2. Altered Cellular Metabolism
• Even in the presence of ample oxygen, cancer cells demonstrate a
distinctive form of cellular metabolism characterized by high levels of
glucose uptake and increased conversion of glucose to lactose
(fermentation) via the glycolytic pathway
• This phenomenon, called the Warburg effect and also known as
aerobic glycolysis
• “Warburg metabolism” is not cancer specific, but instead is a general
property of growing cells that becomes “fixed” in cancer cells.
4. Autophagy
• Tumor cells often seem to be able to grow under marginal
environmental conditions without triggering autophagy,
• Suggesting that the pathways that induce autophagy are deranged.
• In keeping with this, several genes that promote autophagy are tumor
suppressors.
5. Evasion of Cell Death
• Tumor cells frequently contain mutations in genes that regulate
apoptosis, making the cells resistant to cell death.
• There are two pathways that lead to apoptosis: the extrinsic pathway,
triggered by the death receptors FAS and FAS-ligand; and the intrinsic
pathway (also known as the mitochondrial pathway
• Cancer cells are subject to a number of intrinsic stresses that can
initiate apoptosis, particularly DNA damage, but also metabolic
disturbances stemming from dysregulated growth as well as hypoxia
caused by insufficient blood supply
6. Immortality
• Tumor cells, unlike normal cells, are capable of limitless replication.
• Most normal human cells have a capacity of at most 70 doublings.
Thereafter, the cells lose the ability to divide and enter replicative
senescence.
• This phenomenon has been ascribed to progressive shortening of
telomeres at the ends of chromosomes
• Markedly eroded telomeres are recognized by the DNA repair
machinery as double-stranded DNA breaks, leading to cell cycle arrest
,mediated by TP53 and RB.
8. Sustained Angiogenesis
• Even if a solid tumor possesses all of the genetic aberrations that are
required for malignant transformation, it cannot enlarge beyond 1 to
2 mm in diameter unless it has the capacity to induce angiogenesis
• Growing cancers stimulate neoangiogenesis, during which vessels
sprout from previously existing capillaries.
• Neovascularization has a dual effect on tumor growth: perfusion
supplies needed nutrients and oxygen, and secreting growth factors
• Permitting tumor cells access to these abnormal vessels, angiogenesis
also contributes to metastasis.
9. Invasion and Metastasis
• Invasion, and metastasis, the major causes of cancer-related
morbidity and mortality, result from complex interactions involving
cancer cells, stromal cells, and the extracellular matrix (ECM)
• These interactions can be broken down into a series of steps
consisting of local invasion, intravasation into blood and lymph
vessels
• Transit through the vasculature, extravasation from the vessels,
formation of micrometastases, and growth of micrometastases into
macroscopic tumors
11. Metastasis
• Some variation in metastasis clearly relates to inherent differences in
the behavior of particular tumors
• However, tumor size and type cannot adequately explain the behavior
of individual cancers, and it is still open to question whether
metastasis is merely probabilistic (a matter of chance multiplied by
tumor cell number and time)
• OR reflects inherent differences in metastatic potential from tumor to
tumor (a deterministic model)
• The deterministic model proposes that metastasis is inevitable with
certain tumors because the tumor harbors cells with a specific
metastatic phenotype
12. Evasion of Immune Surveillance
• The specific factors that govern the outcome of interactions between
tumor cells and the host immune system are numerous
• Cancer cells express a variety of antigens that stimulate the host
immune system
• Despite the antigenicity of cancer cells, the immune response to
established tumors is ineffective, and in some instances may actually
promote cancer growth
• Defining mechanisms of immune evasion and “immunomanipulation”
by cancer cells has led to effective new immunotherapies that work
by reactivating latent host immune responses.
14. CARCINOGENIC AGENTS
• Carcinogenic agents inflict genetic damage, which lies at the heart of
carcinogenesis.
Three classes of carcinogenic agents have been identified:
(1) Chemicals,
(2) radiant energy,
(3) Microbial products.
19. CLINICAL ASPECTS
• Both malignant and benign tumors may cause problems because of:
(1) Location and impingement on adjacent structures,
(2) Hormone synthesis (paraneoplastic syndromes)
(3) Bleeding and infections
(4) Rupture or infarction,
(5) cachexia
21. Grading and Staging of Cancer
• when compared with grading, staging has proved to be of greater
clinical value
• Grading of a cancer is based on the degree of differentiation of the
tumor cells and, in some cancers, the number of mitoses and the
presence of certain architectural features
• The staging of solid cancers is based on the size of the primary lesion,
its extent of spread to regional lymph nodes, and the presence or
absence of bloodborne metastases
22. Tumor Markers
• Biochemical assays for tumor-associated enzymes, hormones, and
other tumor markers in the blood cannot be utilized for definitive
diagnosis of cancer;
• However, they are used with varying success as screening tests and
have utility in monitoring the response to therapy or detecting
disease recurrence
23. Molecular Diagnosis
• Because each T cell and B cell has unique antigen receptor gene
rearrangements, polymerase chain reaction (PCR)–based detection of
rearranged T-cell receptor or immunoglobulin genes allows
monoclonal (neoplastic) and polyclonal (reactive) proliferations to be
distinguished
• Certain genetic alterations are associated with a poor prognosis
• Another emerging use of molecular techniques is for detection of
minimal residual disease after treatment
• Diagnosis of hereditary predisposition to cancer.
Clinically, the “glucose-hunger” of tumors is used to visualize tumors via positron emission tomography (PET) scanning, in which patients are injected with 18F-fluorodeoxyglucose, a glucose derivative that is preferentially taken up into tumor cells (as well as normal, actively dividing tissues such as the bone marrow). Most tumors are PET-positive, and rapidly growing ones are markedly so
Aerobic glycolysis provides rapidly dividing tumor cells with metabolic intermediates that are needed for the synthesis of cellular components, whereas mitochondrial oxidative phosphorylation does not.
The reason growing cells rely on aerobic glycolysis becomes readily apparent when one considers that a growing cell has a strict biosynthetic requirement; it must duplicate all of its cellular components—DNA, RNA, proteins, lipid, and organelles—before it can divide and produce two daughter cells. While oxidative phosphorylation yields abundant ATP, it fails to produce any carbon moieties that can be used to build the cellular components needed for growth (proteins, lipids, and nucleic acids)
By contrast, in actively growing cells only a small fraction of the cellular glucose is shunted through the oxidative phosphorylation pathway, such that on average each molecule of glucose metabolized produces approximately four molecules of ATP
a major function of mitochondria in growing cells is not to generate ATP, but rather to carry out reactions that generate metabolic intermediates that can be shunted off and used as precursors in the synthesis of cellular building blocks
As might be guessed, metabolic reprogramming is produced by signaling cascades downstream of growth factor receptors, the very same pathways that are deregulated by mutations in oncogenes and tumors suppressor genes in cancers. Thus, whereas in rapidly dividing normal cells aerobic glycolysis ceases when the tissue is no longer growing, in cancer cells this reprogramming persists due to the action of oncogenes and the loss of tumor suppressor gene function. Some of the important points of cross-talk between pro–growth signaling factors and cellular metabolism are shown in Fig. 6.23 and include the following: • Growth factor receptor signaling. In addition to transmitting growth signals to the nucleus, signals from growth factor receptors also influence metabolism by upregulating glucose uptake and inhibiting the activity of pyruvate kinase, which catalyzes the last step in the glycolytic pathway, the conversion of phosphoenolpyruvate to pyruvate. This creates a damming effect that leads to the buildup of upstream glycolytic intermediates, which are siphoned off for synthesis of DNA, RNA, and protein. • RAS signaling. Signals downstream of RAS upregulate the activity of glucose transporters and multiple glycolytic enzymes, thus increasing glycolysis; promote shunting of mitochondrial intermediates to pathways leading to lipid biosynthesis; and stimulate factors that are required for protein synthesis. • MYC. As mentioned earlier, pro-growth pathways upregulate expression of the transcription factor MYC, which drives changes in gene expression that support anabolic metabolism and cell growth. Among the MYCregulated genes are those for several glycolytic enzymes and glutaminase, which is required for mitochondrial utilization of glutamine, a key source of carbon moieties needed for biosynthesis of cellular building blocks
Whether autophagy is always bad from the vantage point of the tumor, however, remains a matter of active investigation and debate. For example, under conditions of severe nutrient deprivation, tumor cells may use autophagy to become “dormant,” a state of metabolic hibernation that allows cells to survive hard times for long periods. Such cells are believed to be resistant to therapies that kill actively dividing cells, and could therefore be responsible for therapeutic failures. Thus, autophagy may be a tumor’s friend or foe depending on how the signaling pathways that regulate it are “wired” in a given tumor
apoptosis, or regulated cell death, refers to an orderly dismantling of cells into component pieces, which are then efficiently consumed by neighboring cells and professional phagocytes without stimulating inflammation
These stresses are enhanced manyfold when tumors are treated with chemotherapy or radiation therapy, which kill tumor cells by activating the intrinsic pathway of apoptosis. Thus, there is strong selective pressure, both before and during therapy, for cancer cells to develop resistance to intrinsic stresses that may induce apoptosis
Accordingly, evasion of apoptosis by cancer cells occurs mainly by way of acquired mutations and changes in gene expression that disable key components of the intrinsic pathway, or that reset the balance of regulatory factors so as to favor cell survival in the face of intrinsic stresses
Such an inappropriately activated repair system results in dicentric chromosomes that are pulled apart at anaphase, resulting in new double-stranded DNA breaks. The resulting genomic instability from the repeated bridge– fusion–breakage cycles eventually produces mitotic catastrophe, characterized by massive apoptosis. It follows that for tumors to acquire the ability to grow indefinitely, loss of growth restraints is not enough; both cellular senescence and mitotic catastrophe must also be avoided
In cells in which TP53 or RB mutations are disabled by mutations, the nonhomologous end-joining pathway is activated in a last-ditch effort to save the cell, joining the shortened ends of two chromosomes
If during crisis a cell manages to reactivate telomerase, the bridge–fusion–breakage cycles cease, and the cell is able to avoid death. However, during this period of genomic instability that precedes telomerase activation, numerous mutations could accumulate, helping the normal stem cells, is absent from or present at very low levels in most somatic cells. By contrast, telomere maintenance is seen in virtually all types of cancers. In 85% to 95% of cancers, this is due to upregulation of the enzyme telomerase. A few tumors use other mechanisms, termed alternative lengthening of telomeres, which depend on DNA recombination. Of interest, in a study of the progression from colonic adenoma to colonic adenocarcinoma, early lesions had a high degree of genomic instability with low telomerase expression, whereas malignant lesions had complex karyotypes with high levels of telomerase activity, consistent with a model of telomere-driven tumorigenesis in human cancer. Thus, it appears that unregulated proliferation in incipient tumors leads to telomere shortening, followed by chromosomal instability and the accumulation of mutations. If telomerase is then reactivated in these cells, telomeres are extended and these mutations become fixed, contributing to tumor growth.
Like normal tissues, tumors require delivery of oxygen and nutrients and removal of waste products; presumably the 1- to 2-mm zone represents the maximal distance across which oxygen, nutrients, and waste can diffuse to and from blood vessels
While the resulting tumor vasculature is effective at delivering nutrients and removing wastes, it is not entirely normal; the vessels are leaky and dilated, and have a haphazard pattern of connection, features that can be appreciated on angiograms
How do growing tumors develop a blood supply? The current paradigm is that angiogenesis is controlled by a balance between angiogenesis promoters and inhibitors; in angiogenic tumors this balance is skewed in favor of promoters
The local balance of angiogenic and anti-angiogenic factors is influenced by several factors: • Relative lack of oxygen due to hypoxia stabilizes HIF1α, an oxygen-sensitive transcription factor mentioned earlier, which then activates the transcription of proangiogenic cytokines such as VEGF. These factors create an angiogenic gradient that stimulates the proliferation of endothelial cells and guides the growth of new vessels toward the tumor. • Mutations involving tumor suppressors and oncogenes in cancers also tilt the balance in favor of angiogenesis. For example, p53 stimulates expression of antiangiogenic molecules, such as thrombospondin-1, and represses expression of proangiogenic molecules, such as VEGF. Thus, loss of p53 in tumor cells provides a more permissive environment for angiogenesis. • The transcription of VEGF also is influenced by signals from the RAS-MAP kinase pathway, and gain-offunction mutations in RAS or MYC upregulate the production of VEGF. Notably, elevated levels of VEGF can be detected in the serum and urine of a significant fraction of cancer patients
Predictably, this sequence of steps may be interrupted at any stage by either host-related or tumor-related factors. For the purpose of discussion, the metastatic cascade can be subdivided into two phases: (1) invasion of ECM and (2) vascular dissemination and homing of tumor cells
Invasion of Extracellular Matrix Human tissues are organized into a series of compartments separated from each other by two types of ECM: basement membranes and interstitial connective tissue (Chapter 1). Although organized differently, each type of ECM is composed of collagens, glycoproteins, and proteoglycans. Tumor cells must interact with the ECM at several stages in the metastatic cascade (see Fig. 6.27). A carcinoma first must breach the underlying basement membrane, then traverse the interstitial connective tissue, and ultimately gain access to the circulation by penetrating the vascular basement membrane. This process is repeated in reverse when tumor cell emboli extravasate at a distant site. Invasion of the ECM initiates the metastatic cascade and is an active process that can be resolved into several sequential steps (Fig. 6.28): • Loosening of intercellular connections between tumor cells
Local degradation of the basement membrane and interstitial connective tissue
Because of their invasive properties, tumor cells frequently escape their sites of origin and enter the circulation.
Several factors seem to limit the metastatic potential of circulating tumor cells. While in the circulation, tumor cells are vulnerable to destruction by host immune cells (discussed later), and the process of adhesion to normal vascular beds and invasion of normal distant tissues may be much more difficult than the escape of tumor cells from the cancer. Even following extravasation, tumor cells that have been selected for growth in the originating tissue may find it difficult to grow in a second site due to lack of critical stromal support or because of recognition and suppression by resident immune cells. Indeed, the concept of tumor dormancy, referring to the prolonged survival of micrometastases without progression, is well described in melanoma and in breast and prostate carcinoma
Despite these limiting factors, if neglected, virtually all malignant tumors will eventually produce macroscopic metastases. The site at which metastases appear is related to two factors: the anatomic location and vascular drainage of the primary tumor, and the tropism of particular tumors for specific tissues
for example, small cell carcinoma of the lung virtually always metastasizes to distant sites, whereas with some tumors, such as basal cell carcinoma, metastasis is the exception rather than the rule. In general, large tumors are more likely to metastasize than small tumors, presumably because (all other things being equal) large tumors will have been present in the patient for longer periods of time, providing additional chances for metastasis to occur
One possibility is that only rare tumor cells accumulate all of the mutations necessary for metastasis, and that this accounts for the inefficiency of the process. However, identification of metastasis-specific mutations and metastasis-specific patterns of gene expression has proven to be difficult. An alternative idea is that some tumors acquire all of the mutations needed for metastasis early in their development, and that these are the tumors that are fated to be “bad actors.” Metastasis, according to this view, is not dependent on the stochastic generation of metastatic subclones during tumor progression, but is an intrinsic property of the tumor that develops early on during carcinogenesis. These mechanisms are not mutually exclusive, and it could be that aggressive tumors acquire a metastasis-permissive gene expression pattern early in tumorigenesis, yet also require some additional random mutations to complete the metastatic phenotype. Nor can all blame be placed on tumor cells: as mentioned earlier, there is evidence that the makeup of the stroma, the presence of infiltrating immune cells, and the degree and quality of angiogenesis also influence metastasis
Evasion of Immune Surveillance
Long one of the “holy grails” of oncology, the promise of therapies that enable the host immune system to recognize and destroy cancer cells is finally coming to fruition, largely due to a clearer understanding of the mechanisms by which cancer cells evade the host response.
Tumor Antigens. As we have discussed, cancer is a disorder that is caused by driver mutations in oncogenes and tumor suppressor genes, which in most instances are acquired rather than inherited. In addition to pathogenic driver mutations, cancers, due to their inherent genetic instability, also accumulate passenger mutations. These may be particularly abundant in cancers that are caused by mutagenic exposures (e.g., sunlight, smoking). All of these varied mutations may generate new protein sequences (neoantigens) that the immune system has not seen and therefore is not tolerant of and can react to. In some instances, unmutated proteins expressed by tumor cells also can stimulate the host immune response. • One such antigen is tyrosinase, an enzyme involved in melanin biosynthesis that is expressed only in normal melanocytes and melanomas. It may be surprising that the immune system is able to respond to this normal self-antigen. The probable explanation is that tyrosinase is normally produced in such small amounts and in so few normal cells that it is not recognized by the immune system and fails to induce tolerance. • Another group of tumor antigens, the cancer-testis antigens, are encoded by genes that are silent in all adult tissues except germ cells in the testis—hence their name. Although the protein is present in the testis it is not expressed on the cell surface in a form that can be recognized by CD8+ T cells, because sperm do not express MHC class I molecules. Thus, for all practical purposes these antigens are tumor specific and are therefore capable of stimulating anti-tumor immune responses.
Immune Evasion by Cancers. Since the immune system is capable of recognizing and eliminating nascent cancers, it follows that tumors that reach clinically significant sizes must be composed of cells that are either invisible to the host immune system or that express factors that actively suppress host immunity. The term cancer immunoediting has been used to describe the ability of the immune system to promote the darwinian selection of the tumor subclones that are most able to avoid host immunity or even manipulate the immune system for their own malignant purposes
Genomic Instability as an Enabler of Malignancy The preceding section identified the eight defining features of malignancy, all of which appear to be produced by genetic alterations involving cancer genes. How do these mutations arise? Although humans are awash in environmental agents that are mutagenic (e.g., chemicals, radiation, sunlight), cancers are relatively rare outcomes of these encounters. This state of affairs results from the ability of normal cells to sense and repair DNA damage. The importance of DNA repair in maintaining the integrity of the genome is highlighted by several inherited disorders in which genes that encode proteins involved in DNA repair are defective. Individuals born with inherited defects in DNA repair genes are at greatly increased risk for the development of cancer. Defects in three types of DNA repair systems—mismatch repair, nucleotide excision repair, and recombination repair—are presented next. While these discussions focus on inherited syndromes, a point worthy of emphasis is that sporadic cancers often incur mutations in DNA repair genes as well; this in turn enables the accumulation of mutations in cancer genes that contribute directly to development of cancer
Chemical Carcinogens
Direct-acting agents require no metabolic conversion to become carcinogenic. They are typically weak carcinogens but are important because some of them are cancer chemotherapy drugs (e.g., alkylating agents) used in regimens that may cure certain types of cancer
The designation indirect-acting refers to chemicals that require metabolic conversion to an ultimate carcinogen. Some of the most potent indirect chemical carcinogens are polycyclic hydrocarbons that are created with burning of fossil fuels, plant, and animal material
Mechanisms of Action of Chemical Carcinogens Because malignant transformation results from mutations, it should come as no surprise that most chemical carcinogens are mutagenic. Indeed, all direct and ultimate carcinogens contain highly reactive electrophile groups that form chemical adducts with DNA, as well as with proteins and RNA. Any gene may be the target of chemical carcinogens, but understandably it is the mutation of important cancer genes, such as RAS and TP53, that is responsible for carcinogenesis. Indeed, specific chemical carcinogens, such as aflatoxin B1, produce characteristic mutations in TP53, such that detection of mutations within particular codons strongly points toward aflatoxin as the causative agent. Such specific “mutational signatures” also exist for cancers caused by UV light, tobacco smoke, and other environmental carcinogens and are proving to be useful tools in epidemiologic studies of carcinogenesis. Carcinogenicity of some chemicals is augmented by subsequent administration of promoters (e.g., phorbol esters, hormones, phenols, certain drugs), which are by themselves nontumorigenic. To be effective, repeated or sustained exposure to the promoter must follow the application of the mutagenic chemical, or initiator
Radiation Carcinogenesis Radiation, whatever its source (UV rays of sunlight, radiographs, nuclear fission, radionuclides), is an established carcinogen. Unprotected miners of radioactive elements have a 10-fold increased incidence of lung cancers. A follow-up study of survivors of the atomic bombs dropped on Hiroshima and Nagasaki disclosed a markedly increased incidence of leukemia after an average latent period of about 7 years, as well as increased mortality rates for thyroid, breast, colon, and lung carcinomas. The nuclear power accident at Chernobyl in the former Soviet Union continues to exact its toll in the form of high cancer incidence in the surrounding areas. More recently, it is feared that radiation release from a nuclear power plant in Japan damaged by a massive earthquake and tsunami will result in significantly increased cancer incidence in the surrounding geographic areas. Therapeutic irradiation of the head and neck can give rise to papillary thyroid cancers years later. The oncogenic properties of ionizing radiation are related to its mutagenic effects; it causes chromosome breakage, chromosomal rearrangements such as translocations and inversions, and, less frequently, point mutations. Biologically, doublestranded DNA breaks seem to be the most important form of DNA damage caused by radiation
Viral and Microbial Oncogenesis Many DNA and RNA viruses have proved to be oncogenic in animals as disparate as frogs and primates. Despite intense scrutiny, however, only a few viruses have been linked with human cancer. The following discussion focuses on human oncogenic viruses. Also discussed is the role of the bacterium Helicobacter pylori in gastric cancer. Oncogenic RNA Viruses Although the study of animal retroviruses has provided spectacular insights into the molecular basis of cancer, only one human retrovirus, human T-cell leukemia virus type 1 (HTLV-1), is firmly implicated in the pathogenesis of cancer in humans. HTLV-1 causes adult T-cell leukemia/lymphoma (ATLL), a tumor that is endemic in certain parts of Japan, the Caribbean basin, South America, and Africa, and found sporadically elsewhere, including the United States. Worldwide, it is estimated that 15 to 20 million people are infected with HTLV-1. Similar to the human immunodeficiency virus, which causes AIDS, HTLV-1 has tropism for CD4+ T cells, and hence this subset of T cells is the major target for neoplastic transformation. Human infection requires transmission of infected T cells via sexual intercourse, blood products, or breastfeeding. Leukemia develops in only 3% to 5% of the infected individuals, typically after a long latent period of 40 to 60 years. There is little doubt that HTLV-1 infection of T lymphocytes is necessary for leukemogenesis, but the molecular mechanisms of transformation are not certain. In contrast to several murine retroviruses, HTLV-1 does not contain an oncogene, and no consistent pattern of proviral integration next to a proto-oncogene has been discovered.
Several aspects of HTLV-1’s transforming activity are attributable to Tax, the protein product of the tax gene
Human Papillomavirus Scores of genetically distinct types of HPV have been identified. Some types (e.g., 1, 2, 4, and 7) cause benign squamous papillomas (warts) in humans (Chapters 18 and 24). Genital warts have low malignant potential and are also associated with low-risk HPVs, predominantly HPV-6 and HPV-11. By contrast, high-risk HPVs (e.g., types 16 and 18) cause several cancers, particularly squamous cell carcinoma of the cervix and anogenital region. In addition, at least 20% of oropharyngeal cancers, particularly those arising in the tonsils, are associated with high-risk HPVs. The oncogenic potential of HPV can be related to products of two early viral genes, E6 and E7 (Fig. 6.33), each of which has several activities that are pro-oncogenic. • Oncogenic activities of E6. The E6 protein binds to and mediates the degradation of p53, and also stimulates the expression of TERT, the catalytic subunit of telomerase, which you will recall contributes to the immortalization of cells. E6 from high-risk HPV types has a higher affinity for p53 than E6 from low-risk HPV types, a property that is likely to contribute to oncogenesis. • Oncogenic activities of E7. The E7 protein has effects that complement those of E6, all of which are centered on speeding cells through the G1-S cell cycle checkpoint. It binds to the RB protein and displaces the E2F transcription factors that are normally sequestered by RB, promoting progression through the cell cycle. As with E6 proteins and p53, E7 proteins from high-risk HPV types have a higher affinity for RB than do E7 proteins from low-risk HPV types. E7 also inactivates the CDK inhibitors p21 and p27, and binds and presumably activates cyclins E and A
high-risk HPVs encode oncogenic proteins that inactivate RB and p53, activate cyclin/ CDK complexes, and combat cellular senescence
Epstein-Barr Virus EBV, a member of the herpesvirus family, was the first virus linked to a human tumor, Burkitt lymphoma
Effects of Tumor on Host Location is crucial in both benign and malignant tumors. A small (1-cm) pituitary adenoma can compress and destroy the surrounding normal gland, giving rise to hypopituitarism. A 0.5-cm leiomyoma in the wall of the renal artery may encroach on the blood supply, leading to renal ischemia and hypertension. A comparably small carcinoma within the common bile duct may induce fatal biliary tract obstruction. Signs and symptoms related to hormone production are often seen in patients with benign and malignant neoplasms arising in endocrine glands. Adenomas and carcinomas arising in the beta cells of the pancreatic islets of Langerhans can produce hyperinsulinism, sometimes fatal
Cancer Cachexia Many cancer patients suffer progressive loss of body fat and lean body mass, accompanied by profound weakness, anorexia, and anemia—a condition referred to as cachexia. There is some correlation between the size and extent of spread of the cancer and the severity of the cachexia
Paraneoplastic Syndromes Symptom complexes that occur in patients with cancer and that cannot be readily explained by local or distant spread of the tumor or by the elaboration of hormones indigenous to the tissue of origin of the tumor are referred to as paraneoplastic syndromes
They appear in 10% to 15% of patients with cancer, and their clinical recognition is important for several reasons: • Such syndromes may represent the earliest manifestation of an occult neoplasm. • In affected patients, the pathologic changes may be associated with significant clinical illness and may even be lethal. • The symptom complex may mimic metastatic disease, thereby confounding treatment
The most common paraneoplastic syndromes are hypercalcemia, Cushing syndrome, and nonbacterial thrombotic endocarditis, and the neoplasms most often associated with these and other syndromes are lung and breast cancers and hematologic malignancie
Grading schemes have evolved for each type of malignancy, and generally range from two categories (low grade and high grade) to four categories. Criteria for the individual grades vary in different types of tumors and so are not detailed here, but all attempt, in essence, to judge the extent to which the tumor cells resemble or fail to resemble their normal counterparts
The major staging system currently in use is the American Joint Committee on Cancer Staging. This system uses a classification called the TNM system—T for primary tumor, N for regional lymph node involvement, and M for metastases. TNM staging varies for specific forms of cancer, but there are general principles
PSA, used to screen for prostatic adenocarcinoma, is one of the most frequently used tumor markers in clinical practice. Prostatic carcinoma can be suspected when elevated levels of PSA are found in the blood. However, PSA screening also highlights problems encountered with use of virtually every tumor marker. Although PSA levels often are elevated in cancer, PSA levels also may be elevated in benign prostatic hyperplasia (Chapter 18). Furthermore, there is no PSA level that ensures that a patient does not have prostate cancer. Thus, the PSA test suffers from both low sensitivity and low specificity, and its use as a screening tool has become quite controversial
The PSA assay is extremely valuable, however, for detecting residual disease or recurrence following treatment for prostate cancer. Other tumor markers used in clinical practice include carcinoembryonic antigen (CEA), which is elaborated by carcinomas of the colon, pancreas, stomach, and breast, and alpha fetoprotein (AFP), which is produced by hepatocellular carcinomas, yolk sac remnants in the gonads, and occasionally teratocarcinomas and embryonal cell carcinomas. Like PSA, CEA and AFP can be elevated in a variety of nonneoplastic conditions and thus also lack the specificity and sensitivity required for the early detection of cancers, but they may be useful in monitoring disease once the diagnosis is established. With successful resection of the tumor, these markers disappear from the serum; their reappearance almost always signifies recurrence
Many hematopoietic neoplasms, as well as a few solid tumors, are defined by particular translocations, so the diagnosis can be made by detection of such translocations. For example, fluorescence in situ hybridization (FISH) or PCR analysis (Chapter 7) can be used to detect translocations characteristic of Ewing sarcoma and several leukemias and lymphomas. PCR-based detection of BCR-ABL transcripts can confirm the diagnosis of chronic myeloid leukemia (Chapter 12). Finally, certain hematologic malignancies are now defined by the presence of point mutations in particular oncogenes. For example, as mentioned earlier, the diagnosis of another myeloid neoplasm called polycythemia vera requires the identification of specific mutations in JAK2, a gene that encodes a nonreceptor tyrosine kinase
Therapeutic decision-making. Therapies that directly target specific mutations are increasingly being developed, and thus detection of such mutations in a tumor can guide the development of targeted therapy, as discussed later. It is now becoming evident that certain targetable mutations transgress morphologic categories. One example involves a valine for glutamate substitution in amino acid 600 (V600E) of the serine/threonine kinase BRAF, which you will recall lies downstream of RAS in the growth factor signaling pathway. Melanomas with the V600E BRAF mutation respond well to BRAF inhibitors, whereas melanomas without this mutation show no response. Subsequently, it was realized that the same V600E mutation is also present in a subset of many other diverse cancers, including carcinomas of the colon and thyroid gland, most hairy cell leukemias, and many cases of Langerhans cell histiocytosis
