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Pathology_Robbins. Improvements are only possible with greater understanding of the “escape routes” through which tumor cells sidestep the effects of the angiogenesis inhibitors that are now in use. Vascularizationoftumorsisessentialfortheirgrowthandiscontrolledbythebalancebetweenangiogenicandantiangiogenicfactorsthatareproducedbytumorandstromalcells. HypoxiatriggersangiogenesisthroughtheactionsofHIF-1α onthetranscriptionoftheproangiogenicfactorVEGF. Manyotherfactorsregulateangiogenesis;forexample,p53inducessynthesisoftheangiogenesisinhibitorthombospondin-1,whileRAS,MYC,andMAPKsignalingallupregulateVEGFexpressionandstimulateangiogenesis. VEGFinhibitorsareusedtotreatanumberofadvancedcancersandprolongtheclinicalcourse,butarenotcurative.


Pathology_Robbins

Pathology_Robbins. VEGFinhibitorsareusedtotreatanumberofadvancedcancersandprolongtheclinicalcourse,butarenotcurative. 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 ( Fig. 6.27 ). 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


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Pathology_Robbins. 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 (


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Pathology_Robbins. Fig. 6.28 • Loosening of intercellular connections between tumor cells. As mentioned earlier, E-cadherins act as intercellular glues, and their cytoplasmic portions bind to β-catenin (see Fig. 6.22 ). Adjacent E-cadherin molecules keep the cells together; in addition, as discussed earlier, E-cadherin can transmit anti-growth signals by sequestering β-catenin. E-cadherin function is lost in almost all http://ebooksmedicine.net Fig. 6.27 Themetastaticcascade:Thesequentialstepsinvolvedinthehematogenousspreadofatumor. Clonal expansion, growth, diversification, angiogenesis Adhesion to and invasion of basement membrane Interaction with host lymphoid cells Adhesion to basement membrane epithelial cancers, either by mutational inactivation of E-cadherin genes, activation of β-catenin genes, or inappropriate expression of the SNAIL and TWIST transcription factors, which suppress E-cadherin expression.


Pathology_Robbins

Pathology_Robbins. • Local degradation of the basement membrane and interstitial connective tissue. Tumor cells may either secrete proteolytic enzymes themselves or induce stromal cells (e.g., fibroblasts and inflammatory cells) to elaborate proteases. Multiple different proteases, such as matrix metalloproteinases (MMPs), cathepsin D, and urokinase plasminogen activator, have been implicated in tumor cell invasion. MMPs regulate tumor invasion not only by remodeling insoluble components of the basement membrane and interstitial matrix but also by releasing ECM-sequestered growth factors, which have chemotactic, angiogenic, and growth-promoting effects. For example, MMP-9 is a gelatinase that cleaves type IV collagen of the epithelial and vascular basement membrane and also stimulates release of VEGF from ECM-sequestered pools. Benign tumors of the breast, colon, and stomach show little type IV collagenase activity, whereas their malignant counterparts overexpress this enzyme. Concurrently, the levels


Pathology_Robbins

Pathology_Robbins. ECM-sequestered pools. Benign tumors of the breast, colon, and stomach show little type IV collagenase activity, whereas their malignant counterparts overexpress this enzyme. Concurrently, the levels of metalloproteinase inhibitors are reduced so that the balance is tilted greatly toward tissue degradation. Indeed, overexpression of MMPs and other proteases has been reported for many malignant tumors.


Pathology_Robbins

Pathology_Robbins. Fig. 6.28 Sequenceofeventsintheinvasionofepithelialbasementmem-branesbytumorcells.Tumorcellsdetachfromeachotherbecauseofreducedadhesivenessandattractinflammatorycells.Proteasessecretedfromtumorcellsandinflammatorycellsdegradethebasementmembrane.Bindingoftumorcellstoproteolyticallygeneratedbindingsitesandtumorcellmigrationfollow.LamininType IV collagen Basement membrane Cadherins A LOOSENING OF INTERCELLULAR JUNCTIONS Type IV collagen cleavage Plasminogen activator Type IV collagenase Matrix metalloproteaseB DEGRADATION OF ECM C MIGRATION AND INVASION Laminin receptor Fibronectin receptor Autocrine motility factor Fibronectin http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Changes in attachment of tumor cells to ECM proteins. Normal epithelial cells have receptors, such as integrins, for basement membrane laminin and collagens that are polarized at their basal surface; these receptors help to maintain the cells in a resting, differentiated state. Loss of adhesion in normal cells leads to induction of apoptosis, while, not surprisingly, tumor cells are resistant to this form of cell death. Additionally, the matrix itself is modified in ways that promote invasion and metastasis. For example, cleavage of the basement membrane proteins, collagen IV, and laminin by MMP-2 or MMP-9 generates novel sites that bind to receptors on tumor cells and stimulate migration.


Pathology_Robbins

Pathology_Robbins. Locomotion is the final step of invasion, propelling tumor cells through the degraded basement membranes and zones of matrix proteolysis. Migration is a complex, multistep process that involves many families of receptors and signaling proteins that eventually impinge on the actin cytoskeleton. Such movement seems to be potentiated and directed by tumor cell–derived cytokines, such as autocrine motility factors. In addition, cleavage products of matrix components (e.g., collagen, laminin) and some growth factors (e.g., insulin-like growth factors I and II) have chemotactic activity for tumor cells. Stromal cells also produce paracrine effectors of cell motility, such as hepatocyte growth factor/scatter factor (HGF/ SCF), which binds to receptors on tumor cells. Concentrations of HGF/SCF are elevated at the advancing edges of the highly invasive brain tumor glioblastoma multiforme, supporting their role in motility.


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Pathology_Robbins. It also has become clear that the stromal cells surrounding tumor cells are not merely a static barrier for tumor cells to traverse but rather constitute a variable environment in which reciprocal signaling between tumor cells and stromal cells such as fibroblasts and immune cells enable multiple cancer hallmarks (discussed later). For example, a variety of studies have demonstrated that tumor-associated fibroblasts exhibit altered expression of genes that encode ECM molecules, proteases, protease inhibitors, and various growth factors, all of which can influence tumor invasion and extravasation. The most successful tumors may be those that can co-opt the activities of stromal cells to their own nefarious purposes. Vascular Dissemination and Homing of Tumor Cells


Pathology_Robbins

Pathology_Robbins. Vascular Dissemination and Homing of Tumor Cells Because of their invasive properties, tumor cells frequently escape their sites of origin and enter the circulation. It is now recognized from studies of “liquid biopsies,” blood samples taken from patients with solid tumors, that millions of tumor cells are shed daily from even small cancers; hence both tumor cells and tumor-derived DNA can be detected in circulation. Most of these tumor cells circulate as single cells, while others form emboli by aggregating and adhering to circulating blood elements, particularly platelets. Given the ease with which tumor cells access the circulation, it is apparent that the ability of cancers cells to leave the circulation, invade, and grow to clinically significant sizes at other sites in the body is (fortunately for the patient) highly inefficient.


Pathology_Robbins

Pathology_Robbins. 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. Dormancy of tumor cells at distant sites may well be the last defense against clinically significant metastatic disease.


Pathology_Robbins

Pathology_Robbins. 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. As mentioned earlier, most metastases occur in the first capillary bed available to the tumor, hence the frequency of metastases to liver and lung. Many observations, however, suggest that natural pathways of drainage do not wholly explain the distribution of metastases. For example, prostatic carcinoma preferentially spreads to bone, bronchogenic carcinomas tend to involve the adrenal glands and the brain, and neuroblastomas spread to the liver and bones. Such organ tropism may be related to the following mechanisms: Tumor cells may have adhesion molecules whose ligands are expressed preferentially on the endothelial cells of the target organ.


Pathology_Robbins

Pathology_Robbins. Tumor cells may have adhesion molecules whose ligands are expressed preferentially on the endothelial cells of the target organ. Chemokines may have an important role in determining the target tissues for metastasis. For instance, many cancers express the chemokine receptor CXCR4, which has been implicated in the extravasation of circulating tumor cells originating from tumors such as breast cancer. In some cases, the target tissue may be a nonpermissive environment, “unfavorable soil,” so to speak, for the growth of tumor seedlings. For example, although they are well vascularized, skeletal muscle and spleen are rarely sites of metastasis.


Pathology_Robbins

Pathology_Robbins. It must be admitted, however, that although particular tumors “prefer” certain metastatic sites, the precise localization of metastases cannot be predicted in individual patients with any form of cancer. Evidently, much to the dismay of medical students, many tumors have not read the relevant chapters of pathology textbooks! Although the molecular mechanisms of colonization are still being unraveled, a consistent theme seems to be that tumor cells secrete cytokines, growth factors, and proteases that act on the resident stromal cells, which in turn make the metastatic site habitable for the cancer cell. With a better molecular understanding of the mechanisms of metastasis, the clinician’s ability to target them therapeutically will be greatly enhanced. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Of central importance in oncology is the question, why do only some tumors metastasize? It is sobering to realize that satisfying answers are still lacking. Some variation in metastasis clearly relates to inherent differences in the behavior of particular tumors; 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. 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


Pathology_Robbins

Pathology_Robbins. 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).


Pathology_Robbins

Pathology_Robbins. The deterministic model proposes that metastasis is inevitable with certain tumors because the tumor harbors cells with a specific metastatic phenotype. As discussed earlier, as tumor cells grow they randomly accumulate mutations, creating subclones with distinct combinations of mutations. 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.


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Pathology_Robbins. 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.


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Pathology_Robbins. Another open question is whether there are genes whose principal or sole contribution is to control programs of gene expression that promote metastasis. This question is of more than academic interest, because if altered forms of certain genes promote or suppress the metastatic phenotype, their detection in a primary tumor would have both prognostic and therapeutic implications. Among candidates for such metastasis oncogenes are those encoding SNAIL and TWIST, transcription factors whose primary function is to promote epithelial-to-mesenchymal transition (EMT). In EMT, carcinoma cells downregulate certain epithelial markers (e.g., E-cadherin) and upregulate certain mesenchymal markers (e.g., vimentin, smooth muscle actin). These molecular changes are accompanied by phenotypic alterations such as morphologic change from polygonal epithelioid cell shape to a spindly mesenchymal shape, along with increased production of proteolytic enzymes that promote migration and invasion. These


Pathology_Robbins

Pathology_Robbins. such as morphologic change from polygonal epithelioid cell shape to a spindly mesenchymal shape, along with increased production of proteolytic enzymes that promote migration and invasion. These changes are believed to favor the development of a promigratory phenotype that is essential for metastasis. Loss of E-cadherin expression seems to be a key event in EMT, and SNAIL and TWIST are transcriptional repressors that downregulate E-cadherin expression. How expression of these master regulator transcription factors is stimulated in tumors is not clear; however, experimental models suggest that interactions of tumor cells with stromal cells are a key stimulus for this change. Thus, acquisition of a metastatic phenotype may not require a set of mutations but may be an emergent property arising from the interactions of tumor cells and stroma.


Pathology_Robbins


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Pathology_Robbins. 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. Paul Ehrlich first conceived the idea that tumor cells can be recognized as “foreign” and eliminated by the immune system. Subsequently, Lewis Thomas and Macfarlane Burnet formalized this concept by coining the term immune surveillance, based on the premise that a normal function of the immune system is to constantly “scan” the body for emerging malignant cells and destroy them. This idea has been supported by many observations—the direct demonstration of tumor-specific T cells and antibodies in patients; data showing that the extent and quality of immune infiltrates in cancers often correlates with outcome; the increased incidence of certain cancers in immunodeficient people and mice; and most recently and most


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Pathology_Robbins. that the extent and quality of immune infiltrates in cancers often correlates with outcome; the increased incidence of certain cancers in immunodeficient people and mice; and most recently and most directly, the dramatic success of immunotherapy in the treatment of several cancers.


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Pathology_Robbins. http://ebooksmedicine.net The specific factors that govern the outcome of interactions between tumor cells and the host immune system are numerous and are still being defined. In the face of this complexity, it is helpful to consider a few overarching principles: Cancer cells express a variety of antigens that stimulate the host immune system, which appears to have an important role in preventing the emergence of cancers. Despite the antigenicity of cancer cells, the immune response to established tumors is ineffective, and in some instances may actually promote cancer growth, due to acquired changes that allow cancer cells to evade anti-tumor responses and foster pro-tumor responses. Defining mechanisms of immune evasion and “immunomanipulation” by cancer cells has led to effective new immunotherapies that work by reactivating latent host immune responses.


Pathology_Robbins

Pathology_Robbins. Defining mechanisms of immune evasion and “immunomanipulation” by cancer cells has led to effective new immunotherapies that work by reactivating latent host immune responses. 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.


Pathology_Robbins

Pathology_Robbins. 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.


Pathology_Robbins

Pathology_Robbins. 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.


Pathology_Robbins

Pathology_Robbins. An additional important class of tumor antigens consists of viral proteins that are expressed in cancer cells transformed by oncogenic viruses. The most potent of these antigens are proteins produced by cells that are latently infected with DNA viruses, the most important of which are human papilloma virus (HPV) and Epstein-Barr virus (EBV). There is abundant evidence that cytotoxic T lymphocytes (CTLs) recognize viral antigens and play important roles in surveillance against virus-induced tumors through their ability to recognize and kill virus-infected cells. Most notably, multiple cancers associated with oncogenic viruses, including HPV-associated cervical carcinoma and EBV-related B cell lymphomas, occur at significantly higher rates in individuals with defective T cell immunity, such as patients infected with HIV.


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Pathology_Robbins. Effective Immune Responses to Tumor Antigens. Assuming that the immune system is normally capable of eliminating emerging cancers, we may ask, what are the key components of an effective host immune response? It appears likely that immune reactions to cancers are initiated by the death of individual cancer cells, which occurs at some frequency in all cancers due to dysregulated growth, metabolic stresses, and hypoxia due to insufficient blood supply. When tumor cells die they release “danger signals” (damage associated molecular patterns, see Chapter 5) that stimulate innate immune cells, including resident phagocytes and antigen presenting cells. It is believed that some of the dead cells are phagocytosed by dendritic cells, which migrate to draining lymph nodes and present tumor neoantigens in the context of MHC class I molecules, a process termed cross-presentation. The displayed tumor antigens are recognized by antigen-specific CD8+ T cells, which become activated, proliferate,


Pathology_Robbins

Pathology_Robbins. in the context of MHC class I molecules, a process termed cross-presentation. The displayed tumor antigens are recognized by antigen-specific CD8+ T cells, which become activated, proliferate, differentiate into active CTLs, and home to the site of the tumor, where they recognize and kill tumor cells presenting neoantigens in the context of their own MHC class I molecules (


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Pathology_Robbins. Fig. 6.29 ). IFN-γ-producing T helper cells of the Th1 subset, which may be induced by recognition of tumor antigens, can activate macrophages and also contribute to the destruction of tumors. As will be discussed shortly, some the strongest evidence for the importance of CTL responses in immunosurveillance stems from the characterization of established human cancers, which often feature acquired mutations that prevent CTLs from recognizing tumor cells as “foreign”. It also has been noted in large studies of a wide variety of human tumors that high levels of infiltrating CTLs and Th1 cells correlate with better clinical outcomes. While other cell types such as natural killer cells also have been implicated in anti-tumor responses, the quality and strength of CTL responses are believed to be of preeminent importance.


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Pathology_Robbins. 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. Since CTL responses appear to be the most important defense that the host has against tumors, it should come as http://ebooksmedicine.net CTL killing of tumor Afferent Migration of lymphatictumor-specific vesselCTL to tumor Activation of tumor antigen-specific CD8+ T cell


Pathology_Robbins

Pathology_Robbins. CTL killing of tumor Afferent Migration of lymphatictumor-specific vesselCTL to tumor Activation of tumor antigen-specific CD8+ T cell Fig. 6.29 Cross-presentation of tumor antigens and induction of CD8+ cytotoxic T cell antitumor response. (Modified from Abbas AK, Lichtman AH, Pillai S: Cellular and molecular immunology, ed 9, Philadelphia, 2018, Elsevier.) no surprise that tumor cells show a variety of alterations that abrogate CTL responses. These include acquired mutations in β2-microglobulin that prevent the assembly of functional MHC class I molecules, and increased expression of a variety of proteins that inhibit CTL function. These proteins work by activating what is referred to as immune checkpoints, inhibitory pathways that normally are crucial for maintaining self-tolerance and controlling the size and duration of immune responses so as to minimize collateral tissue damage.


Pathology_Robbins

Pathology_Robbins. One of the best-characterized immune checkpoints involves a protein called PD-L1 (programmed cell death ligand 1), which is often expressed on the surface of tumor cells (Figure 6.30 ). When PD-L1 engages its receptor, PD-1, on CTLs, the CTLs become unresponsive and lose their ability to kill tumor cells. Experimental studies have identified several other immune checkpoint pathways, involving different ligands and receptors, which also have been implicated in immunoevasion by tumors. Of these, the best characterized involves CTLA4, another receptor expressed on T cells that inhibits T cell function.


Pathology_Robbins

Pathology_Robbins. The discovery of checkpoints that shut off anti-tumor immunity has led to the development of antibodies that block these checkpoints and release the brakes on the immune response. Current checkpoint blockade therapies have resulted in response rates of 10–30% in a variety of solid tumors (melanoma, lung cancer, bladder cancer, and others), and even higher rates in some hematologic malignancies such as Hodgkin lymphoma (Chapter 12). Because these checkpoints evolved to prevent responses to self antigens (Chapter 5), it is not surprising that patients treated with checkpoint blockade therapy develop various autoimmune manifestations, such as colitis and other types of systemic inflammation. Most of these reactions can be controlled with anti-inflammatory agents.


Pathology_Robbins

Pathology_Robbins. The remarkable response of advanced cancers to immune checkpoint inhibitors has energized other work focused on harnessing the immune system to combat cancer. These include efforts to develop personalized tumor vaccines using neoantigens identified in the tumors of individual patients, as well as new kinds of adoptive immunotherapy. The most advanced of the latter are patient-derived CTLs that are engineered to express chimeric antigen receptors (CARs). CARs have extracellular domains consisting of antibodies that bind tumor antigens and intracellular domains that delivered signals that activate CTLs following their engagement with antigen on the surface of tumor cells. CAR T cells are potent killers of tumor cells and have produced long-term remissions in patients with certain leukemias, such as B cell acute lymphoblastic leukemia (Chapter 12). However, CAR T cells also are associated with serious complications related to cytokines released from the activated CTLs, and it remains to


Pathology_Robbins

Pathology_Robbins. such as B cell acute lymphoblastic leukemia (Chapter 12). However, CAR T cells also are associated with serious complications related to cytokines released from the activated CTLs, and it remains to be seen if they will become a routine part of cancer treatment.


Pathology_Robbins

Pathology_Robbins. Beyond complications of immunotherapy, it also should be recognized that the host immune response to tumors is not an unalloyed blessing. For example, tumors release incompletely characterized factors that alter the function of certain immune cells, such as macrophages and Th2 lymphocytes, in a fashion that is suspected of promoting angiogenesis, tissue fibrosis, and the accumulation of alternatively activated (M2) macrophages, which you will recall from Chapter 5 are associated with suppression of the immune response during wound healing. These types of responses may promote tumor growth, the converse of what one would expect from a protective anti-tumor immune response.


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Pathology_Robbins. To summarize, while the future appears very bright for cancer immunotherapy, important hurdles remain to be cleared. At present, response and resistance to immune checkpoint inhibitors are unpredictable, and new biomarkers are needed to better tailor therapies for individual patients. This will entail the development of new diagnostic tests to gauge both the host immune response and the likely means of immune evasion in individual cancers. There is reason to believe that immune checkpoint inhibitors may be more effective if given before the patient receives chemotherapy (which is immunosuppressive) or in combination with certain targeted therapies directed against tumor cells, and many well-designed clinical trials will need to be conducted before these questions are answered. Currently available immunotherapies are effective in some cancers but not others. Thus, there is a need for development of safe adaptive therapies that are


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Pathology_Robbins. Tumor peptide-MHC Tumor peptide-MHC Primed CTL capableCD28 of killing tumor cells molecularimmunology,ed 9,Philadelphia,2018,Elsevier.) effective in a wide variety of cancers. With all of these caveats, it seems certain that the field of oncology is on the threshold of transformative therapeutic advances, all made possible by careful study of the normal immune response and its myriad variations in cancers. Tumorcellscanberecognizedbytheimmunesystemasnon-selfanddestroyed. Antitumoractivityismediatedbypredominantlycell-mediatedmechanisms.TumorantigensarepresentedonthecellsurfacebyMHCclassImoleculesandarerecognizedbyCD8+CTLs. The different classes of tumor antigens include products ofmutated genes, overexpressed or aberrantly expressed proteins,andtumorantigensproducedbyoncogenicviruses. Immunosuppressedpatientshaveanincreasedriskfordevelopmentofcancer,particularlytypescausedbyoncogenicDNAviruses.


Pathology_Robbins

Pathology_Robbins. Immunosuppressedpatientshaveanincreasedriskfordevelopmentofcancer,particularlytypescausedbyoncogenicDNAviruses. Inimmunocompetentpatients,tumorsmayavoidtheimmunesystembyseveralmechanisms,includingselectiveoutgrowthof antigen-negative variants, loss or reduced expression ofhistocompatibility molecules, and immunosuppression mediatedbyexpressionofcertainfactors(e.g.,TGF-β,PD-1ligands)bythetumorcells. •Antibodies that overcome some of these mechanisms ofimmuneevasionarenowapprovedfortreatmentofpatientswithadvancedformsofcancer. Genomic Instability as an Enabler of Malignancy


Pathology_Robbins

Pathology_Robbins. •Antibodies that overcome some of these mechanisms ofimmuneevasionarenowapprovedfortreatmentofpatientswithadvancedformsofcancer. 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.


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Pathology_Robbins. 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.


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Pathology_Robbins. Hereditary nonpolyposis colon carcinoma (HNPCC) syndrome dramatically illustrates the role of DNA repair genes in predisposition to cancer. This disorder, characterized by familial carcinomas of the colon affecting predominantly the cecum and proximal colon (Chapter 14), results from defects in genes involved in DNA mismatch repair. When a strand of DNA is being repaired, the products of mismatch repair genes act as “spell checkers.” For example, if there is an erroneous pairing of G with T, rather than the normal A with T, the mismatch repair genes correct the defect. Without these “proofreaders,” errors accumulate at an increased rate. Mutations in at least four mismatch repair genes have been found to underlie HNPCC (Chapter 15). Each affected individual inherits one defective copy of one of several DNA mismatch repair genes and acquires the second “hit” in colonic epithelial cells. Thus, DNA repair genes affect cell growth only indirectly—by allowing mutations in other genes


Pathology_Robbins

Pathology_Robbins. of one of several DNA mismatch repair genes and acquires the second “hit” in colonic epithelial cells. Thus, DNA repair genes affect cell growth only indirectly—by allowing mutations in other genes during the process of normal cell division. A characteristic finding in the genome of patients with mismatch repair defects is microsatellite instability (MSI). Microsatellites are tandem repeats of one to six nucleotides found throughout the genome (Chapter 1). In normal people, the length of these microsatellites remains constant. By contrast, in patients with HNPCC, these satellites are unstable and increase or decrease in length. Although HNPCC accounts for only 2% to 4% of all colonic cancers, MSI can be detected in about 15% of sporadic cancers due to acquired mutations that disrupt the function of mismatch repair genes.


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Pathology_Robbins. Xeroderma pigmentosum is an autosomal recessive disorder caused by a defect in DNA repair that is associated with a greatly increased risk for cancers arising in sun-exposed skin. Ultraviolet (UV) rays in sunlight cause cross-linking of pyrimidine residues, preventing normal DNA replication. Such DNA damage is repaired by the nucleotide excision repair system. Several proteins are involved in nucleotide excision repair, and the inherited loss of any one of these can give rise to xeroderma pigmentosum.


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Pathology_Robbins. A group of autosomal recessive disorders comprising Bloom syndrome, ataxia-telangiectasia, and Fanconi anemia is characterized by hypersensitivity to DNA-damaging agents, such as ionizing radiation (in Bloom syndrome and ataxia-telangiectasia), or to DNA cross-linking agents, such as nitrogen mustard (in Fanconi anemia). Their phenotype is complex and includes, in addition to predisposition to cancer, features such as neural symptoms (in ataxiatelangiectasia), anemia (in Fanconi anemia), and developmental defects (in Bloom syndrome). The gene mutated in ataxia-telangiectasia is ATM, which encodes a protein kinase that is important in “sensing” DNA damage caused by ionizing radiation and then directing p53 to initiate the DNA damage response, as described earlier.


Pathology_Robbins

Pathology_Robbins. Evidence for the role of DNA repair genes in the origin of cancer also comes from the study of hereditary breast cancer. Germ line mutations in two genes, BRCA1 and BRCA2, account for 50% of cases of familial breast cancer. In addition to breast cancer, women with BRCA1 mutations have a substantially higher risk for developing epithelial ovarian cancers, and men have a slightly higher risk for developing prostate cancer. Likewise, germ line mutations in the BRCA2 gene increase the risk for developing breast cancer in both men and women, as well as cancers originating from the ovary, prostate, pancreas, bile ducts, stomach, melanocytes, and B lymphocytes. Although the functions of BRCA1 and BRCA2 have not been elucidated fully, cells with a defective version of these genes develop chromosomal breaks and severe aneuploidy. Indeed, both genes seem to function, at least in part, in the homologous recombination DNA repair pathway. For example, BRCA1 forms a complex with other proteins in


Pathology_Robbins

Pathology_Robbins. breaks and severe aneuploidy. Indeed, both genes seem to function, at least in part, in the homologous recombination DNA repair pathway. For example, BRCA1 forms a complex with other proteins in the homologous recombination pathway and also is linked to the ATM kinase pathway. BRCA2 was identified as one of several genes mutated in Fanconi anemia, and the BRCA2 protein has been shown to bind to RAD51, a protein required for homologous recombination. Similar to other tumor suppressor genes, both copies of BRCA1 and BRCA2 must be inactivated for cancer to develop. Although linkage of BRCA1 and BRCA2 to familial breast cancers is well established, these genes are rarely inactivated in sporadic cases of breast cancer. In this regard, BRCA1 and BRCA2 are different from other tumor suppressor genes, such as APC and TP53, which are frequently inactivated in sporadic cancers.


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Pathology_Robbins. Cancers Resulting From Mutations Induced by Regulated Genomic Instability: Lymphoid Neoplasms


Pathology_Robbins

Pathology_Robbins. A special type of DNA damage plays a central role in the pathogenesis of tumors of B cells and T lymphocytes. As discussed earlier, adaptive immunity relies on the ability of B cells and T cells to diversify their antigen receptor genes. Immature B cells and T progenitors both express a pair of gene products, RAG1 and RAG2, that carry out V(D)J segment recombination, permitting the assembly of functional immunoglobulin and T-cell receptor genes. In addition, after encountering antigen, mature B cells express a specialized enzyme called activation-induced cytosine deaminase (AID), which catalyzes both immunoglobulin gene class switch recombination and immunoglobulin diversification through somatic hypermutation. Errors that occur during antigen receptor gene assembly and immunoglobulin gene class switching and diversification provide fertile soil for many of the mutations that cause lymphoid neoplasms, discussed in detail in Chapter 12.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Mutationsincurredinlymphocytesexpressinggeneproductsthatinducegenomicinstability(RAG1,RAG2,AID)areimportantinthepathogenesisoflymphoidneoplasms. Infiltrating cancers provoke a chronic inflammatory reaction. In patients with advanced cancers, this inflammatory reaction can be so extensive as to cause systemic signs and symptoms, such as anemia (the so-called “anemia of chronic disease”), fatigue, and cachexia. However, studies carried out on cancers in animal models suggest that inflammatory cells also modify the tumor microenvironment to enable many of the hallmarks of cancer. These effects may stem from direct interactions between inflammatory cells and tumor cells, or through indirect effects of inflammatory cells on other resident stromal cells, particularly cancer-associated fibroblasts and endothelial cells. Proposed cancer-enabling effects of inflammatory cells and resident stromal cells include the following:


Pathology_Robbins

Pathology_Robbins. Release of factors that promote proliferation. Infiltrating leukocytes and activated stromal cells have been shown to secrete a wide variety of growth factors, such as EGF, and proteases that can liberate growth factors from the extracellular matrix (ECM). Removal of growth suppressors. As mentioned earlier, the growth of epithelial cells is suppressed by cell–cell and cell–ECM interactions. Proteases released by inflammatory cells can degrade the adhesion molecules that mediate these interactions, removing a barrier to growth. Enhanced resistance to cell death. Detachment of epithelial cells from basement membranes and from cell–cell interactions can lead to a particular form of programmed cell death called anoikis. It is suspected that tumor-associated macrophages may prevent anoikis by expressing adhesion molecules such as integrins that promote direct physical interactions with tumor cells.


Pathology_Robbins

Pathology_Robbins. Angiogenesis. Inflammatory cells release numerous factors, including VEGF, that stimulate angiogenesis. Invasion and metastasis. Proteases released from macrophages foster tissue invasion by remodeling the ECM, while factors such as TNF and EGF may directly stimulate tumor cell motility. As mentioned earlier, other factors released from stromal cells such as TGF-β may promote epithelial-mesenchymal transition (EMT), which may be a key event in the process of invasion and metastasis.


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Pathology_Robbins. Evasion of immune destruction. A variety of soluble factors released by macrophages and other stromal cells are believed to contribute to an immunosuppressive tumor microenvironment. The leading suspects include TGF-β and other factors that either favor the recruitment of immunosuppressive T regulatory cells or suppress the function of CD8+ cytotoxic T cells. Furthermore, there is abundant evidence in cancer models and emerging evidence in human disease that advanced cancers contain mainly alternatively activated (M2) macrophages (Chapter 3). M2 macrophages produce cytokines that promote angiogenesis, fibroblast proliferation, and collagen deposition, all of which are commonly observed in invasive cancers and in healing wounds, giving rise to the notion that cancers are like “wounds that do not heal.”


Pathology_Robbins

Pathology_Robbins. A thorough understanding of how cancers “manipulate” inflammatory cells to support their growth and survival remains elusive. However, the results from animal studies are intriguing and raise the possibility of therapies directed at tumor-induced inflammation and its downstream consequences. An example of one such intervention involves aspirin and other COX-2 inhibitors, use of which is associated with a decreased risk of colorectal cancer in several epidemiological studies. Important clinical considerations emerge from the principles presented in the foregoing discussion of the hallmarks of cancer: These hallmarks provide a road map for the development of new therapeutic agents for the treatment of cancer ( Fig. 6.31 ETIOLOGYOFCANCER:CARCINOGENICAGENTS


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Pathology_Robbins. Fig. 6.31 ETIOLOGYOFCANCER:CARCINOGENICAGENTS 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, and (3) microbial products. Chemicals and radiant energy are documented causes of cancer in humans, and oncogenic viruses are involved in the pathogenesis of tumors in several animal models and some human tumors. In the following discussion, each class of agents is considered separately; of note, however, several may act in concert or sequentially to produce the multiple genetic abnormalities characteristic of neoplastic cells.


Pathology_Robbins

Pathology_Robbins. More than 200 years ago, the London surgeon Sir Percival Pott correctly attributed scrotal skin cancer in chimney sweeps to chronic exposure to soot. On the basis of this observation, the Danish Chimney Sweeps Guild ruled that its members must bathe daily. No public health measure since that time has achieved so much in the control of a form of cancer. Subsequently, hundreds of chemicals have been shown to be carcinogenic in animals. http://ebooksmedicine.net


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Pathology_Robbins. http://ebooksmedicine.net EGFR inhibitors Aerobic glycolysis inhibitors Telomerase inhibitors Proapoptotic BH3 mimetics Selective anti-inflammatory drugs Sustaining proliferative signaling Inducing angiogenesis Activating invasion and metastasis Deregulating cellular energetics Resisting cell death Enabling replicative immortality Tumor-promoting inflammation Cyclin-dependent kinase inhibitors Immune activating anti-CTLA4 mAb Inhibitors of VEGF signaling MDM2 inhibitors Inhibitors of HGF/c-Met Evading growth suppressors Avoiding immune destruction Genome instability and mutation Fig. 6.31 Therapeutictargetingofthehallmarksofcancer.(From Hanahan D,Weiberg RA:The hallmarks of cancer: the next generation. Cell144:646, 2011.) Some of the major agents are presented in Table 6.5. A few comments on a handful of these are offered next.


Pathology_Robbins

Pathology_Robbins. Some of the major agents are presented in Table 6.5. A few comments on a handful of these are offered next. 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 (e.g., Hodgkin lymphoma), only to evoke a subsequent, second form of cancer, usually leukemia. This situation is even more tragic when the initial use of such agents has been for non-neoplastic disorders, such as rheumatoid arthritis or granulomatosis with polyangiitis. The associated risk for induced cancer is low, but its existence dictates judicious use of such agents. The designation indirect-acting refers to chemicals that require metabolic conversion to an ultimate carcinogen.


Pathology_Robbins

Pathology_Robbins. 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. For example, benzo[a]pyrene and other carcinogens formed during the combustion of tobacco are implicated in the causation of lung cancer, and in olden days, benzo[a]pyrene created during the burning of coal was likely responsible for the high incidence of scrotal cancer in chimney sweeps. Polycyclic hydrocarbons also may be produced from animal fats during the process of broiling meats and are present in smoked meats and fish. In the body, benzo[a]pyrene is Table 6.5 Major Chemical Carcinogens Anti-cancerdrugs(cyclophosphamide,chlorambucil,nitrosoureas,andothers) Benz(a)anthraceneBenzo(a)pyreneDibenz(a,h)anthracene3-Methylcholanthrene7,12-Dimethylbenz(a)anthracene Aromatic Amines,Amides,Azo Dyes


Pathology_Robbins

Pathology_Robbins. Benz(a)anthraceneBenzo(a)pyreneDibenz(a,h)anthracene3-Methylcholanthrene7,12-Dimethylbenz(a)anthracene Aromatic Amines,Amides,Azo Dyes NitrosamineandamidesVinylchloride,nickel,chromiumInsecticides,fungicidesPolychlorinatedbiphenyls http://ebooksmedicine.net metabolized to epoxides, which form covalent adducts (addition products) with molecules in the cell, principally DNA, but also with RNA and proteins. The aromatic amines and azo dyes constitute another class of indirect-acting carcinogens. Before its carcinogenicity was recognized, β-naphthylamine was responsible for a 50-fold increased incidence of bladder cancers in heavily exposed workers in the aniline dye and rubber industries. Examples of other occupational carcinogens are listed in


Pathology_Robbins

Pathology_Robbins. Table 6.5 . Because indirect-acting carcinogens require metabolic activation for their conversion to DNA-damaging agents, much interest is focused on the enzymatic pathways that are involved, such as that mediated by the cytochrome P-450–dependent monooxygenases. The genes that encode these enzymes are polymorphic, and enzyme activity varies among individuals. It is widely believed that the susceptibility to chemical carcinogenesis depends at least in part, on the specific allelic form of the enzyme that is inherited. Thus, it may be possible in the future to assess cancer risk in a given individual by genetic analysis of enzyme polymorphisms.


Pathology_Robbins

Pathology_Robbins. A few other agents merit brief mention. Aflatoxin B1 is of interest because it is a naturally occurring agent produced by some strains of Aspergillus, a mold that grows on improperly stored grains and nuts. A strong correlation has been found between the dietary level of this food contaminant and the incidence of hepatocellular carcinoma in some parts of Africa and the Far East. Additionally, vinyl chloride, arsenic, nickel, chromium, insecticides, fungicides, and polychlorinated biphenyls are potential carcinogens in the workplace and about the house. Finally, nitrites used as food preservatives have caused concern, since they cause nitrosylation of amines contained in food. The nitrosamines thus formed are suspected to be carcinogenic. Mechanisms of Action of Chemical Carcinogens


Pathology_Robbins

Pathology_Robbins. 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.


Pathology_Robbins

Pathology_Robbins. 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 ( Fig. 6.32 ). The initiation-promotion sequence of chemical carcinogenesis raises an important question: Since promoters are not mutagenic, how do they contribute to tumorigenesis? Although the effects of tumor promoters are pleiotropic, Metabolic activation Additional mutationsProliferation Normal cell CARCINOGEN MALIGNANT NEOPLASM PRENEOPLASTIC CLONE Cell proliferation: Altered differentiation Permanent DNA lesion: Initiated cell Binding to DNA: Adduct formation Electrophilic intermediates Detoxification DetoxificationINITIATIONDNA repair Cell death PROMOTION Excretion


Pathology_Robbins

Pathology_Robbins. induction of cell proliferation is a sine qua non of tumor promotion. It seems most likely that while the application of an initiator may cause the mutational activation of an oncogene such as RAS, subsequent application of promoters leads to clonal expansion of initiated (mutated) cells. Forced to proliferate, the initiated clone of cells accumulates additional mutations, developing eventually into a malignant tumor. Indeed, the concept that sustained cell proliferation increases the risk for mutagenesis, and hence promotes neoplastic transformation, also is applicable to human carcinogenesis. For example, endometrial hyperplasia (Chapter 19) and increased regenerative activity that accompanies chronic liver cell injury are associated with the development of cancer in these organs. Were it not for the DNA repair mechanisms discussed earlier, the incidence of chemically induced cancers in all likelihood would be much higher. As mentioned previously, the rare hereditary disorders of


Pathology_Robbins

Pathology_Robbins. it not for the DNA repair mechanisms discussed earlier, the incidence of chemically induced cancers in all likelihood would be much higher. As mentioned previously, the rare hereditary disorders of DNA repair, including xeroderma pigmentosum, are associated with greatly increased risk for developing cancers induced by UV light and certain chemicals.


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Pathology_Robbins

Pathology_Robbins. 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.


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Pathology_Robbins. 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, double-stranded DNA breaks seem to be the most important form of DNA damage caused by radiation.


Pathology_Robbins

Pathology_Robbins. The oncogenic effect of UV rays merits special mention because it highlights the importance of DNA repair in carcinogenesis. Natural UV radiation derived from the sun can cause skin cancers (melanomas, squamous cell carcinomas, and basal cell carcinomas). At greatest risk are fair-skinned people who live in locales such as Australia and New Zealand that receive a great deal of sunlight. Nonmelanoma skin cancers are associated with total cumulative exposure to UV radiation, whereas melanomas are associated with intense intermittent exposure—as occurs with sunbathing. UV light has several biologic effects on cells. Of particular relevance to carcinogenesis is the ability to damage DNA by forming pyrimidine dimers. This type of DNA damage is repaired by the nucleotide excision repair pathway. With extensive exposure to UV light, the repair systems may be overwhelmed, and skin cancer results. As mentioned earlier, patients with the inherited disease xeroderma pigmentosum have a defect in


Pathology_Robbins

Pathology_Robbins. With extensive exposure to UV light, the repair systems may be overwhelmed, and skin cancer results. As mentioned earlier, patients with the inherited disease xeroderma pigmentosum have a defect in the nucleotide excision repair pathway. As expected, there is a greatly increased predisposition to skin cancers in this disorder.


Pathology_Robbins

Pathology_Robbins. Ionizingradiationcauseschromosomebreakage,chromosomerearrangements,and,lessfrequently,pointmutations,anyofwhichmayaffectcancergenesandtherebydrivecarcinogenesis. UVraysinsunlightinducetheformationofpyrimidinedimerswithinDNA,leadingtomutationsthatcangiverisetosquamouscellcarcinomasandmelanomasoftheskin. 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. 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.


Pathology_Robbins

Pathology_Robbins. 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.


Pathology_Robbins

Pathology_Robbins. 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. In leukemic cells, however, viral integration shows a clonal pattern. In other words, although the site of viral integration in host chromosomes is random (the viral DNA is found at different locations in different cancers), the site of integration is identical within all cells of a given cancer. This would not occur if HTLV-1 were merely a passenger that infects cells after transformation; rather, it means that HTLV-1 must have been present at the moment of transformation, placing it at the “scene of the crime.” http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. The HTLV-1 genome contains the gag, pol, env, and long-terminal-repeat regions typical of all retroviruses, but, in contrast to other leukemia viruses, it contains another gene referred to as tax. Several aspects of HTLV-1’s transforming activity are attributable to Tax, the protein product of the tax gene. Tax is essential for viral replication, because it stimulates transcription of viral RNA from the 5′ long-terminal repeat. However, Tax also alters the transcription of several host cell genes and interacts with certain host cell signaling proteins. By doing so, Tax contributes to the acquisition of several cancer hallmarks, including the following:


Pathology_Robbins

Pathology_Robbins. Increased survival and growth of infected cells. Tax appears to interact with PI3 kinase and thereby stimulate the downstream signaling cascade, which you will recall promotes both cell survival and metabolic alterations that enhance cell growth. Tax also upregulates the expression of cyclin D and represses the expression of multiple CDK inhibitors, changes that promote cell cycle progression. Finally, Tax can activate the transcription factor NF-κB, which promotes the survival of many cell types, including lymphocytes. Increased genomic instability. Tax may also cause genomic instability by interfering with DNA-repair functions and inhibiting cell cycle checkpoints activated by DNA damage. In line with these defects, HTLV-1–associated leukemias tend to be highly aneuploid.


Pathology_Robbins

Pathology_Robbins. The precise steps that lead to the development of adult T-cell leukemia/lymphoma are still not known, but a plausible scenario is as follows. Infection by HTLV-1 causes the expansion of a nonmalignant polyclonal cell population through stimulatory effects of Tax on cell proliferation. The proliferating T cells are at increased risk for mutations and genomic instability due to the effects of Tax and possibly other viral factors as well. This instability allows the accumulation of oncogenic mutations and eventually a monoclonal neoplastic T-cell population emerges. The most common driver mutations identified thus far are predicted to enhance T cell receptor signaling and stimulate NF-κB activation. HTLV-1causesaTcellleukemiathatisendemicinJapanandtheCaribbean.


Pathology_Robbins

Pathology_Robbins. Fig. 6.33 TransformingeffectsofHPVE6andE7proteins.TheneteffectofHPVE6andE7proteinsistoimmortalizecellsandremovetherestraintsoncellproliferation. As with RNA viruses, several oncogenic DNA viruses that cause tumors in animals have been identified. Five DNA viruses—HPV, Epstein-Barr virus (EBV), Kaposi sarcoma herpesvirus (KSHV, also called human herpesvirus-8 [HHV-8]), a polyoma virus called Merkel cell virus, and hepatitis B virus (HBV)—are of special interest because they are strongly associated with human cancer. KSHV and Kaposi sarcoma are discussed in Chapter 5. Merkel cell virus is associated with a particular cancer, Merkel cell carcinoma, that is too rare to merit further discussion. The others are presented here. We also briefly touch on the oncogenic effects of hepatitis C virus, an RNA virus, during our discussion of HBV, since both viruses share an association with chronic liver injury and liver cancer.


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Pathology_Robbins. 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.


Pathology_Robbins

Pathology_Robbins. 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.


Pathology_Robbins

Pathology_Robbins. Oncogenic activities of E7. The E7 protein has effects that complement those of E6, all of which are centered on http://ebooksmedicine.net 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.


Pathology_Robbins

Pathology_Robbins. An additional factor that contributes to the oncogenic potential of HPVs is viral integration into the host genome. In benign warts, the HPV genome is maintained in a non-integrated episomal form, while in cancers, the HPV genome is randomly integrated into the host genome. Integration interrupts a negative regulatory region in the viral DNA, resulting in overexpression of the E6 and E7 oncoproteins. Furthermore, cells in which the viral genome has integrated show significantly more genomic instability, which may contribute to acquisition of pro-oncogenic mutations in host cancer genes.


Pathology_Robbins

Pathology_Robbins. To summarize, high-risk HPVs encode oncogenic proteins that inactivate RB and p53, activate cyclin/ CDK complexes, and combat cellular senescence. Thus, it is evident that HPV proteins promote many of the hallmarks of cancer. The primacy of HPV infection in the causation of cervical cancer is confirmed by the effectiveness of HPV vaccines in preventing it. However, infection with HPV itself is not sufficient for carcinogenesis, and full-blown transformation requires the acquisition of mutations in host cancer genes, such as RAS. A high proportion of women infected with HPV clear the infection by immunologic mechanisms, but others do not, some because of acquired immune abnormalities, such as those that result from HIV infection. As might be expected, women who are coinfected with high-risk HPV types and HIV are at particularly high risk for developing cervical cancer.


Pathology_Robbins

Pathology_Robbins. EBV, a member of the herpesvirus family, was the first virus linked to a human tumor, Burkitt lymphoma. Burkitt lymphoma is an aggressive tumor that is endemic in certain parts of Africa and occurs sporadically elsewhere. In endemic areas, the tumor cells in virtually all affected patients carry the EBV genome. Since its initial discovery in Burkitt lymphoma some 50 years ago, EBV has been detected within the cells of a surprisingly diverse list of other tumors, including most nasopharyngeal carcinomas and a subset of T cell lymphomas, NK cell lymphomas, gastric carcinomas, and even, in rare instances, sarcomas, mainly in the immunosuppressed.


Pathology_Robbins

Pathology_Robbins. The manner in which EBV causes B cell tumors such as Burkitt lymphoma is complex and incompletely understood, but best appreciated by considering its effects on normal B cells. EBV uses the complement receptor CD21 to attach to and infect B cells. In vitro, such infection leads to polyclonal B cell proliferation and generation of immortal B lymphoblastoid cell lines. One EBV-encoded gene, LMP1 (latent membrane protein 1), acts as an oncogene, as proven by its ability to induce B cell lymphomas in transgenic mice. LMP1 promotes B cell proliferation, mimicking


Pathology_Robbins

Pathology_Robbins. Etiology of Cancer: Carcinogenic Agents233 the effects of a key surface receptor known as CD40. CD40 is normally activated by interaction with CD40 ligands expressed mainly on T cells. By contrast, LMP1 is constitutively active and stimulates signaling through the NF-κB and JAK/STAT pathways, both of which promote B cell proliferation and survival. Thus, the virus “borrows” a normal B cell activation pathway to promote its own replication by expanding the pool of infected cells. Another EBV-encoded protein, EBNA2, transactivates several host genes, including cyclin D and the SRC family of protooncogenes. In addition, the EBV genome contains a viral cytokine, vIL-10, that was pirated from the host genome. This viral cytokine can prevent macrophages and monocytes from activating T cells and killing virally infected cells. In immunologically normal persons, the EBV-driven polyclonal B cell proliferation is readily controlled by cytotoxic T cells, and the affected patient either remains


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Pathology_Robbins. killing virally infected cells. In immunologically normal persons, the EBV-driven polyclonal B cell proliferation is readily controlled by cytotoxic T cells, and the affected patient either remains asymptomatic or experiences a self-limited episode of infectious mononucleosis. However, a small number of EBV-infected B cells downregulate expression of immunogenic viral proteins such as LMP-1 and EBNA2 and enter a long-lived pool of memory B cells that persist throughout life.


Pathology_Robbins

Pathology_Robbins. Given these observations, how then does EBV contribute to the genesis of endemic Burkitt lymphoma? One possibility is shown in Fig. 6.34 . In regions of the world where OUTGROWTH OF NEOPLASTIC CLONE: BURKITT LYMPHOMA Fig. 6.34 Possible evolution of EBV-induced Burkitt lymphoma.


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Pathology_Robbins. Fig. 6.34 . In regions of the world where OUTGROWTH OF NEOPLASTIC CLONE: BURKITT LYMPHOMA Fig. 6.34 Possible evolution of EBV-induced Burkitt lymphoma. Burkitt lymphoma is endemic, concomitant infections such as malaria impair immune competence, allowing sustained B-cell proliferation. Eventually, cytotoxic T cells eliminate most of the EBV-infected B cells, but a small number survive. It appears that lymphoma cells emerge from this residual population only with the acquisition of specific mutations, most notably translocations that activate the MYC oncogene. It should be noted that in nonendemic areas 80% of these tumors are unrelated to EBV, but virtually all endemic and sporadic tumors possess the t(8;14) translocation or other translocations that dysregulate MYC. Thus, although sporadic Burkitt lymphomas are triggered by mechanisms other than EBV infection, they appear to develop through similar oncogenic pathways.


Pathology_Robbins

Pathology_Robbins. The oncogenic role played by EBV is more direct in EBV-positive B-cell lymphomas in immunosuppressed patients. Some individuals with AIDS or who receive immunosuppressive therapy for preventing allograft rejection develop EBV-positive B-cell tumors, often at multiple sites. These proliferations are polyclonal at the outset but can evolve into monoclonal neoplasms. In contrast to Burkitt lymphoma, the tumors in immunosuppressed patients usually lack MYC translocations and uniformly express LMP-1 and EBNA2, which, as discussed, are antigenic and can be recognized by cytotoxic T cells. These potentially lethal proliferations can be subdued if T cell function can be restored, as may occur with withdrawal of immunosuppressive drugs in transplant recipients.


Pathology_Robbins

Pathology_Robbins. Nasopharyngeal carcinoma also is associated with EBV infection. This tumor is endemic in southern China, in some parts of Africa, and in the Inuit population of the Arctic. In contrast to Burkitt lymphoma, 100% of nasopharyngeal carcinomas obtained from all parts of the world contain EBV. The integration site of the viral genome is identical (clonal) in all of the tumor cells within individual tumors, excluding the possibility that EBV infection occurred after tumor development. The uniform association of EBV with nasopharyngeal carcinoma suggests that EBV has a central role in the genesis of the tumor, but (as with Burkitt lymphoma) the restricted geographic distribution indicates that genetic or environmental cofactors, or both, also contribute to tumor development. Unlike Burkitt lymphoma, LMP-1 is expressed in nasopharyngeal carcinoma cells and, as in B cells, activates the NF-κB pathway. NF-κB, in turn, upregulates the expression of factors such as VEGF and matrix


Pathology_Robbins

Pathology_Robbins. Burkitt lymphoma, LMP-1 is expressed in nasopharyngeal carcinoma cells and, as in B cells, activates the NF-κB pathway. NF-κB, in turn, upregulates the expression of factors such as VEGF and matrix metalloproteases that may contribute to oncogenesis.


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Pathology_Robbins. The relationship of EBV to the pathogenesis of Hodgkin lymphoma, yet another EBV-associated tumor, is discussed in Chapter 12. HPVisassociatedwithbenignwarts,aswellascervicalcancer. TheoncogenicityofHPVisrelatedtotheexpressionoftwoviraloncoproteins,E6andE7,whichbindtothep53andRBtumorsuppressors,respectively,neutralizingtheirfunction. E7fromlow-riskstrainsofHPV(whichgiverisetobenignwarts). EBVisimplicatedinthepathogenesisofBurkittlymphomas,lymphomasinimmunosuppressedpatients,Hodgkinlymphoma,uncommonT-cellandNK-celltumors,nasopharyngealcarcinoma,asubsetofgastriccarcinoma,andrarelysarcomas. CertainEBVgeneproductscontributetooncogenesisbystimulatingnormalB-cellproliferationpathways.ConcomitantcompromiseofimmunecompetenceallowssustainedB-cellproliferation,leadingeventuallytodevelopmentoflymphoma.


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Pathology_Robbins. The epidemiologic evidence linking chronic HBV and hepatitis C virus (HCV) infection with hepatocellular carcinoma is strong (Chapter 16). It is estimated that 70% to 85% of hepatocellular carcinomas worldwide are caused by HBV or HCV. However, the mode of action of these viruses in tumorigenesis is not fully elucidated. The HBV and HCV genomes do not encode any viral oncoproteins, and although the HBV DNA is integrated within the human genome, there is no consistent pattern of integration in liver cells. Indeed, the oncogenic effects of HBV and HCV are multifactorial, but the dominant effect seems to be immunologically mediated chronic inflammation with hepatocyte death, leading to regeneration and genomic damage. Although the immune system generally is thought to be protective, recent work has demonstrated that in the setting of unresolved chronic inflammation, as occurs in viral hepatitis or chronic gastritis caused by H. pylori (see later), the immune response may become


Pathology_Robbins

Pathology_Robbins. recent work has demonstrated that in the setting of unresolved chronic inflammation, as occurs in viral hepatitis or chronic gastritis caused by H. pylori (see later), the immune response may become maladaptive, promoting tumorigenesis.


Pathology_Robbins

Pathology_Robbins. As with any cause of hepatocellular injury, chronic viral infection leads to the compensatory proliferation of hepatocytes. This regenerative process is aided and abetted by a plethora of growth factors, cytokines, chemokines, and other bioactive substances produced by activated immune cells that promote cell survival, tissue remodeling, and angiogenesis. The activated immune cells also produce other mediators, such as reactive oxygen species, that are genotoxic and mutagenic. A key molecular step seems to be activation of the nuclear factor-κB (NF-κB) pathway in hepatocytes caused by mediators derived from the activated immune cells. Activation of the NF-κB pathway blocks apoptosis, allowing the dividing hepatocytes to incur genotoxic stress and to accumulate mutations. Although this seems to be the dominant mechanism in the pathogenesis of virus-induced hepatocellular carcinoma, both HBV and HCV also contain proteins within their genomes that may more directly promote the


Pathology_Robbins

Pathology_Robbins. this seems to be the dominant mechanism in the pathogenesis of virus-induced hepatocellular carcinoma, both HBV and HCV also contain proteins within their genomes that may more directly promote the development of cancer. The HBV genome contains a gene known as HBx, and hepatocellular cancers develop in mice engineered to have HBx transgenes. HBx can directly or indirectly activate a variety of transcription factors and several signal transduction pathways, and may interfere with p53 function. In addition, viral integration can cause secondary rearrangements of chromosomes, including multiple deletions that may harbor unknown tumor suppressor genes.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net HCV, an RNA virus, also is strongly linked to the pathogenesis of liver cancer. The molecular mechanisms used by HCV are even less well defined than those for HBV. In addition to chronic liver cell injury and compensatory regeneration, components of the HCV genome, such as the HCV core protein, may have a direct effect on tumorigenesis, possibly by activating a variety of growth-promoting signal transduction pathways. Between70%and85%ofhepatocellularcarcinomasworldwideareduetoinfectionwithHBVorHCV. TheoncogeniceffectsofHBVandHCVaremultifactorial,butthedominanteffectseemstobeimmunologicallymediatedchronicinflammation,withhepatocellularinjury,stimulationofhepatocyteproliferation,andproductionofreactiveoxygenspeciesthatcandamageDNA. TheHBxproteinofHBVandtheHCVcoreproteincanactivateavarietyofsignaltransductionpathwaysthatalsomaycontributetocarcinogenesis.


Pathology_Robbins

Pathology_Robbins. TheHBxproteinofHBVandtheHCVcoreproteincanactivateavarietyofsignaltransductionpathwaysthatalsomaycontributetocarcinogenesis. H. pylori infection is implicated in the genesis of both gastric adenocarcinomas and gastric lymphomas. First incriminated as a cause of peptic ulcers, H. pylori now has acquired the dubious distinction of being the first bacterium classified as a carcinogen.


Pathology_Robbins

Pathology_Robbins. The scenario for the development of gastric adenocarcinoma is similar to that for HBVand HCV-induced liver cancer. It involves increased epithelial cell proliferation on a background of chronic inflammation. As in viral hepatitis, the inflammatory milieu contains numerous genotoxic agents, such as reactive oxygen species. The sequence of histopathologic changes consists of initial development of chronic inflammation/gastritis, followed by gastric atrophy, intestinal metaplasia of the lining cells, dysplasia, and cancer. This sequence takes decades to complete and occurs in only 3% of infected patients. Like those of HBV and HCV, the H. pylori genome also contains genes directly implicated in oncogenesis. Strains associated with gastric adenocarcinoma have been shown to contain a “pathogenicity island” that contains cytotoxin-associated A gene (CagA). Although H. pylori is noninvasive, CagA is injected into gastric epithelial cells, where it has a variety of effects, including the


Pathology_Robbins

Pathology_Robbins. island” that contains cytotoxin-associated A gene (CagA). Although H. pylori is noninvasive, CagA is injected into gastric epithelial cells, where it has a variety of effects, including the initiation of a signaling cascade that mimics unregulated growth factor stimulation.


Pathology_Robbins

Pathology_Robbins. As mentioned earlier, H. pylori is associated with an increased risk for the development of gastric lymphomas as well. The gastric lymphomas are of B-cell origin, and because the transformed B cells grow in a pattern resembling that of normal mucosa-associated lymphoid tissue (MALT), they have been referred to as MALT lymphomas (Chapter 12). Their molecular pathogenesis is incompletely understood but seems to involve strain-specific H. pylori factors, as well as host genetic factors, such as polymorphisms in the promoters of inflammatory cytokines such as IL-1β and tumor necrosis factor (TNF). It is thought that


Pathology_Robbins

Pathology_Robbins. H. pylori infection leads to the activation of H. pylori–reactive T cells, which in turn cause polyclonal B cell proliferation. In time, a monoclonal B cell tumor emerges from the proliferating B cells, perhaps as a result of accumulation of mutations in growth regulatory genes. In keeping with this model, early in the course of disease, eradication of H. pylori with antibiotics causes regression of the lymphoma by removing the antigenic stimulus for T cells. MALT lymphoma is thus a remarkable example of a tumor that depends on signals elicited by interactions with host immune cells for its continued growth and survival. H. pylori infectionhasbeenimplicatedinbothgastricadenocarcinomaandMALTlymphoma.


Pathology_Robbins

Pathology_Robbins. H. pylori infectionhasbeenimplicatedinbothgastricadenocarcinomaandMALTlymphoma. ThemechanismofH. pylori–inducedgastriccancersismulti-factorial,includingimmunologicallymediatedchronicinflammation,stimulationofgastriccellproliferation,andproductionofreactiveoxygenspeciesthatdamageDNA.H. pylori pathogenicitygenes,suchasCagA, alsomaycontributebystimulatinggrowthfactorpathways. ItisthoughtthatH. pylori infectionleadstopolyclonalB-cellproliferationsandthateventuallyamonoclonalB-celltumor(MALTlymphoma)emergesasaresultofaccumulationofmutations.


Pathology_Robbins

Pathology_Robbins. ItisthoughtthatH. pylori infectionleadstopolyclonalB-cellproliferationsandthateventuallyamonoclonalB-celltumor(MALTlymphoma)emergesasaresultofaccumulationofmutations. The importance of neoplasms ultimately lies in their effects on patients. Although malignant tumors are of course more threatening than benign tumors, morbidity and mortality may be associated with any tumor, even a benign one. Indeed, both malignant and benign tumors may cause problems because of (1) location and impingement on adjacent structures, (2) functional activity such as hormone synthesis or the development of paraneoplastic syndromes, (3) bleeding and infections when the tumor ulcerates through adjacent surfaces, (4) symptoms that result from rupture or infarction, and (5) cachexia or wasting. The following discussion considers the effects of a tumor on the host, the grading and clinical staging of cancer, and the laboratory diagnosis of neoplasms.


Pathology_Robbins

Pathology_Robbins. 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.


Pathology_Robbins

Pathology_Robbins. 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. Similarly, some adenomas and carcinomas of the adrenal cortex disrupt homeostatic mechanisms by elaborating steroid hormones (e.g., aldosterone, which induces sodium retention, hypertension, and hypokalemia). Such hormonal activity is more likely with a well-differentiated benign tumor than with a corresponding carcinoma. http://ebooksmedicine.net A tumor may ulcerate through a surface, with consequent bleeding or secondary infection. Benign or malignant neoplasms that protrude into the gut lumen may become caught in the peristaltic pull of the gut, causing intussusception (Chapter 15) and intestinal obstruction or infarction.


Pathology_Robbins

Pathology_Robbins. 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. However, cachexia is not caused by the nutritional demands of the tumor. Although patients with cancer often are anorexic, current evidence indicates that cachexia results from the action of soluble factors such as cytokines produced by the tumor and the host, rather than reduced food intake. In patients with cancer, calorie expenditure remains high, and basal metabolic rate is increased, despite reduced food intake. This is in contrast with the lower metabolic rate that occurs as an adaptive response in starvation. The basis of these metabolic abnormalities is not fully understood. It is suspected that TNF and other cytokines produced by macrophages in response to tumor cells or by the tumor cells themselves


Pathology_Robbins

Pathology_Robbins. The basis of these metabolic abnormalities is not fully understood. It is suspected that TNF and other cytokines produced by macrophages in response to tumor cells or by the tumor cells themselves mediate cachexia. TNF suppresses appetite and inhibits the action of lipoprotein lipase, preventing the release of free fatty acids from lipoproteins. There is no satisfactory treatment for cancer cachexia other than removal of the underlying cause, the tumor.


Pathology_Robbins

Pathology_Robbins. 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 paraneoplastic syndromes are diverse and are associated with many different tumors (


Pathology_Robbins

Pathology_Robbins. Table 6.6 ). 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 malignancies. Hypercalcemia in cancer patients is multifactorial, but the most important mechanism is the synthesis of a parathyroid hormone–related protein (PTHrP) by tumor cells. Also implicated are other tumor-derived factors, such as TGF-α and the active form of vitamin D. Another possible mechanism for hypercalcemia is widespread osteolytic metastatic disease of bone; of note, however, hypercalcemia resulting from skeletal metastases is not a paraneoplastic syndrome. Cushing syndrome arising as a paraneoplastic phenomenon usually is related to ectopic production of ACTH or ACTH-like polypeptides by cancer cells, as occurs in small cell carcinoma of the lung.


Pathology_Robbins

Pathology_Robbins. Paraneoplastic syndromes also may manifest as hypercoagulability, leading to venous thrombosis and nonbacterial thrombotic endocarditis (Chapter 11). Other manifestations are clubbing of the fingers and hypertrophic osteoarthropathy in patients with lung carcinomas (Chapter 13). Still others are discussed in the consideration of cancers of the various organs of the body.


Pathology_Robbins

Pathology_Robbins. Methods to quantify the probable clinical aggressiveness of a given neoplasm and its apparent extent and spread in the individual patient are necessary for arriving at an accurate prognosis and for comparing end results of various treatment protocols. For instance, the results of treating well-differentiated thyroid adenocarcinomas localized to the thyroid gland will on average be very different from those obtained from treating highly anaplastic thyroid cancers that have invaded the neck organs. Systems have been developed to express, at least in semiquantitative terms, the level of differentiation, or grade, and extent of spread of a cancer within the patient, or stage, as parameters of the clinical gravity of the disease. Of note, when compared with grading, staging has proved to be of greater clinical value.


Pathology_Robbins

Pathology_Robbins. Grading. 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. 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. Although histologic grading is useful, the correlation between histologic appearance and biologic behavior is less than perfect. In recognition of this problem and to avoid spurious quantification, it is common practice to characterize a particular neoplasm in descriptive terms, for example, well-differentiated, mucin-secreting adenocarcinoma of the stomach, or poorly differentiated pancreatic adenocarcinoma.


Pathology_Robbins

Pathology_Robbins. Staging. 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 blood-borne metastases. 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. The primary lesion is characterized as T1 to T4 based on increasing size. T0 is used to indicate an in situ http://ebooksmedicine.net MyastheniaBronchogeniccarcinoma,thymomaImmunologic DisordersofthecentralandperipheralBreastcarcinoma,teratomaImmunologicnervoussystems Osseous, Articular, and Soft-Tissue Changes NephroticsyndromeVariouscancersTumorantigens,immunecomplexes ACTH, Adrenocorticotropichormone;IL-1, interleukin-1;TGF-α, transforminggrowthfactor-α;TNF, tumornecrosisfactor.


Pathology_Robbins

Pathology_Robbins. NephroticsyndromeVariouscancersTumorantigens,immunecomplexes ACTH, Adrenocorticotropichormone;IL-1, interleukin-1;TGF-α, transforminggrowthfactor-α;TNF, tumornecrosisfactor. lesion. N0 would mean no nodal involvement, whereas N1 to N3 would denote involvement of an increasing number and range of nodes. M0 signifies no distant metastases, whereas M1 or sometimes M2 reflects the presence and estimated number of metastases. In modern practice, grading and staging of tumors are being supplemented by molecular characterization, described later. Cachexia, definedasprogressivelossofbodyfatandleanbodymass,accompaniedbyprofoundweakness,anorexia,andanemia,iscausedbyreleaseofcytokinesbythetumororhost. Paraneoplasticsyndromes,definedassystemicsymptomsthatcannotbeexplainedbytumorspreadorbyhormones appropriatetothetissue,arecausedbytheectopicproductionandsecretionofbioactivesubstancessuchasACTH,PTHrP,orTGF-α.


Pathology_Robbins

Pathology_Robbins. Gradingoftumorsisdeterminedbycytologicappearanceandisbasedontheideathatbehavioranddifferentiationarerelated,withpoorlydifferentiatedtumorshavingmoreaggressivebehavior. Staging(extentoftumor),determinedbysurgicalexplorationorimaging,isbasedonsize,localandregionallymphnodespread,anddistantmetastases.Stagingisofgreaterclinicalvaluethangrading. Every year the approach to laboratory diagnosis of cancer becomes more complex, more sophisticated, and more specialized. For virtually every neoplasm mentioned in this text, the experts have characterized several subcategories; we must walk, however, before we can run. Each of the following sections attempts to present the state of the art, avoiding details of technologies. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net In most instances, the laboratory diagnosis of cancer is not difficult. The two ends of the benign–malignant spectrum pose no problems; in the middle, however, lies a “no man’s land” where the wise tread cautiously. Clinicians tend to underestimate the contributions they make to the diagnosis of a neoplasm. Clinical and radiologic data are invaluable for optimal pathologic diagnosis. Radiation-induced changes in the skin or mucosa can be similar to those of cancer. Sections taken from a healing fracture can mimic an osteosarcoma. The laboratory evaluation of a lesion can be only as good as the specimen submitted for examination. The specimen must be adequate, representative, and properly preserved.


Pathology_Robbins

Pathology_Robbins. Several sampling approaches are available, including excision or biopsy, fine-needle aspiration, and cytologic smears. When excision of a lesion is not possible, selection of an appropriate site for biopsy of a large mass requires awareness that the margins may not be representative and the center may be largely necrotic. Requesting frozen section diagnosis is sometimes desirable, as, for example, in determining the nature of a mass lesion or in evaluating the regional lymph nodes in a patient with cancer for metastasis. This method, in which a sample is quick-frozen and sectioned, permits histologic evaluation within minutes. In experienced, competent hands, frozen section diagnosis is accurate, but there are particular instances in which the superior histologic detail provided by more time-consuming routine methods is needed. In such instances, it is better to wait a few days, despite the drawbacks, than to perform inadequate or unnecessary surgery.


Pathology_Robbins

Pathology_Robbins. Fine-needle aspiration of tumors is another approach that is widely used. It involves aspiration of cells from a mass, followed by cytologic examination of the cells after they have been spread out on a slide. This procedure is used most commonly with readily palpable lesions affecting the breast, thyroid gland, lymph nodes, and salivary glands. Modern imaging techniques permit extension of the method to deeper structures, such as the liver, pancreas, and pelvic lymph nodes. Use of this diagnostic modality obviates surgery and its attendant risks. Although it entails some difficulties, such as small sample size and sampling errors, in experienced hands it can be reliable, rapid, and useful.


Pathology_Robbins

Pathology_Robbins. Cytologic (Papanicolaou) smears provide another method for the detection of cancer. Historically, this approach has been used widely for discovery of carcinoma of the cervix, often at an in situ stage, but now it is used to investigate many other forms of suspected malignancy, such as endometrial carcinoma, bronchogenic carcinoma, bladder and prostate tumors, and gastric carcinomas; for the identification of tumor cells in abdominal, pleural, joint, and cerebrospinal fluids; and, less commonly, for evaluation of other forms of neoplasia. Neoplastic cells are less cohesive than others and are therefore shed into fluids or secretions ( Fig. 6.35 ). The shed cells are evaluated for features of anaplasia indicative of their origin from a tumor. The


Pathology_Robbins

Pathology_Robbins. Fig. 6.35 ). The shed cells are evaluated for features of anaplasia indicative of their origin from a tumor. The Fig. 6.35 (A)NormalPapanicolaousmearfromtheuterinecervix.Large,flatcellswithsmallnucleiaretypical.(B)Abnormalsmearcontainingasheetofmalignantcellswithlargehyperchromaticnuclei.Nuclearpleomorphismisevident,andonecellisinmitosis.Afewinterspersedneutrophils,muchsmallerinsizeandwithcompact,lobatenuclei,areseen.(Courtesy of Dr. Richard M. DeMay, Department of Pathology, University of Chicago, Chicago, Illinois.) gratifying control of cervical cancer is the best testament to the value of the cytologic method.


Pathology_Robbins

Pathology_Robbins. Immunohistochemistry offers a powerful adjunct to routine histologic examination. Detection of cytokeratin by stains performed with specific monoclonal antibodies points to a diagnosis of undifferentiated carcinoma rather than large cell lymphoma. Similarly, detection of prostate-specific antigen (PSA) in metastatic deposits by immunohistochemical staining allows definitive diagnosis of a primary tumor in the prostate gland. Immunocytochemical detection of estrogen receptors allows prognostication and directs therapeutic intervention in breast cancers. Flow cytometry is used routinely in the classification of leukemias and lymphomas. In this method, fluorescently labeled antibodies against cell surface molecules and differentiation antigens are used to obtain the phenotype of malignant cells (Chapter 12).


Pathology_Robbins

Pathology_Robbins. 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. The application of these assays is considered with many of the specific forms of neoplasia discussed in other chapters, so only a few examples suffice here. 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,


Pathology_Robbins

Pathology_Robbins. 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 non-neoplastic conditions and thus also lack the specificity and sensitivity required for the early detection of cancers, but they may be


Pathology_Robbins

Pathology_Robbins. Like PSA, CEA and AFP can be elevated in a variety of non-neoplastic 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. CEA is further discussed in Chapter 15 and alpha fetoprotein in Chapter 16.