Neoplasia Chapter 5 PDF

CHAPTER 5 Neoplasia OUTLINE 6. Describe the types of agents that have been implicated in the...

CHAPTER 5 Neoplasia OUTLINE 6. Describe the types of agents that have been implicated in the development of cancers (chemical carcinogens, radiation, De!nitions oncogenic viruses, and inherited mutations). Frequency and Signi!cance 7. List the manifestations of cancer and describe how cancer Cancer Is a Disease of Genes causes them. Transformation 8. Describe and compare the major forms of cancer therapy. Carcinogenesis Is a Multistep Process 9. De!ne stage, describe how it is determined for different cancers, Causes of Altered Gene Expression and describe how it correlates with prognosis and survival. The Natural History of Cancer 10. De!ne, describe, and use in context all the words in bold Invasion and Metastasis print in this chapter. Stage: Prognosis and Treatment Clinical Detection: Screening and Diagnosis KEY TERMS Mass Pain adenoma-carcinoma sequence malignancy Obstruction angiogenesis metastasis Hemorrhage anorexia mutation Pathologic Fracture benign neoplasia Infection cachexia occult blood Anemia cancer oncogene Cachexia carcinogen oncogenic virus Hormone Production carcinoma p53 tumor suppressor gene Diagnosis carcinoma in situ palliative care Risk Factors cellular atypia paraneoplastic syndrome Death chemical carcinogenesis Pap smear Practice Questions chemotherapy progression clone promotion differentiated prostate-speci!c antigen (PSA) OBJECTIVES dysplasia radiation extravasation radiation therapy 1. List the most common carcinomas and indicate how they familial cancer syndrome risk factors differ in frequency, sex ratios, and survival rate. false negative sarcoma 2. List the cancers that occur predominantly in each of the false positive screening procedure !rst three decades of life, in middle-aged persons, 5- or 10-year survival stage and in older adults. grade surgical removal 3. Describe how a cell becomes neoplastic—that high-risk HPV targeted therapy is, the"relationship of initiation and progression to hormonal therapy tissue diagnosis transformation. inherited genetic mutation TNM system 4. Describe the role of oncogenes and tumor suppressor initiation Transformation genes in cancer development. intravasation tumor 5. Describe what is meant by the multistep model of leukemia tumor suppressor gene carcinogenesis. lymphoma ultraviolet light 63 64 CHAPTER 5 Neoplasia De!nitions !e topic of this chapter is neoplasia, which we will spe- ci$cally de$ne as a “heritably altered, relatively autono- mous, new growth of cells.” !ere are many terms used in the vernacular to refer to this type of disease, but they do not carry the same speci$c de$nition. Tumor refers to any mass or swelling. In fact, it is the medical term that identi$es the edema that accompanies in#ammation. !is term therefore does not di%erentiate a neoplastic from a non-neoplastic process, and it does not di%eren- tiate a benign from a malignant neoplasm. Benign neoplasms are generally localized, discrete masses of cells that remain con$ned to their site of origin (Figure 5–1). Some benign neoplasms, such as smooth muscle tumors of the uterus, may become very large without causing any symptoms. Others, such as a meningioma in the brain, may cause symptoms or even death despite their small size, because they impinge on vital structures. Whether they are large or small, produce symptoms or not, benign neoplasms generally remain in the tissue in which they originated, and do not spread FIGURE 5–2 Invasion. This is an image of a carcinoma in the to others. Malignant neoplasms, in contrast, are de$ned kidney. The kidney has been cut in half and opened, so the two sides are mirror images of one another. The benign renal parenchyma is by their potential to spread beyond their site of origin. the brown tissue at the bottom, marked with a white asterisk. The Malignant neoplasms are also called malignancies, or, in carcinoma is the yellow nodule between the white arrows. Note that the vernacular, cancer. the carcinoma has replaced the renal parenchyma and is invading out Invasion refers to direct extension of neoplastic cells beyond the con!nes of the kidney into the perirenal adipose tissue into surrounding tissue without regard to tissue boundar- (left-hand arrow). Compare with Figure 5–1. ies (Figure 5–2). For example, a malignancy arising from the epithelial cells of the colon does not remain local- ized to the colonic mucosa, as a benign polyp does, but Distant lymph nodes rather develops the ability to invade the deeper tissues of the colonic wall. In other words, invasion is continuous growth of the tumor into and through other tissue types Regional lymph nodes adjacent to its site of origin. Metastasis means transplan- tation of cells to an entirely new site. For this to occur, the neoplastic cells must be transported through vascular Lung Bone channels or body spaces and must be able to grow at the new site. Malignant neoplasms most often metastasize Primary Liver to the lymph nodes, lungs, liver, and bone (Figure 5–3). breast carcinoma FIGURE 5–3 Typical pattern of metastasis from a breast cancer. For carcinomas, metastasis via lymphatics usually precedes metastasis via the blood. Table 5–1 compares and contrasts the growth charac- teristics of benign and malignant neoplasms. Some of the features in the table will be described later in the chapter. !e su"x -oma refers to a tumor. Like the term tumor, this su"x does not necessarily distinguish between a neo- plastic or non-neoplastic growth. For example, a hema- toma is a localized collection of blood that often produces FIGURE 5–1 Benign neoplasm in the parotid gland. a swelling; a granuloma is an aggregate of in#ammatory  De!nitions 65 TABLE 5–1 Comparison of Growth TABLE 5–3 Names of Malignant Neoplasms Characteristics of Benign and"Malignant Neoplasms Cell or Tissue of Origin Name Growth Epithelium Carcinoma Characteristic Benign Malignant Squamous epithelium Squamous cell carcinoma Growth rate slow rapid Basal cell of epithelium Basal cell carcinoma (unique Borders encapsulated irregular, to skin) in!ltrative Colonic mucosa Adenocarcinoma of colon Metastasis none present, late in disease Breast glands Adenocarcinoma of breast course Bronchial epithelium of Bronchogenic carcinoma Mitotic !gures rare frequent lung Differentiation well-differentiated poorly Prostatic glands Adenocarcinoma of prostate differentiated Bladder mucosa Urothelial carcinoma Nuclear size normal enlarged Endometrium Adenocarcinoma of Nucleoli small, inconspicuous large, prominent endometrium Cervix Squamous cell carcinoma of"cervix TABLE 5–2 Names of Benign Neoplasms Stomach mucosa Adenocarcinoma of stomach Cell or Tissue of Origin Name Pancreatic ducts Adenocarcinoma of"pancreas Squamous epithelium Squamous papilloma Connective tissue and Sarcoma Glandular or surface columnar Adenoma muscle epithelium Lymphoid tissue Lymphoma Fibrous tissue Fibroma Bone marrow Leukemia Adipose tissue Lipoma Plasma cells in Multiple myeloma Cartilage Chondroma bone marrow Bone Osteoma Cartilage Chondrosarcoma Blood vessels Hemangioma Bone Osteosarcoma Smooth muscle Leiomyoma Fibrous tissue Fibrosarcoma Nerve sheath Neurilemmoma Smooth muscle Leiomyosarcoma Other cells that forms a discrete, rounded lesion in tissues. !e su"x is most commonly used in conjunction with neo- Glial cells Glioma plasms, however, and for all intents and purposes -oma signi$es a neoplastic growth. Tables 5–2 and 5–3 list Melanocytes Malignant melanoma names given to benign and malignant neoplasms. Benign neoplasms usually are named by the suf- Germ cells Teratoma $x -oma appended to the name of the tissue of origin. 66 CHAPTER 5 Neoplasia Malignant neoplasms are classi$ed into carcinomas or sarcomas. Carcinoma refers to a malignant neoplasm TABLE 5–4 Incidence of the 15 Most Common of epithelial tissues. !ese are further speci$ed by type Cancers in the United States of epithelium, and the tissue or the organ in which they arise. For example, cancers arising from the glandular Type of Cancer Incidence epithelium of the breast are called adenocarcinoma of the breast, while a cancer arising from liver cells is Breast 234,190 called hepatocellular carcinoma. !e term sarcoma is Lung & bronchus 221,200 used if the malignancy arises from mesenchymal, or connective, tissue. A few neoplasms of nonepithelial or Prostate 220,800 ambiguous origin and unpredictable clinical behavior have names that do not follow this classi$cation system Colon and rectum 132,700 (e.g., gastrointestinal stromal tumor, pancreatic neuro- endocrine tumor). Other clearly malignant neoplasms Urinary bladder 74,000 have been given names that make them sound benign. It is very important to recognize these as malignant neo- Melanoma 73,870 plasms. A lymphoma is a malignancy of lymphoid cells; a melanoma is a malignant neoplasm of melanocytes; Non-Hodgkin lymphoma 71,850 glioma is used to refer to all neoplasms, benign or malig- nant, of the supporting cells of the brain (glial cells); and Thyroid 62,450 hepatoma is an old name that has been replaced with the more accurate hepatocellular carcinoma. Kidney & renal pelvis 61,560 Frequency and Signi!cance Uterine corpus 54,870 Cancer ranks as the second leading cause of death in the United States. !e term cancer encompasses a large vari- Leukemia 54,270 ety of malignant neoplasms whose behavior, treatment, Pancreas 48,960 and causes vary considerably. !e prognosis of a cancer depends on the natural history of that type of cancer, the Oral cavity & pharynx 45,780 extent of spread at the time of discovery, and the e"cacy of existing therapy for that particular type of cancer. In Liver & intrahepatic bile duct 35,660 general, the incidence of malignant tumors is about twice the mortality rate. Stated di%erently, the overall survival Stomach 24,590 rate of cancer is approximately 50%. However, there is great variability in the behavior of di%erent cancers. Other 241,620 Some types, such as carcinoma of the pancreas, almost always kill the patient, whereas others, such as basal cell carcinoma of the skin, are more of a nuisance than a threat to life if adequately treated. hospital statistics. Consequently, these two common skin !ree important variables relating to cancer frequency cancers are often omitted from overall collections of can- and signi$cance are site of development, gender, and age. cer statistics. Carcinomas outnumber sarcomas by 6 to 1. Aside from skin cancers, carcinomas of the lung, Table 5–4 and Figure 5–4 compare the incidence of colon, breast, and prostate are the most common types the most common cancers in the United States. !e most of cancer (Table 5–5). common cancers of humans are actually basal and squa- Lung cancer is responsible for about one quarter of all mous cell carcinomas of the skin, accounting for about cancer deaths. Treatment is relatively ine%ective (approxi- 40% of all cancers and 99% of all skin cancers. Despite mately 18% have 5-year survival), but prevention by their frequency, they are very seldom fatal because they avoidance of cigarette smoke could dramatically reduce are readily detected, grow slowly, metastasize only rarely, its incidence. It appears that dietary factors contribute to and can be completely excised. In contrast, malignant the development of colon cancer, but precisely what these melanoma represents only 1% of all skin malignancies factors are is not known and, therefore, its development but is fatal in about 20% of patients. !us, the least com- cannot entirely be prevented. Screening colonoscopy can mon type accounts for a large proportion of the mortal- identify and remove precancerous lesions of the colon ity associated with cancers of the skin. In addition to and rectum, and signi$cantly decrease the incidence of being the most common cancers, basal and squamous colon cancer in the screened population. Unfortunately, cell carcinomas are the only common cancers that are only approximately 50% of people who should have the frequently treated in a physician’s o"ce and thus escape screening procedure actually do undergo it, for a variety of  Cancer Is a Disease of Genes 67 Stomach Oral cavity & pharynx 1% 3% Colon and rectum 8% Liver & intrahepatic Leukemia Other bile duct 3% 15% Pancreas 2% Non-Hodgkin 3% lymphoma 4% Lung & bronchus Thyroid 13% 4% Kidney & renal pelvis 4% Urinary bladder Prostate Breast Melanoma 4% 13% 14% 4% Uterine corpus 3% FIGURE 5–4 Relative incidence of 15 most common cancers in the United States (2015 data; both sexes.) Data from Cancer Facts and Figures 2015, American Cancer Society. reasons, including lack of insurance and unwillingness to less frequent in younger people, some types occur pre- undergo the discomfort of colonoscopy and its preceding dominantly in the young. All of the common cancers of bowel preparation. !erefore, the impact of screening on young people listed in Table 5–6 are nonepithelial. the incidence of colorectal carcinoma is less than it could be. Breast cancer is often detected early and is quite acces- Cancer Is a Disease of Genes sible to surgical and radiation therapy, but its high inci- Cancers arise in a variety of circumstances and in a vari- dence still accounts for a large number of cancer deaths. ety of organs, which suggests that more than one factor is Prostate cancer is a disease of older men, so its impact involved in the development of any neoplasm. Moreover, on mortality statistics is lessened by the fact that these patients are likely to die of other diseases that a&ict older experimental studies indicate that cancers go through adults. Leukemias and lymphomas have variable survival progressive changes before becoming clinically evident. rates, depending on the speci$c type. Aggressive radiation At the beginning of the chapter, we de$ned neoplasia as a and chemotherapy of leukemias and lymphomas are asso- “heritably altered, relatively autonomous new growth of ciated with more complications than surgical therapy, cells.” !is de$nition implies that the basic event leading which is the $rst-line treatment for most solid cancers. to the development of a neoplasm is a genetic alteration In general, cancer is much more common in older in a cell that is transferred to subsequent generations of persons; this is particularly true for carcinomas. Of the cells and confers a growth advantage. Cells are continu- 10 most common carcinomas, most have a peak fre- ally undergoing damage to their genetic codes. quency in the 70s (Table 5–6). Cancers of the breast and Very robust gene repair mechanisms detect this damage female genital tract tend to occur a little earlier. Of'the and halt the cell in its proliferative cycle until the damage many other less common types of cancer, most have a can be repaired. If it can’t be repaired, the cell is induced to characteristic age incidence. Although cancer is much undergo apoptosis. Occasionally, the cell can divide despite TABLE 5–5 Frequency of and Deaths from Common Cancers in Men and Women (All Races and Ages) in the United States Relative Incidence Cancer Deaths Males/Females (per"100,000 Population) (per"100,000 Population) Relative 5-Year Survival (%) Prostate/breast 120/125 20/21 99/90 Lung 66/48 56/36 18 Colon and Rectum 46/35 18/12 65 Data from Jemal A, et al. Cancer statistics. CA Cancer J Clin. 2006;56:106–130. (Published by the American Cancer Society.) 68 CHAPTER 5 Neoplasia TABLE 5–6 Peak Age of Occurrence of Particular Kinds of Malignancies 0–20 Years 20–40 Years 40–70 Years Osteogenic sarcoma Hodgkin lymphoma Prostate cancer Acute lymphocytic leukemia Thyroid cancer Colon cancer Neuroblastoma Testicular cancer Pancreatic cancer Wilms tumor of kidney Cervical cancer Bladder cancer Retinoblastoma Stomach cancer Medulloblastoma of cerebellum Endometrial carcinoma Ovarian carcinoma Non-Hodgkin lymphoma Lung cancer Breast cancer Melanoma the genetic alterations, in which case these changes become a formidable barrier to invasion. However, during the “$xed” in the genome so that the daughter cells inherit development of cancer, new mutations are continually an altered genetic code. !e cell lineage that inherits this arising that impart to the neoplastic population the abil- genetic defect is called a clone of the originally altered cell. ity to evade the host’s growth control mechanisms. For Many genetic changes are silent, which means there is example, the neoplastic cells may develop the ability to no change in the structure of function of cells. In order to produce enzymes that digest the extracellular matrix, be carcinogenic, or promote the development of cancer, thereby allowing them to migrate into neighboring tis- the genetic alteration has to provide the cell with some sues; or, they may develop proteins on their cell surfaces kind of a growth advantage. !is can be in the form of that prevent immune recognition; or, they may develop enhanced survival of the cell lineage, more rapid prolifera- the ability to stimulate the growth of new capillaries, so tion, or simply delayed death, any of which will result in they can better tap into the host’s blood supply. net growth of that particular clone of cells. Table"5–7 lists In the following sections, we will look more closely at some of the changes that can occur secondary to genetic types of genetic alterations that predispose to the devel- alterations that give cells a growth advantage. opment of cancer, explore the processes of invasion and Of all the mutations that occur in cells, very few lead metastasis, revisit the important concept that multiple to cancer, and most cells with the potential to develop overt malignancy do not do so. As common as cancer is in the population, in the context of the continuous TABLE 5–7 Changes that Confer a Growth genetic turnover that is occurring in our cells, it is actu- Advantage ally a very rare event. Moreover, a single genetic altera- Increased rate of mitosis !cell proliferation tion does not cause cancer. A cell line must undergo a series of genetic changes for it to develop the ability to Decreased rate of apoptosis cell death proliferate, invade, and metastasize. In familial cancer syndromes, patients inherit a genetic alteration that sets Increased response to !cell proliferation them up for developing cancers at an earlier age than in hormonal signals the normal population; but even in these settings, the development of cancer is not invariable. Clearly, there Decreased response to !cell proliferation must be an interplay between various, as yet poorly growth inhibitory signals understood, environmental and genetic factors for the development of a malignant growth. Production of enzymes that Invasion !e de$nition of neoplasia also includes “relative digest extracellular matrix autonomy” of the cell line, meaning it is not dependent on the host to regulate its growth. In a way, a neoplasm Ability to evade the Metastasis behaves as if it were a parasitic organism, deriving oxy- organisms’ immune system gen and nutrients from the host while growing indepen- dently of the host’s regulatory mechanisms. Neoplasms Ability to stimulate growth of Metastasis new vessels are never entirely autonomous: at the very least, they depend on the host for oxygen and nutrients. !ey Ability to use alternate Growth in inhospitable also respond to growth promoting stimuli such as hor- sources of energy environment mones. Increasingly, we are understanding how critical the immune system is in detecting tumor cells and con- Immortality cell death trolling their spread. Extracellular matrix itself forms  Transformation 69 genetic events are required for a cancer to be able to substitution of a single nucleic acid (a “point mutation”), invade and metastasize, and explore the causes of genetic loss of one or several nucleic acids (deletion), #ipping of mutations. a large nucleic acid sequence (inversion), or exchange of large sections of chromatin from one chromosome to Transformation another (translocation). In addition, epigenetic events, !e initial step in development of a neoplasm (Figure"5–5) such as phosphorylation of nucleic acid residues, also is nonrepair of a genetic defect before the cell under- impact gene transcription and translation. goes division, so that genetic alteration is “$xed” in the !e genes that are altered during transformation are genome of subsequent daughter cells. !is is called classi$ed as oncogenes and tumor suppressor genes. transformation, with the implication that a normal cell In normal cells, the transitions from one phase of the is “transformed” into one that has the potential to gener- cell cycle to another, in other words, from quiescence to ate a neoplastic clone. As already mentioned, any ran- growth, to DNA transcription, and to mitosis, are highly dom change in the genetic code will not transform a cell regulated by extracellular, intercellular and intracellular or cell' line. Rather, in order for it to have carcinogenic signals. Some of the proteins that control these transi- potential, the genetic change must occur in a gene that tions are called proto-oncogenes. !ese are genes that controls growth. are normally present and necessary for the cell to grow !ere are many types of genetic changes that can and divide in concert with other cells. !ey encode pro- alter the expression of a gene. A mutation, technically teins that are growth factors, growth factor receptors speaking, is a change in a base pair or short sequence of on cell membranes, signal transducing molecules that pairs that alters the way in which the gene is read during translate binding of the receptor into an intracellular translation, with subsequent changes to protein struc- signal, transcription proteins, or cell cycle regulatory ture and function. In general usage, however, we use the molecules. Illustrated in Figure 5–6 is the Ras/Raf sig- word mutation to refer to any type of genetic change, be it nal transducing pathway, that carries a signal received Normal cell Transformation: Mutation in tumor suppressor Transformation events gene or oncogene Establishment of clone of cells with that mutation Tumor cell Progression: Tumor cell variants Additional mutations Loss of control of cell division Multiple cell lines (clones) Genetic heterogeneity Tumor cells that have growth advantage: Ability to evade growth Clonal expansion inhibitory signals Nonantigenic of surviving cell Ability to evade immune variants system Invasive Ability to grow autonomously Metastatic Ability to generate growth of own blood supply Requiring fewer Human solid Immortality growth factors malignancy FIGURE 5–5 Development of cancer through gradual accumulation of genetic changes. 70 CHAPTER 5 Neoplasia TABLE 5–8 Examples of Oncogenes Growth factor Bridging Farnesyl membrane anchor Name Function Cancer protein KRAS Signal transduction Colon cancer Inactive BRAF Signal transduction Melanoma RAS Active RAS TGFA Growth factor Hepatocellular Growth factor GDP carcinoma receptor Activates GTP Cyclin-D Cell cycle regulator Mantle cell lymphoma GAP Inactivation by hydrolysis of GTP ERBB1 Growth factor receptor Squamous cell carcinoma of the RAF Active RAS lung c-MYC Regulation of Burkitt lymphoma transcription MAPK Activation of transcription PDGF Growth factor receptor Leukemia FIGURE 5–6 The Ras/Raf signal transduction pathway. additionally and importantly detect and repair defec- tive DNA before the cell can transition through the cell from the extracellular environment, via the EGFR trans- cycle and undergo mitosis. Mutations in tumor suppres- membrane protein, into the nucleus of a cell to stimu- sor genes that deactivate them or cause them to lose late transcription. Each of these proteins is normally in functionality, can result in the cell undergoing mitosis a resting, or inactive state. Activation of the $rst protein with altered DNA. Because these are deactivating muta- (the extracellular domain of the EGFR receptor binds to tions, both alleles have to be mutated for the regulatory a growth factor) results in activation of the next protein function of tumor suppressor genes to be lost. !ese are in the transducing system, and so on along the chain. the types of genes that are implicated in familial cancer !e genes coding for any of these proteins are proto- syndromes. oncogenes. When a mutation happens in one of these !e most common tumor suppressor gene to be genes so that the protein is constitutively activated, mutated, and the gene most commonly mutated in cancers meaning continually in an “on” state, the proto- generally, is p53. Over 50% of cancers carry homozygous oncogene has transformed into an oncogene. When the mutations in this gene. !e protein p53 is called a “molec- protein cannot be inactivated, the signal to the nucleus ular policeman” because it guards over the integrity of the to transcribe its genetic material and to prepare for cell’s genome (Figure 5–7). When it detects DNA dam- mitosis is continuously present. In other words, onco- age, it halts the cell in its cycle and recruits DNA repair genes code for proteins that dysregulate the commu- machinery to reverse the damage. If the damage cannot nication system that controls cell growth and division. be repaired, p53 permanently arrests the cell, so the cell Mutations that cause transformation of a proto- cannot undergo division and eventually dies without hav- oncogene into an oncogene are activating mutations; in ing given rise to a transformed clone of cells, or it induces other words, the changes are expressed in an autosomal the cell to undergo apoptosis, so the cell and its defective dominant fashion: only one allele needs to be mutated genetic code are permanently removed from the tissue. If for altered protein function to have a phenotypic e%ect. the DNA can be repaired, p53 steps aside and lets the cell !ese kinds of mutations are not inherited in familial go through division. If both alleles of p53 are inactivated, cancer syndromes because they would be lethal to the the policing function is lost: the cell proliferates even in developing embryo. Very many oncogenes have been the presence of DNA damage, and the daughter cells then identi$ed in human cancers: some of the more common have defective genetic templates. If the defective genes are ones are listed in Table 5–8. oncogenes, the new cell population is well on its way to Tumor suppressor genes, as their name implies, code becoming malignant. Other examples of tumor suppres- for proteins that normally inhibit growth. !ese proteins sor genes are given in Table 5–9. can have functions similar to proto-oncogenes, such as Oncogenes and tumor suppressor genes that directly transcription factors, cell surface receptors, cell cycle a%ect transcription and DNA repair during the cell cycle regulating proteins and signal transducers, but they are by far the most common types of genes implicated in  Transformation 71 DNA p53 accumulates damage and binds to DNA Oncogenic stress Hypoxia Transcription dependent and independent effects on targets Normal cell (p53 normal) p21 GADD45 BAX Senescence (CDK inhibitor) (DNA repair) (apoptosis gene) G1 arrest Ionizing radiation Carcinogens Mutagens Successful repair Repair fails No DNA repair, no senescence DNA p53-dependent Mutant damage genes not activated cells No cell cycle arrest Expansion and additional mutations Cell with mutations Malignant or loss of p53 tumor FIGURE 5–7 Function of p53. the development of a neoplastic growth; however, altera- before they die. Some genetic alterations can impart tions in the function of many other proteins that directly the ability to go through the cell cycle inde$nitely. An or indirectly control growth can contribute to carcino- example is an activating mutation in the telomerase gene. genesis, as well. Large families of proteins control apop- Telomerase is an enzyme that adds short, condensed tosis, for example. Mutations in these can cause the cell nucleic acid sequences to the ends of chromosomes that to ignore a signal to undergo programmed cell death: its protect the coding regions of the chromosomes from persistence will lead to growth of the cell population sim- damage during mitosis. Telomerase is very active during ply because new cells are being produced normally but the the embryonic period, when cells are rapidly dividing, old ones don’t go away. An example is a mutation in the and in some adult somatic tissues that have a high turn- anti-apoptotic molecule bcl-2, which occurs in indolent over rate, such as hematopoietic cells, but it is expressed B-cell lymphomas. !e B-cells do not necessarily prolifer- at very low levels, if at all, in most mature somatic cells. ate more rapidly than normal lymphocytes; they simply As a result, the little bits of telomeres that break o% the don’t die. !e tumors grow because of a slow addition of ends of chromosomes during mitosis are not replaced, malignant cells rather than their rapid proliferation. and when the telomeres become so short that they can Cancer cells can also acquire immortality. Normal no longer protect the coding regions of the chromo- somatic cells can undergo a limited number of cell cycles somes, the cell dies. Cells that express telomerase can 72 CHAPTER 5 Neoplasia not have the ability to digest extracellular tissue in order TABLE 5–9 Examples of Tumor Suppressor to invade; or a clone that is immortal because it expresses Genes telomerase may not necessarily have the ability to stim- ulate the growth of new vessels. Multiple “hits” to the Name Function Cancer genome are required for a collection of cells to acquire a malignant phenotype (Figure 5–8). !is may be why most APC Inhibition of signal Colon cancer cancers occur in older people: the cells acquire genetic transduction alterations through the lifetime of the individual, and it is NF1 Inhibition of signal Neuro!bromatosis the cumulative e%ect of the genetic alterations that leads transduction to development of a malignancy. In familial cancers, the $rst “hit” is inherited. In famil- RB Regulation of cell cycle Retinoblastoma ial retinoblastoma, a defective allele of the RB1 gene, which regulates the cell cycle by inhibiting transcription P16/INK4 Regulation of cell cycle Melanoma factors and thereby preventing the cell from entering the S phase (DNA transcription) of the cell cycle, is inherited BRCA1 DNA repair Breast cancer from one of the parents. Early in childhood, the second allele of RB1 becomes mutated, and the clone with now circumvent death by continuously elongating the ends of homozygously mutated RB1 is no longer arrested in the their chromosomes. G1 phase of the cell cycle and proliferates. With this type of cancer, only two genetic “hits” are required for the Carcinogenesis Is a Multistep Process development of cancer. Adults can develop retinoblas- toma, but this is very rare, probably because the retinal Just because a cell has been transformed by a genetic muta- cells in adults are stable, while in very young children, the tion does not mean that cancer will inevitably develop. A single gene codes for only one protein and each protein retinal cells are still immature and normally proliferat- has a very speci$c function. Usually, there is a lot of redun- ing, therefore more likely to develop genetic alterations. dancy in growth control, so even as important a molecule Children with inherited RB1 mutations are more likely to as p53 or KRAS cannot solely be responsible for carcino- develop cancers in other organ systems after they survive genesis. Moreover, the ability to invade and metastasize treatment for the original retinoblastoma, because all of requires additional functions or capabilities that have to their somatic cells have one mutated RB1 allele. be acquired through changes in the genome. For example, On the other end of the spectrum are cancers that have a clone that is not responsive to apoptotic signals still may hundreds, if not thousands, of mutations by the time they come to clinical attention. Most sporadic cancers, such as colon cancer or pancreatic cancer, Avoiding immune Evading growth have extremely complex genetic pro- destruction suppressors $les due to the accumulation of muta- tions during their development. !e adenoma-carcinoma sequence, $rst Sustaining Enabling described for colon cancer, illustrates proliferative replicative signaling immortality this concept (Figure 5–9). APC is the most commonly mutated gene in colon cancers. In one form of familial colon cancer, familial adenomatous polyposis (FAP), the “$rst hit” is an Deregulating Tumor- inherited mutation in the APC gene. cellular promoting energetics inflammation When the colonic mucosa is examined at this stage, either by colonoscopy or microscopy, there is no morphologic abnormality: the mucosa appears Activating completely normal. Even when addi- Resisting tional mutations develop, such as invasion and cell death metastasis a mutation in the other APC allele, or in genes coding for the molecule !-catenin, KRAS or p53, there may Inducing Genomic instability angiogenesis (mutator phenotype) not be any morphologic evidence that the tissue is genetically abnormal. With each additional mutation, the FIGURE 5–8 New functions a neoplastic growth must acquire in order to become malignant. cells develop the ability to proliferate  Transformation 73 Normal colon Mucosa at risk Adenomas Wild-type TP53 Mucosa Oncogene-induced Submucosa senescence Muscularis Carcinoma propria Germ-line (inherited) Methylation or somatic (acquired) abnormalities mutations of cancer Inactivation of Proto-oncogene suppressor genes normal alleles mutations Homozygous loss (“first hit”) (“second hit”) of additional cancer Additional mutations suppressor genes Gross chromosomal alterations TP53 at 17p13 APC at APC K-RAS LOH at 18q21 Telomerase 5q21 !-catenin at 12p12 (SMAD 2 and 4) Many other genes FIGURE 5–9 Adenoma-carcinoma sequence in colonic neoplasia. or evade destruction, and over time, a neoplastic clone along in their natural history—are genetically analyzed, develops in the form of a polyp. A polyp is an overgrowth they show a bewildering array of mutations in a large vari- of epithelial tissue that rises up from the surface of the ety of genes. In essence, every cancer, even those arising mucosa. Not all polyps are neoplastic: only a particular in a single organ, such as breast cancer or colon cancer, type of polyp, called an adenomatous polyp, harbors neo- can be thought of as a genetically unique entity. !is is plastic genetic mutations. And, polyps are not malignant: one reason why it is so di"cult to develop a “magic bullet” they do not have the ability to invade and metastasize. against cancer. A drug e%ective at mitigating or reversing Additional mutations are required for the development of the e%ects of one genetic mutation will be e%ective in only clones within the neoplasm that are capable of producing the small subset of malignancies in which that mutation is enzymes that digest extracellular matrix, impart mobility a driving force in promoting uncontrolled growth. to cells, allow them to evade immune detection, and allow Malignancies can be thought of as small, nasty little them to gain access to the blood or lymphatic stream so experiments in evolution. Because the normal checks on they can travel to other tissues. However, if adenomatous the cell cycle are overridden, ignored or simply absent in polyps are left in place, they can acquire these additional transformed cells, the genome acquires more or less random functions or abilities by further genetic alterations. !e mutations which accumulate over subsequent generations recognition that some polyps can develop into cancers and form the substrate for evolutionary selection. Over time, is the reason that periodic screening colonoscopies are the originally transformed clone, that had just one mutation, recommended to patients beginning at 50 years of age. develops into a population of several subclones, each with a Removal of a colonic polyp in e%ect removes a neoplas- variety of di%erent mutations. !is immense genetic varia- tic population of cells before it can become a malignancy. tion allows for selection of subclones that are better able to Scientists have been able to detect the molecular (genetic) survive and proliferate and will therefore outgrow the oth- alterations in colon cancer because the precursor lesions ers. In fact, most cells in malignant neoplasms die because are so amenable to removal, and therefore to genetic they either have so many genetic mutations that they can analysis. For most other kinds of cancer, the precursor no longer support essential cell processes, or the mutations lesions are not easily detected by direct visualization and they acquired do not give them a growth advantage. Other are more di"cult to remove, however, an adenoma–car- subclones almost randomly develop the ability to harness cinoma sequence is hypothesized for the development of alternate sources of energy, invade into surrounding tissue, most epithelial cancers. metastasize to other organs, stimulate the growth of new While the gene mutated in the “$rst hit” of many can- vessels, or acquire other functions that give them the abil- cers has been identi$ed, the sequence of additional muta- ity to proliferate. All evolutionary processes take time, and tions and the genes involved are highly variable. When those that occur in cancer are no di%erent. From the origi- metastatic lesions—in other words, cancers that are far nal transformative event to the development of a metastatic 74 CHAPTER 5 Neoplasia process can take years. For example, the progression from an adenomatous polyp to invasive carcinoma can take TABLE 5–10 Examples of Chemical 10'years or more, and the development of an adenoma- Carcinogens tous polyp itself takes decades. While some malignancies can cause death of a patient very soon after it comes to Chemical Carcinogen Neoplasm clinical attention, the original transformation may have occurred decades prior—but it was clinically silent. Tobacco smoke Lung cancer (and many others) A#atoxin Liver cancer Causes of Altered Gene Expression Four causes of carcinogenic mutations are recognized: Azo dyes Bladder cancer chemicals, radiation, infectious agents, and familial predisposition. Asbestos Mesothelioma !e recognition of a high incidence of scrotal skin cancer in London chimney sweeps led to the discovery Benzene Leukemia that repeated occupational exposure to coal tar was car- cinogenic. Later, through experimentation, methylcho- Vinyl chloride Angiosarcoma (liver) lanthrene, a chemical coal tar, was identi$ed as a speci$c polycyclic hydrocarbon that could cause cancer. Since Coal tar Scrotal cancer then, a large number of natural and synthetic compounds have been discovered that are potentially carcinogenic. Excess estrogen Uterine cancer In chemical carcinogenesis, illustrated in a mouse model in Figure 5–10, the transformative event is called initiation. An initiating chemical causes a mutation that Proliferation in and of itself will not cause the neoplastic becomes $xed in the genome. Another chemical or irritant cells to become malignant: additional genetic alterations is required to stimulate cell proliferation, or promotion of are required. !is last step, the acquisition of more muta- growth. !e sequence of exposure to the initiating and tions, is called progression. promoting chemical are important: if the promoter is Many types of human cancer are known to be associated applied before the initiator, neoplasia does not develop with exposure to carcinogenic chemicals in the workplace because the cells still have a normal genome. If the pro- including certain dyes, vinyl chloride, alkylating agents, and moter is not applied soon after the initiating event, neo- asbestos (Table 5–10). Hormones can also be considered plasia will also not develop, presumably because the cells to be chemicals that can initiate certain types of cancer. of the transformed clone will have come to the end of their For example, administration of estrogen for the treatment life cycle and died. Only if the genetic mutation is $xed and of symptoms of menopause in women has been shown to the cells are induced to proliferate will neoplasia develop. increase the incidence of uterine cancer. Based on present knowledge, the cancer-inducing chemical agent(s) a%ecting the largest number of people is/are contained in cigarette Initiator smoke. Smokers have a 10- to 50-fold greater chance of (first) developing bronchogenic carcinoma than nonsmokers, and the risk can be signi$cantly correlated with the number of Promoter packs smoked per day and duration of smoking. Squamous (second) cell carcinomas of the oral region, larynx, and esophagus Invasive squamous and carcinomas of the urinary bladder are also signi$cantly cell carcinoma associated with cigarette smoking. Initiated Ionizing radiation consists of high-energy waves that cells damage atoms by stripping them of electrons, hence “ion- izing” them. Ionizing radiation is not selective; it damages any atom it comes in contact with, but in the setting of this Promoter discussion on carcinogenesis, it is particularly the damage continued incurred on DNA that is pertinent. As with any other type of carcinogenic process, if the DNA damage is not cor- Benign tumor rected by the next round of cell division, mutations will be $xed in the genome. !e e%ect of ionizing radiation is dose-dependent: the minute amount of radiation a person is exposed to during a routine dental X-ray is not harmful, while the amount of ionizing radiation released during a nuclear accident or in the vicinity of an exploded atomic FIGURE 5–10 Initiation, promotion, and progression of cancer. bomb can immediately be lethal.  Transformation 75 X-radiation and gamma radiation (the type of radiation most commonly in fair-skinned individuals because mel- released from nuclear accidents) are well known to anin, the pigment that imparts a dark color to skin, is cause cancers in individuals. A latent period of months protective against the ionizing e%ect of ultraviolet light. to decades can intervene between the exposure and Squamous and basal cell carcinomas of the skin typically the appearance of neoplasms. Examples of radiation- develop in older individuals on sun-exposed areas, such induced cancer include thyroid carcinoma and leukemia as the face and ears. !ey are thought to be linked to developing in victims of the Hiroshima and Nagasaki cumulative life-time exposure to sunlight. !e strongest atomic blasts and victims of the Chernobyl nuclear risk factor for the development of melanoma of the skin power plant accident. Before the adverse e%ects of ion- is a history of blistering sunburns, and the incidence of izing radiation were discovered, up to 75% of thyroid melanoma is highest in fair-skinned individuals living in carcinomas in children were preceded by “therapeutic” sunny locations (Florida, Australia) or engaged in occu- radiation to the head and neck, often for benign condi- pations where they are exposed to ionizing radiation tions such as acne or acute tonsillitis. Before the adverse from the sun, such as $shing and farming. e%ects of X-radiation were known, radiologists and radi- Not many microorganisms have been identi$ed that ology technicians not uncommonly developed cancers. cause cancers in humans, but there is no doubt that !ey now wear protective aprons made of heavy metals, they can do so. Only one bacterium, Helicobacter pylori such as lead, that absorb ionizing energy. Patients who (which infects the mucosa of the stomach and causes underwent radiation therapy are at risk of developing gastritis), has been identi$ed as a carcinogen in humans, a second malignancy at the site of radiation. !e risk is but several oncogenic viruses are known. !ese can be dose-dependent: the higher the exposure, the more likely DNA or RNA viruses. !e oncogenic pathway that is it is that a second cancer may develop. !is is often a best understood is that driven by high-risk HPV. !e sarcoma. For example, patients who underwent radiation genetic code of this oncogenic virus is spliced into the therapy for advanced breast cancer may develop angio- infected host cell’s DNA and is transcribed as the cell sarcoma of the breast years after the initial treatment. goes through the cell cycle. !e proteins produced from Ultraviolet light from sunlight is a form of radiation the high-risk HPV genes promote accelerated replica- to which we are exposed all the time. It causes the for- tion of cells by binding and inactivating proteins derived mation of pyrimidine dimers in DNA. Because the from tumor suppressor genes (including p53 and RB), skin is exposed to ultraviolet light, and in fact protects as well as proteins that are involved with regulating the internal organs from the damage incurred by radiation cell cycle. Host cells proliferate in an unregulated man- from sunlight, it is the organ most at risk for develop- ner, and errors in the host’s DNA accumulate with sub- ing sunlight-induced cancers (Figure 5–11). !ese arise sequent rounds of cell division. Other viruses linked A B FIGURE 5–11 Examples of common skin cancers. A. Squamous cell carcinoma. A mounded-up, hyperkeratotic, scaly lesion on the hand of an elderly person. B. Basal cell carcinoma. A pearly lesion with rolled borders and central ulceration. Courtesy of Yale Residents’ Slide Collection, Dermatology Department, Yale University School of Medicine. 76 CHAPTER 5 Neoplasia TABLE 5–11 Examples of Carcinogenic TABLE 5–12 Examples of Familial Cancer Microorganisms Syndromes Microbe Cancer Gene Cancer Syndrome Human papilloma virus (HPV) Cervical cancer RB Retinoblastoma (high risk) Regulates cell cycle Ebstein-Barr virus (EBV) Burkitt lymphoma p53 Li-Fraumeni syndrome (cancers halts the cell cycle until in many different organs) Helicobacter pylori Gastric lymphoma DNA is repaired Hepatitis B and Hepatitis C Hepatocellular carcinoma APC Familial adenomatous polyposis viruses (HBV and HCV) Intracellular signaling and (colon cancer) inhibition of transcription Human T-cell leukemia virus T-cell leukemia Type 1 (HTLV-1) BRCA1 Familial breast and ovarian Repair of double-stranded cancers DNA breaks to cancers in humans are listed in Table 5–11, but the MSH2, MLH1, PMS2, MSH6 Lynch syndrome (cancers in exact pathway by which they induce transformation and DNA mismatch repair genes many different organs) growth is not as well understood as that of high-risk HPV. Some of these cancers are preceded by many years MEN1 Multiple endocrine neoplasia Tumor suppressor gene (MEN) neoplasia in pancreas, of low-grade, chronic in#ammation, which appears also parathyroid and pituitary gland to play a role in carcinogenesis. !e infected cells are not necessarily killed by the in#ammation, but contin- ued expression of growth factors in the in#ammatory population, such as retinoblastoma, but even in these environment that normally promote healing, regenera- cases, their sporadic (nonfamilial) occurrence is more tion and repair, drive rapid host cell turnover, which in common than familial cases. For example, more than turn predisposes to proliferation of cells despite DNA 50% of retinoblastoma is nonfamilial—it did not occur damage. Moreover, there is geographic variation in the in the prior generation and the patient’s o%spring are development of virally induced cancers. EBV, for exam- not at greater risk of developing it, either. Finally, the ple, is ubiquitous: EBV resides as a latent infection in genes involved in driving cancer in familial settings are up to 90% of the adult population in the United States. not necessarily those that are most important in their However, the incidence rate of Burkitt lymphoma is sporadic counterparts. For example, only approximately much higher in certain areas of Africa than in the United 20% of sporadic ovarian cancers and 10% of sporadic States. Other, as yet not understood, factors are obvi- breast cancers harbor a BRCA1 gene mutation. ously involved in the induction of viral carcinogenesis. Many familial cancer syndromes have been identi- $ed and more are discovered every year. In these syn- The Natural History of Cancer dromes, an inherited genetic mutation puts patients at Cancers have a long life history, most of which occurs risk of developing cancer at a younger age than typical before there is any lesion that can be clinically detected. for that cancer type, because they already have sustained !e multiple genetic “hits” required to turn a normal cell a “$rst hit” in their genome. Some of them are very rare, into a neoplastic growth capable of invading and metas- others more common. Table 5–12 lists just a few of the tasizing develop over years. !e earliest “hits” may not hundreds of known familial cancer syndromes, each result in a changed phenotype: if they were examined of which is caused by mutation(s) in di%erent genes. microscopically, the cells would look normal. With fur- In fact, even in a single gene, the location of the exact ther accumulation of mutations, morphologic features mutation that disables the resultant protein can be vari- of malignancy develop, in the form of cellular atypia able. For example, in retinoblastoma, the mutation can (Figure 5–12), or the degree to which the appearance of vary from a single base pair substitution, to insertions neoplastic cells diverges from that of mature, nonma- of a few base pairs, to large deletions. Similarly, in famil- lignant cells. Features of atypia include enlarged nuclei, ial breast cancer due to BRCA1 mutations, thousands decreased amounts of cytoplasm, irregular nuclear of di%erent defects have been described, each of which placement in a cell, multiple nucleoli, large nucleoli, confers a slightly di%erent risk for the subsequent devel- and frequent mitotic $gures. !ese $ndings re#ect our opment of breast or ovarian carcinoma. Many cancers understanding of cancer as a genetic disease that causes that arise in the familial setting are rare in the general uncontrolled growth: nuclei are enlarged because of  The Natural History of Cancer 77 A B FIGURE 5–12 Atypia. In comparison to the cells in A, those in B are atypical. A shows normal colonic glands. The nuclei of the cells are arranged at the periphery of the glands, and a droplet of mucin distends the cytoplasm toward the luminal surface. The cells and their nuclei are uniform in size. In the colonic carcinoma in B, the cells are no longer arranged in a regular pattern, the nuclei are overlapping one another and have irregular shapes and sizes, and the cells do not contain mucin droplets. excess chromosomal material; multiple, enlarged nucle- breast we use the term “carcinoma in situ.” Dysplasias oli are translating genetic codes into proteins at a faster are recognized precursor lesions for carcinomas, but the (and presumably uncontrolled) rate than normal, and precursors of sarcomas are unfortunately not morpho- mitotic $gures indicate frequent cell division. logically recognizable. A neoplastic clone may be atypical in appear- At this stage of development of neoplasia, surgical ance but still localized to its tissue of origin. !is type excision of the lesion would be curative: the cells have of abnormality is a dysplasia. Dysplastic cells have not yet spread beyond their site of origin, so removal of acquired some of the genetic alterations necessary for the neoplastic clone prevents the development of overt the development of overt malignancy, but they do not malignancy. While we tentatively consider in situ or high necessarily become malignant. Examples of dysplastic grade dysplastic lesions to have malignant potential, they epithelial lesions include the tubular adenoma of the are not per se malignant: they do not have the ability to colon already discussed in the context of the adenoma- invade or metastasize. carcinoma sequence, and dysplasia of the cervix, or cel- lular atypia and disregulated growth of the squamous lining of the cervix induced by the human papilloma- Invasion and Metastasis virus (HPV). Dysplasias can range from low grade, or What di%erentiates an in situ from an invasive carcinoma exhibiting minimal atypia, to high grade, or exhibiting is whether the cells have broken through the basement the amount of atypia one would expect to see in an inva- membrane to which epithelial cells are normally anchored sive lesion. High-grade dysplasias are considered to be in (Figure 5–13). To invade, malignant cells must be able to situ lesions, or cancers that are still “in place.” !e words elaborate enzymes that destroy the basement membrane high-grade dysplasia and in situ carcinoma essentially and the underlying connective tissue. !ey must then also mean the same thing; it is only a matter of convention be able to move into the new niche that has opened for whether to use one or the other phrase. Tubular adeno- their growth and tap into the host’s blood supply at that mas of the colon that show a high degree of atypia are location. When the neoplastic cells grow contiguously designated as having high-grade dysplasia, but in the into surrounding tissue, they form a mass that alters the 78 CHAPTER 5 Neoplasia A B C FIGURE 5–13 Development of squamous cell carcinoma. A. Normal squamous epithelium. The basal cell layer is the darker blue zone at the base of the epithelium. The basal cells are tethered to a very thin basement membrane (not seen at this magni!cation), that separates the epithelium from the underlying connective tissue. B. Carcinoma in situ. The epithelium is hypercellular in comparison to normal, and the basal layer is greatly expanded, occupying about half the width of the epithelium. There is still a sharp demarcation between the epithelium and the underlying connective tissue. C. Invasive carcinoma. This photograph is taken at much lower magni!cation than the other two. The epidermis is the thin band at the very top of the tissue. Epithelial cells have broken through the basement membrane and are present in detached clusters that have invaded deeply into the connective tissue. composition and appearance of the tissue (Figure 5–14). Sometimes, they provoke proliferation of $brous tissue, so the lesion becomes very $rm. !e central areas of the tissue may become necrotic due to inadequate oxygenation. In addition, the neoplastic cells destroy the normal structures that were present. !ey may erode into vessels, causing hemorrhage into the lesion. !ey may destroy the epithelial lining of a mucosal surface, resulting in ulceration. Invasion is a local process: the cells have moved from their site of origin in a continuous fashion into adjacent tis- sue. !eoretically, surgical excision of such a mass should achieve a cure. Indeed, small, relatively localized invasive cancers can be cured with surgical excision. !e larger the tumor gets and the farther it grows into adjacent tissues, however, the less likely is it that surgical excision will be curative. !is is because some of the malignant subclones will have developed the ability to metastasize, or to move to distant sites of the body in a noncontiguous fashion. Metastasis refers to the noncontiguous spread of malignant cells to di%erent areas in the body, for exam- ple when colon cancer appears in the brain, or nodules of breast cancer grow in the lung, or when any cancer spreads to lymph nodes (Figure 5–15). Metastasis occurs fairly late in the natural history of malignant neoplasms, because it involves a complicated sequence of events and requires a large number of additional growth-promoting capabilities (Figure 5–16). First, the malignant cells must have acquired the abil- ity to invade into neighboring tissue, as already described. !is requires the production of enzymes capable of digest- ing basement membrane and extracellular proteins. !e FIGURE 5–14 This is an image of a sarcoma that has invaded the tibia. The tumor is the dense white tissue. The granular red and malignant cells must then be able to grow through the wall yellow tissue at either end of the specimen is the marrow cavity of a vessel, either a blood vessel or a lymphatic capillary. of the bone. Note the irregular margins of the sarcoma where it is !is is called intravasation, and is dependent on production growing diffusely through the marrow space.  The Natural History of Cancer 79 of additional enzymes capable of breaking apart the base- ment membrane to which endothelial cells are anchored, * and the junctions between the cells of the vessel wall and the vessel lining. Once in the vessel, the cells must be able to evade the host’s immune system. Circulating lympho- cytes and monocytes recognize the tumor emboli as “for- eign” and rapidly clear them from the circulation. If the embolus is capable of surrounding itself with a platelet coat, however, it evades immune detection because it is * hidden from the immune cells. !e #ow of blood can carry the tumor cell or cluster of cells, which is called a “tumor embolus,” to distant sites. !e liver and lungs, $ltering the * body’s blood through vast expanses of capillaries and sinu- soids, are the organs in which metastases most frequently occur. !e tumor embolus then must adhere again to the vessel wall, at a distant site, and migrate back out of it. !is is the inverse of the process of intravasation, and referred to as extravasation. Finally, the tumor cells must be able to FIGURE 5–15 Metastasis. This is a cross section of a liver. There are numerous nodules in the liver, even some apparent on the establish themselves in the new location. !is may require capsular surface (top). These are metastases from a pancreatic the ability to stimulate growth of its own blood supply, or adenocarcinoma. angiogenesis. !e ability to invade and metastasize are the de$ning features of a malignancy. If a neoplasm demon- strates invasion or metastatic growth at the time of clinical detection, it is by de$nition Clonal expansion, malignant. Treatment of neoplastic growths Transformed Dysplasia cell growth, diversification is dependent on the clinical assessment of the degree to which a malignancy has spread Accumulation of throughout the body. genetic changes that Carcinoma confer growth advantage in-situ Stage: Prognosis and Treatment !e prognosis of a cancer and its treatment Basement membrane Adhesion to and in any individual patient derive from knowl- Primary invasion of basement edge of the natural history of malignancies. tumor membrane !e secondary e%ects of invasion often Invasion bring the tumor to clinical attention. For Passage through example, a colon cancer that has invaded extracellular matrix through the bowel wall could present with colonic perforation; cervical cancer that has Host Intravasation widely in$ltrated the pelvis can cause ure- lymphocyte teral obstruction; a carcinoma arising in the Interaction with host head of the pancreas can cause jaundice by lymphoid cells obstructing the common bile duct. Platelets In general, the more widely a cancer has Tumor cell embolus spread in the body at the time it is detected, Extracellular matrix the more likely it will result in death. Adhesion to Metastasis However, the characteristics of a malignancy endothelium that correlate with survival and its pattern of spread vary from one type of tumor to the Extravasation next. To prognosticate and design therapy that is most likely to be e%ective, the stage Metastatic deposit of the tumor must be determined. Stage describes the extent of spread of a cancer Metastatic Angiogenesis in the body. Universally, it is designated tumor by the TNM system, whereby T describes Growth the tumor itself, N describes the extent of lymph node metastasis, and M describes whether distant metastasis has occurred. FIGURE 5–16 Steps in metastasis. Usually, the N and M designations simply 80 CHAPTER 5 Neoplasia re#ect whether metastases to the lymph nodes or distant organs, respectively, are present, although for some can- TABLE 5–14 Stage Grouping by TNM cers (e.g., breast cancer) further separation of N accord- Classi!cation for Colon ing to the number of involved lymph nodes and the size Carcinoma of the metastatic deposit within them is also necessary for accurate stage designation. T is the most variable fac- Stage T N M tor. !e characteristics de$ning T vary from one organ to the next, but generally consist of a combination of the Stage I T1 N0 M0 size of the tumor and the extent to which it has invaded T1 N0 M0 surrounding tissues. Table 5–13 lists the TNM grouping criteria for colon carcinoma. Stage IIA T3 N0 M0 !e possible combinations of T, N, and M correspond to di%erent stages of cancer spread. For all cancers, there Stage IIB T3 N0 M0 are four stages, with stage I representing the most local- ized manifestation, and stage IV connoting metastatic Stage IIIA T1 or T2 N1 M0 spread. How the various T, N, and M classi$cations are combined in stages again varies from one organ to the Stage IIIB T3 or T4 N1 M0 next. !ese classi$cations are based on numerous stud- ies and observations and are continuously being revised