Kleinsmith_ch1 - BENIGN AND MALIGNANT TUMORS Now that you...

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Unformatted text preview: BENIGN AND MALIGNANT TUMORS Now that you have been introduced to some basic statis- tics related to cancer incidence and mortality, we are ready to consider the underlying biology of the disease. No matter where a cancer arises and regardless ofthe cell type involved, the disease can be defined by a combination of two properties: the abiiity of cells to proliferate in an uncontrolled fashion and their obit'ity to spread throughout the body. Although cell proliferation is therefore a defining feature of the disease, it does not mean that every new growth of tissue is a cancer. To the contrary, most new tissue growths are not cancers. We will therefore begin by considering the common types of tissue growth and the criteria that need to be met before a growth can be diag— nosed as being cancer. Hypertrophy and Hyperplasie Involve an Increase in the Size or Number of Normal Cells In many situations, new tissue growth occurs as part of a normal physiologicai response to a particular stimulus. For example, if you were to start a new job that involves [a] Hypertrophy {c} Dysplasia id) Neoplasla lifting heavy objects, your muscles would soon grow larger in response to the physical activity. Professional athletes and body builders adapt this principle when they use weight—lifting exercises to build muscle mass. yet the growing muscles on their arms and legs are not signs of cancer! Or perhaps you want to learn how to play the guitar. You will find that after a few days of practice, the skin on the tips of your fingers becomes thickened with calluses from pressing on the strings. Once again, the growing calluses on your fingertips are not signs of cancer. The preceding examples illustrate two types of new tissue growth, neither of which is cancer. The increase in muscle mass triggered by exercise arises from the growth of individual muscle cells rather than an increase in the number of muscle cells. Such tissue growth based on an increase in cell size is called hypertrophy (Figure l-3a). In contrast, calluses are produced by hyperplasia, a process in which cell division creates an increased number of normal cells (Figure l-3b). In both cases, the process is potentially reversible. If you stop exercising or stop playing the guitar. the size of your muscles will decrease or your calluses will disappear. - Increase in cell size ' Normal organization - increase in celi number - Normal organization - Disorganized growth - Disorganized growth - Net increase in number of dividing cells Figure 1-3 Four Major Types [II New Tissue Gromh. Hypertrophy is tissue growth based on an increase in cell size, and hyperplasia is tissue growth based on an increase in cell number. Hypertrophy and hyperplasia both maintain normal tissue organization and are potentially reversible. Dysplasia is an abnormal growth process that disrupts normal tissue organization. Areas of dysplasia can revert back to normal or can develop into neoplasia. ln neoplasia, disorganized and uncontrolled growth leads to a net increase in the number of dividing cells. Red shading is used to identify cells that are capable of dividing. 4 Chapter1 What Is Cancer? Dysplasia and Neoplasia Are Characterized by Abnormalities in Cell Organization and Proliferation When a piece of tissue in which hypertrophy or hyper- plasia has occurred is examined with a microscope, the cell and tissue organization will look relatively normal. in contrast, the next type of tissue growth to be considered, called dysplasia, is an abnormal growth proCess that produces tissue in which proper cell and tissue organiza- tion have been disrupted [Figure l-3c). The extent of the abnormalities varies across a broad range referred to as mild, moderate, or severe dysplasia. One site in which dysplasia commonly arises is the uterine cervix. As we will see in Chapter 11, the Pap smear is a routine screening procedure that can detect uterine dysplasia in its early stages before it has progressed to a tnore serious condi- tion. Dysplasia has two possible outcomes. In sortie cases, especially in its less severe forms, dysplasia is reversible and the tissue will revert back to normal appearance and behavior. Alternately, dysplasia can become more severe, eventually progressing to a more dangerous form of tissue growth known as neoplasia. Neoplasia is an abnormal type of tissue growth in which cells proliferate in an uncontrolled, relatively autonomous fashion, leading to a continual increase in the number of dividing cells {Figure l—3d). This loss of growth control creates a proliferating mass of abnormal cells called a neoplasm or tumor. Uncontrolled prolif- eration does not mean that tumor cells always divide more rapidly than normal cells. The crucial issue is not the rate of cell division btit rather the relationship between cell division and cell differentiation, the process by which cells acquire the specialized properties that distinguish different types of cells from one another. Cell differentiation is a trait of multicellular organisms, which are composed of complex mixtures of specialized or “differentiated” cell types for example, nerve, muscle, bone, blood, cartilage, and fat—brought together in various combinations to form tissues and organs. The various types of differentiated cells are distinguished from one another by differences in their structural organization and in the products they manufacture. For example. red blood cells produce hemoglobin, nerve cells synthesize chemicals that transmit nerve impulses, pancreatic islet cells make insulin, and so forth. In addition to manufacturing such specialized products, differentiated cells often lose the capacity to divide. In normal tissues, the rates of cell division and cell differentiation are kept in proper balance. To illustrate, let us briefly consider normal cell proliferation in the skin, where new cells are continually being produced to replace the cells being shed from the outer surfaces of the body. These replacement cells are generated through the division of undifferentiated cells located in the basal layer of the skin (Figure 1—4, top). Each time one of these basal cells divides, it gives rise to two cells with differing fates: One cell stays in the basal layer and retains the capacity to divide, whereas the other cell loses the capacity to divide and undergoes differentiation as it leaves the basal layer and moves toward the outer skin surface. As it differentiates, the migrating cell gradually acquires a flat— tened shape and begins to tnake keratin, the fibrous structural protein that itnparts mechanical strength to the outer layers of the skin. The fully differentiated, thin flat cells that form the outer layer of the skin look almost like scales and are referred to as squamous cells. Because only one of the two cells produced by each basal cell division normally retains the capacity to divide, there is no increase in the total number of dividing cells. Cell divisions are simply creating new differentiated cells to replace the ones that are being lost from the outer surface of the skin. A similar phenomenon takes place in the bone marrow, where new blood cells are produced to replace aging blood cells that are constantly being destroyed, and in the lining of the gastrointestinal tract, where new cells are produced to replace the cells that are being shed. In each of these situations, cell division is care— fully balanced with cell differentiation so that no net accumulation of dividing cells takes place. In tumors, this finely balanced arrangement is disrupted and some ceil divisions give rise to two cells that both continue to divide, thereby feeding a progressive increase in the number of dividing cells {see Figure 1—4, bottom right). If the cells divide quickly, the tumor will rapidly increase in size; if the cells divide more slowly, tumor growth will be slower. But regardless of how slow or fast the cells divide, the tumor will continue to grow because new cells are being produced in greater numbers than needed. As the dividing cells accumulate, the normal organization and function of the tissue gradually become disrupted (Figure 1-5}. Malignant Tumors (Cancers) Are Capable of Spreading by Invasion and Metastasis Now that the concept ofa tumor has been introduced, we are finally ready to define the term cancer. The meaning of this word is based on differences in the growth patterns of tumors that allow them to be subdivided into two fttnda— mentally different categories. One group consists of benign tumors, which grow in a confined local area, In contrast, malignant tumors can invade surrounding tissues, enter the bloodstream, and spread to distant parts of the body by a process called metastasis. The term cancer is a generic term that refers to any malignant tumor—that is, any tumor capable of spreading by inva- sion and metastasis. Table 1—] summarizes some of the properties of benign and malignant tumors. One distinguishing feature is that malignant tumors are frequently life threatening, whereas benign tumors usually are not. The reason for the Benign and Malignant Tumors Normal Growth Outer skin surface / Shedding of dead cells Squamous cells Cell l l . _ T migration l - Basal layer (dividing cells} Tumor Growth Underlying Basal lamina Underlylng tissue tissue 0 0 O c; 0/ o “7/ 0/ \O \O/ D " \. 0/ “*0 \fl / 0 \O x, O 0 \q / \O / K” \m \ 0 Figure 1-4 Comparison of Normal and Neoplastic Growth in the Epithelium at the Skin. {lop ltfli} In normal epithelial growth. proliferation of cells located in the basal layer gives rise to new cells that migrate toward the outer surface of the skin. changing shape and losing the capacity to divide. l'liip right] In neoplastic growth, this orderly process is disrupted and some of the cells that migrate toward the outer surface retain the capacity to divide. In both diagrams, lighter shading is used to distinguish cells that retain the capacity to divide. {Bottom} Schematic diagram illustrating the fate ol'dividing cells. In normal skin, each cell division in the basal layer gives rise to one cell that retains the capacity to divide h, {lighter color) and one that differentiates thereby losing the capacity to divide. its a result. I no net accumulation of dividing cells occurs. In neoplastic growth. the balance between cell i- division and cell differentiation is disrupted. thereby leading to a progressive increase in the . l number of dividing cells t lighter color}. dillcrence is that the cells ofa malignant tumor have often spread to other parts of the body by the time a person is diagnosed as ltaving cancer. A surgeon will frequently be able to remove the original tumor, but cancer cells that have already spread through the body are difficult to locate and treat. i'V-lalignant tumors therefore tend to he more hazardous than benign ones, although some excep— tions do occur. For example, the most common forms of skin cancer rarely metastasize and are easy to diagnose and remove, so these skin cancers are hardly ever fatal. Certain benign tumors, on the other hand, arise in surgi— cally inaccessible locations, such as the brain, making them hazardous and potentially life threatening Differences in growth rate and state of differentiation . are also common between benign and malignant tumors. Benign tumors generally grow rather slowly and are com— posed of tt-‘c’ll-dtflifl‘c’nflared cells, meaning that the cells bear a close structural and functional resemblance to the normal cells of the tissue in which the tumor has arisen. Malignant tumors, on the other hand. often {but not Chapter1 What Is Cancer? always} grow more rapidly and their state of differentia— tion is variable, ranging from relatively well—differentiated tumors to tumors whose cells are so poorly differentiated that they bear almost no resemblance to the original cells from which they were derived. Benign and Malignant Tumors Are Named Using a Few Simple Rules Because tumors can arise from a variety of cell types located in different tissues and organs, some basic conventions have been established to facilitate the naming of tumors. Depending on their site of origin, cancers are grouped into three main categories. (1) Carcinomas are cancers that arise front the epithelial cells that form Covering layers over external and internal body surfaces. Carcinomas are by far the most common type of malignant tumor, accounting for roughly 90% of all human cancers. {2} Sarcomas are cancers that originate in supporting tissues such as bone, cartilage, blood vessels, fat, fibrous tissue. and muscle. They are the Figure 1-5 Colon Cancer Specimen Viewed by Light Microscopy. Mallgnant The left side shows normal colon tissue covered by an epithelium containing numerous tubular mucous glands. 0n the right side, proliferating cancer cells derived from the epithelium have disrupted the organized pattern of mucous glands and are invading the underlying tissue. ICourtesy of Gerald I). Abrams} rarest group of human cancers, accounting for about 1% of the total. (3) The remaining cancers are the lymphomas and leukemias, which arise from cells of lymphatic and blood origin. The term iymphomn refers to tumors of linnphocytes (white blood cells) that grow mainly as solid masses of tissue, whereas leukemins are cancers in which malignant blood cells proliferate mainly in the bloodstream. Within each of the three groups, individual cancers are named using prefixes that identify the cell type involved. For example, consider a cancer arising from a Table 1-1 Some Properties of Benign and Malignant Tumors Benign Malignant Spreads by invasion and metastasis Often Growth pattern Local growth oiin Life threatening Rarely Usually slow May be rapid State ofdifferentiation Well differentiated \"ariable _—__—.—_._.— Growth rate gland cell, which is a specialized type of epithelial cell. Such a cancer is named by inserting the prefix orienti— [meaning “gland") in front of cm'cinoma (the term for epithelial cancers). yielding the name ridertm‘arcinomn. Depending on the organ where it originated, the tumor might be called a lung adenocarcinoma, a colon adenocar- cinoma, a breast adenocarcinoma, and so forth. What if the tumor were benign instead of malignant? In this case the suffix —oma is used instead of -cnrcinomn. yielding the name adenomn. Cancers of supporting tissue origin are named in a similar fashion, except the suffix —srirr'rmirt is employed instead of -mrcinomn. Thus a cancer of bone cells is called an osteosnrcorrrn (the prefix osten- means “bone”), and a benign tumor of bone is an osrcrmm. Once you know the meanings of the prefixes that designate each of the common cell types, it is relatively straightforward to construct the proper technical names for a wide variety of tumors. The meanings of these prefixes, and the ways in which they are combined to create tumor names, are summarized in 'I‘able 1—2. Malignant tumors can usually be recognized by the presence of “carcinoma” or "sarcoma" in their name, but there are several exceptions. For example, Benign and Malignant Tumors despite their l‘ienign—sounding names, melanomas are malig— nant tumors of pigmented cells, lit-'tttpltorttris are malignant tumors til—lymphocytes, and ttn’clomrts are malignant tumors (II—hone marrow cells. the tumor names listed in 'l‘ahle 1—2 rel-er to the site at which a tumor initially arises—the so—callecl primary tumor. littl‘ example. a tttmor discovered in a person's liver might be a liver adenocarcinoma. but it might also consist ol' stomaclt or colon cancer cells that had ntetastasixed to [lie livcr via the l‘Iloodslream and began growing there. In such cases. the tumor is not a liver cancer l‘llll rather a colon or stomach cancer that has metastasixed to the liver. WAYS IN WHICH CANCERS DIFFER 'l'he need to have distinctive names for the various kinds of cancer is not just an academic exercise; it rellects the tact that the various types of cancer often behave like dit— t'erent diseases. For example, cancers grow at varying rates. look till-IL‘I‘L‘III when observed with a microscope. metasta— size at varying frequencies. spread to different sites. and respond dit‘lerently to various treatments. Differences are even exhibited by cancers of the same type. In other words. all melanomas do not behave the same, all lung adcnocarcinotnas do not behave the same, and so forth. In Table 1-2 Naming Tumors the following sections. we will brielly discuss sotne ol‘ the tnore important ways in which cancers dil‘t‘er. Cancers Vary in Their Site and Cell Type of Origin The lii‘st and most obvious way in which cancers dit‘t‘er t‘t'ont one another is in their site of origin. We saw earlier in the chapter that the most common cancers in the United States arise in the skin, prostate. breast, lung, and colon. While these five sites account for more than FS‘l-i: of all cancers, the disease can originate in almost any [issue of the body. Table l—3 provides a list of more than 40 locations where cancer tnay arise and the frequency of its occurrence at each site. Even when cancers develop in the same tissue or organ, different forms of the disease can be distinguished based on the cell type involved. For example, a skin cancer might be a basal cell carcinoma, a squamous cell carcinoma. or a melanoma. The situation is even more complex for lung cancer, where at least seven main types have been distinguished [squamous cell carcinoma. small cell carcinoma. large cell carcinoma. adenocarcinoma, adenosquantous carcinoma. carcinoid tumor. and bronchial gland carcinot‘nal. Subdivisions even occur within these seven groups; for example‘ large cell carcinoma is further divided into giant cell carcinoma and Prefix Cell Type Benign Tumor Malignant Tumor Tumors of epithelial origin .\deno- tiland Basal cell liasal cell Squamous cell Squamous cell .\|elatto- l'igmented cell 'l'et'ato- Muhipotential cell Adenoma .-\Llct‘toc.trcinonta Basal cell adettotna Ker-atoacatttltottta Mole 'i'eratotna 'l'ttmors of supporting tissue origin {:lttll‘ltli'tl (Iar'tilage liiliro- Fibroblast llernangio— lilood vessels Smooth muscle leiutnyo- l.l[‘t1- lull Meningio- Meninges .\i_\'tt- Muscle Usleti- [itttte lthalnlomyn- Striated muscle Tumors of blood and lymphatic origin lympho- l._\'tttphoc‘}'lc‘ l'.r_vthro- l-.r_\'t|n'oc_\'le .\II\'clt:- litittc tttart'ow {Ihondroma Iiibroma l'letnangiotn a |.eiotnyoma lipoma Meningioma Myoma (islet-ma Rhahdo tn yoma Itasal cell carcinoma Squamous cell carcinoma Melanoma' 'leratocarcinoma tjhondrosarcotna }-iht'os-.trcot‘na }Ieniattgiosareottta l.eiomyosarconta liposarcoma _\.1ettingiosarcoma _\l_vosarcottta Usteosarcoma Rhabdomyosarcoma l._\'l'l'lpl'lt}ttl.t' or lymphocytic leukemia |-'.r_vthroct'tic leukemia Myelon‘ta' or t‘nyelogenotts leukemia ‘Kute that certain tumors. such as melanoma. lyntphonta. anti nn'eloma. .trc malignant tit-spnc a Iwnign-sounding name. 8 Chaptert What Is Cancer? clear cell carcinoma. A similar level of complexity exists in Cancers Vary in Their Survival Hates many other organs, explaining why cancer ends up - v . ll‘c in 11: v ' a "in“."t *‘ l behavrngltke hundreds oi drtierent diseases. t 1" on 101 "m ledg‘" th ll U “r” “m 1‘1“ 13mph lhe main threat comes from the ability of cancer cells to enter the bloodstream and spread to distant organs. lt' circu— Tab191'3 ESlimated New Cancercases and Deaths lating cancer cells enter a vital organ such as the liver. '0' the Year 2005 in the Un'ted States brain. or kidneys. the growth of cancer cells in these loca— ___________.____._——-———-—- Primary Site New Cases Deaths tions can disrupt tissue organization and destroy normal cells. eventually leading to organ Failure and death, In Ski"l1“"”“d“'1”m"i' I'i'l‘fluu‘m” mm] addition, some cancer cells produce substances that "mil-‘1“ 353m“ “‘33” interfere with the function of the immune system. thereby “WEN “3‘93" “U37” making people more susceptible to potentially lethal Lungli'k'lmlmti1“"‘lk'hll‘l 17357” “‘351” infections. 'l'he drugs or radiation treatments that are (Zulnnantlrectum 14129:: Sagan commonly used to treat cancer patients also tend to t‘rtnary bladder auto lttso inhibit immune function. again creating the risk of infec- Mshnmm lslsllll 39.580 17,-.” tions that can be lethal. Finally. the presence of cancer cells in the body sometimes triggers cm‘ltexirt. a life—threatening Kon- l-lodgkin's lymphoma infill) | LJ.10[l Uta-memdummm mm} T 3”] condition clutracternted by extensive weight loss. weak— Kidney land renal pelvisl fitnlhil [Loon "cam and mi‘l‘lmminmn‘ ' I _ Although most cancers are potentially hie threat— l’attcr'eas 33.150 3.! .500 . , t _ , ' H _ _ ening for one or more ol the preceding reasons. the lhvmttl 3.1.09” 1.19:1 . ...L _ ' dangers vary enormously because ol drlierences In how Ovary 22.330 lt\._‘ll -_ _ __ _ ‘_ I _ ‘_ _ _ - last cancers grim and how frequently they metastasrre. - - 1 ‘ 7‘ . - . . . I ‘ “mam 'l‘é‘w “’93” One way ot comparing the risks associated with various "ri‘1T‘-‘“"”""""“””F'5“'m “3”” “7“” kinds of cancer is to examine the five-year survival rate. l-it't‘r 15-43“ which is defined as the percentage of cancer patients who h‘lt'elrtgenousleukemia}. lsjho 9.2130 are still alive live years after initial diagnosis. As shown in Multiplenit'clotna 15.980 11._too Figure I—o. live—year survival rates vary significantly" Esophagus 14.33:: 1357-11 ranging from 99% lit-'e—vear survival for skin cancer to mehmvt-u.lwkrmim 1550“ MN” less than 2091) live-year survival for cancers of the lung. utrim mm m 3—“ 3 T m esophagus. liver, and pancreas. “mm. H. “T” l 3.)“ The rates illustrated in liigure H: are averages for all I r (J W] 1 __n cancers arising in each organ. Because different tvpes of ,J 't'IlK .‘ n 3.; ‘ Soft tissues 9.410 3.490 l’ltarvns 8.590 3.130 .' Nonmelanomastm — Testis H.010 sun P - -- Tnnguc than 133:: mm“? - I Gallbladder. other biliary Tt-ISIJ _t..‘~-I0 Tesus —l I'lotlgkin's disease llvrnphomal 7.350 I.-ll0 ME‘lanoma r__ l Other nonepilhelial skin ta.-llll 3.810 Breast Small intestine 3.420 1.070 5 Bladder ] Other digestive 3.2m 3.-lt]0 é Uterine cervix :: U Ulherleukentia -l.35i] (Ltfiil' “5 Colon :: CU .. _- auto 2 a ‘““‘ " “ “ t: Ovary Vulva s.s?n am _ _ Stomach — Utheroral cavity 3.050 I570 _ _,, Lun - Bones and iotnls 2.100 [.2 l0 9 Ureter. other urinary organs 25in 7:30 Emphagu" - Other respiratory 3‘_t;“stl 3hr; Liver - \fitginamtber tent-ale genital 2.1-0} h‘ltl Pancreas I Eye and orbit 1.12:: no ' ' T ' . too Other endocrine l.%[l 830 O _ 50 _ _ _ Five-year survwal [‘40] Penis. other male genital 1.470 .170 A“ mm Sim. 3mm, “.33” Figure 1-6 Five-Year Survival Rates for Selected Types of Cancer. ___________————-—-—— (lancer survival rates are lot the l‘nited States during the period Based on data than Lancer l-irt'ls c- l’ierrrrs 2005 :.-\t|ant.t. t ..-\: .-\nre1it.m l‘N5 Jilllt]. Based on data Irom { 'trntr-r hr.- t" i'iJ‘U'IW't" -""i-'." ' -\ll\iltl.t. ti.\: _ (Lancer Society. 100%. p. -I. -\1tier'ic.ln t once-r hm ictv Jltllh .p. 1 Ways Il'l t-“tlllieli Cancers Dilior 9 cells can beconte cancerous in any given organ, such averages often mask important information. In the case of skirt cancer, for example, the overall 99% rate does not tell you that the five—year survival rate for basal cell carci— noma of the skin is greater tltan 99.9‘Eb, which means that fewer than 1 person iIt ltllltl dies from it. in contrast, melanoma a skin cancer arising from pigmented cells has a five—year survival rate of roughly 90%. While 90% is still relatively ltiglt, it means that melanoma kills about 1 person in it]. compared with 1 iii lUUO for basal cell carcinoma. i\-'lelanonta is thus IOU times more dangerous than basal cell carcinoma, even tltough both are forms of skin cancer. Despite the usefulness of five—year survival statistics in making such comparisons, a note of caution is required regarding their interpretation. Five-year survival is calcu— lated starting from the time ofdingnosis, which means that this statistic is influenced by differences in detection rates. To illustrate, let us consider two hypothetical wonten, named Carol and Diane, who both develop breast cancer at age 50. Suppose that Carol has her cancer detected that same year at an annual medical exattt, whereas Diane does not have ready access to medical care and her cancer isn't detected until she discovers it three years later at age 53. ll“ Carol and Diane were both to die of breast cancer at age 5?, the five—year survival statistics would indicate that (Iarol was alive five years after diagnosis {diagnosis at 50, death at 57) whereas Diane was not [diagnosis at 53, death at 5?}. Yet both women developed cancer at the same time and died at the same time! (Iarol was simply diagnosed earlier and was therefore represented as being alive in the five-year survival statistics, whereas Diane was not. This tendency for survival rates to appear to be improved by early diagnosis when no improvement has actually occurred is called lead time bias. Although we will see later that early diagnosis really does improve a persons chances of being cured, this example illustrates that the phenom— enon of lead time bias makes it impossible to reach such a conclusion based on five—year survival statistics alone. Cancers Vary in Their Appearance Given the large number of differettt kinds of cancer, it is perhaps not surprising to find that cancers seldont look exactly alike, either to the naked eye or under the microscope. Because of this diversity, various technical terms have been introduced to describe a given cancer’s appearance. For example, the term polyp is used to describe arty mass of tissue that arises from the wall of a hollow orgatt, such as the colon, and protrudes into the lumen, often attached to the wall by a relatively thin stalk. Calling something a “polyp” does no tnore than describe what the tissue growth looks like to the naked eye. A polyp might be a benign or a malignant tumor, or it might not even be a tumor at all (for example, nasal polyps are inflammatory swellings of the tissue lining the nose). Cancers also have a distinctive appearance when they are viewed with a microscope, and this appearance usually 10 Chapter 1 What Is Cancer? provides the basis for cancer diagnosis. Thus when a person exhibits symptoms or signs that suggest the possible presence of cancer, a doctor will usually cut out a small piece of tissue for microscopic examination. The process of removing tissue for diagnostic purposes is called a biopsy, and examination of the tissue specimen is carried out by a specialist called a pathologist. By looking at a biopsy specimen under a microscope, a pathologist can determine whether a tumor is presettt, whether it is benign or malignant, and the cell type involved. Although pathologists cannot rely on arty single trait. cancer cells usually exhibit a number ofdistinctive features that together facilitate the diagnosis of a cancer from its nticroscopic appearance {'I‘able 1—4}. For example, cancer cells frequently have large, irregularly shaped nuclei, prontinent nucleoli, and a high ratio of nuclear size to cytoplasmic volume: they also exhibit significant variations itt cell size and shape accompanied by a loss of normal tissue organization. To varying extents, cancer cells lose the specialized structural and biocltemical properties exhibited by normal cells residing in the tissue of origin; itt other words, cancer cells undergo a loss ofcell differentiation. In addition, the boundary separating cancer cells from the surrounding normal tissue will usually be poorly defined and tumor cells may be seen penetrating into adjacent tissues. Benign tumors, on the other ltattd, have a relatively distinct outer boundary that clearly separates the tutnor cells front the surrounding tissue. Cancers also tettd to be characterized by an excessive number of di\-’ldittg cells, so a large number of cells may be caught in the actual process of undergoing division Table 1-4 Some Differences in the Microscopic Appearance of Benign and Malignant Tumors Trait Benign Malignant Nuclear size Small Large NFC ratio Low Iliglt (ratio of nuclear size to cytoplasmic volume] Pleontorphic [irregular shape] Nuclear shape Regular Mitotic index Low High (relative number ofdividing cells Normal Welldifferentiated Poorlydifferentiated tanaplastici1 'l‘issue organization Disorganized Differentiation \V’ell defined t“elicapstil;tteci"l Tumor boundary l’oorly defined {mitosis} when a tissue specimen is prepared for micro- scopic examination. The percentage of cells detected in the process of dividing, called the mitotic index, is mea— sured by examining a biopsy specimen with a microscope, counting the number of cells undergoing mitosis in a given area of tissue, and dividing it by the total number of cells in that area. Cancers generally have a higher mitotic index than benign tumors, and [aster-grmving cancers will have a higher mitotic index than slower—growing cancers. Tumor Grading ls Based on Differences in Microscopic Appearance When a sufficient number of the preceding traits are seen upon microscopic examination of a biopsy specimen, a atholo ist can conclude that cancer is aresent, even if P g . invasion and metastasis have not yet occurred. In other words, these microscopic traits indicate the presence of a tumor that, if left untreated, will eventually spread by invasion and metastasis. The severity of the observed microscopic abnormalities can vary widely among cancers, even for cancers involving the same cell type and organ. This variability has led pathologists to devise systems for tumor grading in which cancers of the same type are assigned different numerical grades based on their microscopic appearance. [.ower numerical grades [e.g., grade ll are assigned to tumors whose cells are well differentiated {resemble normal tissue in cell structure and organization}, divide slowly (low mitotic index), and exhibit only modest abnormalities in the traits listed in Table [-4. Higher numbers le.g.. grade 4} are assigned to tumors containing rapidly dividing, poorly differentiated cells that exhibit severe abnornutlities in the traits listed in Table [—4. The highest~grade cancers contain cells that are said to be anaplastic, which means that they are so poorly dif— ferentiated and abnormal in appearance and organization that they bear little resemblance to the cells of the tissue in which the tumor arose. Such anaplastic, high—grade cancers tend to grow and spread more aggressively and be less responsive to therapy than lower-grade cancers whose cells have a tnore normal appearance. As a result, patients with l()\\"t.‘t'-gl'itclt.‘ cancers often have a better prognosis for long—term survival than those with higher— grade cancers (Figure l—F, left}. 'l‘umor grades lend to remain fairly constant for each person's cancer, although a low—grade cancer may occasionally evolve over time into a higher-grade. cancer. While tumor grading provides some general informa- tion regarding the likely behavior of a given cancer, tumors of the same grade do not always behave in the same way. It has been known for many years that patients with cancers that cannot be distinguished from one another by any traditional criteria, including cell type and grade, may nonetheless exhibit different outcomes when patients receive the satne treatments. The reason for this differing behavior appears to be related to the molecular and genetic properties of different tumors. One poo-'erful 100 too .c so 80 E E '5 so so “a: 8 40 40 h d; .2 “- 20 20 a . a T 2 3 l' 2 3 Tumor stage Tumor grade Figure 1—? Effect at Turner Grade and Stage on Survival Rates. The data are live-year survival statistics for breast cancer. i left] Lower—grade cancers, whose cells are better differentiated and more closely resemble normal cells, have better survival rates than higher-grade cancers, which are poorly differentiated and bear little resemblance to normal cells. {Right} In this figure, stage J refers to localized breast cancer, stage 2 is breast cancer that has spread to regional lymph nodes, and stage 3‘ is breast cancer that has metastasixed to distant sites. The data show that survival is notch better for cancers detected at earlier stages. lltased on data from (I. \s'. lflslon and l. U. |I|li.\, llistoptttltologi- l‘) -: l‘J‘Jl I: -ltt.’t [ figure .‘il'. and (Initrrr Forts c" figures Jiltlfi (Atlanta. ti.-\: .-\mcrican ( Lancer Roticly. ltlllil, p. |T._ approach for assessing these properties is DNA niicroarmy analysis (p. 191), a technique that allows the activity of thousands of genes to be measured simultaneously. The use of DNA microarray techniques has allowed researchers to take tumors that appear to be identical by other criteria and subdivide them into groups based on differing patterns of gene expression. In Chapter 1|, we will see how sttch approaches permit cancers to be grouped into categories that respond differently to various treatments, thereby facilitating the development of treat— ment strategies that are tailor—made for each patient. Cancers Vary in Their Clinical Stage Another means of categorizing cancers, called tumor staging, employs a series of criteria to estimate how far a person's cancer has progressed at the time of diagnosis. Unlike tumor grading, which is a description of micro— scopic appearance that tends to be relatively consistent over time, tumor staging is a description of how large a tumor has grown and how far it has spread, which are traits that by definition change with time. The most widely used system for tumor staging is the TNM system (“'I'” for Tumor size. “N” for lymph Node, “M " for h-‘letastasisl. In this system, the folloo-‘ing three questions are asked: {1} How large is the tumor and how far has it invaded into surrounding tissues? [3} Are lymph nodes “positive” for cancer cells; that is, have cancer cells spread to regional lytnph nodes? (3} To what extent have cancer cells metastasixed to other organs? Based on the answers to these questions, cancers are assigned a stage number. A lower stage number means that a cancer has been detected Ways in Which Cancers Drift-9r 11 relatively early and has not yet begun to spread, in general. the higher the stage number. the ntore diflicult it is to treat the disease successfully {see Figure l—T. right 1. Thus tttmor stage. grade. cell type. and site of origin all play important roles in affecting the outcome of a cancer patients disease. 'ihe bottotn line is that linding out that someone has ‘cancer" doesn‘t tell you very much abottt the seriousness of the conditiott. In the absence of knowledge regarding cell type. site of origin. grade. and stage. the mere fact that a person has cancer reveals little about how it will behave. how it should be treated. and the prospects l-tll' long-term stt]‘\'i\'al_ CANCER: AN INTRODUCTORY OVERVIEW Now that you understand what the term t'mirer means. we are ready to consider the ttnderlying biology of the disease. lit'uttt a biological point of view. several broad questions quickly come to mind: What kinds of cellular abnormali- ties allow cancers to grow and spread in an unrestrained fashion? What causes cancer? What role do genes play in the development of cancer? How is cancer detected and treated? Lian cancer be prevented? in the remainder of the chapter. we will examine how this textbook is organized to address each of these questions in detail. What Kinds of Cellular Abnormalities Allow Cancers to Grow and Spread in an Unrestrained Fashion? (lancer is a disease of abnormal cells. We have already seen that a central malfunction is the ability of cancer cells to proliferate in an ttncontrolled fashion. producing an ever- increasing number of cells without regard to the needs of the rest of the body. To understand the mechanisms responsible for such behavior. you need to know how the proliferation and survival of normal cells are controlled. When these control mechanisms are compared in normal cells and cancer cells. a number of important differences become apparent. 'I‘hese differences will be described in {ihapter 2. “Profile of a (lancer Cell.“ Although uncontrolled proliferation is a defining featttre of cancer cells. it is not the property that makes the disease so dangerous. After all. the cells of benign tumors also proliferate in an uncontrolled fashion. but benign tumors are rarely life threatening because the cells remain in their original location. The hazards posed by cancer cells come from uncontrolled proliferation combined with the ability to spread throughout the body. Spreading of cancer is a complex process involving multiple steps. l-irst. tumors must trigger the development of blood vessels that supply nutrients and oxygen to the tumor and remove waste prod— ucts. Without this step. tumors cannot grow beyond a tiny sire. After tumors have triggered the formation of a blood supply. cancer cells invade through surrounding tissues. enter the circttlatory system. travel throughout the body. 12 Chapter1 What Is Cancer"? and establish new tumors at distant sites. The cellular traits and mechanisms that make each of these steps possible will be described in (lhapter 5. llow ( Saucers Spread." What Causes Cancer? 'l'he uncontrolled proliferatitm of cancer cells. combined with their ability to spread throughout the body. makes cancer a potentially life—threatening disease. What causes the emergence of such cells that have the ability to destroy the organism of which they are a part? The conversion of normal cells into cancer cells is a complex. multistcp process that typically takes many years to unfold. ltespite the complexity of this process. however. many of its initi- ating causes are known. in (ibapter -l (“Identifying the Causes of (lancer-"l. we will see how scientists have gone about uncovering the causes of cancer. followed by an introduction to the main classes of cancer—causing agents that have been identified. lo the following four chapters. the agents that cause cancer will be examined in detail. (Lhapter 5 t“(ihemicals and (lancer"II describes how chemicals trigger the devel— opment of cancer: Chapter o t'“l{atliation and Cancer".t examines the ability of radiation to cause the disease: Chapter 7 t“lnlectious Agents and (lanceri‘t deals with the ability of infectious agents to cause cancer: and tin-ally. Chapter 8 [“l-leredity and (Iancer‘it discusses the influ— ence of heredity on cancer risk. What Ftole Do Genes Plaitr in the Development of Cancer? The causes of cancer described in (Shapters 5 through 8 are quite diverse. but they often lead to the same outcome. namely gene mutations. .-\ large body ofevidence points to the pivotal role played by mutations in the development of cancer. 'l'bes‘e cancer—causing mutations can be triggered by chemicals. radiation. or infectious agents. or they may arise spontaneously. arise from errors in l).\.—\ replication. or be inherited. But regardless of these differences in how they arise. cancer—related mutations affect the same two classes of genes: oncogenes and Honor suppressorgenes. Oncogene-as are defined as genes whose presence can lead to cancer. they arise by mutation from normal genes that code for proteins involved in stimulating cell prolific-ra— tion and survival. Hy producing abnormal forms or excessive quantities of these proteins. oncogenes contribttte to the uncontrolled proliferation and survival of cancer cells. ln (.ibapter 9 t“0ncogenes" t. we will see how normal genes are converted into oncogenes and how the proteins produced by oncogenes contribute to the development of cancer. In contrast to oncogenes. which are abnormal genes whose activity can lead to cancer. tumor suppressor genes are rtormnl genes whose deletion or loss of function can likewise lead to cancer, 'l'umor suppressor genes produce proteins that either directly or indirectly exert a restraining inllttence on cell prolileration and survival. The loss of sttch proteins can therefore allow cell proliferation and survival to eyade normal restraints and controls. in Chapter t0 [“Tumor Suppressor ( ienes and (lancer (.)\-'el'\-'ie\-\-'"]. we will examine the pthu-‘ays at‘t'ected by tumor suppressor genes and will see how detects in such pathways contribute to cancer development. Understanding the behavior ot‘ cancer-related genes requires some lamiliarity with DNA structure and func— tion. This book assumes that have a understamling ol' the relationship between DNA and genes that is at least equivalent to that provided by a readers basic typical introductory biology course. For reyiew purposes. Figure l—b‘ illustrates the building blocks of DNA. .-'\s shown in this tigure. DNA chains are constructed from varying sequences of building blocks called nucleotides. [Zach nucleotide contains a sugar. at phos— phate group. and a nitrogen—containing base that may be adenine on. guanine [(1). cytosine {C}. or thymine {T}. An intact DNA molecule consists ot‘ two intertwined DNA chains wound into a double helix that is held together by tour hydrogen bonds between the base adenine t.-\] in one chain and thymine iii in the other. or between the base guanine ttii in one chain and cytosine [(2] in the other [see Iiigure 2—i-l ]. 'l'he base sequence of one chain there- fore determines the base sequence of the opposing chain. and the two chains oi the DNA double helix are said to be held together by complementary base pairing. the way in which this complementary relationship makes DNA replication possible will be reviewed in Chapter 2. A gene is any nucleotide sequence in DNA that codes for a htnctional product. in most cases a protein chain. The flow of iniormation Ironi a DNA gene to a protein chain occurs in a two—step process called transcription and translation tliigure [—9]. During transcription. the base sequence in one strand ot' the DNA double helix serves as the template tor the synthesis oi a complementary molecule oth'a, The base-pairing rules are similar to those used in making DNA escept that RNA utilixes the base uracil [U] where DNA would use thymine {'1'}. The RNA molecules produced by protein—coding genes function as messenger RNAS {mRNAst that in turn guide the synthesis of protein chains in a process known as translation. During transla— tion, ntRNA associates with ribosomes and the genetic information in the mRNA is read in units of three bases called codons. Most eodons speciiy an amino acid. but a few function as stop signals that mark the end oi a protein chain. The net effect ot' the two—step process is that the nucleotide sequence ol'l)I\'.-\ molecules is used to guide the production ot‘ protein molecules. which in turn pert'orni most cellular functions. :\s we will see in Chapters LJ and it)‘ disruptions in these pl‘oteins— caused by either DNA mutations or changes in the way DNA is expressed lie at the heart ol‘ cancer cell behayior. How Is Cancer Detected and Treated? During the past several decades. great strides haye been made in unraveling the molecular and genetic almormalities exhibited by cancer cells. One oi the hopes tor such research Nucleotide structure q Phosphate K—“L group N H O N b Nucleotide // x" I t/ A} \I I, 0 Base \__ x.- t Sugar J CH4 \ P .. 0 pg N.- I N ? Nucleotide l/x -- H \‘t 2/ O \ f ‘,—.I’ J Base pairing in DNA :/ | ' o ThyminetT] : “QM.” f ' U rearing [A] ' r it ._- J Sugar-phosphate backbone Sugar-phosphate backbone Figure 1—8 Building Blocks 0! DNA. t rapt t).\‘.-\ is built i'mm chains ot' nucleotides. which are building blocks composed oi" a sugar. a phosphate group. and .i nitrogen--containing base. I itilrrum: .-\ DNA molecule consists ol two chains held together by hydrogen bonds between the buses cytosine I(‘.i and guanine :(ilor betuecn the bases thymine ill and adenine I. .-\ :. is that our growing understanding ot' the mechanisms responsible tor the deyelopment ot‘ cancer will eyenlnally lead to improved strategies tor diagnosing and treating the disease. The bottom line. ol‘ course. is the urgent desire tor a {Iconic-t: All |n‘.rt.1rtm:totj.= C's-Dretot-z: 13 ...
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Kleinsmith_ch1 - BENIGN AND MALIGNANT TUMORS Now that you...

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