Supplemental reading
Degeneration
Traditionally the light microscopic morphologic changes indicative of nonlethal injury to cells are called degenerations. It is important to understand that the term degeneration always implies reversible injury. The morphologic expressions of cell injury visible with the light microscope involve principally the cytoplasm. The nucleus is remarkably unaffected, save, perhaps, for some clumping of the chromatin against the nuclear membrane. three distinctive patterns of degeneration can be recognized: cellular swelling, hydropic degeneration and fatty change. There is some virtue in differentiating among these three patterns because they offer clues to the nature of the injury. For example, fatty change in the liver is characteristic of alcoholism but is rare in viral hepatitis. Conversely, the acute stages of viral hepatitis typically are marked by striking hydropic degeneration (ballooning) of liver cells. However, it must not be assumed that individual agents always induce specific morphologic alterations; at best the correlations are imperfect. Sometime an injurious influence first induces cellular swelling, followed by hydropic degeneration, in turn leading to fatty change. Such a sequence is not invariable, however. sometimes cellular swelling passes directly to fatty change or, alternatively, the manifestations of cell injury may not progress further.
Fatty change is the most ominous of the cellular degenerations and commonly encountered in the liver, heart and kidneys. Although reversible, it often implies severe injury and may even forebode cell death. It is characterized microscopical by the accumulation of fat vacuoles within parenchymal cells. Early there are numerours small vacuoles dispersed throughout the cytoplasm, creating a foamy appearance under the light microscope, but nucleus is not displaced. More intense lipid accumulation leads to coalescence of these small droplets into one or more very large vacuoles, which frequently distend the cell and displace the nucleus, sometimes compressing it against the plasma membrane. Indeed, in very advanced fatty change, the cell may appear to be transformed to a fat storage cell. Sufficient accumulation may distend the cell until it ruptures the plasma membrane and coalesces with adjacent cell into a so-called fatty cyst. Whatever the size of the vacuoles, with routine tissue stains(e. g. , hematoxylin and eosin) they appear as cleared spaces. Standard histologic techniques employ lipid solvents which remove the vacuolar contents. However, with appropriate aqueous fixatives and frozen section techniques, the lipid content can be preserved and stained with Sudan Ⅳ or Oil Red O, imparting a red –orange coloration to the lipid globules.
Congestion (hyperemia)
Congestion, or hyperemia, is the presence in the vessels of a tissue or organ of more than the normal amount of blood. Congestion is of two types, active (arterial) and passive(venous), and it may be acute(of short duration) or chronic (long-standing).
Passive congestion is due to an impairment of venous drainage. It may be more or less generalized as in congestive heart failure, in which the entire pulmonary or systemic circulation, or both, may be involved. Localized passive congestion may result from venous occlusion by thrombi or ligatures or from venous compression by adjacent diseased organs. The passive congestion that follows obstruction of one or only a few veins is often transient because of the generally abundant collateral circulation in the venous system. In such cases large collateral veins often develop from previously insignificant vessels. In an organ involved by passive hyperemia, the volume of blood is increased, but the rate of blood flow is decreased.
In chronic passive congestion, the persistent decrease of blood flow leads to ischemic (not pressure) atrophy of the more sensitive parenchymal cells, while the stromal cells tend to proliferate. Repeated capillary hemorrhages produce hemosiderin deposits. The eventual microscopic picture is characterized by widely dilated capillaries packed with red cells; atrophy, degeneration, and even disappearance of some of the parenchymal cells; fibrosis; and deposits of hemosiderin in macrophages and free in the tissues. Edema is a frequently associated lesion. The organs most frequently involved by chronic passive congestion are the lungs, liver, spleen, and pancreas.
The lungs in chronic passive congestion are large, heavy, and frequently edematous. The cut section oozes blood freely and has a rubbery firmness and a rusty brown color (brown induration of the lung). In very severe cases the lung bases may be firm, gray, and relatively bloodless because of severe fibrosis. The large pulmonary arteries are sclerotic with lipid or fibrous intimal plaques. The microscopic changes include markedly dilated septal capillaries which bulge into the alveolar, edema and fibrosis of the alveoli septa with eventual loss of capillaries, cuboidal alveolar lining cells, and many hemosiderin-laden macrophages in the alveoli. The small pulmonary vessels may show fibrous or muscular thickening of their walls.
The liver in chronic passive congestion is initially enlarged but eventually becomes smaller than normal. The external and especially the cut surfaces have a mottled appearance with a continuous purple background (central areas) in which are spaced round or branching, slightly bulging tracts of yellowish tan tissue averaging 1 mm in size (portal areas). This yellow and purple mottling is similar to the cut surface of a nutmeg seed—hence, “ nutmeg liver”. Microscopically the sinusoids are markedly dilated, especially centrally where the liver cells are atrophic (ischemic atrophy due to sluggish blood flow) and may show fatty degeneration, while the periportal cells are normal. In severe cases necrosis of central liver cells occurs and leads to extravasation of red blood cells into the spaces previously occupied by the liver cells—hemorrhagic central necrosis.
(From textbook of Pathology, Bruce. Fallis, M. D. p40-41)
Definition and Nature of Inflammation
When living tissue are injured, a series of changes, which may last for hours, days or weeks, occurs in and around the area of injury. This response to injury is known as inflammation, the term being derived from the Latin inflamare meaning to burn.
The injury is abnormal, but the body's reaction, inflammation, is a normal, if complex, physiological reaction, the only one possible in the circumstances of that particular injury. Its purpose is to localize and eliminate the causative agent, to limit tissue injury and then to restore the tissue to normality or as close to normality as possible. This reactive nature of inflammation was first recognized by John Hunt (1794), who, after his studies of war wounds, concluded: ‘Inflammation is itself not to be considered as a disease, but as a salutary operation consequent either to some violence or some disease.’
Many different types of injury may evoke inflammation. They may be physical agents, chemical substances, hypersensitivity reaction, microbial infections, and necrosis of tissue and so on. The reaction in the first few hours after injury is stereotyped and widely different kinds of injury cause a similar initial response-the acute inflammatory reaction. The terms acute and chronic refer to the duration of the response. Acute inflammation lasts for days or a few weeks; chronic inflammation persists for weeks, months or even years.
The inflammatory response is usually beneficial, indeed it is essential in combating most infections and in limiting the harmful effects of many toxic agents. However it is not always of benefit. There are many situations when destruction of tissue or other untoward effects are due not to the damaging agent but to one or other aspect of the body's response to injury. For example in acute inflammation of the larynx, there may be sufficient inflammatory swelling to obstruct the airway and cause death from asphyxia. Inflammation is best considered not as a single process but as a collection of distinct processes, each of which may have evolved for defense against injury, but each of which has also potentially deleterious effects.
The Mechanism of Cancer Metastasis
Metastasis is the spread of cancer from a primary tumor to distant sites of the body and is a defining feature of cancer. Three steps, as follows, are necessary for production of metastasis: (1) Invasion of cancer cells into lymphatic or blood vessels or into appropriate tissue spaces. (2) Detachment of the cells with embolization or other mechanical transport, and (3) lodgment and progressive growth of the cells in a new location. Every cancer has its own particular growth characteristics, including the ability to invade and metastasize, the time required for metastasis, and the place to which metastases occur. Metastatic ability of a tumor is, of course, influenced by its location, since the nature of the vascular supply of the primary site is important. Many cancers cell seem to be capable of entering the first step in the development of metastasis without necessarily continuing the process to the point of completion. For example, blood vessel invasion is relatively common in many cancers, but it does not necessarily mean that metastasis has already taken place, or that it will. Transport, the second step in the development of metastasis, is more or less mechanical. It is assisted by natural movements of the part, such as peristalsis and by excessive manipulation of the tumor by the patient or physician. Again, however even the presence of tumor cells in the blood stream does not necessarily mean that metastasis will take place. There is considerable evidence that tumor cells are often embolic in blood or lymphatic vessels without production of metastasis. Many tumor cells must be lost along the course.
It is evident that the third step in the development of metastasis is of much importance, tumor cells must lodge and grow in their new location. Not all organs and tissues are equally susceptible to the development of metastases. For example, metastases are relatively uncommon in the spleen or in skeletal muscle, although both must receive many tumor emboli. Conversely, metastases grow well in the liver. Such difference in the "soil" are not well understood and may be related to such factors as variation in vascular size and permeability, local nourishment and local resistance.
Arteriosclerosis
Arteriosclerosis is a hardening and thickening of the walls of arteries. It is a generic term which includes several somewhat different lesions. The most common type of arteriosclerosis, termed arteriosclerosis without qualification, or atherosclerosis to emphasize the fatty plaques (atheromas), is characterized by anatomic changes mainly in the intima. Special types of arteriosclerosis are given qualifying names. Because of the increasing average age of the populace and the decreasing incidence of most infectious diseases, arteriosclerosis, through its effects on various organs, especially the heart and brain, has now become the most important single cause of death in the United States.
Arteriosclerosis is usually a generalized change, but its severity may vary in different regions of the body. The larger vessels are involved mainly, and changes are most readily seen in the aorta. The arteriosclerotic aorta is dilated and often somewhat elongated and tortuous. Scattered irregularly over the intima are elevated, pearly gray, hard plaques with round or irregular outlines. Yellow halos surround some of the plaques. Section of a plaque reveals a superficial layer of hyaline connective tissue and a soft, yellow or orange, grumous or mushy center. In severe cases the large plaques are ulcerated and partly covered by flat mural thrombi. Other plaques may be calcified as thin, curved, scaly plates. Between the plaques the intima is diffusely thickened, gray, and opaque and is frequently longitudinally wrinkled because of post-mortem retraction (not pitted as in syphilitic aortitis). The aorta as a whole is rigid and inelastic. These changes are most severe in the lower abdominal aorta and in the iliac arteries. Plaques tend to localize particularly about the openings of branches, and there is usually an especially severe plaque at the site of insertion of the ligamentum arteriosum.
In general, the muscular arteries undergo the changes of arteriosclerosis later in life than does the aorta, and the resultant plaques are more fibrous and less lipidized. An exception to this generalization is the coronary arteries, which sometimes undergo arteriosclerosis rather early in life, especially in men. Cases of coronary arteriosclerosis without significant arteriosclerosis of the aorta or other vessels are not infrequent in men between ages 30 and 50. Coronary plaques are mainly fatty in type and occur predominantly in the proximal parts of the arteries. Cerebral arteriosclerosis occurs late in life, and the basilar and middle cerebral arteries are most severely involved. Arteriosclerosis often affects the internal carotid arteries, especially near the bifurcation of the common carotids and within the skull. Abdominal arteries, with the exception of the splenic artery, are rarely the seat of severe arteriosclerosis, except at their origins from the aorta, until quite late in life. Peripheral arteries, chiefly those of the lower extremities, are often sclerotic; the most severe changes occur in the femoral and popliteal arteries. The pulmonary arteries are usually almost free of arteriosclerosis.
(From textbook of Pathology, Bruce. Fallis, M. D. p394-396)
Obstructive emphysema
Obstructive emphysema is a chronic, usually progressive, largely irreversible pulmonary disease characterized by persistent overdistention of the lungs and gradual loss of pulmonary tissue . The pulmonary changes are diffuse but not always uniform and are caused by obstruction to air flow, especially during expiration. The obstruction to airflow is usually the result of chronic inflammation of the bronchial tree, and in England the term “chronic bronchitis ” is essentially synonymous with obstructive emphysema.
Obstructive emphysema is a very common disease and is found to some degree in about one-third of all autopsies. In England, where this disease is apparently somewhat more common than in the United States, “chronic bronchitis”is surpassed as a cause of death only by heart disease, cerebrovascular accidents, and cancer and constitutes the cause of 10 percent of all medical visits to general physicians. Obstructive emphysema is more common in men than in women (about 10:1), usually occurs after age 40, and is not definitely familial, although there may be a constitutional predisposition.
At autopsy in a case of obstructive emphysema the thoracic cage is usually enlarged with an increased anteroposterior diameter (barrel chest). The diaphragm may be hypertrophied, measuring up to 1cm in thickness, and is usually low and flat. When the sternum is removed, the voluminous lungs overfill the thoracic cage and bulge outward through the incision in the chest wall. Extensive fibrous pleural adhesions are usually present. The lungs, after removal from the chest, remain large and do not collapse. They are soft, fluffy, relatively bloodless, and usually darkly pigmented by carbon. After they have been transected, the lungs collapse and lie flat on the cutting board, and the fact that pulmonary tissue has been lost is obvious.
(From textbook of Pathology, Bruce. Fallis, M. D. p292-293)
Cirrhosis
Cirrhosis is a collective term, which includes those chronic liver diseases in which hepatic injury is associated with fibrosis of the liver. Cirrhosis is, thus, essentially synonymous with chronic productive hepatitis. Cirrhosis is characterized anatomically by (1) widespread but not necessarily uniform involvement of the liver; (2) degeneration, necrosis, and usually regeneration of liver cells; and (3) fibrosis of the liver, sometimes associated with partial or complete loss of lobular architecture. Most cases of cirrhosis are progressive and terminate in death due usually to failure of liver function or complications of portal venous hypertension.
The classification of cirrhosis is based on the anatomic changes in the liver. Unfortunately this anatomic classification correlates only imperfectly with the incompletely known causes of cirrhosis; i. e. , a given type of cirrhosis may have several different causes, and the same factor may cause different types of cirrhosis under different circumstances. The most important types of cirrhosis (with common synonyms) are (1) portal cirrhosis (Laennec’s cirrhosis, alcoholic cirrhosis, fatty nutritional cirrhosis; when the term cirrhosis is used without qualification, portal cirrhosis is usually implied), (2) postnecrotic cirrhosis (coarse nodular cirrhosis, healed yellow atrophy, posthepatitic cirrhosis, chronic hepatitis), and (3) biliary cirrhosis (obstructive cirrhosis). Later in the chapter a section is devoted to each of these types of cirrhosis. Uncommon types of cirrhosis in the United States include cardiac cirrhosis (congestive cirrhosis), the pigmentary cirrhosis of hemochromatosis, and zooparasitic cirrhosis caused by the liver fluke or by schistosomiasis.
The cirrhotic liver is usually abnormal in size, shape, consistency, and color, the exact changes varying with the type of cirrhosis. The liver may be enlarged by an infiltration of fat or other materials. On the other hand, progressive loss of parenchymal cells and retraction of fibrous tissue lead to reduction of liver size. In a given case, the liver may be enlarged early (“hypertrophic cirrhosis”), only to shrink progressively as time passes so that the liver is small at the time of death (“atrophic cirrhosis”). In some cases, the left lobe of the liver is injured severely than the right and becomes disproportionately small, probably because the left lobe receives nutritionally inferior blood from the splenic and inferior mesenteric veins while the right lobe receives blood from the superior mesenteric veins (this results from a “streamline flow” in the short portal vein). Although the overall shape of the liver is usually retained, the external and cut surfaces are usually nodular (hobnail liver) with projecting masses of soft liver tissue separated by sunken bands of gray fibrous tissue. Because of the increase of fibrous tissue, the liver is firm or hard and cuts with increased resistance. The color of the cirrhotic liver varies and consists of one or more of the following: red-brown (liver parenchyma), gray (fibrous tissue), yellow (fat), and orange or green (bile).
(From textbook of Pathology, Bruce. Fallis, M. D. pP353-354)
Peptic Ulcer
Peptic ulceration occurs in the stomach and duodenum. Both acute and chronic forms are founded, the latter being more common.
Clinical Features. Approximately 10 per cent of the adult male populations are affected by peptic ulceration. The male incidence is higher, the proportion being 3:2 for gastric ulcer and 10:1 for duodenal ulcer. Duodenal ulcers are three to four times as common as gastric ulcers and most occur between the ages of 30 and 40 years, a decade or so earlier than gastric ulcers. In about 20 per cent of the latter a duodenal ulcer is or has been present all in almost all instances it precedes the gastric lesion.
The history is very important and the diagnosis may often be made on to alone. Periodic epigastria pain occurs after meals, discomfort from a gastric ulcer being noted half to one hour after food whilst the stomach is still full, gradually passing off as the organ empties, or relieved by vomiting. In a duodenal ulcer, a long post parricidal interval of two to three hours offend exists before pain is apparent and it may then occur immediately before next meal. Both food and alkalis relieve the pain initally, although relief is greater in a duodenal than in a gastric ulcer. Involvement of the pancreas may produce backache, which can mistakenly be attributed to an orthopedic lesion. Nocturnal pain, at times sufficient to wake the patient from sleep, is often a feature of a duodenal ulcer. Flatulent dyspepsia may be the main symptom and aggravation by a fatty diet will stimulate gall bladder disease. The appetite generally remains with loss of weight. Lassitude and malaise may occur with secondary anemia from chronic blood loss. Mental irritability is often prominent, but between attacks the patient is usually eel and symptom free. Remissions, initially lasting months or years, become shooter and the attacks more frequent. The latter may persist for days or weeks and are often related to dietary indiscretion or periods of intense worry or strain.
On examination the main physical sign is tenderness in the epigastrium or right hypochondria, but between attacks this may be absent.
Chronic Glomerulonephritis
Symptomatic chronic glomerulonephritis is preceded by latent glomerulonephritis. In the latent stage there are no symptoms, but the presence of slight hematuria and proteinuria indicates the gradual progression of glomerular inflammation；the blood pressure is normal at first but eventually becomes elevated. Latent glomerulonephritis may heal but usually passes imperceptibly into chronic glomerulonephritis. The clinical course of chronic glomerulonephritis is characterized by the insidious onset of progressive， irrevocable renal failure and hypertension. Hematuria and proteinuria occur but are usually slight. About one patient in four will have one or multiple exacerbations resembling acute glomerulonephritis，usually after a streptococcal infection. The hypertension may become malignant，and some degree of congestive heart failure is common. Death is due to uremia and usually occurs in adolescence or early adult life，about one year after the first symptoms of uremia.
In the history of patients with chronic glomerulonephritis there may have been an initial attack of acute glomerulonephritis，usually 5 to 15 years previously. However，many patients with chronic glomerulonephritis give no history of acute glomerulonephritis；it is unclear whether such cases represent a different disease from those cases which begin with acute glomerulonephritis or merely instances in which a mild acute glomerulonephritis was overlooked or forgotten by the patient. A carefully taken history often reveals a partial or complete nephrotic syndrome（see Membranous Glomerulonephritis and the Nephrotic Syndrome）several years before the onset of chronic glomerulonephritis.
At autopsy in a case of chronic glomerulonephritis the kidneys grossly are very small (about 50 gm each)，especially in long-standing cases in persons beyond adolescence. Each renal capsule strips with great difficulty to reveal a coarsely granular，firm，very pale，grayish white kidney.On the cut surface the renal architecture is obscure，and the cortex is very thin. Microscopically the changes are diffuse but not entirely uniform. Progressive hyalinization of the glomerular tufts obliterates the glomerular capillaries，and eventually the hyaline glomerulus fuses with the thickened glomerular capsule to produce a small，pink，acellular ball. Such hyaline globules may finally be resorbed，so that no trace of the preexistent glomerulus remains. Because the peritubular capillaries arise from the efferent glomerular arterioles，glomerular hyalinization causes ischemic tubular atrophy involving most of the tubules. There is severe interstitial fibrosis，both collapse and productive in type，and the interstitial tissue is infiltrated by lymphocytes. A few partially hyalinized glomeruli still contain some patent capilaries and are only focally adherent to such glomeruli usually undergo compensatory hypertrophy in an attempt to maintain renal function；they are dilated，and their epithelial cells are large. Such hypertrophied nephrons produce the coarse granules seen on the external surface of the kidney grossly. Secondary vascular changes are caused by hypertension and consist of arteriolosclerosis（hyaline or hyperplastic） or arteriolar necrosis. Either benign or malignant nephrosclerosis may be superimposed on the other renal changes. The type and severity of the vascular changes depend on the severity and duration of the hypertension and the age of the patient.
(From textbook of Pathology, Bruce. Fallis, M. D. p489)
Tuberculosis
Tuberculosis (phthisis, consumption) is caused by Mycobacterium tuberculosis. The tubercle bacillus is an aerobic bacterium, which grows slowly. Within limits, an increased oxygen tension stimulates its growth, which is perhaps a factor in its usual localization in the lungs. There are three strains of Mycobacterium tuberculosis. Infection with the bovine strain is acquired by ingestion of milk from infection cows, and most cases occur in children with the initial lesions in the tonsils and cervical lymph nodes (scrofula) or in the intestine and mesenteric lymph nodes. Infection with the bovine strain is rare in the United States because of eradication of tuberculosis in cattle and pasteurization of milk but constitutes about 10 per cent of tuberculosis elsewhere. The avian strain rarely if ever causes progressive tuberculosis in man. The human strain causes almost all cases of tuberculosis in the United States, and the remainder of the discussion of tuberculosis deals with this strain. Infection with the atypical mycobacterium is discussed later.
The tubercle bacillus has a waxy cell wall which is in part responsible for its acid-fast character (i. e. , it resists decolorization by acids after having been stained by certain aniline dyes). The tubercle bacillus is rich in phospholipid, and this lipid is apparently related to the granulomatous inflammation and tubercles which occur in tuberculous lesions. The protein fraction of the bacillus, tuberculoprotein, is evidently responsible in some way for the development of bacterial hypersensitivity during infection (see under Determinants of Tuberculous Lesions). Tubercle bacilli produce neither an exotoxin nor an endotoxin, and tissue injury during infection is dependent mainly on bacterial hypersensitivity.
The source of infection with the human strain is persons with chronic pulmonary tuberculosis. Usually infection results from continued close exposure to a tuberculous patient, e. g. , a household contact. Transmission is by airborne bacilli. From the lung lesions the bacilli are expelled in droplets by coughing. Although these droplets are, of course, infectious, they quickly settle out of the air. However, the tubercle bacillus resists drying (but not direct sunlight) because of its waxy cell wall and survives up to several months in dried sputum. Dust from dried sputum is the chief source of airborne bacilli and is the major vehicle of infection.
Tuberculosis is endemic in all countries and is the most important chronic infectious disease. In 1900 tuberculosis was the most frequent cause of death in the United States. The mortality rate of tuberculosis has declined for many decades primarily as a result of an improvement in general living conditions in most countries. Better methods of diagnosis, isolation, and treatment may have contributed to the more rapid rate of this decline in recent years. Epidemiologic studies have not clarified all the causes of long-term variations in the rate of tuberculous mortality, but urbanization and substandard living conditions seem to be the most important factors in increasing the rate.
(From textbook of Pathology, Bruce. Fallis, M. D. p221)