis produced by other causes: hemochromatosis, Wilson's disease,
a-1 antitrypsin deficiency, syphilis, metabolic congenital diseases, etc.
• cryptogenic (idiopathic) cirrhosis
Pathogenetic classification
• congenital cirrhosis (congenital metabolic disorders)
• acquired cirrhosis (alcohol consumption, chronic viral hepatitis, etc.)
Atrophic cirrhosis (Laennec' s cirrhosis)
Risk factors: chronic viral hepatitis (HBV, HCV)

alcohol consumption, toxic substances, etc.
Pathogenesis:
- chronic inflammation - - .► zonal bridging necrosis and fibrosis - - .► destruction of the
hepatic architecture - - .► abnormal regeneration of the liver - - .► regenerative nodules
of hepatocytes, separated by fibrous septa
Macroscopic view
- hard and shrunken liver with sharp edges and nodular surface
- on cross-section : irregular yellowish nodules separated by greyish fibrous septa
Microscopic view:
- loss of normal lobular architecture
- regenerative nodules of hepatocytes, separated by fibrous septa
- necrosis of hepatocytes - infrequently observed
- fatty changes - in alcoholic cirrhosis.
190
Postnecrotic cirrhosis
Risk factors: fulminant hepatitis, toxic substances, autoimmune diseases, etc.

Macroscopic view:
- the nodules are larger than in case of atrophic cirrhosis (macronodular cirrhosis)
Microscopic view:
- large regenerative nodules of hepatocytes
- expanded fibrous septa and scarring areas
Biliary cirrhosis
Primary sclerosing clwlangitis

Definition: idiopathic autoimmune progressive disorder that leads to inflammation
and obliterative fibrosis affecting the intra- and extrahepatic bile ducts
Consequences: bile stasis, biliary cirrhosis
Macroscopic view: enlarged green liver, hard on palpation
Microscopic view:
- lymphocytic infiltrate, fibrosis and stenosis of intra- and extrahepatic bile ducts
- regenerative nodules of hepatocytes and fibrous septa - in late stages
Clinical features: fatigue, itching (bile salts into the bloodstream), jaundice and
hyperlipemia ± xanthelasma
Sex predilection: female to male 1 :2
Associated autoimmune diseases: ulcerative colitis, Crohn's disease, etc.
Complications: carcinoma of the bile ducts
Primary biliary cirrhosis
Definition: idiopathic autoimmune progressive disorder of the liver that leads to the
inflammation and scarring of the small intrahepatic bile ducts
Clinicopathological features: same as primary sclerosing cholangitis, plus serum
antimitochondrial antibodies
Sex predilection: female to male 6: 1
Associated autoimmune diseases: Sjogren's syndrome, scleroderma, thyroidits,
glomerulonephritis, celiac disease, etc.
Complications: hepatocellular carcinoma
Secondary biliary cirrhosis
Etiology: bile duct obstruction - gallstones, strictures, pancreatic tumors, etc.
Morphology: green liver, hard on palpation
19 1
Evolution and consequences of hepatic cirrhosis
Hepatic cirrhosis is characterized by:

• progressive failure of the hepatocellular functions and
• collateral circulation
- due to damaged liver architecture and portal hypertension
Portal hypertension
Pathogenesis: increased hepatic vascular resistance

increased hydrostatic pressure
Consequences:
a) splenomegaly
b) collateral circulation
• portosystemic shunts
- portal vein - superior cava vein:
esophageal varices
- portal vein - inferior cava vein:
hemorrhoids
caput medusae (engorged subcutaneous veins around the umbilicus)
• cavo-caval anastomoses
- superior cava vein and inferior cava vein:
dilated subcutaneous veins in the lateral abdominal walls
Complications:
- rupture of the esophageal varices - hematemesis or severe hemorrhages
- phlebothrombosis (portal vein)
- congestion of the gastrointestinal tract - indigestion
- ascites (vascular decompensation)
192
Hepatocellularfailure
Normal liver Hepatocellular Clinical feature

failure
protein synthesis hypoalbuminemia - edema
decreased colloid - serosal effusions, ascites
osmotic pressure - malnutrition (cachexia)
- muscle wasting
(hypoproteinemic
cardiomyopathv)
synthesis of clotting factors hypocoagulability - purpura, spider nevi
- bleeding, anemia
synthesis of lipid enzymes hypercholesterolemia - xanthelasma, steatorrhea
bilirubin coniungation hyperbilirubinaemia - jaundice
estrogen metabolism hyperestrogenism - gynecomastia, testicular
atrophy, hormonal disorders
aldosteron metabolism hyperaldosteronism - edema, ascites
- sodium and water
retention
elimination of toxic brain toxicity - hepatic encephalopathy
metabolits (detoxification) (amonium) - hepatic coma
- fetor hepaticus (liver breath)
glycogen storage hypoglycemia - fatigue, neurologic
disorders, hypoglycemic
coma
Table 5. Clinicopathological features of liver failure in patients with hepatic

cirrhosis
Decompensated cirrhosis
Definition: the collateral veins fail to compensate portal hypertension (vascular
decompensation) and/or the incompetence of the liver parenchyma to preserve its
functions (parenchymatous decompensation)
Clinico-pathological features
• vascular decompensation
- generalized edema
- ascites (portal hypertension + hepatocellular failure)
• parenchymatous decompensation
- jaundice, hepatic coma, encephalopathy (hepatocellular failure)
193
Other consequences: hepatocellular carcinoma
- cirrhosis can be associated with liver cell dysplasia which can lead to malignant
transformation - hepatocellular carcinoma (see 'Tumors of the liver')
Causes of death
- hemorrhages (e.g. rupture of the esophageal varices)
- heart failure (hypoproteinemic cardiomyopathy)
- liver failure - hepatic coma
- infections
- encephalopathy
- portal vein thrombosis
- hepatocellular carcinoma.
ALCOHOLIC LIVER INJURY
Evolutive steps:
1. Steatosis
- macroscopic view: enlarged yellow and friable liver, round edges (fatty change)
- microscopic view: accumulation of lipid droplets in the hepatocytes (steatosis)
2. Alcoholic hepatitis
- microscopic view: steatosis, minimal inflamatory infiltrate, focal necrosis of the
hepatocytes and progressive fibrosis
3. Alcoholic cirrhosis
- macroscopic view: pale shrunken/hard liver, sharp edges (atrophic cirrhosis)
- microscopic view: steatosis + regenerative nodules of hepatocytes + fibrosis.
Pathogenesis
1. acetaldehyde, the main substance of alcoholic metabolism can produce either
direct hepatotoxicity or can stimulate collagen synthesis
2. chronic alcohol consumption can produce:
a) disorders of lipid metabolism - fatty change or steatosis
b) disorders of protein metabolism - accumulation of alcoholic hyalin (Mallory
bodies) in hepatocytes
c) direct hepatotoxicity - individual necrosis of hepatocytes
d) disorders of intestinal digestion and malabsorption
194
Alcohol consumption
Disorders of intestinal
----- l
digestion and malabsorption
Steatosis
r
Direct damages
of the hepatocytes
Alcohol
l hepatitis
low level of the
lipotropic substances
I
Ethanol - Acetaldehyde
Collagen synthesis - ALCOHOLIC (ATROPHIC) CIRR HOSIS
Fig. 83. The evolutive steps in alcoholic liver disorders
encephalopathy
splenomegaly
j
�scites f
,,,..,
caput rnedusae
��
t hemorrhoids
testiculal' ah·ophy
Fig. 84. Consequences of hepatic cirrhosis
195
Fig. 85. Steatosis of the liver
Fig. 86. Atrophic cirrhosis. Note the sharp edges and nodular surface (A, B). On
cross-section, the yellow areas (C) are regenerative nodules separated by fibrous
septa, which can be also observed under microscope (D)
196
TUMORS OF THE LIVER
1. Pseudotumors
Hamartomas
- rare tumor-like congenital lesions
• focal nodular hyperplasia
- a mass of connective tissue which contains small bile ducts
• hemangioma
- the cavernous type is most common (see 'General Pathology')
Liver cysts
• simple cysts: without clinical significance
• choledocal cysts: congenital cysts of the bile ducts
• hydatid cysts (echinococcosis or hydatid disease):
- etiology: fecal-oral infection with Echinococcus granulosus
- risk factors: hunters, shepherds, etc.
- macroscopic view : one large well-defined cyst covered by a fibrous capsule;
subjacent, a fibrous laminated wall contains daughter cysts; inside the cyst, a clear
fluid with hydatid antigens
- microscopic view: the outer laminated layer under which there is the inner
germinative layer with round-shaped daughter cysts (scolices)
- complications: rupture of the cyst - anaphylactic shock - death.
I
ufer laminated layer
. � /.
- ��-vfl �
. • \�� · �inner layer
G
. f : -:\ � �¼� -
. ilou#;httr cysts ~ · __ -�,
,.;
Fig. 87. Hydatid cyst of the liver (see 'Pseudotumors of the liver')
197
2. Benign tumors
Adenoma
- risk factors: consumption of anabolic, androgenic or estrogenic steroids
contraceptive pills
3. Premalignant disorders'
• hepatic cirrhosis
• chronic hepatitis (HBV, HCV)
• hepatobilia,y parasitosis
• intrahepatic lithiasis
• cholangitis
• primary sclerosing cholangitis
4. Malignant tumors
WHO (World Health Organization) histological classification

- tumors arising from the hepatocytes: hepatocellular carcinoma
- tumors arising from bile ducts: cholangiocarcinoma
bile duct cystadenocarcinoma
- combined hepatocellular and cholangiocarcinoma
- hepatoblastoma
- tumors arising from the mesenchymal elements: angiosarcoma
embryonal sarcoma
rhabdomyosarcoma
- other tumors
Hepatocellular carcinoma
Risk/actors: hepatic cirrhosis, alcoholic liver diseases
chronic viral hepatitis (HBV, HCV)
dietary substances (e.g. aromatic amines)
mycotoxins produced by Aspergillus flavus (aflatoxins)
Macroscopic view: solitary or, more frequent, multifocal tumors (satellitosis)
Microscopic view: trabecular arrangement of tumor cells ± fibrous septa
other features : acinary, tubular structure, etc .
Clinical features: weight loss, jaundice, elevated serum alpha-fetoprotein level
Outcome: poor prognosis
198
Prognostic factors: elevated serum alpha-fetoprotein level
multiple tumors more than 5 cm
vascular invasion
Differential diagnosis
- liver metastases
- increased levels of alpha-fetoprotein: testicular teratoma, ovarian yolk sac tumor
Cholangiocarcinoma (Adenocarcinoma of the bile ducts)

Risk/actors:
- Chinese liver fluke (Clonorchis sinensis) or Opisthorchis viverrini � cholangitis
- intrahepatic lithiasis
- ulcerative colitis
- primary sclerosing cholangitis
Morphology: gland-forming carcinoma
Prognostic factors: underlying liver diseases
intrahepatic extension of the tumor
vascular invasion
direct spread
Angiosarcoma
Risk/actors: vinyl chloride (PVC manufactures), radiological contrast substances
Prognosis: highly destructive tumor but metastases usually occur in advanced
stages
Hepatoblastoma
- a rare embryonal tumor which occurs in children younger than five years old
Outcome: favourable prognosis in early stages

- the liver is one of the most common organs involved in metastatic process
because the portal vein and its branches receives the blood from the gastrointestinal
tract but also from the spleen and other organs
- morphology: solitary or multiple tumors throughout the liver parenchyma
Lymphomatous and leukemic infiltrates

- small multiple infiltrates which can occur in patients with lymphomas or chronic
lymphocytic leukemia.
199
Fig. 88. Tumors of the liver. A. Multifocal hepatocellular carcinoma;
C. Solitary cholangiocarcinoma; C-D. Solitary metastases;
E-F. Multiple metastases
200
PATHOLOGY OF THE GALLBLADDER
AND BILIARY TREE
Cholelithiasis (gallstones)
Inflammations: Cholecystitis and cholangitis
Tumors of the gallbladder and biliary tree
CHOLELITHIASIS (GALLSTONES)
Localization: gallbladder (80-90%), biliary tree (10%)

Risk factors
- the four 'F's: Female, Fat, Forty, Fertile
- chronic cholecystitis
- diabetes mellitus
- hypercholesterolemia
- chronic hemolysis (hemolytic anemia)
- Crohn's disease - decreased ilea! absorption of bile acid
Composition of gallstones
- yellowish: cholesterol
- black-green: bile pigment
- white-gray: calcium carbonate
- mixed composition (80%)
Morphology of gallstones
- solitary or multiple stones
- smooth or faceted surfaces (multiple gallstones)
- radial structure (radiation from a central deposit) or
- concentric structure (concentric layers of calcium, bile pigment or cholesterol)
Complications
- cholecystitis, cholangitis --+ liver abscesses
- obstruction of the bile ducts --+ dilated gallbladder filled with clear fluid
(hydrops), mucus (mucocele) or pus (empyema)
--+ mechanical jaundice
- biliary cirrhosis
- colicky right hypochondria! pain (biliary colic)
- pancreatitis
- squamous metaplasia --+ squamous carcinoma
- premalignant condition --+ adenocarcinoma
- mechanical obstructive ileus (rarely)
201
CHOLECYSTITIS AND CHOLANGITIS
Definitions
- cholecystitis = inflammation of the gallbladder
- cholangitis = inflammation of the biliary ducts
- cholelithiasis
- bacterial/parasitic ascending infection
- biliary stasis (post-surgery, severe trauma, bums, postpartum, etc.)
Acute cholecystitis
Classification
- catarrhal, phlegmonous or gangrenous cholecystitis
- calculous or noncalculous cholecystitis
- healing (resolution)
- transformation into chronic cholecystitis
- empyema of the gallbladder
- pericholecystitis - - -► peritoneal abscesses
- perforation - - --► peritonitis
- ascending infection - - -► cholangitis - - -► liver abscesses
- septicemia
Clinical features
- colicky right hypochondria! pain (biliary colic)
- fever, anorexia, tachycardia, sweating, nausea, vomiting ± jaundice
Chronic cholecystitis
Etiology: prolonged cholecystitis or repeated attacks of acute cholecystitis

Macroscopic view
• fibrous cholecystitis
- fibrous thickening of the wall, mucosa! thickening
• atrophic cholecystitis
- thin wall and atrophic mucosa
• porcelain gallbladder
- extensive dystrophic calcification and wall rigidity
Microscopic view
- fibrosis or atrophy of the muscularis, minimal lymphocytic infiltrate
- outpouchings of the mucosa through muscularis (Rokitansky-Aschoff sinuses)
202
- mucocele = dilated gallbladder filled with mucus
- transformation into acute cholecystitis
- malignant transformation
Clinical features
- colicky epigastric or right upper quadrant pain
- nausea, vomiting, intolerance to fatty foods
Cholangitis
Etiology: usually ascending infections (cholecystitis)

- both intra- or extrahepatic bile ducts can be involved
Complications: liver abscesses, biliary cirrhosis, pancreatitis, septicemia, etc.
A
'c.- I
I 1111 "I'" 11 1nr111 p11 TIIIJ11!1 11111 pi 111 'I ,i u I'
1 I • It ll tz
Fig. 89. Gallstones with radial structure (B) and concentric lamellar structure (C)
203
Fig. 90. Cholecystitis and gallstones. A. Acute colecystitis and bile pigment stones;
B. Chronic atrophlc cholecystitis with wall thlning and mucosa! atrophy;
C. Chronic fibrous cholecystitis with wall thickening;
D. Porcelain gallbladder
204
TUMORS OF THE GALLBLADDER AND BILIARY TREE
1. Benign tumors
• adenoma
• papilloma
• fibroma, etc.
2. Premalignant disorders
• gallstones (90% of carcinomas of gallbladder)

• chronic cholecystitis
• squamous metaplasia
3. Malignant tumors
Carcinoma ofthe gallbladder

Macroscopic view: infiltrating or exophytic (fungating) tumor
Microscopic types (WHO):
- adenocarcinomas (90% of the cases)
- adenosquamous carcinomas, squamous cell carcinomas
- undifferentiated carcinomas, other types
Spread: direct invasion of the liver, systemic and lymphatic spread
Outcome: poor prognosis
Prognostic factors:
- depth of tumor infiltration: T l - 5-year survival rate 50%; T2 - 29%
- vascular invasion
- histological type and degree
Carcinoma of the extrahepatic bile ducts

- a very rare tumor, usually adenocarcinoma, which can be associated with
ulcerative colitis
Carcinoma of the ampulla of Valer

Microscopic type: adenocarcinoma
Complications: mechanical jaundice, pancreatitis, etc.
205
PATHOLOGY OF THE PANCREAS
Regressive processes and congenital disorders
Pancreatitis
Pancreatic tumors: Tumors of the exocrine pancreas
Tumors of the endocrine pancreas
Diabetes mellitus
REGRESSIVE PROCESSES AND MALFORMATIONS
Regressive processes: pancreatic atrophy

pancreatic lipomatosis
Congenital disorders: congenital pancreatic cysts
cystic fibrosis (see 'General Pathology')
PANCREATITIS
Acute pancreatitis
Etiology
• infective pancreatitis
- viruses (e.g. mumps virus), bacteria, etc.
• non-infective pancreatitis :
- gallstones (40% of the cases)
- alcohol consumption, fatty foods, alimentary excesses (50% of the cases)
- other causes: tumors -t obstruction of the pancreatic ducts
bile reflux
shock (vascular insufficiency)
hypothermia, trauma
iatrogenic causes (surgical interventions, steroids, etc.)
genetic factors
• idiopathic pancreatitis
Pathogenesis involves intrapancreatic activation of pancreatic enzymes:
- proteases -t destruction of the vessel walls -t hemorrhages and vein thrombosis
- lipases -t digestion and necrosis of the intra- and peripancreatic fatty tissue
(steatonecrosis) - fatty acids (+ glycerol) -t fatty acids + Calcium - soap
formation -t destruction of the parenchymal islets
206
Morphology of acute pancreatitis
• mild pancreatitis
- white patches of necrotic fatty tissue (steatonecrosis) + inflammation
• severe pancreatitis (hemorrhagic necrosis of the pancreas)
- hemorrhages, steatonecrosis of the intra- and peripancreatic tissue, inflammation
• mild pancreatitis
- healing, recurrent attacks -+ chronic pancreatitis
• severe pancreatitis:
- peripancreatic abscesses
- shock -+ death
- healing with fibrosis -+ diabetes mellitus, malabsorption
Clinicalfeatures
- severe abdominal pain which radiates to the back
- nausea, vomiting
- elevated serum amylase and lipase levels ± hypocalcemia, hyperglycemia
CHRONIC PANCREATITIS
Etiology: alcohol consumption (70% of the cases)

genetic causes (1-2% of the cases): hemochromatosis (bronze diabetes)
cystic fibrosis
Systemic Lupus Erythematosus
stenosis of the bile/pancreatic ducts (gallstones, fibrosis, etc.)
autoimmune pancreatitis
idiopathic pancreatitis
Morphology: fibrosis + atrophy of the glandular parenchyma
- acute exacerbations
- intestinal malabsorption of fat (decreased quantity of lipases)
- stone formation in the pancreatic ducts
- diabetes mellitus (destruction of pancreatic islet cells)
Clinical features
- recurrent abdominal and back pain, weight loss, steatorrhea
- diagnosis is based on:
ERCP (Endoscopic Retrograde Cholangiopancreatography)
MRCP (Magnetic Resonance Cholangiopancreatography)
Core needle biopsy
207
PANCREATIC TUMORS
1. Tumors of the exocrine pancreas
1 . 1 . Benign tumors
• serous/mucinous cystadenoma
• ductal papilloma
1 .2. Malignant tumors
Pancreatic malignant tumors are the fourth leading cause of cancer-related death.
Ductal adenocarcinoma
Localization: head ( 65-70% of the cases), pancreatic tail or pancreatic body
Macroscopic view:
- ill-defined, scar-like tumor
- pancreatic duct dilatation, distal to the tumor
Microscopic types (WHO):
- adenocarcinoma - well, moderately or poorly differentiated
- mucinous noncystic carcinoma
- signet ring cell carcinoma
- other types: adenosquamous carcinoma, mixed ductal-endocrine carcinoma, etc.
Prognosis: extremely short-term survival (5-year survival rate 3-5%)
insidious onset, 80% of tumors are diagnosed in advanced stages
Prognostic factors:
- tumor stage (Tl - tumor :S 2 cm; T2 > 2 cm; T3,4 - invasion of the main arteries)
- metastases: nonmetastatic adenocarcinoma - median survival time: 12-20 months
metastatic adenocarcinoma - median survival time: 3-6 months
Clinical features:
- mechanical jaundice, weight loss
- flitting venous thrombosis (trombophlebitis migrans) - Trousseau's sign
Cystadenocarcinoma
- a rare tumor most commonly located in the pancreatic tail
- prognosis is better than in case of ductal adenocarcinoma
Acinar cell carcinoma

- a very rare tumor with unfavourable prognosis.
208
2. Tumors of the endocrine pancreas
(Pancreatic neuroendocrine tumors, Islet cell tumors)
- rare endocrine tumors which can be either benign or malignant (10% of the cases)
- better prognosis than adenocarcinomas (5-year survival rate 55%)
- classified according to the secreted hormones
Insulinoma:
- the most common tumor of the endocrine pancreas
- clinical features: hypoglycemia, confusion, psychic disorders
Glucagonoma
- clinical features: secondary diabetes, skin rashes, migratory erythema
Gastrinoma
- clinical features: peptic ulcers (Zollinger-Ellison syndrome)
Vipoma
- clinical features: achlorhydria+diarrhea ( Verner-Morrison syndrome)
Somatostatinoma
- clinical features: secondary diabetes, achlorhydria, gallstones
Carcinoid tumor
- clinical features: usually asymptomatic, with normal levels of serotonine in
plasma and urine (nonfunctioning tumor)
209
Fig. 91 . The normal aspect of pancreas (A,E) and ampulla of Yater (B), acute
pancreatitis with hemorrhages and white-yellow patches of steatonecrosis (C-D)
and pancreatic adenocarcinoma (F)
210
DIABETES MELLITUS
Definition: a complex metabolic disease characterized by glucose intolerance due

to disorders of the pancreatic beta-cells in the islets of Langerhans
Classification: primary diabetes - type 1 , type 2
secondary diabetes
Type 1 diabetes Uuvenile onset)

Pathogenesis:
- progressive immune mediated destruction of beta-cells
Predisposing factors: genetic factors
environmental factors: Coxsakie B, mumps viruses
cell-mediated immunity (type II hypersensitivity reaction)
Occurence: most commonly in children and young adults
Treatment: insulin-dependent diabetes
Type 2 diabetes (maturity onset)

Pathogenesis:
- defects of beta-cell function
- insulin secretion can be normal but the decreased number of insulin receptors
leads to insulin resistance
Predisposing/actors: genetic factors, dietary habits (obesity)
Occurence: middle age (usually obese patients)
Treatment: weight reduction, oral hypoglicemic drugs
Secondary diabetes (type 3 diabetes)

Etiology:
- hyperglycemic hormone secretion:
endocrine diseases: glucocorticoids (Cushing's syndrome)
Growth Hormone (acromegaly),
neuroendocrine tumors: glucagon (glucagonomas)
adrenaline and noradrenaline (phaechromocytoma)
somatostatinoma (somatostatin)
- metabolic disorders: hemochromatosis (bronze diabetes)
- chronic pancreatitis, fibrosis
Gestational diabetes (type 4 diabetes)

- reversible diabetes which can occur during pregnancy - overweight newborns.
211
Consequences of diabetes
1 . hyperglicemia -+ polyuria and glycosuria -+ osmotic diuresis and loss of

+
Na and K+ -+ hypovolemia -+ dehydration -+ polydipsia
2. decreased protein synthesis
3. lipolysis and hyperlipemia
4. free fatty acids can be converted into ketone bodies -+ ketoacidosis -+
electrolytes depletion (mainly in type 1 diabetes)
Complications of diabetes
• atherosclerosis -+ myocardial infarction, stroke, limb gangrene, etc.

• microangiopathies
- retinopathy -+ diabetic blindness
- glomerulopathy: hyaline arteriolosclerosis and thickening of the basement
membrane of the glomerular capillaries (Kimmelstiel-Wilson lesion)
• neuropathy
• immunodeficiencies -+ opportunistic infections
• disorders of pregnancy
- overweight newborns
- neonatal hypoglycemia
- toxemia (eclampsia)
• hyperglycemic coma
• insulin overdose -+ hypoglycemic coma
Causes of death
• renal failure
• myocardial infarction
• stroke
• opportunistic infections
• septic shpck
• hypo-/hyperglycemic coma
212
PATHOLOGY OF THE
KIDNEY AND URINARY TRACT
2 13
PATHOLOGY OF THE KIDNEY
Glomerular diseases
Tubular disorders
Interstitial nephritis
Renal tuberculosis
Vascular disorders of the kidney
Renal sinus lipomatosis
Uremia
Renal tumors
Cysts and malformations
GLOMERULAR DISEASES
Glomerulonephritis with nephritic syndrome

Glomerulonephritis with nephrotic syndrome
Chronic glomerulonephritis
Secondary glomerulonephritis
Glomerulopathy
• nephritic syndrome
- albuminuria + hematuria ± hypertension
• nephrotic syndrome
- albuminuria + hypoalbuminemia + edema + hypercholesterolemia
Glomerulonephritis with nephritic syndrome
Acute, endocapillary (post-streptococcal) glomerulonephritis

Mesangioproliferative glomerulonephritis
Rapidly progressive (crescentic) glomerulonephritis
1. Acute, endocapillary (post-streptococcal) glomerulonephritis

Etiology:
- streptococcal infections (Lancefield group A �-hemolytic streptococcus)
- other infections (viruses, pneumococci, staphylococci, toxoplasmosis, etc.)
- most commonly occurs in children and young patients
214
Pathogenesis: subepithelial immune complex (IgG) deposition (between the
epithelial cells of the Bowman's capsule and the basement membrane that lines the
glomerular capillaries)
Microscopic view:
- diffuse glomerular enlargement and neutrophilic infiltrate
- swollen endothelial cells and luminal narrowing of the glomerular capillaries
Evolution: healing or transformation into mesangioproliferative glomerulonephritis
Clinical features:
- fever and nausea, most commonly 7-14 days after a pharyngitis
- nephritic syndrome
- high anti-streptolysin O (ASLO) titre
2. Mesangioproliferative glomerulonephritis
Etiology:
- prolonged acute endocapillary glomerulonephritis or
- IgA nephropathy (Berger's disease), which usually occurs after respiratory
infections, enteritis or hepatic cirrhosis
Pathogenesis: mesangial lgG or IgA immune complex deposition
Microscopic view:
- mesangial enlargement, mesangial cell proliferation
Evolution:
- healing or renal failure (Berger's disease)
Clinical features: nephritic syndrome
3. Rapidly progressive (crescentic) glomerulonephritis
Etiology:
- primary disease: severe acute endocapillary or IgA glomerulonephritis
- secondary disease: Wegener granulomatosis, Goodpasture syndrome, etc.
- mainly affects young males
Pathogenesis: subepithelial immune complex deposition (anti GBM = glomerular
basement membrane)
Macroscopic view: enlarged kidneys with spotted surface (small hemorrhages)
Microscopic view:
- crescentic proliferation of the parietal cells lining Bowman' s capsule which
compress the glomerular capillaries
- without treatment - renal failure - death in several months
Clinical features:
- nephritic syndrome
- ANCA (antineutrophil cytoplasmic antibody) in serum - 85% of the cases
215
Glomerulonephritis with nephrotic syndrome
Minimal change glomerulonephritis

Glomerulonephritis with focal glomerulosclerosis
Membranous glomerulonephritis
Membranoproliferative (Mesangiocapillary) glomerulonephritis
1. Minimal change glomerulonephritis

Etiology:
- primary disease or caused by drug sensitivity or Hodgkin's lymphoma
- mainly affects boys younger than five years old
Macroscopic view:
- enlarged yellow kidney (fatty kidney)
Microscopic view:
- normal glomeruli or minimal mesangial cell proliferation
- fatty changes of the tubular epithelium ('lipoid nephrosis')
Electron microscopic view:
- fusion of podocyte foot processes
- minimal proliferation of the mesangial cells
Evolution:
- healing (treatment with steroids) or transformation into focal glomerulosclerosis
Clinical features:
- nephrotic syndrome or only recurrent albuminuria
2. Glomerulonephritis with focal glomerulosclerosis
Etiology: - primary disease
- secondary disease: HIV infection
Hodgkin's lymphoma
heroin consumption
transplanted kidney
- mainly occurs in males; afected age group between 1 1 -40 years
Pathogenesis:
- glomerular IgM and C3 immune complex deposits
Microscopic view:
- focal glomerulosclerosis, glomerular hyalinization and tubular lesions
Electron microscopic view:
- fusion of podocyte foot processes
Evolution:
- not responding to steroids, unfavourable prognosis
Clinical features:
- nephrotic syndrome
216
3. Membranous glomerulonephritis
Etiology:
- primary disease, mainly in adults
- secondary disease: infections (HBV, syphilis, etc.)
drugs (e.g. penicillin), heroin
paraneoplastic disease: lung carcinomas, melanomas
Systemic lupus erythematosus
Pathogenesis:
- subepithelial immune complex (lgG) deposition
Microscopic view:
- subepithelial immune complexes - spike-like aspect of the basement membrane
- thickening of the basement membrane (in late stages)
- without cellular proliferation ! ! !
Evolution:
- unfavourable prognosis in primary disease
Cfinical features:
- nephrotic syndrome ± hypertension (50% of the cases)
4. Membranoproliferative (Mesangiocapillary) glomerulonephritis (MPGN)
• MPGN type I - caused by immune complexes
- etiology: - primary disease, especially in young females
- secondary disease: infections (HBV, HCV, etc.)
- microscopic view:
- subepithelial immune complexes
- thickened, duplicated basement membrane ('tram-track' appearance)
- proliferation of the mesangial cells
- evolution : unfavourable prognosis
- clinical features: nephrotic syndrome
• MPGN type 2 - dense deposit disease
- etiology: transplanted kidney or idiopathic disease
- pathogenesis: activation of the complement system (C3)
- microscopic view:
- thickening of the basement membrane and proliferation of the rnesangial ce11s
- lack of immune complexes
- electron microscopic view: dense lipid deposits (lipoproteins)
- clinical features: nephrotic syndrome
217
Chronic glomerulonephritis
Definition: prolonged glomerular inflammation, as a result of the following types

of glomerulonephritis: - mesangioproliferative glomerulonephritis
- glomerulonephritis with focal glomerulosclerosis
- membranous glomerulonephritis
- membranoproliferative glomerulonephritis
Macroscopic view:
- both kidneys are small, with granular surface
Microscopic view:
- progressive sclerosis and hyalinization of the glomeruli
- tubular atrophy, destruction of some tubules and dilatation of the remnant tubules
- interstitial fibrosis
- chronic renal failure
- hypertension
- uremia.
Secondary glomerulonephritis
Definition: glomerulonephritis associated with the following systemic disorders:

• Systemic lupus erythematosus
- pathogenesis: type III hypersensitivity reaction
- morphology: membranous or chronic glomerulonephritis
• Goodpasture syndrome
- crescentic glomerulonephritis, pulmonary hemorrhages and hemosiderosis
- idiopathic disease
• Polyarteritis nodosa
- necrotizing arteritis involving small and medium-sized arteries in adults,
including the kidney (see 'Arteritis')
- morphology: lesions of the glomerular capillaries
- consequences, complications: hematuria, renal infarcts, etc.
• Wegener's granulomatosis
- immune necrotizing arteritis which occurs especially in the upper respiratory tract
but also affects the lungs, kidneys and skin (see 'Arteritis')
- morphology: crescentic glomerulonephritis.
218
Bowman's capsule
endothelial
Bowman's endothelial
capsule cells
Fig. 92. Schematic representation of the normal glomerular structure
Fig. 93. Glomerulonephritis. A. Normal structure of the glomerulus. B. Acute

poststreptococcal glomerulonephritis, with glomerular neutrophilic infiltrate. C-D.
Crescentic glomerulonephritis with spotted aspect of the kidney (C) and crescentic
thickening of the Bowman's capsule
2 19
Glomerulopathy
Definition: disorder of the structure and/or function of glomeruli which occurs

during the following systemic disorders:
• diabetic glomerulopathy
Microscopic view:
- thickening of the capillary wall and mesangial expansion
- focal or diffuse glomerulosclerosis and 'fibrinoid caps' on the surface of the
glomerular capillary (Kimmelstiel-Wilson lesion)
- can be associated with tubulointerstitial lesions
Clinical features: nephrotic syndrome
Complications: chronic renal failure, death
• renal amyloidosis
Etiology: secondary generalized amyloidosis or multiple myeloma
Complications: chronic renal failure, nephrotic syndrome
• A/port's disease
Etiopathogenesis: mutation in the gene encoding collagen IV - damaged
basement membrane - renal failure
- mainly occurs in males, in the second decade of their life; the prognosis is more
favourable in females, survival beyond the fifth decade is possible
Associated lesions: deafness
ocular abnormalities (dislocation of the lens, cataracts)
TUBULAR DISORDERS
Definition: damages of the epithelial cells of the renal tubules or obstruction of the
tubular lumens which can have several causes
Acute hypoxic tubular necrosis ('Shock kidneys')
Definition:
- dystrophy or necrosis of the proximal tubular epithelium due to severe hypoxia
Etiology: shock (cardiovascular collapse)
Macroscopic view: pale, swollen cortex and hyperemic renal pyramids
Microscopic view: dystrophy or necrosis of the proximal tubular epithelium
220
Pathomechanism: hemodynamic disorders -+ systemic hypoperfusion -+ renal
ischemia and hypoxia -+ spasm of the arcuate arteries -+ arterial blood reflux into
the interlobular arteries -+ hypoperfusion of the renal cortex and hyperemia of the
medulla (renal pyramids) -+ dystrophic lesions of the tubular epithelium of
proximal tubules -+ tubular necrosis -+ tubular regeneration or acute renal failure
Causes of death:
- hypokalemia -+ cardiac arrhythmias
- acute renal failure due to tubulonecrosis ± hypoxic glomerular lesions
Clinical features:
- oliguria (< 100 ml urine each 24 hours) ± cardiac arrhythmias.
Toxic and infectious tubular necrosis
Definition: dystrophy and/or necrosis of the tubular epithelium due to a toxic or

infectious process
Etiology:
- heavy metals (mercury, arsenic, chromium, bismuth, etc.)
- organic solvents (carbon tetrachloride, chloroform)
- diethylene glycol (antifreeze fluid), dioxane
- drugs: antibiotics, cytotoxic/non-steroidal anti-inflammatory drugs
mercurial diuretics, anaesthetics, radiographic contrast substances
- pesticides
- septicemia, pyemia
Macroscopic view: swollen pale kidneys
Microscopic view:
- dystrophy of the proximal tubular epithelium (granular, hydropic or vacuolar)
- necrosis of the proximal tubular epithelium and dystrophic calcifications
Evolution: acute renal failure -+ healing with tubular regeneration or death
Obstructive tubular lesions
Definition: acute obstruction of the renal tubules

Etiology: - hemoglobinuria (hemolysis), myoglobinuria (crush injury)
- bilirubinuria (hemolysis, hepatocellular failure)
- paraproteinuria (multiple myeloma: Bence-Jones paraproteins)
- urate crystals (primary or secondary gout)
- oxalate (diethylene glycol ingestion)
Microscopic view: tubular obstruction and secondary epithelial dystrophy or
necrosis (in severe forms).
221
Other tubular disorders
Storage tubulopathy
Definition: disorders of tubular epithelium due to intracellular accumulation of
various substances:
• hyaline - during nephrotic syndrome
• lipids - in hyperlipemia or nephrotic syndrome (membranoproliferative
glomerulonephritis with dense deposits)
• glucose - intravenous administration of glucose
• glycogen - diabetes mellitus, pancreatic tumors, von Gierke's disease
Congenital tubulopathy
• Fanconi syndrome (defective tubular reabsorption)
• Lightwood-Albright syndrome (tubular acidosis)
Fig. 94. Renal tubular disorders. A-B. 'Shock kidney' with pale cortex and
hyperemic pyramids (A), with proximal tubulonecrosis (B); C-D. Tubular lesions
due to intraluminal accumulation of Hemoglobin (C) and bilirubin (D)
222
INTERSTITIAL NEPHRITIS
Definition: inflammation of the renal interstitium which can or cannot be

associated with tubular and/or glomerular disorders
Infective interstitial nephritis
Pyelonephritis = interstitial nephritis associated with the inflammation of the renal

pelvis and calyces
Acute pyelonephritis
- one or both kidneys can be involved
Etiology:
- ascending infection with E. Coli (50% of the cases), Klebsiella, Proteus, etc.
- predisposing factors: urinary stasis
Macroscopic view:
- renal congestion
- small abscesses in the renal cortex and yellowish striae in the pyramids
Microscopic view:
- polymorphic interstitial infiltrate and abscesses
- neutrophils in the tubules
- inflammatory tubular destruction
Complications:
- pyonephrosis (dilated calyces and renal pelvis filled with pus)
- renal papillary necrosis, in patients with diabetes mellitus
- perinephric abscesses
- septicemia
Clinical features:
- dysuria (painful micturition)
- pyuria (pus in the urine), bacteriuria (bacteria in the urine),
Chronic pyelonephritis
- chronic inflammation of the renal interstitium that can produce renal parenchymal
scarring and can lead to chronic renal failure if both kidneys are affected
Etiology:
- untreated or repeated acute pyelonephritis
- chronic urinary stasis
Macroscopic view:
- atrophk kidney with irregular surface
Microscopic view:
- expanded fibrotic areas, lymphocytic infiltrate, glomerular sclerosis
223
- atrophic or dilated tubules, filled with eosinophilic colloid-like material which
resembles thyroid follicles (thyroidisation)
Clinical features: - bacteriuria, leukocytosis (elevated serum leukocytes level)
- fever, chronic renal failure
- secondary renal hypertension
Non-infective (aseptic) interstitial nephritis
Acute aseptic interstitial nephritis

Etiology: drugs (penicillin, sulphonamides, anticoagulant drugs, etc.)
viruses (e.g. infective mononucleosis - EBV), vaccines or
can be associated with autoimmune and allergic disorders
Morphology: - interstitial edema
- inflammatory infiltrate (lymphocytes+plasma cells+eosinophils)
- secondary tubular damage
Chronic aseptic interstitial nephritis
Etiology: drugs (e.g. paracetamol, aspirine), obstructive tubular disorders
Morphology:
- renal atrophy
- interstitial inflammatory infiltrate, fibrosis and tubular atrophy
Obstructive nephropathy
Etiology:
- renal or extrarenal disorders that can lead to chronic urinary stasis: renal stones,
congenital malformations/tumors of the urinary tract, prostatic hyperplasia/tumors,
retroperitoneal tumors, etc.
Consequences:
• hydronephrosis
- fibrosis and dilatation of the renal pelvis and calyces which are filled with a clear
serous fluid and are associated with the progressive atrophy of the renal
parenchyma
RENAL TUBERCULOSIS
- in case of secondary tuberculosis, the most commonly affected organs are the
lungs, kidneys and genital organs
• milliary tuberculosis
- affect the kidneys during systemic spread (small granulomas on the renal surface)
• solitary renal tuberculosis
- pathomecanism: reactivation of the renal dormant primary isolated foci
224
- morphology: cheese-like, caseous masses in the renal medulla or an ulcerated
nodule which communicates with the calyceal system; in severe forms, tuberculous
pyonephrosis can be associated with the replacement of renal parenchyma by
caseous material (necrosis)
- clinical features: sterile pyuria and Mycobacterium tuberculosis in the urine.
Fig. 95. Pyelonephritis. A, B. Acute pyelonephritis with pyoneph:rosis;

C-D. Chronic pyelonephritis with thyroidisation of the renal tubules
Fig. 96. Renal tuberculosis. A, B. Milliary tuberculosis;

C. Tuberculous pyonephrosis
225
VASCULAR DISORDERS OF THE KIDNEY
Arterial and arteriolar damages
Renal arteriosclerosis
Definition: atherosclerosis of the small and medium-sized renal arteries, with no
clinical significance
Macroscopic view: medium-sized depressed areas on the renal surface
Microscopic view: atherosclerosis and segmental interstitial fibrosis
Renal arteriolosclerosis
Definition: hyalinization of the small renal arteries and afferent arterioles
Etiology: benign hypertension
Macroscopic view: shrunken kidneys with granular surface
Microscopic view: - glomerular hyalinization
Renal arteriolonecrosis
Definition: necrosis of the afferent arterioles and glomeruli, which can lead to
decreased filtration rate, renal failure and uremia
Etiology: malignant hypertension
Macroscopic view: spotted enlarged kidneys with necrotic areas
Microscopic view: - fibrinoid necrosis of the afferent arterioles and glomeruli
Renal infarction
Definition: obstruction of one of the branches of the renal artery
Etiology: thromboembolism
Morphology:
- acute white infarct - pale bulging area defined by a hyperemic narrow rim
- organizing infarct - scar tissue, depressed area (see 'General Pathology')
226
Lesions produced by microthrombosis
Pregnancy-related lesions
Definition: morpho-functional renal disorders during pregnancy
• pre-eclampsia: hypertension + proteinuria + edema
• eclampsia: hypertension+albuminuria+clinical fits
Microscopic view: swollen endothelial and mesangial cells
Evolution: regression after treatment of hypertension and/or after pregnancy
Diffuse cortical necrosis
Definition: bilateral hemorrhages and/or necrotic areas on the renal surface
Etiology: Disseminated Intravascular Coagulation (DIC), severe shock
Clinical features: anuria, uremia, renal failure
Thrombotic microangiopathy
Definition: primary or secondary diseases characterized by the presence of thrombi

in the capillaries, arterioles and small arteries of different organs, including kidney
Etiology: - toxins (e.g. verotoxin - E.coli)
- drugs (e.g. cyclosporine A, estrogens)
- bacteria (Streptococcus pneumoniae, Salmonella typhi, etc.)
- viruses (e.g. HIV)
- hereditary deficiency of von Willebrand factor (VIIlth clotting factor)
- iatrogenic: pregnancy-related, bone marrow transplantation
- immune disorders, tumors
Clinicopathologic features:
• hemolytic uremic syndrome:
- primary disease of infancy and childhood or secondary disease (E. coli)
- acute renal failure + hemolytic anemia + thrombocytopenia ± bloody diarrhea
• thrombotic thrombocytopenic purpura (Moschkowicz syndrome)
- same characteristics except renal failure
Evolution: if untreated, high rate of mortality
RENAL SINUS LIPOMATOSIS

Definition: progressive increase of fat content at the level of the renal sinus
Etiology:
- physiological aging
- obesity, steroids
- replacement of renal parenchyma in case of renal atrophy/destructive processes
Consequences: without clinical impact
227
Fig. 97. Vascular disorders of the kidney. A. Small minute hemorrhages in a
patient with DIC; B. Diffuse cortical necrosis in a patient with DIC;
C. Acute white renal infarction defined by a hyperemic narrow rim;
D. Renal organizing infarct - depressed fibrotic scar
228
Fig. 98. Renal sinus lipomatosis (A) and vascular disorders of the kidney (B-D).
B. Renal arteriosclerosis - the arrows show depressed areas; C-D. Renal
arteriolosclerosis - granular surface (C) and glomerular hyalinization (D)
UREMIA
Etiology: acute or chronic renal failure

Associated lesions:
- cerebral edema, pharyngitis, pulmonary edema
- fibrinous inflammations: pericarditis, pleuritis, gastritis, colitis
- anemia and minute hemorrhages
229
RENAL TUMORS
1 . Benign tumors
• adenoma - tubular or papillary architecture

• oncocytoma - large brown tumor with eosinophilic granular cells
- usually without clinical symptoms
• angiomyolipoma
• hamartomatousfibroma - usually localized in the renal pyramids
2. Malignant tumors
Renal cell carcinoma

- 90% of all renal malignant tumors, in adults
Macroscopic view: yellow tumor mass, usually in the upper part of the kidney
Microscopic view:
• classical form (Grawitz tumor, clear cell carcinoma)
- nests of tumor cells with clear cytoplasm
• other types: papillary carcinoma, chromophobe carcinoma
Paraneoplastic syndromes:
- polycythemia (erythropoietin secretion)
- hypercalcemia (produces parathyroid hormone-related peptide)
- hypertension (renin secretion)
Outcome: unfavourable prognosis
distant metastases - shortly or many years after surgical removal
Carcinoma of the renal pelvis
Risk factors: renal stones, pyonephrosis, chronic urinary stasis or pyelonephritis
Macroscopic view: papillary or flat tumor which invades the renal pelvis
Microscopic types: urothelial carcinoma (transitional cell carcinoma),
adenocarcinoma (rarely), squamous cell carcinoma, undifferentiated carcinoma
Prognosis: unfavourable, usually diagnosed in advanced stages
Nephroblastoma (Wilms' tumor)
- the most common childhood kidney tumor which may be associated with other
genetic abnormalities; good prognosis in early stages
Sarcomas - rarely
3. Metastases (Secondary tumors)
- lung carcinomas, melanomas or direct spread from the surrounding organs
230
KIDNEY MALFORMATIONS AND CYSTS
Renal cysts
Simple retention cyst: no clinical significance
Congenital solitary cyst: - 5-10 cm in diameter, serous content

- differential diagnosis: renal tumor
Polycystic kidney disease

• autosomal dominant (adult) type
- morphology: enlarged kidney with several serous cystic spaces
- clinical features: back pain, hematuria or asymptomatic patients
hypertension in the adult life
- complications: brain hemorrhage, uremia
• autosomal recessive (childhood) type
- occurs more rarely but causes renal failure in newborns
- incompatible with life
- morphology: cystic dilatation of the collecting ducts
Renal malformations
• agenesis - lack of one or both kidneys and their embryological structures

• aplasia - lack of development of one or both kidneys
• hypoplasia - abnormally small kidneys
- normal or smaller nephrons
- the renal artery is small in size and length
• dystopia (ectopic kidneys) - abnormal location (e.g. in the pelvis)
• floating kidney - renal fixation disorder
• fused kidney:
- horseshoe kidney (ren arcuatus) - fusion of the lower (or upper) poles
- duplex kidney (ren duplex) - kidney with two separate pelvicalyceal systems
- ren sigmoideum - S-shaped fusion of both kidneys
- disc-like kidney (ren placentatus) - complete fusion of the kidneys forming a
disk-like mass with two ureters
231
Fig. 99. Horseshoe kidney (left) and polycystic kidney - adult type (right)
Fig. 1 00. Kidney tumors. A-B. Grawitz tumor; C. Urothelial carcinoma with
papillary structure; D. Renal metastases from a lung carcinoma
232
PATHOLOGY OF THE URINARY TRACT
DILATATION OF THE URINARY TRACT
• hydroureter
- dilatation of one or both ureters filled with clear serous fluid
• hydronephrosis
- dilatation of renal pelvis and calyces and atrophy of the renal parenchyma
Etiology:
- obstruction of the pelviureteric junction : stones, tumors, tuberculosis, etc.
- obstruction of the middle part of the ureter: stones, tumors, cystic ureteritis, etc.
- obstruction of the lower ureter: stones
tumors - ureters, urinary bladder, uterine cervix
lymph node metastases
- obstruction below the urinary bladder: urethral stricture/tumors
prostatic hyperplasia/tumors
urethritis, prostatitis, etc.
URINARY CALCULI (STONES)
Localization: anywhere in the urinary tract but most commonly in the renal pelvis
Complications:
- obstruction of the urinary tract - hematuria, hydroureter, hydronephrosis
- pyelonephritis
- malignant transformation - carcinoma of the ureter or renal pelvis
Clinical features: renal colic, dull ache in the loins, urinary tract infections
INFLAMMATION OF THE URINARY TRACT
Acute inflammation
- predisposing factors: female gender, stones, catheterisation, urinary stasis
• acute urethritis/cystitis
- etiology: usually ascending infections
- morphologic types: catarrhal-purulent, fibrinous or hemorrhagic inflammation
- complications: pyelonephritis (frequently), septicemia (rarely)
Chronic inflammation
- etiology: repeated acute inflammations, stones, repeated trauma
radiotherapy, cytotoxic drugs into the urinary bladder, etc.
- complications: squamous cell metaplasia or glandular metaplasia - carcinoma
233
- Candida - after antibiotherapy, in immunosupressed patients
- tuberculous cystitis.
TUMORS OF THE URINARY TRACT
1. Benign tumors
Urothelial papilloma (papillary urothelial neoplasm of low malignant potential)
2. Malignant tumors
Transitional cell (urothelial) carcinoma

- localization: urinary bladder > renal pelvis > ureter > urethra
- risk factors: smoking (50% of the cases), drugs
aromatic amines (dye manufacturing)
rubber manufacturing industry, polycyclic aromatic hydrocarbons
genetic factors
Macroscopic view: usually multiple tumors
superficial papillary tumors - 80% of the cases
invasive solid tumors - (18%)
ulcerated tumors (2%)
Microscopic view: from well to poorly differentiated tumors (G1, G2, G3)
Metastastases in: lymph nodes (pelvis, retroperitoneum), bones, lung, etc.
Prognostic factors:
- tumor stage: pTl - invasion of the subepithelial connective tissue
pT2 - invasion of the muscularis propria
pT3 - invasion of the perivesical tissue
pT4 - invasion of other surrounding organs: prostate, uterus, etc.
- morphology: papillary tumors have a more favourable prognosis
Clinical features: - hematuria, painful micturition (dysuria)
- increased frequency of micturition
Squamous cell carcinoma
- risk factors: chronic inflammations ----* squamous metaplasia ----* carcinoma
Adenocarcinoma - rarely.
3. Metastases
- direct spread from prostate, uterine or rectal carcinomas
234
Fig. 101. Inflammations and tumors of the urinary tract. A-C. Urinary stones in the
renal pelvis (A) and calyces (B), coraliform aspect (C). D-F. Hydrometer (D) and
hydronephrosis with atrophy of the renal parenchyma. G-H. Hemorrhagic cystitis.
235
PATHOLOGY OF THE FEMALE GENITAL
SYSTEM, PREGNANCY AND BREAST
236
PATHOLOGY OF THE FEMALE GENITAL
SYSTEM
Pathology of the ovary

Pathology of the fallopian tube
Pathology of the uterine cervix and corpus
Pathology of the vagina
Pathology of the vulva
PATHOLOGY OF THE OVARY
NONTUMOR LESIONS
Vascular disorders
- rupture of graafian follicles or the corpus luteum -t ovarian hemorrhages
- ovarian torsion -t hemorrhagic infarction, acute abdomen
Ovarian edema
- ovarian enlargement due to stromal accumulation of transudate
- etiology: ovarian torsion (angiolymphatic obstruction) or other unknown causes
- consequences: abdominal pain, menstrual disorders, etc.
Atrophy of the ovaries
- etiology: senile involution, radiotherapy, etc.
Ovarian endometriosis
- ectopic endometrial nests in the ovary, often bilateral
- complications: formation of cysts, adhesions, infertility
malignant transformation (1 %)
OVARIAN INFLAMMATIONS (OOPHORITIS)
Acute oophoritis
- purulent inflammation (in most of cases), usually associated with salpingitis
- etiology: ascending bacterial infections or fistulas (e.g. appendicitis)
- complications: periovarian inflammation
tubo-ovarian abscess
peritonitis
- clinical features: pelvic pain, fever, vaginal discharge
237
Chronic oophoritis
-etiology: ascending infection or recurrent acute oophoritis
- complications:
- hydrosalpinx (dilated fallopian tubes, filled with clear serous fluid)
- pyosalpinx (pus in the dilated fallopian tubes)
- periovarian adhesions
- tubo-ovarian cyst
- infertility (in case of bilateral oophoritis)
NON-NEOPLASTIC CYSTS
Solitaryfollicular cyst (cysticfollicle)

- cystic dilatation of the ovarian follicles ± hyperestrogenism
Luteal cyst (corpus luteum cyst)
- ovarian cyst lined by luteinized granulosa cells
Polycystic ovarian syndrome (Stein-Leventhal syndrome)
- multiple follicular cysts, usually associated with hyperandrogenism
- associated disorders: oligomenorrhea (light and irregular menstrual cycle)
anovulation, obesity, hirsutism, virilism, etc.
Endometriotic cyst ('chocolate cyst' of the ovary)
- blood-filed cysts due to endometriosis
Serous epithelial inclusion cysts
- cystic dilatations lined by Mlillerian epithelium
Complications of non-neoplastic cysts: ovarian torsion
OVARIAN TUMORS
Classification according to WHO (World Health Organization)
Epithelial tumors (80% of the cases)

Benign: Serous/mucinous cystadenoma
Benign endometrioid cystadenoma
Benign Brenner (transitional cell) tumor
Benign clear cell tumors
Borderline: Serous/mucinous borderline tumor
Endometrioid borderline tumor
Malignant: Serous/mucinous cystadenocarcinoma
Endometrioid adenocarcinoma
Transitional cell carcinoma
Others: clear cell cystadenocarcinoma, carcinosarcoma, etc.
238
Sex cord-stromal tumors (5-10%)
Granulosa cell tumor group
Thecoma-fibroma group
Sertoli-Leydig cell tumor group (androblastomas)
Steroid-cell tumors
Germ cell tumors (10-20%)
Mature teratoma (Dermoid cyst)
Immature teratoma
Dysgerminoma (ovarian seminoma)
Choriocarcinoma
Yolk sac tumor
Mixed germ cells tumor
Other tumors (<5%)
Lymphomas
Carcinoid tumors
Epithelial tumors
1. Benign tumors
Serouslmucinous cystadenoma
- usually occurs in women between 20-45 years of age
Macroscopic view:
- uni- or multilocular smooth-walled cyst with or without papillary projections
- serous/mucinous content
- uni- (mucinous type) or bilateral (serous type) tumor
- usually without necrosis
Microscopic view: papillary adenoma with cystic dilatation
the lining epithelium is mucinous or serous-type
Complications: rupture, torsion, superinfection, malignant transformation
Brenner tumor (Benign transitional cell tumor)
Macroscopic view: solid tumors which can contain cystic areas
1 0-20% of them are bilateral
Microscopic view: sheets of transitional cells and microcysts
- 1 % of the cases can present malignant transformation
Benign endometrioid cystadenoma
- usually unilateral tumors that arise from ovarian endometrioid islets
239
2. Borderline tumors
Definition: atypical cells proliferation without crossing the basement membrane

Serous/mucinous borderline tumors
- 50-60% of the cases are serous and 40-50% mucinous type
Macroscopic view:
- cystic tumor with mucin- or serum-filled cavities
- intracystic papi,llary projections and/or surface papillary excrescences
- uni- or bilateral tumor (40%)
Microscopic view:
• serous borderline tumor
- papillae lined with stratified cuboidal or columnar epithelium with nuclear atypia
• mucinous borderline tumor
- papillae lined with stratified intestinal-type epithelium with nuclear atypia
Complications:
- non-invasive or invasive peritoneal implants (pseudomyxoma peritonei)
- invasive implants -➔ metastazing tumor
- cystadenocarcinoma
Endometrioid borderline tumor
- proliferation of atypical endometrium-type glands, without stromal invasion
3. Malignant epithelial tumors
Protective factors: oral contraceptive pills and pregnancy

Risk factors:
- BRCA l /BRCA2 gene mutations within a family
- MMR genes mutations + microsatellite instability (Lynch syndrome) -
endometrioid ovarian carcinoma + colorectal cancer
Clinical features: back/abdominal pain, urinary symptoms, weight loss, ascites
palpation or ultrasound examination : abdominal mass
paraneoplastic syndrome - rare
Prognosis: most cases diagnosed in an advanced stage
Metastases: usually lymph nodes, peritoneal cavity, lung, liver and pleura
Serous/mucinous cystadenocarcinoma
- primary tumor or malignant transformation of a cystadenoma/borderline tumor
- 65% of serous respectively 10% of mucinous cystadenocarcinomas are bilateral
- occurs mainly in the seventh decade
Macroscopic view:
- solid or cystic tumors, with hemorrhages and necrosis, on the cut surface
240
Microscopic view:
- glandular, papillary or solid architecture
Prognostic factors:
1. tumor grade (GI , G2, G3)
2. tumor stage (FIGO/pTNM ) - FIGO = International Federation of Gynecology and Obstetrics
- stage I (pT I): tumor limited to ovaries - 5 year survival rate: 90%
- stage II (pT2): invasion of other pelvic structures ± ascites - 5 year survival: 60%
- stage III (pT3): peritoneal metastases outside the pelvis - 5 year survival: 30%
- stage IV (pM I): distant metastases (liver, bones, etc.) - 5 year survival: 10%
Endometrioid adenocarcinoma
- malignant variant of the benign endometrioid cystadenoma
- 15-20% of the cases are bilateral and can be associated with the endometrioid
carcinoma of the endometrium
Macroscopic view: solid tumor mass, uni- or bilateral
Microscopic view:
- similar to the endometrioid carcinoma of the uterine corpus
- papillae + atypical glands ± squamous metaplasia
3. Secondary tumors (metastases)
- gastric signet ring cell carcinoma

----+ bilateral ovarian metastases (Krukenberg's tumor)
- appendiceal, colorectal carcinoma
- breast carcinoma
- cervical cancer
- pancreatic carcinoma
- other tumors: lung cancer, lymphoma, melanoma, etc.
241
Fig. 1 02. Ovarian bilateral solid carcinoma with perit@neal carcinomatosis, in a
23-year old HIV-infected woman. The arrows show the ovaries
Fig. 103. Ovarian tumors. A-B. Serous borderline tumor with papillary
excrescences; C. Benign tumor of the right ovary, with ovarian torsion
242
Ovarian sex-cord/stromal tumors
Definition: tumors that arise from the ovarian stromal and sex-cord cells
surrounding the ovarian follicles; most of them are benign but malignant variant
can also occur
Clinical features:
- the tumor cells secrete estrogen, progesteron or androgen (30% of the cases)
- uterine bleeding, endometrial hyperplasia/adenocarcinoma, hirsutism
Granulosa cell tumor group
Definition: tumors that arise from the granulosa cells of the tertiary mature follicles
- postrnenopausal women are more frequently affected (adult type) but juvenil type
is also common in young patients
Clinicopathological classification:
• adult type (95% of the cases)
- 20% of them are malignant
- secretes estrogen and can recur several years after surgical intervention
- 5-year survival rate 70-90%
• juvenile type (5% of the cases)
- 5% of them are malignant
- 5-year survival rate 90%
Macroscopic view: unilateral tumors with hemorrhages and necrotic areas
Microscopic view: nests and cords of granulosa cells, with grooved nuclei
• adult type
- tumor cells surround a central eosinophilic space (Call-Exner body)
• juvenile type
- hyalinized nodules, rarely Call-Exner bodies
Clinical features: elevated serum inhibin level
Thecoma
Definition: benign tumor which arises usually in postmenopausal women, from the
thecal cells of the tertiary mature follicles; the tumor cells secrete estrogen
Macroscopic view:
- unilateral solid yellow to gray-white tumor with a pale fleshy cut surface
Microscopic view: spindle cells that contain lipids
Fibroma - Meigs syndrome = ovarian fibroma + ascites + hydrothorax
Sertoli-Leydig cell tumor group (androblastomas)
- uncommon ovarian tumors which occur in young women (20-30 years old)
- usually benign unilateral tumors which secrete androgen
- well, moderately or poorly differentiated
- microscopic view: testicular-type structures
243
Germ cell tumors
Definition: benign or malignant tumors which arise from germ cells and mainly
affect children and young females
Teratoma
• mature teratoma
- benign tumor composed of mature, adult-type tissues, derived from all three
germinal layers (ectoderm, endoderm, mesoderm)
- solid (rarely) or cystic tumor (dermoid cyst), usually lined with squamous
epithelium, filled with sebaceous yellow material and hair
• struma ovarii
- a variant of mature teratoma composed of thyroid tissue
- clinical features: asymptomatic or, rarely, hyperthyroidism
• immature teratoma
- potentially malignant tumor composed of immature neural and mesenchymal
tissue; good prognosis after chemotherapy (5-year survival rate: 80%)
Dysgerminoma (ovarian seminoma)
- unilateral ovarian tumor with good prognosis after radiotherapy
- 5 year survival rate: 75-90%
Choriocarcinoma
- rare, highly malignant tumor which secretes human Chorionic Gonadotropin
- differential diagnosis: pregnancy (high levels hCG)
Yolk sac tumor
- malignant tumor, usually diagnosed in advanced stages, with poor prognosis
- secretes alpha-fetoprotein, similarly to hepatocellular carcinomas
Other germ cell tumors:
- embryonal carcinoma, teratocarcinoma - higly malignant tumors
Fig. 104. Dermoid cyst containing teeth
244
PATHOLOGY OF THE FALLOPIAN TUBES
Tubal (ectopic) pregnancy
Definition: pregnancy developing outside the uterus, in the fallopian tubes
Localization: ampulla (80%), isthmus (10%), infundibulum (5%)
Predisposing/actors: chronic salpingitis, endometriosis

congenital malformations of the fallopian tubes
Complications:
• tubal abortion ----+ hematosalpinx
• rupture of the fallopian tubes ----+ hemoperitoneum
Clinical features: acute lower abdominal pain, pelvic pain, vaginal bleeding, etc.
Salpingitis
Definition: inflammation of the fallopian tubes

Etiology: ascending bacterial infection
Predisposing/actors: endometrial infection (e.g. intrauterine device)
Acute salpingitis
- catarrhal or purulent inflammation
- complications: pyosalpinx, tubo-ovarian abscess, peritonitis
Chronic salpingitis
- fibrous or obstructive inflammation
- complications: tubo-ovarian cyst, infertility, ectopic pregnancy, hydro/pyosalpinx
Salpingitis isthmica nodosa
- non-inflammatory nodular thickening of the tubal isthmus
- microscopic view: smooth muscles and glandular hyperplasia
- consequence: i�fertility, ectopic pregnancy
Tuberculous salpingitis
- the fallopian tubes are the most common female genital organs affected by
tuberculosis
- complications: infertility
245
Non-neoplastic cysts
- common lesions which can occur during chronic salpingitis
- tubo-ovarian cyst, paraovarian/paratubal cysts
- with no clinical impact
Tumors of the fallopian tubes

• benign tumors:
- metaplastic papillary tumor, adenomatoid tumor (mesothelioma), etc.
• premalignant (metaplastic) lesions:
- decidual/mucinous/transitional/squamous metaplasia
• malignant tumors:
- serous/mucinous adenocarcinoma - highly malignant tumor, which can present
peritoneal/lymphatic spread; familial BRCAl gene mutations can be determined
Fig. 105. Hydrosalpinx (A) and paraovarian cyst (B)
246
PATHOLOGY OF THE UTERINE CERVIX
Cervicitis
Definition: inflammation of the uterine cervix (endo- and exocervicitis)
Acute cervicitis
- morphology: catarrhal or purulent inflammation
- etiology: infective cervicitis - bacteria, Chlamydia, Mycoplasma, Herpes-virus
non-infective cervicitis - trauma, irritative substances
Chronic cervicitis
- consequences:
- squamous metaplasia (endocervix) - dysplasia - squamous cell carcinoma
- retention Naboth's cysts
- glandular hyperplasia - can be the consequence of contraceptives or pregnancy
• exocervicitis
- inflammation of the exocervix (vaginal part of the cervix)
- macroscopic view: red erosions with a concentric ring-like pattern, around the
external orifice of the cervical canal
HPV (Human papilloma viruses) related epithelial lesions
- high-oncogenic potential: HPV types 16, 18, 45, 56, 58

- intennediary oncogenic potential: HPV types 31, 33, 35, 39, 51
- low oncogenic potential: HPV types 6, 11, 42, 43, 44, 53
1. Koilocytosis
- large cells with vacuolated cytoplasm and pyknotic nuclei in the cervical
epithelium, observed in Pap smears or cervical biopsies
2. Metaplasia
- the endocervical columnar epithelium is replaced by squamous epithelium
- mainly involves the transformation zone of the cervix
3. Dysplasia
Definition: disorder of cell proliferation and differentiation of the squamous
metaplastic epithelium and/or of the exocervical squamous epithelium
Synonyms: Cervical Intraepithelial neoplasia (CIN)
Squamous intraepithelial lesion (SIL)
247
Morphological classification
• mild dysplasia (CIN I, LGSIL - low grade SIL)
- disorders in the above one-third of the epithelium
• moderate dysplasia (CIN 2, HGSIL = high grade SIL)
- disorders in the above two-third of the epithelium
• severe dysplasia or in situ carcinoma (CIN 3, HGSJL)
- atypical cells occupy the entire thickness of the epithelium
4. Genital warts or codyloma acuminatum

- benign tumors typically located in the vulva, vagina and/or exocervix.
Tumors of the uterine cervix
1. Benign tumors
• endo-cervical polyp
- simple polyp lined by the columnar mucinous epithelium
• condyloma acuminatum - HPV-related disease
• leiomyoma - very rare
2. Malignant tumors
Riskfactors (WHO)
- HPV infections (90% of the cases)
- multiple partners/partner's multiple partners
- poor hygiene
- no male circumcision
- high parity
- oral contraceptives
- smoking
- sexually transmitted diseases
- HIV infections, immunosuppression
- poor nutritional status
Protectivefactors
- monogamy
- proper hygiene
- without smoking/contraceptives
- anti-HPV vaccine, etc.
248
Invasive squamous cell carcinoma
Macroscopic view: exophytic/polypoid or endophytic/infiltrative/ulcerated tumor

Steps of malignization: CIN 3 -+ microinvasive carcinoma -+ invasive carcinoma
• microinvasive carcinoma
- stromal invasion :S 5mm in depth and :S 7 mm in horizontal spread, clinically
undetectable, diagnosed only by microscopy
- treatment: tumor excision without hysterctomy, without radiochemotherapy
• invasive carcinoma
- clinically visible lesion
Tumor stage (FIGO/pTNM)
• stage I (pTl) - tumor limited to cervix - 5 year survival - 80-95%
- IA - stromal invasion :S 3mm in depth and :S 7 mm in horizontal spread
- lymph node metastases < 1 % of the cases
- recurrence - 0.9% of the cases
- 1B - stromal invasion 3-5mm in depth and :S 7 mm in horizontal spread
- lymph node metastases 2% of the cases
- recurrence - 4% of the cases
• stage II (pT2) - 5 year survival rate - 60%
- invasion beyond uterus but not to pelvic wall or to lower third of vagina
• stage III (pT3) - 5 year survival - 30-35%
- invasion of the pelvic wall and/or to lower third of vagina and/or associated with
hydronephrosis or renal failure
• stage I V (pT4/Ml) - 5 year survival rate - 15-20%
- invasion of urinary bladder or rectum (pT4) and/or
- distant metastases (pM l ) - lung, liver, bone, peritoneal spread
- supraclavicular/mediastinal/paraaortic lymph nodes
Complications:
- hemorrhages, superinfection, fistula that opens into the rectum, vagina, bladder
- compression of the surrounding organs
- invasion of the ureters -+ hydronephrosis, pyelonephritis
Other malignant tumors
Adenocarcinoma - highly malignant tumor which occurs mainly in young women

- risk factor: contraceptive pills
Small cell carcinoma - highly malignant
Sarcoma
Other tumors: malignant melanoma, lymphoma, etc.
249
PATHOLOGY OF THE UTERINE CORPUS
Endometrial atrophy
- thinning of the endometrium: senile involution, radiotherapy
Endometrial hyperplasia
Etiology: hyperestrogenism - hormonal disorders (perimenopausal and/or obesity)

drugs (e.g. Tamoxifen)
ovarian sex-cord tumors
Macroscopic view: thickening of the endometrium
Microscopic view:
• simple hyperplasia without atypia
- proliferation of the endometrial glands and stroma, without atypia
• complex hyperplasia without atypia
- hyperplasia of the endometrial glands with reduced stroma ('back to back'
glandular arrangement), without atypia
• simple or complex atypical hyperplasia
- same microscopic features and atypia
Complications:
- complex atypical hyperplasia - endometrial carcinoma (20% of the cases)
Clinicalfeatures: asymptomatic or abnormal uterine bleeding
Treatment: simple/complex hyperplasia without atypia - progestative drugs
complex atypical hyperplasia - hysterectomy
Endometritis
Acute endometritis
- etiology: post-delivery, post-abortion, ascending bacterial infection
- morphology: purulent, necrotizing or hemorrhagic endometritis
- complications: myometritis (inflammation of the myometrium)
salpingitis, peritonitis
septicemia, pyaemia
- clinical features: fever, leukocytosis, vaginal discharge
Chronic endometritis
- etiology: intrauterine contraceptive device, senile atrophy, etc.
- consequence: infertility
Tuberculous endometritis
- direct spread from the fallopian tubes
250
Endometriosis
Definition:
• endometriosis - endometrial islets (glands and stroma) in other genital
(ovary, parametrium, vagina, vulva) or extragenital organs (abdominal wall,
Douglas pouch, urinary bladder, intestines, skin, nasal mucosa, etc.)
• adenomyosis - endometrial islets in the myometrium
Consequences: during menstrual cycle the endometrial islets can present the same
transformations as in the normal endometrium, including bleeding
Complications: cystic dilatations ('chocolate cysts' in ovary), pelvic inflammation,
pelvic pain, infertility, malignant transformation (endometrioid carcinoma)
Tumors of the uterine corpus
1. Benign tumors
Leiomyoma
- myometrial tumor that arises from the smooth muscle fibers and usually occurs
in women of reproductive age (30-40 years)
Classification according to their location
• intramural leiomyoma - confined to the myometrium
• submucosal leiomyoma - protrusion into the uterine cavity
• subserosal leiomyoma - grows towards the serosa
Macroscopic view: solitary or multiple, various sizes, round, white-greyish, well
defined tumors, with solid whorled appearance on cut surface
Microscopic view: fascicles of smooth muscle fibers with few or no mitoses
Complications: abnormal uterine bleeding
compression of the urinary bladder and/or ureters
Particular types:
• intravenous leiomyomatosis without atypia
• adenomyoma - proliferation of smooth muscle fibers and glands
Endometrial polyp
- simple polyp which usually occurs in postmenopausal women
- complications: uterine bleeding, ulceration, superinfection, endometritis, etc.
251
2. Malignant tumors
Endometrial carcinoma
Leiomyosarcoma
Endometrial stromal sarcoma - low or high grade
Carcinosarcoma
Other tumors: adenocarcinoma with squamous metaplasia
adenosquamous carcinoma, etc.
Endometrial carcinoma
- commonly occurs in case of nulliparity and diabetes, obesity or late menopause

Macroscopic view: diffusely infiltrating or exophytic tumor
Clinicopathological classification
• type I - endometrioid adenocarcinoma and its variants (85-90%)
- malignant transformation of atypical endometrial hyperplasia
- commonly occurs in perimenopausal women (< 60 years old)
- can be associated with the polycystic ovary syndrome
- variants: squamous differentiation, villoglandular, secretory and ciliated cell
- 5-year survival rate: 85-90%
• type II - non-endometrioid adenocarcinoma (1 0-1 5% of the cases)
- usually occurs in case of atrophic endometrium, in post-menopausal women
- morphology: high grade serous adenocarcinoma
clear cell, squamous cell or undifferentiated carcinoma (rarely)
- outcome: highly aggressive tumor, unfavourable prognosis compared to type I
- 5-year survival rate: 30-70%
FIGO/pTNM stage
• stage I (pTJ) - tumor confined to corpus uteri (endometrium±myometrium)
that can present endocervical glandular involvement; 5-year survival rate: 75-90%
• stage II (pT2) - invasion of the stromal connective tissue of the cervix
- 5-year survival rate: 70%
• stage III (pT3) - invasion of the salpinx, vagina or parameters
- 5-year surviva rate 1: 45-60%
• stage IV (pT4/MJ) - invasion of the intestinal and/or bladder mucosa (pT4)
± distant metastases (pMl): lung, liver, bone, etc.; 5-year survival rate: 15%
252
Congenital uterine abnormalities
Aplasia - defective or lack of development of the uterus

Hypoplasia - abnormally small uterus
Uterus didelphys (uterus duplex separatus) - double cervix, double uterine corpus,
often double vagina as a result of incomplete fusion of the Mtillerian duct; each
uterus communicates with its ipsilateral fallopian tube
Uterus bicornis bicollis (uterus septus) - double cervix, double uterine corpus with
separated cervical communication but the body walls are partially fused
Uterus bicornis unicollis - double uterine corpus which fuse before opening into a
single cervix
Uterus subseptus - the uterine cavity presents a midline septum
Fig. 106. Benign uterine tumors
253
PATHOLOGY OF THE VAGINA
Hematocolpos - accumulation of blood in the vagina, usually in case of an
imperforate hymen
Vaginal atrophy - senile involution, radiotherapy
Trauma - rupture during delivery or sexual abuse
Other nontumor lesions - endometriosis, mtillerian cyst
- recto-vaginal fistula (e.g. Crohn's disease)
- vaginal prolapse (after delivery)
Vaginal inflammations
Acute vaginits
- bacterial, fungal or parasitic infections: Gardnerella vaginalis, Neisseria
gonorrhea, Candida albicans, Trichomonas vaginalis, etc.
Chronic vaginitis
- etiology: senile atrophy, radiotherapy
Malakoplakia
- chronic inflammation usually caused by Escherichia coli
- mainly occurs in postmenopausal women
- predisposing factors: malfunction of the macrophage activity
- macroscopic view: small plaques or ulcerated areas
- microscopic view: lymphocytes, neutrophils and plasma cells
Michaelis-Gutmann bodies in the macrophages
- clinical features: vaginal bleeding and foul-smelling discharge
- outcome: benign evolution with surgery and/or antibiotics
Tumors of the vagina
Benign tumors
- Mullerian papilloma, fibroma, hemangioma, etc.
Vaginal intraepithelial neoplasia(VAIN 1,2,3)
Malignant tumors
- squamous cell carcinoma , adenocarcinoma - mainly in elderly women
- botryoid sarcoma: mainly in girls, good prognosis after radiotherapy
- rarely (from uterine or ovarian carcinoma)
254
PATHOLOGY OF THE VULVA
Trauma - rupture during delivery
Edema - hypoalbuminemic edema
Varices - pregnancy, pelvic tumors
Inflammations
Infective vulvitis:
- etiology: - bacterial, viral or fungal infections (e.g. Herpes virus, Candida)
- syphilis - primary chancre and secondary syphilis (condyloma latum)
- Calymmatobacterium granulomatosis - granuloma inguinale
- Chlamydia trachomatis - lymphogranuloma venereum
- fungi - dermatophytoses (erythematous plaque with peripheral scale)
Non-infective vulvitis:
- predisposing factors: diabetes, uremia, poor hygiene, psoriasis
intimate lotions (irritant contact dermatitis)
- atopic dermatitis - chronic pruritic dermatitis
Lichen planus
- idiopathic disease characterized by presence of purple pruritic papules on skin
- usually self-limited
Bartholinitis - inflammations of the Bartholin's glands - cyst formation, abscess
Tumors
Benign tumors
- papilloma, condyloma acuminatum (HP V-related), fibroma, lipoma
-papillary hidradenoma - tumor of the vulvar sweat glands
- tumors of the Bartholins glands - adenoma
Premalignant lesions
• leukoplakia - white dysplastic hyperkeratotic patches
• kraurosis vulvae - pruritic leukoplakia + vulvar atrophy
• squamous hyperplasia
• lichen sclerosus - squamous hyperplasia + hyperkeratosis ± dysplasia
• dysplastic nevi
Vulvar intraepitltelial neoplasia (VIN 1,2,3)
- synonyms: intraepithelial squamous cell carcinoma, Bowen's disease
Malignant tumors
• invasive squamous cell carcinoma, adenocarcinoma, melanoma, etc.
255
PATHOLOGY OF PREGNANCY
Spontaneous abortion
Ectopic pregnancy
Toxemia of pregnancy
Pathology of the placenta
Gestational trophoblastic lesions
Delivery complications
Spontaneous abortion
Definition: miscarriage before the 2gth week of intrauterine life

Classification:
• complete abortion
- expulsion of the fetal and placental material during early pregnancy (during the
first 10- 12 weeks of pregnancy)
• incomplete abortion
- incomplete expulsion of the fetus and placental material, in women at their 12th
week of pregnancy
• retained abortion
- spontaneous intrauterine death of fetus, without his natural expulsion
Complications: endometritis, myometritis, septicemia

risk factor for gestational trophoblastic disease
Ectopic pregnancy
- ovular implantation in the fallopian tubes, ovary or abdominal cavity

- risk factors: chronic salpingitis (see 'Pathology of the fallopian tubes')
Toxemia in pregnancy
• preeclampsia
- maternal hypertension, albuminuria and edema (nephropathy)
• eclampsia
- maternal hypertension, albuminuria , edema, convulsions ± DIC
256
PATHOLOGY OF THE PLACENTA
Abnormal placentation
Riskfactors: previous curettages or caesarean section scars

uterine malformations or infections
Classification:
• extrachorial placenta/ion
- the chorionic plate (fetal part of placenta) is smaller than the maternal part
(decidua), as a result the newborn can be underweight
• accesory lobe
- no clinical significance
- can be retained in the uterus after delivery ---+ puerperal acute endometritis
• placenta accreta
- partial or complete absence of the decidua ---+ abnormal implantation ---+ the
chorionic villi penetrates directly into the myometrium
- complications: postpartum uterine hemorrhages, retention of placenta
• placenta praevia
- placental implantation in the lower part of the uterine corpus
- complications: premature labour, hemorrhages, amniotic fluid embolism
Placental inflammations
Riskfactors:
- maternal systemic or ascending infections
- TORCH syndrome: Toxoplasmosis, Rubella, CMV, Herpes virus
Other infections: hepatitis viruses, syphilis, etc.
• placentitis, villitis - inflammation of the chorionic villi

• chorioamniotitis - inflammation of the extraplacental (fetal) membranes
- complications: endometritis, myometritis
• funisitis - inflammation of the umbilical cord
Hemorrhages of the placenta
- hemorrhagic infarction of the placenta

- retroplacental hematoma - during delivery
257
GESTATIONAL TROPHOBLASTIC LESIONS
Hydatidiform mole
Definition: abnormally developed placenta, with hydropic enlargement of the the

chorionic villi and elevated serum human Chorionic Gonadotropin (hCG) levels
Classification:
• complete hydatidiform mole (CHM)
- hydropic change of all villi, without fetal tissue
• partial hydatidiform mole (PHM)
- hydropic villi and nonmolar placental tissue
Etiology: - 46XX karyotype (complete mole) or
- triploid 69XXY karyotype (partial mole)
Macroscopic view:
- the chorionic plate is partially/totally replaced by grape-like vesicles
Complications:
- abortion during early pregnancy
- abnormal uterine bleeding
- fetal malformations (in PHM - e.g. syndactyly)
- persistent gestational trophoblastic disease (10% of CHM, rarely in PHM)
- malignant transformation into choriocarcinoma (3% of CHM, rarely in PHM)
Differential diagnosis: normal pregnancy
Invasive hydatidiform mole
- presence of chorionic villi, trophoblastic cells and hemorrhagic cavities in the

myometrium and/or uterine vessels
- complications: uterine rupture
Nonmolar trophoblastic tumors
• choriocarcinoma
- highly malignant trophoblastic tumor which usually occurs in women with a
previous hydatidiform mole (50% of the cases), several weeks or months before -
very sensitive to radiochemotherapy
• placental-site trophoblastic tumor
- usually occurs years after an antecedent normal gestation
- benign or rarely malignant behaviour, resistant to radiochemotherapy
258
Fig. 107. Complete hydatidiform mole with grape-like vesicular structure
COMPLICATIONS DURING DELIVERY
• uterine rupture, uterine atonia, retention of the placenta

• puerperal infection: endometritis, myometritis, septicemia
• DIC (Disseminated Intravascular Coagulation)
- etiology: amniotic fluid embolism
retroplacentar hematoma
retention of the dead fetus in utero
- consequences: disseminated microthrombosis (stage I)
consumption coagulopathy (stage 1 1) - - ► hemorrhages
Causes of death
Maternal death: thromboembolism, pulmonary embolism by amniotic fluid

hemorrhages (uterine hemorrhage )
Fetal death: aspiration of amniotic fluid
hyaline membrane disease (see 'Respiratory distress syndrome')
259
PATHOLOGY OF THE BREAST
Malformations
Inflammations
Fibrocystic breast changes (disease)
Benign epithelial proliferation
Tumors
MALFORMATIONS
Polymastia - supernumerary breast

Polytltelia - extra nipples
Amastia - absence of one or both breasts (uni/bilateral amastia)
Micromastia (ltypoplasia) - underdevelopment of one or both breasts
Inverted nipple - inward turned nipples
INFLAMMATIONS
Acute mastitis (mammary abscess)

Etiology:
- breastfeeding, bacteria (Staphylococcus aureus, Streptococcus pyogenes, etc.)
- the inferior quadrants of the breast are more involved
Complications: lymphatic spread - breast swelling
systemic spread - septicemia
Clinical features: breast pain (mastalgia), swelling and erythema, fever
hard lump near the nipple
Chronic mastitis
Etiology: stasis of mammary secretion in the ducts
Mammary duct ectasia (periductal mastitis)
Definition: - palpable nodule located near the nipple, with unknown etiology, that
usually occurs in the second half of reproductive or postmenopausal life
Morphology:
- dilatation of the main ducts, around the nipples
- the dilated ducts are filled with a green substance which can be discharged
through the nipples (green or bloody nipple discharge)
- inflammatory infiltrate and fibrosis - nipple retraction
Differential diagnosis: breast tumors
Tuberculous mastitis: systemic spread (rare)
Fat necrosis: foreign body granuloma (lipogranuloma) and fibrnsis
260
FIBROCYSTIC BREAST CHANGES (DISEASE)
Definition: non-neoplastic lesion in young or perimenopausal women, which

consists of proliferation and cystic dilatation of the mammary ducts, surrounded by
fibrotic areas
Etiology: hyperestrogenism
Macroscopic view: ill-defined fibro-fatty areas with cystic aspect on the cut surface
Microscopic view:
- proliferation and cystic dilatation of the mamary ducts
- intraductal proliferation of the ductal epithelium, with papillary or cribriform
(sieve-like) pattern
- adenosis (see below)
- apocrine metaplasia
- fibrosis
Clinical features: pain (menstrual mastalgia)
Differential diagnosis: breast tumors
BENIGN EPITHELIAL PROLIFERATION
Usual ductal hyperplasia

- intraductal epithelial proliferation
- it can or cannot be associated with fibrocystic breast disease
- atypical ductal hyperplasia is a premalignant lesion
Sclerosing adenosis
- lobular and ductal proliferation associated with epithelial and myoepithelial
proliferation and fibrosis
- mamography can present calcification
- differential diagnosis: breast tumor
Radial scar
- stellate scarr tissue which contains foci of the intraductal epithelial proliferation
- differential diagnosis: breast tumor
Gynaecomastia
- definition: non-neoplastic fibroadenomatous hyperplasia of the male breast
- etiology: hyperestrogenism - liver cirrhosis, hyperthyroidism
- tumors: adrenal glands, testis, etc.
- macroscopic view: enlargement of the male breast or a well-defined lump near
the nipple, usually unilateral
- microscopic view: dilated ducts
epithelial proliferation
swollen myxoid or hyalinized stroma.
261
TUMORS
1 . Benign tumors
Fibroadenoma
- most common benign tumor in young women
Macroscopic view: well defined nodule, usually located in the external superior
quadrant of the breast, mobile on palpation, with lobulated aspect on cut surface
Microscopic view: proliferation of ducts and connective fibers
• pericanalicular fibroadenoma
- proliferation of stromal cells around the ducts in a circumferential pattern
• intracanalicular fibroadenoma
- compression of the ducts into clefts by the proliferating stromal cells
Pltyllodes tumor
- a larger variant of fibroadenoma, which shows a laminated structure on cut
surface and can present malignant transformation (phyllodes sarcoma)
Adenoma
- usually nipple adenomas, which can produce skin ulceration
Intraductal papilloma
- middle-aged women are more affected
• central papilloma
- a large elongated solitary tumor, located around the nipple, with extension along
the main ducts; under microscope, papillary proliferation in a dilated duct
• peripheral papilloma
- usually multiple papilloma (papillomatosis), sometimes bilateral
- usually a microscopic finding
Clinical features: nipple discharge in case of central papilloma
Evolution: solitary papilloma does not present malignant transformation
peripheral papillomatosis can lead to malignant transformation
Mesencliymal tumors
a) lipoma
b) hemangioma
c) leiomyoma
d) myofibroblastoma
262
2. Malignant tumors
Epithelial tumors - Breast carcinoma

Other tumors: sarcomas, lymphomas, etc.
2.1.Breast carcinoma
Risk factors: first pregnancy in older women

obesity, radiation
genetic factors (mutations in BRCA1/BRCA2 genes)
Localization: 40-50% of the cases - upper-outer quadrant
20-25% of the cases - around the nipple (central location)
1 0% of the cases - upper-inner quadrant
5-10% of the cases - lower quadrants
2.1.1. In situ (non-invasive) carcinomas
Ductal carcinoma in situ - DCIS (95% of non-invasive carcinomas)

- usually a solitary lesion which occurs in post-menopausal women
Macroscopic view: no lesion but on mammography can present calcifications
Microscopic view: tumor proliferation confined to the ducts
papillary, solid, cribriform (slit-like) pattern or
comedo-carcinoma (central necrosis)
Evolution: can transform into invasive ductal carcinoma
Paget's disease of the nipple

- a particular form of ductal carcinoma in situ, usually located around the nipple
- the tumor cells (Pagefs cells) can invade the epidermis � erosions of the nipples
Lobular carcinoma in situ - LCIS (5% of the non-invasive carcinomas)

- occurs in younger females and can be bilateral and/or multifocal
Macroscopic view: no lesion
Microscopic view: tumor proliferation confined to the acini
Evolution: can transform into invasive lobular carcinoma
263
2.1.2. Invasive breast carcinoma
Clinical features: firm, immobile nodules

the nipple can be retracted
the skin can have an 'orange aspect' ('peau d'orange')
Macroscopic view:
• scirrhous carcinoma - 'scar-like' aspect on cut surface
• medullary carcinoma - 'brain-like' aspect on cut surface
• mucinous carcinoma - 'jelly-like' aspect on cut surface
• inflammatory carcinoma
Invasive ductal carcinoma (80% of the cases)

Macroscopic view: usually scirrhous carcinoma, with irregular or nodular aspect
Microscopic view: atypical glandular structures, from well to poorly differentiated
- particular types: medullary carcinoma, tubular carcinoma, papillary carcinoma
Infiltrating lobular carcinoma (10% of the cases)

Macroscopic view: usually scirrhous carcinoma, irregular and poorly defined
Microscopic view: small cells arranged in linear files of single cells (' Indian files')
dense stroma around the tumor cells
Other tumors
• mucinous carcinoma (3% of the cases)
- macroscopic view: gelatinous aspect
- microscopic view : tumor cells embedded in large amounts of mucin
- prognosis: better than in cases of infiltrating ductal or lobular carcinomas
• medullary carcinoma
- macroscopic view: usually 'brain-like' aspect
- microscopic view: sheets of tumor cells with eosinophilic cytoplasm
• tubular carcinoma
- microscopic view : well differentiated tubular structures, favourable prognosis
2.1.3. Spread of breast carcinomas
Direct spread: muscles, skin, thoracic wall

Lymphatic spread: axillary, subclavicullary, mediastinal lymph nodes
Systemic spread: bone, lungs, liver, brain, adrenal glands
264
2.1 .4. Prognostic factors for breast carcinomas
• tumor size (pT)
- Tis - carcinoma in situ (DCIS, LCIS, Pagefs disease of the nipple)
- pTl - tumor :S 20 mm in greatest dimension
- pT2 - 20-50 mm
- pT3 - tumor > 50 mm in greatest dimension
- pT4 - any size with direct invasion of the chest wall and/or the skin
• lymph node status (pN)
- pN0 - no lymph node metastases
- pNl ,2 - metastases in the axillary and/or ipsilateral internal mammary nodes
- pN3 - metastases in the ipsilateral infraclavicular and/or supraclavicular nodes
• histologic type and degree
• hormonal status - estrogen and progesteron receptors (ER, PR)
• gender, age - more aggressive in males and young patients
2.1.5. Predictive factors for breast carcinomas
- HER-2 mutations - treatment with Herceptine
- positivity for ER, PR - antihormonal therapy with Tamoxifen
Fig. 1 08. Breast lesions. A. Inverted nipple (malformation); B. Retracted nipple

and 'peau d'orange' skin in a woman with breast cancer; C. Mucinous carcinoma;
265
PATHOLOGY OF THE
MALE GENITAL TRACT
266
PATHOLOGY OF THE MALE GENITAL TRACT
Pathology of the testis and epididymis

Pathology of the spermatic cord and seminal vesicles
Pathology of the prostate
Pathology of the penis
Pathology of the scrotum
PATHOLOGY OF THE TESTIS AND EPIDIDYMIS
CONGENITAL AND OTHER NONTUMOR LESIONS
Cryptorchidism (undescended testicle)

- definition: improper descent of the testis during fetal development
the testis can remain in the abdominal cavity or inguinal canal
- surgical intervention is necessary to help descending for a normal spermatogenic
activity and to prevent malignant transformation
Testicular ectopy
- definition: abnormal positioning of the testis in other part of the body than the
abdominal cavity
Monorchidism or unilateral anorchidism
- definition: absence of one testis
Hypogonadism
- definition: spermatogenic failure
- etiology: primary - dysgenesia, Klinefelter's syndrome
secondary - cirrhosis, drugs containing estrogen, alcoholism
Hydrocele
- definition: accumulation of clear fluid in the tunica vaginalis
- etiology: congenital, inflammatory or traumatic lesion
Hematocele
- definition: accumulation of blood in the tunica vaginalis
- etiology: trauma, tumors
Testicular atrophy
- senile involution, estrogenic therapy, radiotherapy, chronic inflammation, etc.
267
INFLAMMATIONS
Orchitis = inflammation of the testis

Epididymitis = inflammation of the epididymis
Acute inflammations
- etiology: - ascending bacterial infection (e.g. gonococci)
- septicemia
- viruses (e.g. mumps)
- trauma
- macroscopic view: enlarged, hyperemic, tender testis
- microscopic view: serous (mumps) or purulent inflammation
- evolution, complications: healing or peritesticular inflammation (periorchitis)
Chronic inflammations
- morphology: expanded fibrosis, testicular atrophy
• idiopathic granulomatous orchitis
- a particular type of chronic orchitis which occurs in middle aged males
- predisposing factors: - urinary infections, trauma
- macroscopic view: unilateral enlargement of the testis with a lobulated cut surface
- microscopic view: giant cell granulomas
• tuberculosis
- the epididymis and the testis are the most common male genital organs affected
by secondary tuberculosis
- complications: periorchitis, fistula, fibrosis, calcification, etc.
• syphilis
- tertiary stage - diffuse inflammation or gumma
TESTICULAR AND EPIDIDYMAL TUMORS
Germ cell tumors

Sex-cord/ gonadal stromal tumors
Adenomatoid tumor - a rare epididymal tumor
Other tumors - malign.ant lymphomas - large B-cell lymphoma
Metastases - lung carcinoma, prostate cancer, melanoma, etc. (rarely)
268
- testicular tumors usually occur in young and middle aged males and have a
relatively good prognosis after a complex oncotherapy
- risk factors: cryptorchidism, hyperestrogenism, gene mutations, radiotherapy
- clinical features: painless enlargement of the testis, hydrocele, hematocele, etc.
Germ cell tumors
Seminoma (30-40% of testicular tumors)

- malignant tumor which usually occurs in 30-50 years of age (classic seminoma)
- spermatocytic seminoma can be detected in elderly patients
- macroscopic view: enlarged testis, with hemorrhages and necroses on cut surface
- microscopic view : sheets of small uniform atypical spermatocyte-like cells
- outcome: good prognosis after radiochemotherapy, in case of classic seminoma
Embryonal carcinoma(JS-20% of testicular tumors)
- malignant tumor which usually occurs in about 20 years old young males
- morphology: solid, tubular or papillary pattern, large areas of necrosis
- outcome: poor prognosis (5 year survival rate: 25-30%)
Teratoma (25-40% oftesticular tumors)
- usually malignant, immature teratoma, composed of immature tissues derived
from all three germinal layers (ectoderm, endoderm, mesoderm)
Yolk sac tumor
- malignant tumor which secretes a-fetoprotein
Choriocarcinoma
- malignant tumor which secretes hCG (human Chorionic Gonadotropin)
- associated lesions: gynecomastia, thyreotoxicosis
- outcome: poor prognosis
Mixed tumors
- mixed embryonal carcinoma and teratoma
- choriocarcinoma and teratoma/embryonal carcinoma
- mixed teratoma and seminoma
- others
Sex-cord/ gonadal stromal tumors
Leydig cell tumor (2% of the testicular tumors)

- a benign tumor that arises from the interstitial Leydig cells
- occurs especially between 30-45 years of age and secretes androgen
Sertoli cell tumor
- a rare benign tumor of the testis
269
Fig. 109. Lesions of testis and epididymis. A. Tuberculous orchiepididymitis;
B-D. Immature malignant teratomas with gelatinous (B), cystic (C) and solid
features (D)
270
PATHOLOGY OF THE SPERMATIC CORD
AND SEMINAL VESICLES
Varicocele
Definition: varicosity of the pampiniform venous plexus, near the spermatic cord
Etiology:
• primary varicocele (usually left-sided) or
• secondary varicocele
- usually bilateral varicocele
- etiology: pelvic veins compression
- consequences: no consequences or infertility
Deferentitis
Definition: ascending infection of the deferent ducts
Atresia of spermatic cord
Definition: congenital failure of the spermatic cord
Torsion of the spermatic cord
- occurs especially in 13-16 years old children
- consequences: hemorrhagic infarction of the testis and epididymis
Spermatocystitis
Definition:inflammation of the seminal vesicles as result of an ascending infection
or during secondary tuberculosis
PATHOLOGY OF THE PROSTATE GLAND

PROSTATITIS
Etiology: bacterial infections (E. coli), urinary stasis or idiopathic prostatitis
Morphology:
• acute prostatitis - hyperemic and swolling of the prostate
• chronic prostatitis
- enlarged, firm, fibrous prostate
- sometimes, small calculi on cut surface (prostatic lithiasis)
• tuberculosis
- enlarged prostate, with caseum on cut surface, usually during systemic spread
Clinicalfeatures ofprostatitis: enlarged firm prostate, disorders of micturition
271
BENIGN PROSTATIC HYPERPLASIA
Definition: nontumor enlargement of the prostate, which usually develops in the

transition zone of the periurethral region, mainly in elderly males; an androgen
dependent lesion whose etiology is related to dihydrotestosterone and estradiol
Macroscopic view:
- enlarged prostate, dysplaying nodular aspect on cut surface
- the lateral and/or dorsal midline lobe can be affected
• subvesical hyperplasia
- hyperplasia of the lateral lobes, below the urinary bladder
• intravesical hyperplasia
- hyperplasia of the dorsal midline lobe, protruding into the urinary bladder
Microscopic view:
- nodular glandular hyperplasia, fibrosis and smooth muscles proliferation
Consequences, complications:
- compression of the prostatic urethra
- atrophy of the remnant prostate
- hypertrophy of the bladder wall (hypertrophic muscle fibers)
- ascending inflammations (cystitis, pyelonephritis)
- bilateral hydroureter, hydronephrosis
- malignant transformation (carcinoma)
- septicemia (rare)
Clinical features:
- increased frequency of micturition, especially during the night (nocturia)
- urinary incontinence, urinary infections.
PROSTATIC CARCINOMA
- the most common malignancy in elderly males, which usually arises from the
glands localized in the peripheral zone of the prostate
- the tumor cells secrete Prostate Specific Antigen (PSA)
Riskfactors: hyperandrogenism, gene mutations
Macroscopic view:
- prostate enlargement, sometimes with necrosis and hemorrhage on cut section
Microscopic view
- most of the cases are well to poorly adenocarcinomas from differentiated
- the histological degree is quantified using the Gleason scoring system and
diagnosis comprises double score: the first is the dominant pattern, the second the
non-dominant one (e.g. 3+3 =6; 3+4=7) - Gleason :S 6 - well differentiated; Gleason
7 - moderately differentiated; Gleason 8-10 - poorly differentiated
272
• Gleason 1 - small, uniform glands
• Gleason 2 - several gland shape and size, more stroma between glands
• Gleason 3 - several irregular glands, separated by fibrous stroma
• Gleason 4 - solid areas (fused glands, epithelial proliferation), few glands
• Gleason 5 - solid nests, no gland formation
Fig. 110. The original Gleason's scale

used for grading prostate carcinoma
(Gleason DF. Histology grading of prostate cancer: a
perspective. Hum Path 23:273-279, 1 992.)
Spread
- direct spread: seminal vesicle, urinary bladder, pelvic wall
- lymphatic spread: sacral, iliac, para-aortic nodes
- systemic spread: bones (Batson's veins - vertebrae), lungs, etc.
Anatomic stage/Prognostic groups

• group I - incidentally diagnosed, clinically undetectable or
- involving of one half of one lobe or less, Gleason :S 6, PSA < 1 0
• group II - tumor confined to the prostate, Gleason :S 7, PSA 2': I O < 20
• group III - direct spread in the bladder and/or seminal vesicles
- without metastases, any Gleason, any PSA
• group IV - lymph node (pNl) and/or distant metastases
Clinicalfeatures: increased frequency of micturition

elevated serum PSA (Prostate Specific Antigen) level.
273
Fig. 1 11 . Lesions of the prostate. A. Tuberculous prostatitis and cystitis.
B-C. Benign prostatic hyperplasia
274
PATHOLOGY OF THE PENIS
• phimosis
- congenital or acquired narrowing of the preputial orifice (thight prepuce)
- the prepuce cannot be retracted over the glans penis
- treatment: circumcision
- complications: stasis of sebaceous material
inflammation, urinary infections, fibrosis
• hypospadias - ventral displacement of the urethral meatus (hypo,Gr.=under)
• epispadias - dorsal displacement of the urethral meatus (epi,Gr.=above)
Inflammations
• balanitis - inflammation of the glans penis
• posthitis - infl ammation of the inner surface of the prepuce
Peyronie's disease
- penile fibromatosis characterized by the painful curvature of the erect penis
Premalignant lesions
• Bowen disease = in situ squamous cell carcinoma (HPV16 - related)
• Erythroplasia of Queyrat = carcinoma in situ of the glans penis
Tumors
• benign tumors: papilloma, condyloma acuminatum or genital warts (HPV)
• malignant tumors: squamous cell carcinoma, melanoma (rare)
PATHOLOGY OF THE SCROTUM

Inflammations
Carcinoma - squamous cell carcinoma
Scrotal swelling - associated with one of the following lesions:
• hydrocele, varicocele
• testicular tumors
• orchiepididymitis
• testicular torsion
• inguinoscrotal hernia
• hypoalbuminemic edema, hyperhydration
• elephantiasis
275
Fig. 112. Hydrocele.
Fig. 113. A. Scrotal edema following parenteral hyperhydration

B-C. Hypoalbuminemic edema, which affects the loose tissue of the eyelid (B)
and the prepuce (C)
276
PATHOLOGY OF THE NERVOUS SYSTEM
277
PATHOLOGY OF THE NERVOUS SYSTEM
Pathology of the dura mater
Pathology of the meninges
Pathology of the cerebral ventricles
Pathology of brain parenchyma
PATHOLOGY OF THE DURA MATER

Thrombosis of the venous sinuses
- etiology: - dehydration (infants)
- congestive heart failure (adults)
- during pregnancy or puerperium
- during pyogenic infecions (septic thrombosis)
Epidural hematoma
- definition: accumulation of blood between the skull and dura mater
- etiology: trauma (especially of the temporal bone)
- clinical features: asymptomatic in the first hours, later with neurologic symptoms
Acute subdural hematoma
- definition: accumulation of blood between dura mater and arachnoid
usually self-limited hemorrhage
- etiology: trauma
spontaneous rupture of : aneurysm
the vertebral arteries (osteophytes)
- consequences: localized fibrosis
Chronic subdural hematoma
- etiology: repeated hemorrhages
- clinical features: headache, confusion
progressive increasing of the intracranial pressure
Pachimeningitis
- definition: inflammation of the dura mater
- morphology: acute-purulent, chronic or tuberculous inflammation
Injuries of the newborn 's cranial cavity during delivery
- consequences: rupture of the falx cerebri or the tentorium cerebelli
278
PATHOLOGY OF THE LEPTOMENINGES
VASCULAR DISORDERS
Subaracltnoid ltemorrltage
Definition: accumulation of blood between the arachnoid and pia mater
Etiology: - trauma
- spontaneous rupture of : saccular (berry) aneurysm
vascular malformations
- large cerebral hematoma with expansion in the ventricular
system and/or subarachnoid space
- hematologic disorders, brain tumors
Subpial ltemorrltage
- definition: accumulation of blood between pia mater and brain parenchyma
- etiology: cerebral hemorrhages
External ltydrocepltalus
- definition: accumulation of the cerebrospinal fluid into the subarachnoid space
- etiology: brain atrophy.
Fig. 1 14. Subdural hematoma (left) and subarachnoidian hemorrhage (right)
279
MENINGITIS
Acute meningitis
Definition: inflammation of the leptomeninges (arachnoid and pia mater)

Etiology:
• serous meningitis - viruses, trauma, leptospirosis, etc.
• purulent meningitis
- perifocal inflammation: otitis, sinusitis, rhinitis
- bacteriaemia, septicemia (e.g. Pneumococcus, Meningococcus)
Morphology:
- pus accumulation in the meningeal (subarachnoid) space
• pneumococcal meningitis - purulent exudate over the convexity of the brain
• meningococcal meningitis - pus on the base of the brain
Evolution, complications: healing or
meningoencephalitis
pyocephalus (pus into the cerebral ventricles)
meningeal fibrosis (rare)
Clinicalfeatures: headache, stiff neck, photophobia, fever, skin rash, etc.
Chronic meningitis
Etiology:
- opportunistic infections (e.g. cryptococcal meningitis)
- infection with Borelia burgdroferi (neuroboreliosis or Lyme disease) - tick-borne
disease characterized by: aseptic meningitis
facial nerve palsy
encephalopathy
polyneuropathies
Evolution, complications: meningeal fibrosis, compression of the brain
Specific meningitis
Tuberculous meningitis - usually basilar meningitis, in the cerebellopontine angle

Neurosyphilis - tertiary stage of syphilis - chronic meningitis (convexity)
Fungal meningitis - opportunistic infections
280
Fig. 115. Meningitis. A. Meningococcal purulent meningitis; B. Basilar
tuberculous meningitis; C. Hemorrhagic tuberculous meningoencephalitis;
D. Pneumococcal meningitis
281
PATHOLOGY OF THE CEREBRAL VENTRICLES
Internal hemocephalus
- definition: accumulation of blood in the cerebral ventricles

- etiology: expansion of cerebral or subarachnoidian hemorrhages
- localization : mainly in the lateral ventricles, rare in the IVth ventricle
Internal hydrocephalus
Definition: accumulation of cerebrospinal fluid in the ventricular system

Etiology:
- hypersecretion of the cerebrospinal fluid: inflammations (meningoencephalitis)
tumors of the choroid plexus
- disorders ofresorption of the cerebrospinal fluid: leptomeningeal fibrosis
- obstacles along the fluid route: tumors, inflammations, malformations
- compensatory hydrocephalus: brain atrophy, stroke, infarction
- congenital hydrocephalus
Inflammations
• pyocephalus
- definition: accumulation of pus in the ventricular system
- etiology: purulent meningitis, brain abscesses
• chronic ependymitis
- etiology: repeated acute inflammation
Tumors
• papilloma, menigioma - in lateral ventricles

• ependymoma - in the IVth ventricle, usually in children
• carcinoma - rare
Complications of ventricular tumors:

- increased intracranial pressure ----+ headache, nausea, vomiting
blurred vision, drowsiness
- tonsillar herniation ----+ herniation of the cerebellum tonsils into the foramen
magnum ----+ compression of the central respiratory centers ----+ death
282
dura mater
;�,r: : •
lateral
,,entricles
aqueduct of Sylvius third ,• entriclt

� i
foramina of
Luschka and
Magendie •I\'
□
I rJ II magnum
Fig. 1 1 6. A. Diagrammatic representation of the ventricular system; B. The

normal aspect of the IVth ventricle; C. Intraventricular hemorrhage
ventricle IV1\ D. Ependymoma; E. Intraventricular hemorrhage - lateral
ventricles; F. Intraventricular meningioma
283
PATHOLOGY OF THE BRAIN PARENCHYMA
Vascular disorders
Inflammation of the brain and spinal cord
Cerebral atrophy
Degenerative diseases
Brain tumors
VASCULAR DISORDERS
Cerebral infarction
Synonyms: liquefaction, laceration, ischemic brain damage, stroke

Definition: brain disorders due to reduction or cessation of the cerebral blood flow
Etiology: - arterial obstruction - solitary infarction
- thrombosis, embolism - usually in the middle cerebral artery
- atherosclerosis of the internal carotid artery
- hypertensive encephalopathy - multiple minute infarctions
- repeated ischemic attacks
Morphology
- pale, friable, edematous area
- loss of sharp delimitation between the grey and white matter
- sometimes, hemorrhagic area (extravasation of erythrocytes)
- brain edema - raised intracranial pressure - death
- resorption - pale cystic area (internal compensatory hydrocephalus) or
glial scar
Intracerebral hemorrhages
Brain apoplexia (stroke)

Definition: acute expanded brain hemorrhages
Etiology: atherosclerosis, hypertension, vascular malformations
rupture of the saccular aneurysms (middle cerebral artery)
spontaneous rupture of Charcot-Bouchard aneurysms (hypertension)
Morphology: hemorrhagic, friable, edematous areas
Evolution, complications: raised intracranial pressure - death
resorption - brown cystic area (hemosiderin)
284
Pontine hemorrhages
Etiology : hypertension, raised intracranial pressure, tonsillar herniation
Evolution: high risk of death
Cerebral purpura
Etiology: blood disorders, acute leukemia, hypoxia, inflammations
Morphology: minute hemorrhages around intact capillary walls (diapedesis)
Cerebral edema
Classification
• vasogenic (pericapillary) edema
- etiology: increased hydrostatic pressure
decreased colloid osmotic pressure
perifocal edema - brain lesions: tumors, hemorrhages, inflammations
- pathomechanism: increased filtration pressure or increased vascular permeability
• cytotoxic (intracellular) edema
- etiology: metabolic disorders, hepatocellular failure
hypervolemia, hyponatremia, hypoxia
- pathomechanism: intracellular accumulation of fluid
Morphology
- flat gyri, narrow sulci, high friability
Consequences of cerebral edema
- resorption
- increased intracranial pressure
- tonsillar herniation - death
Anoxia-related encephalopathy
Etiology: - cardiorespiratory failure
- status epilepticus
- improper anesthesia
Macroscopic view: normal brain or moderately edema
Microscopic view:
- elective neuronal necrosis in the cortex, Ammon horn, thalamus and cerebellum
- coma - death or
disabilities: impaired intellect and memory
behaviour disorders
dysphasia (inability to produce or comprehend language)
285
Fig. 1 1 7. Cerebral infarction (left) and brain apoplexia (right)
Fig. 1 1 8. Normal brain (left) and cerebral edema (right) with flat gyri
286
INFLAMMATIONS OF THE BRAIN AND SPINAL CORD
Encephalitis = infl ammation of the brain parenchyma

Myelitis = inflammation of the spinal cord
Classification:
• non- purulent inflammations
- polioencephalitis, poliomyelitis
- leucoencephalitis, leucomyelitis
- persistent viral encephalitis
- prion (spongiform) encephalopathy
• purulent inflammations
• specific inflammations
1. Non-purulent inflammations
1.1. Polioencephalitis, poliomyelitis
Definition: inflammation of the grey matter of the brain and/or the spinal cord
Microscopic view: perivascular and perineuronal inflammatory infiltrate
neuronophagia
Etiology
• arthropod-borne viruses (arboviruses)
- viral encephalitis transmitted by arthropodes or bloodsucking insects (e.g.
mosquito), sometimes epidemic encephalitis: Japanese B encephalitis (Far East),
Saint Luis encephalitis (United States), Murray Valley encephalitis (Australia and
New Guinea), tick-borne encephalitis (Russia and Eastern Europe)
- evolution, complications: healing, confusion, delirium, coma, death
• other viruses
- Herpes viruses: Herpes simplex, measles, varicella zoster, CMV
microscopic view: intranuclear Cowdry A bodies
- rabies virus: transmitted by dog bite
microscopic view : Babe�-Negri intracytoplasmatic inclusions
consequences, complications: hydrophobia, death
Acute anterior poliomyelitis (Heine-Medin 's disease)
- pathogenesis: polioviruses affect the motor neurons of the anterior horns,
especially from the lumbar and cervical area (paralysis and atrophy of the limb
muscles), and the brainstem (destruction of the respiratory centre - death)
- microscopic view: intranuclear Cowdry B bodies infiltration
287
1 .2. Leucoencephalitis, leucomyelitis
Definition: inflammation or primary immune disease which affect the white

substance of the brain and are characterized by demyelination (loss of myelin) and
axonal preservation
Multiple sclerosis
Definition: primary demyelinating disorder which usually occurs in young females
Etiology: genetic or immune factors
Macroscopic view:
- multifocal demyelinating leukoencephalopathy
- gliosis in brain and spinal cord: grey patches near lateral ventricles, optic nerves,
optic chiasma, brainstem, cerebellum and spinal cord
Microscopic view:
- early stage: areas of demyelination, surrounded by lymphocytes and macrophages
- advanced stage: gliosis (proliferation of astrocytes and microglia)
Clinical features:
- early stage - solitary recurrent neurologic disorders, with long periods of
remission: optic neuritis (inflammation of the optic nerve), diplopia (double
vision), nystagmus (uncontrollable movements of the eyes), vertigo (dizziness),
limb weakness, paraesthesia, bladder dysfunction
- advanced stage: paraplegia (motor/sensory dysfunctions of the lower limbs)
Particular types:
• concentric sclerosis (Balo 's disease)
- concentric demyelination, virally associated, in adults
• diffuse sclerosis (Schilder s disease)
- progressive demyelination in childhood
Post-infective/post-vaccination leucoencephalitis
- self-limiting disease of children or young adults, which occur post-vaccination
(anti-smallpox or rabia) or post-viral inflammations (measles, chicken pox, rubella)
- morphology: demyelination and perivascular inflammatory infiltrate.
1 .3. Persistent viral encephalitis
Subacute sclerosing panencephalitis

- etiology: reactivation of the latent measles virus, post-vaccination
- can occur in children or young adults (4-20 years old), years after measles
Progressive multifocal leucoencephalopathy
- opportunistic infection produced by the polyoma subgroup of papovaviruses.
288
1.4. Prion (Spongiform) encephalopathies
Definition: progressive dementia which affects the adults and is caused by prion
infection (Proteinaceous Infectious Agents)
• kuru
- a rare and fatal cannibalism-related disease (New Zealand, Papua New Guinea)
• Creutifeldt-Jakob disease
- a rare and fatal encephalopathy with unknown etiology
• bovine spongiform encephalopathy ( 'mad cow disease ')
- encephalopathy transmitted from bovines to humans
• fatalfamilial insomnia
- etiology: protein PrPSc misfolding
- clinical features: familial disease which usually occurs between 30-60 years and
consists of progressive to total insomnia, dementia and death; no cure
• sporadicfatal insomnia
- clinical features: progressive insomnia, loss of motor control, h�llucinations,
respiratory failure, death
2. Purulent inflammation
(Brain abscess)
Etiology: pyogenic bacteria

- dir€ct spread from mastoiditis, otitis, sinusitis, meningitis
- systemic spread: septicemia
pulmonary purulent inflammations
infective endocarditis
Riskfactors: trauma (skull fractures)
congenital malformations ( e.g. spina bifida)
iatrogenic lesions (neurosurgery, lumbar puncture)
immunodeficiency
Morphology:
- intraparenchymatous round-shaped cavity with pus
- perifocal vasogenic edema
- resorption
- purulent meningitis
- pyocephalus
- death
Clinicalfeatures: headache, fever, impaired consciousness.
289
3. Specific inflammations
• tuberculosis: tubercles with caseous fusion (tuberculoma of the brain)

• neurosyphilis - progressive dementia
- tabes dorsalis (degeneration of the posterior spinal columns)
• toxoplasmic encephalopathy:
- opportunistic infection or intrauterine infection (see 'Placental inflammations')
• fungal encephalitis: Aspergillus, Candida, Histoplasma, etc.
CEREBRAL ATROPHY
Senile atrophy - aging; not associated with dementia
Pick's disease
- progressive presenile dementia, usually between the ages 40 and 65
- morphology: atrophy of the frontal and temporal lobes
Alzheimer disease
- the common cause of dementia after age 60
- morphology: atrophy of the frontal and temporal lobes
amyloid plaques in the cerebral cortex and around vessels
progressive loss of neurons and synapses.
DEGENERATIVE CEREBRAL DISEASES
1. Primary degenerative diseases

Huntington's disease (Huntington's chorea)
- progressive dementia characterized by involuntary choreiform movements
- usually occurs between the ages 40 and 50
- etiology: mutations in the Huntingtin gene
- macroscopic view: atrophy of the caudate nucleus and of the cortex
- microscopic view: loss of neurons and gliosis
Parkinson disease
- progressive degeneration of neurons which lead to disorders of the motor system
- usually occurs in elderly patients
- morphology: destruction of the nigral system (drugs, toxins, viruses, idiopathic)
- clinical features: involuntary and slow movements, tremor, rigidity
290
Motor neuron diseases
- progressive degeneration of the motor neurons, usually in middle ages
- etiology: familial forms, environmental factors, gene mutations or idiopathic
• amyotropltic lateral sclerosis
- degeneration of the upper neurons of the corticospinal tract
- consequences: spastic paraparesis
• progressive muscular atrophy
- degeneration of the lower neurons of the spinal tract
- consequences: atrophy of the limb muscles
• progressive bulbar palsy (paralysis)
- degeneration of the cranial nerve motor neurons
- consequences: wasting of the tongue muscles
dysarthria (inability to articulate words - motor speech disorders)
dysphagia
2. Secondary degenerative diseases
Congenital metabolic disorders

- phenylketonuria, galactosemia, Hurler' s disease
- lipoidoses (Tay-Sachs, Gaucher and Niemann-Pick diseases)
Wilson's disease (hepatolenticular degeneration)

- etiology: disorders of cooper metabolism (gene mutations)
- consequences: hepatic cirrhosis
brain damages (putamen and caudate nucleus, neuronal loss)
Kayser-Fleischer ring (cooper deposits in the cornea)
Hypovitaminosis
• deficiency of vitamin Bl (Thyamine)
- etiology: alcoholism, malnutrition, acute persistent vomiting
- consequence: Wernicke's encephalopathy (lesions in the mamillary bodies)
- clinical features: loss of consciousness, ophtalmoplegia, nystagmus
ataxia (uncoordinated movement), coma
• deficiency of vitamin Bl2 (Cyancobalamin)
- etiology: pernicious anemia, long-term vegans
Intoxications
- methyl-alcohol, ethanol, pesticides, industrial chemicals
- food additives, drugs, etc.
291
BRAIN TUMORS
1. Primary tumors
• astrocytoma - tumor of the cerebral hemispheres, usually in adult patients

- can present malignant transformation
• anaplastic, pleomorphic and diffuse astrocytoma - malignant behaviour
• glioblastoma - the most malignant tumor in the brain
- median survival 1 0.6 months (AJCC, 2010)
• cerebellar astrocytoma - usually in children, benign tumor
• oligodendroglioma - in children and young adults, benign tumor
• medulloblastoma - in children, usually in the cerebellum
- malignant behaviour
• other tumors: meningioma, meningeosarcoma, etc.
2. Secondary tumors (metastases)
• lung carcinoma
• melanoma
• breast cancer
• prostate cancer
• other carcinomas
3. Consequences of the brain tumors
Intracranial complications
- increased intracranial pressure
- tonsillar herniation - death
- hydrocephalus
- spread through cerebrospinal fluid
- recurrences
Impact oftumor location

• frontal lobe tumor
- changes in personality, intellect or behaviour
- uncoordinated walk
- hemiparesis (weakness of one side of the body)
- hyposmia, anosmia (loss of smell)
- speech difficulties
292
• parietal lobe tumor
- speaking, writing, reading and/or understanding words
- uncoordinated movements
- hemiparesis
- numbness
• occipital lobe tumor
- unilateral loss of vision
• temporal lobe tumor
- 'deja vu' phenomenon (the patient is certain that he has experienced something)
- strange smells
- strange feeling of fear
- speech difficulties
- memory loss
• cerebellar tumor
- imbalance (unsteadiness)
- stiff neck
- dysarthria (motor speech disorder, inability to articulate words)
- nystagmus (involuntary movements of the eyes)
- vomiting
• brain stem tumor
- imbalance (unsteadiness)
- diplopia (double vision)
- vomiting
- difficulty in speaking and swallowing
Prognosticfactors for brain tumors:

- histological type and grade
- tumor location and tumor size
- age of the patient - poor prognosis in children and young patients
- functional neurologic status
- molecular markers (under investigation).
293
Fig. 119. Astrocytoma (top) and glioblastoma (below)
294
PATHOLOGY OF THE
LOCOMOTOR SYSTEM
295
PATHOLOGY OF THE LOCOMOTOR SYSTEM
Bone pathology
Joint pathology
Pathology of the skeletal muscle
BONE PATHOLOGY
Skeletal deformities
Aseptic bone necrosis
Osteoporosis
Congenital disorders of osteogenesis
Acquired metabolic bone diseases
Inflammations: periostitis, osteomyelitis
Bone tumors
SKELETAL DEFORMITIES
Spinal deformities
• kyphosis (kyphos, Gr. = hump)
- abnormal rearward curvature of the thoracic spine
• scoliosis (skolios, Gr. = crooked)
- abnormal lateral curvature of the thoracic and/or lumbar spine
• lordosis
- abnormal inward curvature of the lumbar spine
Lower limb deformities
- bowing of the long bones: - genu varum - 0-shaped legs
- genu valgum - X-shaped legs
ASEPTIC BONE NECROSIS
Definition: avascular bone necrosis (osteonecrosis)

• juvenile (idiopathic) necrosis
- Perthes disease (necrosis of the femoral head)
- Kohler disease (necrosis of the tarsal bones)
• secondary necrosis
- etiology: steroid drugs, radiotherapy, Caisson disease, etc.
- localization: most common, necrosis of the femoral head
296
OSTEOPOROSIS
Definition: decreasing of the bone mass and disorders of bone architecture

Pathogenesis: increasing of osteoclast activity ----+ bone demineralization
Macroscopic view: increased bone fragility, porous bone on cut section
Microscopic view: thin bone trabeculae
Consequences: pain, kyphosis, pathologic fractures
Primary osteoporosis
• postmenopausal osteoporosis (8-10% of postmenopausal females)
- localization: most common in vertebras, pelvis and thorax
skull and the limb bones are not affected
• senile osteoporosis
- localization: whole skeleton is involved
Secondary osteoporosis
- risk factors: steroid drugs
endocrine diseases: hyperthyroidism, Cushing's syndrome
inflammatory bowel diseases
autoimmune diseases (ankylosing spondylitis, lupus erythematosus)
trauma (Sudeck's osteoporosis).
smoking, alcohol consumption, immobilization, etc.
CONGENITAL DISORDERS OF OSTEOGENESIS
Osteogenesis imperfecta
- etiology: deficiency of osteogenesis and collagen synthesis
- affected organs: bones, joints, eyes, ears, skin and teeth
- clinical features: high skeletal fragility, blue sclerae, loss of hearing, etc.
- causes of death: respiratory failure, cerebral hemorrhages, etc.
Fetal chondrodysplasia
- disorders of enchondral osteogenesis
- clinical features: short stature, large head
short limbs, normally-developed trunk
297
ACQUIRED METABOLIC BONE DISEASES
Rickets
Etiopathogenesis: vitamin D deficiency in childhood, under two years of age --+

inadequate bones mineralization --+ disorders of ossification --+ osteoid part of the
bone (unmineralized matrix) is excessively developed
Skeletal deformities: - members - genu varum, genu valgum
- skull - flattening, frontal bossing (craniotabes)
- narrow pelvis
- spine - kyphosis, scoliosis, lordosis
- enlarged costochondral joints (rachitic rosary)
Osteomalacia (malakos, Gr. = soft)
Etiopathogenesis: vitamin D deficiency in adults, especially in pregnant women

Consequences: soft deformated bones (femur, vertebras, pelvis, etc.)
Generalized fibrous osteodystrophy

(Osteitis fibrosa cystica or Recklinghausen's disease) I
Etiology: primary or secondary hyperparathyroidism (renal failure)

Consequences: bone destruction, bone fibrosis
Pagefs disease of bone

(Pagefs deforming osteodystrophy)
Definition: idiopathic disorder of bone remodeling: increased bone turnover in

early stages, followed by osteolysis, in advanced stage
Localization: most common in skull, tibia, pelvis and spine
Clinicopathological features: - thickening of bones, fractures, pain
- thick skull - ' lion-like face' (leontiasis ossea)
- large hat, light skull (Pagefs steal)
- deafness (compression of nerve)
- can be associated with osteosarcomas
- elevated serum calcium level.
298
Fig. 1 20. Pagefs disease
Fibrous dysplasia
- skeletal development abnormality which usually involves the ribs, femur, tibia
and/or skull, in childern and young adults
- morphology: the normal bone is replaced by fibrous connective tissue which
shows metaplastic lamellar bone formation (immature bone-forming mesenchyme)
- monostotic (one rib involvement) or polyostotic form (Jaffe-Lichtenstein disease)
INFLAMMATIONS
Periostitis = periosteum inflammation

Osteomyelitis = bone inflammation
Periostitis
• acute periostitis
- serous or purulent inflammation, usually associated with osteomyelitis
- evolution: healing, bone necrosis or transformation into chronic periostitis
• chronic periostitis - periosteal fibrosis
• specific periostitis - tuberculosis, syphilis
299
Acute osteomyelitis
Etiology:
- bacterial infection: septicemia, compound fractures, orthopedic surgery
- in children, Staphylococcus aureus is the most common bacteria
Macroscopic view: focal bone necrosis (bony sequestrum), which especially
involves the metaphysis, surrounded by reactive new bone formation
Microscopic view: abscesses in the metaphysis and bone marrow
- healing
- direct spread to diaphysis, periosteum, joint (purulent arthritis)
- systemic spread (septicemia)
- prolonged infection - chronic osteomyelitis
Chronic osteomyelitis
Risk factors:
- bone fracture fixation devices, bone or joint prosthesis, etc.
Macroscopic view: chronic abscess with bone sequestrum (dead bone) surrounded
by granulation tissue and reactive osteosclerosis
Microscopic view: chronic abscesses
Particular type:
- Brodie's abscess - subacute purulent osteomyelitis of the tibia
Complications: skin fistula
systemic amyloidosis
septicemia
Specific osteomyelitis
Bone tuberculosis
Pathogenesis: systemic spread or reactivation of the primary dormant foci
Localization:
• spine (> 50% of the cases) - tuberculous spondylitis (Pott 's disease)
- lower thoracic spine or lumbar vertebrae and intervertebral disc
• metaphysis of long bones (tibia, femur)
• tubular bones of the hands (dactylitis)
Consequences: - bone destruction - kyphosis
- direct spread to other vertebrae and the muscles
- systemic spread to synovium (tuberculous arthritis)
- skin fistula, cold abscess
Sarcoidosis
- multisystemic granulomatous inflammation with unknown etiology
300
Fig. 121. Pott's disease
BONE TUMORS
Chondrogenic tumors:
Benign: osteochondroma, chondroma, chondroblastoma
Malignant: chondrosarcoma (see 'General Pathology')
Osteogenic tumors:
Benign: chondromyxoid fibroma, osteoma, osteoid osteoma
non-ossifying fibroma, osteoblastoma
Malignant: osteosarcoma, fibrosarcoma (see 'General Pathology')
Bone marrow tumors:

Benign: benign osteoclastoma
Malignant: malignant osteoclastoma, Ewing's sarcoma
lymphomas, multiple myeloma (plasmacytoma)
Other tumors: · benign: hemangioma, adamantinoma

malignant: angiosarcoma, chordoma
Bone metastases: carcinomas: lung, prostate, breast, thyroid, kidney, stomach, etc.
malignant melanoma, neuroblastoma, etc.
301
Fig. 122. Bone tumors. A. Osteoclastoma of the tibia; B. Femoral osteosarcoma;
C. Metastases from pulmonary carcinoma in the ribs;
D. Multiple myeloma of the skull; E. Metastases from melanoma in the ribs
302
JOINT PATHOLOGY
Degenerative joint diseases
(Arthrosis)
Definition: disorders of articular cartilage which mainly occur in middle-aged and

elderly people
Pathogenesis: cartilage destruction is followed by remodelling of the subjacent
bone tissue which lead to genesis of some small bony outgrowths named
osteophyts
Localization: more frequent in the large joints, cervical and lumbar spine
• coxartrosis - arthrosis of the hip joint
• gonarthrosis - arthrosis of the knee joint
• spondylarthrosis - arthrosis of the vertebral joints
Complications
- pain, joint inflammations (arthritis),
- rupture of the vertebral arteries (osteophyts) � subdural hemorrhages
Arthritis
Infective arthritis
• acute arthritis
- morphology: serous, purulent or hemorrhagic arthritis
- complications: pyarthros = pus accumulation into the joint cavity
• chronic arthritis
- morphopathogenesis: chronic inflammatory infiltrate and granulation tissue
located on the joint surface (degenerative pannus) � cartilage destruction
• tuberculous arthritis
- direct spread from bone tuberculosis (children) or systemic spread (adults)
- consequences: joint blockage (ankylosis)
Non-infective arthritis
• osteoathritis (degenerative joint disease)
- definition: progressive erosion of aiticular cartilage, especially in females
- etiology: primary or secondary disease (repeated trauma, diabetes, etc.)
- localization: large and small joints (interphalangeal joints of the hand)
- morphology: palpable osteophytes of the distal interphalangeal joints (Heberden's
nodes) and proximal interphalangeal joints (Bouchard' s nodes)
303
• rheumatoid arthritis
- chronic systemic autoimmune inflammation which usually occurs in elderly
women, affects the small joints, is associated with elevated serum rheumatoid
factor level and can present organic involvement (heart, lung, blood vessels)
• Still 's disease
- juvenile idiopathic rheumatoid arthritis, associated with generalized
lymphadenopathy, anemia, splenomegaly
• Felty 's syndrome
- adult rheumatoid disease, generalized lymphadenopathy, anemia, splenomegaly
• Marie Striimpell Bechterew 's disease (ankylosing spondyloarthritis)
- painful bone deformities (spine and sacroiliac joint) and osteoporosis - - - ► rigidity
of the spine, especially in young males
• rheumatic fever
- flitting arthritis of the large joints associated with streptococcal infection
• gouty arthritis:
- podagra, gonagra, chiragra (see General Pathology)
• psoriatic arthritis
- autoimmune arthritis of the small joints, usually associated with psoriasis (skin)
• Reiter 's syndrome
- arthritis, urethritis and conjunctivitis
- reactive processes which occur in patients with infections of the gastro-intestinal
tract and/or reproductive system
Other joint lesions
Bursitis
- bursa is a synovial lined sac located over the bone prominences which
communicate to the joint cavity
- etiology of bursitis: repeated trauma (housemaid's knee), arthritis
Tenosynovitis
- definition: inflammation of the synovium that surrounds the tend.ons
Synovial cysts
- pseudotumor with cystic aspect, located near the joint
Tumors
- benign tenosynovial giant cell tumor (knee or hip joints)
- synovial sarcoma - highly-malignant tumor
304
PATHOLOGY OF SKELETAL MUSCLE
Muscle atrophy
Etiology: senile involution, immobilization, cachexia
Systemic myopathies
Definition: skeletal muscle weakness associated with one of the following

systemic diseases
• motor neuron diseases (neurogenic disorders)
- amyotrophic lateral sclerosis
- progressive bulbar palsy (see Brain pathology)
• myogenic disorders
- Duchenne 's muscular dystrophy - muscle degeneration which occurs during
childhood, being caused by mutations in the dystrophin gene and is characterized
by difficulty walking, cardiomyopathy and respiratory failure
- Erb s dystrophy - progressing muscle degeneration which occurs during
childhood and involves muscles of the shoulders, trunk, thigh and pelvic girdle
- myotonic distrophies - a group of congenital disorders characterized by failure of
muscle relaxation associated with other lesions as: cataracts, endocrine and cardiac
disorders
• myastltenia gravis
- autoautoimmune myopathy, caused by antiacetylcholine antibodies
- can be associated with thymic hyperplasia or thymoma
Myositis
Non-specific myositis - perifocal inflammation

Epidemical myalgia - Coxsackie virus
Inflammatory myopathies (Polymyositis and dermatomyositis)
- collagen diseases or secondary paraneoplastic syndromes
Myositis ossificans
- definition: intramuscular fibroblastic proliferation with focal bone formation
- etiology: repeated trauma or idiopathic
- differential diagnosis: soft tissue osteosarcoma
Parasite-related myositis
- Trichinella spiralis, Cysticercosis, etc.
305
BLOOD AND BONE MARROW
PATHOLOGY
306
BLOOD AND BONE MARROW PATHOLOGY
Erythrocyte pathology
Pathology of leukocytes
Bone-marrow pathology
Disorders of blood coagulation and hemostasis
Spleen pathology
ERYTHROCYTE PATHOLOGY
Hematocrit
- definition: the proportion of erythrocytes out of the total blood volume, after
centrifugation; the normal value is about 45%
MCV = Mean corpuscular value of erythrocytes (fl) = erythrocyte size

MCV = Hematocrit (%) x l O (g/1)
Erythrocyte concentration (number per litre)
MCH = Mean corpuscular hemoglobin (pg) = hemoglobin content

MCH = Hemoglobin concentration (g/dl)
Erythrocyte concentration (number per litre)
MCHC = Mean corpuscular hemoglobin concentration (g/dl)

MCHC = Hemoglobin concentration (g/dl)
Hematocrit (%)
Poikilocytosis = abnormally shaped erythrocytes
Anisocytosis = abnormal variation in the size of erythrocytes

• macro-lmicrocytic erythrocytes
- increased/decreased size of erythrocytes (MCV)
Hyper-lhypochromic erythrocytes
- rise/fall of hemoglobin content of erythrocytes (MCH)
307
POLYCYTHEMIA
Definition: increased number of erythrocytes associated with elevated hematocrit

value and hemoglobin concentration
Clinical features: fatigue, headache, splenomegaly
itching after hot bath, skin spots, phlebitis, etc.
Complications: thrombosis, myelofibrosis, secondary leukemia, etc.
• primary disease (Vaquez-Osler disease or Polycythemia rubra vera)
- chronic myeloproliferative disease caused by mutation in the gene JAK2V617F
- most commonly in women over the age of 40
• secondary polycythemia:
- dehydration, shock (hemoconcentration)
- chronic hypoxia: chronic heart/lung disorders, living at high altitudes
- renal cell carcinoma (secretion of erythropoietin)
- tobacco smoking (smokers' polycythemia)
ANEMIA
Definition: decrease in number of erythrocytes associated with reduced hematocrit

value and hemoglobin concentration
Consequences:
- tissue hypoxia and metabolic disorders, especially in the myocardium and liver
Etiology: - the 'ABCD ' rule: Acute blood loss
Bone marrow failure
Chronic diseases
Destruction (hemolysis)
Clinicalfeatures:
- pallor, fatigue (lethargy)
- heart failure and dyspnea, in case of severe anemia
- jaundice, in case of hemolytic anemia
- iron-deficiency anemia: cheilitis, atrophic glossitis
atrophy of nasal mucosa (ozena)
- neurological disorders, in megaloblastic Biermer anemia
308
1. Post-hemorrhagic anemia
Etiology:
- acute blood loss, more than 1 0% � hemorrhagic shock
- chronic occult hemorrhages
Morphology:
- acute bleeding - normocytic anemia
- chronic occult hemorrhages - iron-deficiency anemia (see below)
3. ' Production failure' anemia
Iron deficiency anemia

Etiology: chronic occult hemorrhages, malabsorption, malnutrition
Morphology:
- microcytic hypochromic erythrocytes
- poikilocytosis: pencil cells - flat, elongated erythrocytes
target cells - dark center (with hemoglobin), surrounded by a pale
ring and another peripheral dark ring
Macrocytic anemias
Cause: deficiency of the maturation factors
Morphology: macrocytic-normochromic erythrocytes
• megaloblastic (pernicious) anemia (Biermer s or Addison 's anemia)
- etiology: vitamin B1 2 or folate deficiency due to malnutrition, malabsorption or
antiparietal cells antibodies
Aplastic anemia
- disorders of hematopoiesis
- bone marrow failure: hypoplasia, leukemia
metastases, tuberculosis
drugs, radiations, toxic substances
309
3. Hemolytic anemia
Inherited hemolytic anemia

• thalassemia
- etiology: congenital abnormalities of hemoglobin synthesis (hemoglobin F)
- morphology: stipple erythrocytes - small blue patches on surface
microcytic-hypochromic erythrocytes
tear-drop erythrocytes
• immune hemolytic anemia
- morphology: microspherocytes - small thick erythrocytes
• hereditary spherocytosis
- etiology: congenital defects in the cell membrane of erythrocytes
- morphology: microspherocytes
• sickle cell anemia
- etiology: congenital hemoglobinopathy (hemoglobin S)
- morphology: sickle erythrocytes
Acquired hemolytic anemia

• splenectomy or spleen disorders
- morphology: siderotic granules in the erythrocytes, target erythrocytes
• secondary autoimmune hemolytic anemia
- etiology: drugs, neoplasia (non-Hodgkin lymphomas)
• hemolytic anemia in newborn infants
- Rh incompatibility
• other causes
- chronic inflammations, toxic substances, parasites, iatrogenic
0 0
-
normocyte microcyte round macrocytc oval macrocyte
pencil cell target cell mycrospherocyte tear-drop schistocyte

sickle cell cell
Fig. 123. Abnormally sized (top) and abnormally shaped (below) erythrocytes
3 10
PATHOLOGY OF LEUKOCYTES
Leukocytosis = increased number of circulating leukocytes
- variants: neutrophilia, monocytosis, eosinophilia, basophilia, lymphocytosis
Leukopenia = decrease in the number of circulating leukocytes
- variants: neutropenia, lymphopenia
Pancytopenia = decrease in the number of circulating leukocytes and other blood
cells
LEUKEMIAS
Definition: malignant proliferation of atypical immature leukocytes in the blood

and bone marrow, wich, in advanced stages can be associated with leukemic
infiltrates in tissues and organs: liver, spleen, lymph nodes, meninges, gonads, skin
Consequences: bone marrow failure: erythropenia - anemia
neutropenia - infections
thrombocytopenia - hemorrhages
1 . Acute leukemia
Pathogenesis: mutations in hematopoietic stem cells
Risk factors: radiations, toxins, viruses (e.g. HTLV), etc.
Morphology
• blood: leukocytosis, anemia, thrombocytopenia
• bone marrow: blast cells, bone marrow failure
• organs: hepatomegaly, splenomegaly, leukemic infiltrates
- acute bone marrow failure
- opportunistic infections, acute septicemia
- hemorrhages
- causes of death: septic shock, hemorrhages (e.g. brain), bone marrow failure
Clinical features
- necrotizing or hemorrhagic stomatitis/pharyngitis/laryngitis
- hepatomegaly, splenomegaly, anemia, etc
• acute lymphoblastic leukemia (ALL)
- proliferation of pre-T and pre- B cells (lymphoblasts)
- the most common childhood malignancy
• acute myeloblastic leukemia (AML)
- proliferation of myeloblasts (eosinophils, neutrophils, basophils)
- 5% of childhood leukemias
• acute myeloid leukemia (AML) - rare disease, in young adults
311
Fig. 124. Pulmonary hemorrhages (left) and hepatomegaly (right) in a
24 year old patient with acute myeloid leukemia
2. Chronic myeloid (granulocytic) leukemia (CML)

Occurence: mainly in adults
Morphology
• blood: severe leukocytosis, aplastic anemia, thrombocytopenia
blast cells and Philadelphia chromosome - t(9;22)
• bone marrow: proliferation ofmyeloblasts, promyelocytes, myelocytes
hypoplasia of erythrocytes and megakaryocytes
• organs: massive hepatomegaly, splenomegaly, leukemic infiltrates
Evolution, complications: chronic evolution with acutization (blast crisis)
splenic infarction
Causes of death: infections, hemorrhages, bone marrow failure
3. Chronic lymphocytic leukemia (CLL)

Occurence: mainly in elderly patients
Morphology
• blood: severe leukocytosis (85-90% are lymphoblasts)
aplastic anemia, thrombocytopenia
• bone marrow: lymphocytic infiltration
hypoplasia of erythrocytes, myelocytes and megakaryocytes
• organs: moderate hepatosplenomegaly, leukemic infiltrates
generalized lymphadenopathy (see 'Lymphocytic lymphoma')
Evolution, complications: chronic evolution with remission
Causes of death: infections, hemorrhages, bone marrow failure
3 12
BONE MARROW PATHOLOGY
MYELODYSPLASTIC SYNDROME
Definition: persistent, dysplastic hematopoiesis

pre-leukemic disorder that can progress to acute myeloid leukemia
Morphology: hypercellular marrow - several blast cells and few mature blood cells
Consequences: myelofibrosis (10% of the cases)
Clinical features: anemia, hemorrhages, infections, septicemia
MYELOPROLIFERATIVE DISORDERS
Acute disorders: acute erythroleukemia (Di Guglielmo's disease)

acute myeloid (myelo-monocytic, megakaryocytic) leukemias
Chronic disorders: polycythemia vera (Vaquez-Osler disease)
myelofibrosis
chronic myeloid leukemia
primary (essential) thrombocythemia
DISORDERS OF BLOOD COAGULATION AND

HEMOSTASIS
Clinicalfeatures: minute or large hemonhages throughout the body
Disorders ofprimary hemostasis (thrombocytopenia)
- primary thrombocytopenia (Werlhofs disease)
- secondary thrombocytopenia (e.g. bone marrow failure)
- Moschcowitz disease (Thrombotic thrombocytopenic purpura)
Vascular disorders (increased capillary permeability)
- Henoch-Schonlein purpura - self-limited autoimmune disease during childhood
- hereditary hemorrhagic telangiectasia
Blood coagulation disorders
- hemophilia A and B - defective coagulation factors (VIII and IX)
- females are asymptomatic caniers, males are affected
- deficiency of clotting factor XII
- deficiency of von Willebrand factor
- vitamin K deficiency
- acquired disorders: iatrogenic (drugs), hepatocellular failure, malignancies
hypo- or afibrinogenemia (DIC)
313
SPLEEN PATHOLOGY
• hypoplasia
• accesory spleen - congenital malformations
• splenic irifarction - thromboembolism, leukemia with splenomegaly
• splenic rupture - post-traumatic or spontaneous (in splenomegaly)
• hyperslenism - splenomegaly and pancytopenia
• splenomegaly - chronic systemic congestion
- systemic infections
- metabolic diseases (storage disorders)
- leukemias, lymphomas
- metastases (rare).
Fig. 125. Thrombocytopenic purpura (A) and spleen lesions (B-D).

B. Spleen infarction; C. Malignant lymphoma; D. Spleen metastases
3 14
PATHOLOGY OF THE
ENDOCRINE SYSTEM
315
PATHOLOGY OF THE ENDOCRINE SYSTEM
PATHOLOGY OF THE PITUITARY GLAND
Necrosis
- ischemic necrosis during delivery or shock
Inflammation
- tuberculosis, sarcoidosis (very rare)
Tumors
- cromophobe adenoma - usually inactive, rarely prolactin-secreting
- eosinophil adenoma (GH-, prolactin-secreting)
- basophil adenoma (ACTH-, TSH-secreting)
Endocrine syndromes
- etiology: pituitary hypofunction (inflammation, necrosis, hemorrhages)
pituitary hyperfunction (hyperplasia, adenomas)
• gigantism, acromegaly: hypersecretion of GH (Growth Hormone)
• pituitary nanism: hyposecretion of GH
• adiposo-genital dystrophy (Frohlich syndrome)
• post-partum necrosis (Sheehan's syndrome)
• Simmond 's disease/hypophyseal cachexia: adenohypophysial hypofunction
• diabetes insipidus: neurohypophysial hypofunction
ADRENAL GLANDS DISORDERS

Hypo/unction
- acute failure: hemorrhages, inflammations, Waterhouse-Friderichsen syndrome
(bilateral hemorrhagic necrosis in meningococcal septicemia)
- chronic hypo/unction (Addison 's disease): tuberculosis, metastases, autoimmune
Hype,function
- etiology: primary or secondary hyperplasia, adenoma
• Cushing's syndrome (glucocorticoids)
• adrenogenital syndrome (sex steroid overproduction) ·
• Conn's syndrome or primary hyperaldosteronism (mineralocorticoids)
Tumors of the adrenal cortex: adenoma, carcinoma (rare)
Tumors of the adrenal medulla:
- chromaffin cells - phaeochromocytoma (see 'Apudomas')
- sympathetic nerve cells - neuroblastoma, gangioneuroblastoma, ganglioneuroma
Metastases - lung or kidney carcinomas
316
Fig. 126. Lesions of the adrenal glands. A-B. Waterhouse-Friderichsen syndrome,
with bilateral hemorrhagic necrosis of the adrenal glands (B); C-D. Adenoma; E-F.
Lung carcinoma (E) with metastases in the adrenal glands (F)
3 17
PATHOLOGY OF THE THYROID GLAND
Malformations
- aplasia, hypoplasia, ectopic thyroid tissue (mediastinum, tongue dorsum), cysts
Hyperplasia (Goiter)
- definition: nodular or diffuse enlargement of the thyroid gland

- hypo-, normo- or hyperfunction of the thyroid gland
- etiology: TSH hypersecretion
- particular form: endemic goiter due to iodine deficiency
Inflammations
Acute thyroiditis
- etiology: inflammation of the surrounding tissues or septicemia
Subacute thyroiditis (de Quervain 's or giant cell thyroiditis)

- etiology: viral infections (adenovirus, Coxsackie virus, Echo viruses, etc.) or
autoimmune disease
Chronic thyroiditis
• Hashimoto's thyroiditis (chronic lymphocytic thyroiditis)
- autoimmune disease, characterized by thyroid hypofunction
• Riedel's fibrous thyroiditis
- unknown etiology
Benign tumors
• solid, follicular and oncocytic adenomas

• toxic thyroid adenoma :_ thyroid hyperfunction
318
Malignant tumors
Papillary carcinoma (60-70% of the cases)

- occurs in young adults, mainly women
- good prognosis: 5-year survival rate 90%
Follicular carcinoma (1 5-20% of the cases)

- mainly occurs in the fifth decade of the life, more frequently in women
- minimally invasive carcinoma - microscopic invasion
- widely invasive carcinoma - poor prognosis, lung and bone metastasis
Medullary carcinoma (5-10% of the cases)

- arises from parafollicular C-cells
- the tumor cells secrete calcitonin
- can be part of MEN syndrome (see 'General Pathology')
Undifferentiated carcinoma
- highly malignant tumor
Non-epitltelial tumors
- lymphomas, angiosarcoma
Hyperthyroidism
- Basedow-Graves' disease (immune process): diffuse goiter + exophtalmus

- toxic nodular goiter
- thyroid adenoma
- TSH-secreting pituitary adenoma
- clinical features: emotional lability, heat intolerance, sweating, weight loss,
tachycardia, palpitations, atrial fibrillation in elderly patients
Hypothyroidism
- congenital hypothyroidism: cretinism (growth retardation+oligophrenia)

- acquired hypofunction: dry, thick and scaly skin due to the accumulation of
mucopolysaccharides (myxedema), weight gain, lethargy
3 19
References
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University Press, Tiirgu Mure�, 2006.
3. Bosman FT, Carneiro F, Hruban RH, Theise N D (eds.). WHO Classification of Tumors o f the
Digestive System. Ed. IARC, Lyon, 20 1 0.
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Systems Teterboro, New Jersey, 2005.
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Tumors. Pathology&Genetics. Tumours of the Urinary System and Male Genital Organs. Ed.
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Springer, 2010
7. Fletcher CDM (ed). Diagnostic histopathology of tumors. Third ed. Churchil Livingstone
Elsevier, 2007
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2nd Semester Compendium of Systemic Pathology

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2nd Semester Compendium of Systemic Pathology

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Simona Gurzu loan Jung

Diseases of the pericardium

DISEASES OF THE PERICARDIUM

Hydropericardium (pericardia/ effusion)

Definition: accumulation of a air or gases in the pericardia! cavity

Primary pericarditis is a very rare condition. It is usually associated with the

Evolution and consequences of pericarditis

- primary tumors: malignant mesothelioma - very rarely

Fig. 2. Lesions of the pericardium:

ISCHEMIC HEART DISEASE

Clinical syndromes: - angina

Definition: severe episodes of retrostemal chest pain caused by temporary

Chronic ischemic heart disease

Definition: acute myocardial infarction is the coagulative necrosis of the

The process of healing:

24 h-3 days lack of nuclei hyperemia elevated serum

weeks-months the infarcted area white

Table 1 . Clinicopathological features of myocardial infarction according to the

Causes of death: arrhythmias

right coronary artery

left anterior descending artery

Normal blood supply depending on the coronary artery

antero-septal infarction lateral infarction postero-septal infarction

Fig. 3. Localization of myocardial infarction depends on the obstructed artery

Progressively expanding infarction Posterior infarction

Subendocardial infarction Intramural infarction

Fig. 4. Myocardial infarction

Definition: the increase of myocardial fibers m volume as a compensatory

Morphology of cardiac hypertrophy:

Consequences of cardiac hypertrophy: chronic ischemia, myocardosclerosis,

Clinical features: angina, dyspnea, syncopal attacks, hypertension, arrhythmias.

Definition: the enlargement of heart cavities as a compensatory mechanism to

Definition: diseases of the cardiac muscles unrelated to ischemic heart diseases,

Dilated (congestive) cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy

Iatrogenic (doctor-induced) cardiomyopathies

Other related disease:

The inflammation of the myocardium is rare. Myocarditis is usually an acute

Clinical features: asymptomatic or flu-like symptoms, retrosternal pain, fever,

Diagnosis is based on myocardial biopsy which reveals inflammatory infiltrate

PATHOLOGY OF THE ENDOCARDIUM

Definition: endocarditis which occurs during rheumatic fever as a immune reaction

Simple vegetative endor:arditis

Recurrent vegetative non-infective endocarditis

Definition: colonization of heart valves by microorganisms

Acute (malignant) infective endocarditis

Subacute infective endocarditis

Particular types of endocarditis

Marantic, terminal or cachectic endocarditis

Rheumatoid arthritis - related endocarditis

Loffler 's (idiopathic) endocarditis

Syphilis - related endocarditis

Fig. 1 0. Consequences of endocarditis

Definition: congenital or acquired abnormalities of the cardiac valves

Valvular incompetence (insufficiency)

NYHA staging: I. asymptomatic heart failure

Causes of death: progressive pump failure, arrhythmias, renal failure

Left ventricular failure

Secondary metastatic tumors

Coronary artery bypass grafts

Coronary artery angioplasty

Prosthetic heart valves

Stone heart syndrome

Integral valve prosthesis