Pathology_Robbins

Pathology_Robbins. As the infection spreads, the individual mounts antiviral humoral and cell-mediated immune responses. These responses are evidenced by seroconversion (usually within 3 to 7 weeks of presumed exposure) and by the appearance of virus-specific CD8+ cytotoxic T cells. HIV-specific CD8+ T cells are detected in the blood at about the time viral titers begin to fall and are most likely responsible for the initial containment of HIV infection. These immune responses partially control the infection and viral production, and such control is reflected by a drop in viremia to low but detectable levels by about 12 weeks after the primary exposure.


Pathology_Robbins

Pathology_Robbins. • Chronic phase. In the next, chronic phase of the disease, lymph nodes and the spleen are sites of continuous HIV replication and cell destruction. During this period of the disease, few or no clinical manifestations of the HIV infection are present. Therefore, this phase of HIV disease is called the clinical latency period. Although few peripheral blood T cells harbor the virus, destruction of CD4+ T cells within lymphoid tissues (up to 10% of which may be infected) continues during this phase, and the number of circulating blood CD4+ T cells steadily declines. Eventually, over a period of years, the continuous cycle of virus infection, T-cell death, and new infection leads to a steady decline in the number of Infection of mucosal tissues Infection established in lymphoid tissues, e.g., lymph node Spread of infection Viremiathroughout the body Establishment of chronic Clinical infection; virus concentrated latency in lymphoid tissues; low-level virus production


Pathology_Robbins

Pathology_Robbins. Spread of infection Viremiathroughout the body Establishment of chronic Clinical infection; virus concentrated latency in lymphoid tissues; low-level virus production Destruction of lymphoid tissues:AIDS depletion of CD4+ T cells Fig. 5.39 Pathogenesis of HIV-1 infection. The initial infection starts in mucosal tissues, involving mainly memory CD4+ T cells and dendritic cells, and spreads to lymph nodes. Viral replication leads to viremia and widespread seeding of lymphoid tissue. The viremia is controlled by the host immune response, and the patient then enters a phase of clinical latency. During this phase, viral replication in both T cells and macrophages continues unabated, but there is some immune containment of virus (not shown). A gradual erosion of CD4+ cells continues, and, ultimately, CD4+ T-cell numbers decline and the patient develops clinical symptoms of full-blown AIDS. CTL, Cytotoxic T lymphocyte.


Pathology_Robbins

Pathology_Robbins. Fig. 5.40 ClinicalcourseofHIVinfection.(A)Duringtheearlyperiodafterprimaryinfection,thereisdisseminationofvirus,developmentofanimmuneresponsetoHIV,andoftenanacuteviralsyndrome.Duringtheperiodofclinicallatency,viralreplicationcontinuesandtheCD4+ T-cellcountgraduallydecreases,untilitreachesacriticallevelbelowwhichthereisasubstantialriskforAIDS-associateddiseases.(B)ImmuneresponsetoHIVinfection.AcytotoxicT-lymphocyte(CTL)responsetoHIVisdetectableby2to3weeksaftertheinitialinfection,anditpeaksby9to12weeks.Markedexpansionofvirus-specificCD8+ T-cellclonesoccursduringthistime,andupto10%ofapatient’sCTLsmaybeHIVspecificat12weeks.ThehumoralimmuneresponsetoHIVpeaksatabout12weeks.(A, Redrawn from Fauci AS, Lane HC: Human immunodeficiency virus disease: AIDS and related conditions. In Fauci AS, et al, editors: Harrison’sprinciplesofinternalmedicine, ed 14, New York, 1997, McGraw-Hill, p 1791.) CD4+ T cells in the lymphoid tissues and the circulation.


Pathology_Robbins

Pathology_Robbins. CD4+ T cells in the lymphoid tissues and the circulation. • AIDS. The final phase is progression to AIDS, characterized by a breakdown of host defense, a dramatic increase in plasma virus, and severe, life-threatening clinical disease. Typically the patient presents with long-lasting fever (>1 month), fatigue, weight loss, and diarrhea. After a variable period, serious opportunistic infections, secondary neoplasms, or clinical neurologic disease (grouped under the rubric AIDS indicator diseases or AIDS-defining illnesses, discussed later) emerge, and the patient is said to have developed AIDS.


Pathology_Robbins

Pathology_Robbins. The extent of viremia, measured as HIV-1 RNA levels in the blood, is a useful marker of HIV disease progression and is of value in the management of HIV-infected individuals. The viral load at the end of the acute phase reflects the equilibrium reached between the virus and the host response, and in a given patient it may remain fairly stable for several years. This level of steady-state viremia, called the viral set point, is a predictor of the rate of decline of CD4+ T cells and, therefore, progression of HIV disease.


Pathology_Robbins

Pathology_Robbins. 10 years or more, with stable CD4+ T cell counts and low levels of plasma viremia (usually <500 viral RNA copies/ mL). Remarkably, about 1% of infected individuals have undetectable plasma virus (<50 to 75 RNA copies/mL); these have been called elite controllers. Individuals with such an uncommon clinical course have attracted great attention in the hope that studying them may shed light on host and viral factors that influence disease progression. Studies thus far indicate that this group is heterogeneous with respect to the variables that influence the course of the disease. In most cases, the viral isolates do not show qualitative abnormalities, suggesting that the uneventful course cannot be attributed to a “wimpy” virus. In all cases, there is evidence of a vigorous anti-HIV immune Table 5.15 CDC Classification Categories of HIV Infection


Pathology_Robbins

Pathology_Robbins. Table 5.15 CDC Classification Categories of HIV Infection Because the loss of immune containment is associated with declining CD4+ T cell counts, the Centers for Disease Control and Prevention (CDC) classification of HIV infection stratifies patients into three groups based on CD4+ cell counts: greater than or equal to 500 cells/µL, 200 to 499 cells/µL, and fewer than 200 cells/µL ( Table 5.15 In the absence of treatment, most patients with HIV infection progress to AIDS after a chronic phase lasting from 7 to 10 years, but there are exceptions. In rapid progressors, the middle, chronic phase is telescoped to 2 to 3 years after primary infection. About 5% to 15% of infected individuals are long-term nonprogressors, defined as untreated HIV-1–infected individuals who remain asymptomatic for A.Asymptomatic:acuteA1A2A3(primary)HIV,orpersistentgeneralizedlymphadenopathy B.Symptomatic:noAorB1B2B3Cconditions


Pathology_Robbins

Pathology_Robbins. A.Asymptomatic:acuteA1A2A3(primary)HIV,orpersistentgeneralizedlymphadenopathy B.Symptomatic:noAorB1B2B3Cconditions C.AIDSindicatorconditions:includingconstitutionaldisease,neurologicdisease,orneoplasm DatafromCentersforDiseaseControlandPrevention:1993revisedclassificationsystemandexpandedsurveillancedefinitionforAIDSamongadolescentsandadults.MMWR 41(RR-17):1,1992. http://ebooksmedicine.net response, but the immune correlates of protection are still unknown. Some of these individuals have high levels of HIV-specific CD4+ and CD8+ T-cell responses, and these levels are maintained over the course of infection. The inheritance of particular HLA alleles seems to correlate with resistance to disease progression, perhaps reflecting the ability to mount anti-viral T cell responses. In the following section, we summarize the clinical manifestations of the terminal phase of the disease, full-blown AIDS.


Pathology_Robbins

Pathology_Robbins. In the following section, we summarize the clinical manifestations of the terminal phase of the disease, full-blown AIDS. In the United States, the typical adult patient with AIDS presents with fever, weight loss, diarrhea, generalized lymphadenopathy, multiple opportunistic infections, neurologic disease, and, in many cases, secondary neoplasms. Opportunistic infections account for the majority of deaths in untreated patients with AIDS. Many of these infections represent reactivation of latent infections, which are normally kept in check by a robust immune system but are not completely eradicated because the infectious agents have evolved to coexist with their hosts. The actual frequency of infections varies in different regions of the world, and has been markedly reduced by the advent of highly active anti-retroviral therapy (called HAART or ART), which relies on a combination of three or four drugs that block different steps of the HIV life cycle.


Pathology_Robbins

Pathology_Robbins. Approximately 15% to 30% of untreated HIV-infected individuals develop pneumonia caused by the fungus Pneumocystis jiroveci at some time during the course of the disease. Before the advent of HAART, this infection was the presenting feature in about 20% of cases, but the incidence is much less in patients who respond to HAART. Candidiasis is the most common fungal infection in patients with AIDS, and infection of the oral cavity, vagina, and esophagus are its most common clinical manifestations. In HIV-infected individuals, oral candidiasis is a sign of immunologic decompensation, and often heralds the transition to AIDS. Invasive candidiasis is infrequent in patients with AIDS, and it usually occurs when there is drug-induced neutropenia or use of indwelling catheters.


Pathology_Robbins

Pathology_Robbins. Cytomegalovirus (CMV) may cause disseminated disease, but more commonly affects the eye and gastrointestinal tract. Chorioretinitis used to be seen in approximately 25% of patients, but has decreased dramatically after the initiation of HAART. CMV retinitis occurs almost exclusively in patients with CD4+ T cell counts less than 50 per microliter. Gastrointestinal CMV infection, seen in 5% to 10% of cases, manifests as esophagitis and colitis, the latter associated with multiple mucosal ulcerations.


Pathology_Robbins

Pathology_Robbins. Disseminated bacterial infection with nontuberculous, or atypical, mycobacteria (mainly Mycobacterium aviumintracellulare) also occurs late, in the setting of severe immunosuppression. Coincident with the AIDS epidemic, the incidence of tuberculosis has risen dramatically. Worldwide, almost one third of all deaths in AIDS patients are attributable to tuberculosis, but this compli cation remains uncommon in the United States. Both reactivation of latent pulmonary disease and new primary infection contribute to this toll. As with tuberculosis in other settings, the infection may be confined to lungs or may involve multiple organs. Most worrisome are reports indicating that a growing number of isolates are resistant to multiple anti-mycobacterial drugs.


Pathology_Robbins

Pathology_Robbins. Cryptococcosis occurs in about 10% of AIDS patients. As in other settings with immunosuppression, meningitis is the major clinical manifestation of cryptococcosis. Toxoplasma gondii, another frequent invader of the CNS in AIDS, causes encephalitis and is responsible for 50% of all mass lesions in the CNS. JC virus, a human papovavirus, is another important cause of CNS infections in HIV-infected patients. It causes progressive multifocal leukoencephalopathy (Chapter 23). Herpes simplex virus infection is manifested by mucocutaneous ulcerations involving the mouth, esophagus, external genitalia, and perianal region. Persistent diarrhea, which is common in untreated patients with advanced AIDS, is often caused by infections with protozoans or enteric bacteria.


Pathology_Robbins

Pathology_Robbins. Patients with AIDS have a high incidence of certain tumors, notably Kaposi sarcoma, B cell lymphoma, cervical cancer in women, and anal cancer in men. These tumors are often considered AIDS-defining malignancies. It is estimated that 25% to 40% of untreated HIV-infected individuals will eventually develop a malignancy. Many of these tumors are caused by oncogenic DNA viruses, including Kaposi sarcoma herpesvirus (Kaposi sarcoma), EBV (B cell lymphoma), and human papillomavirus (cervical and anal carcinoma). These viruses establish latent infections that are kept in check in healthy individuals by a competent immune system. The increased risk for malignancy in AIDS patients exists mainly because of failure to contain the infection following reactivation of the viruses and decreased cellular immunity against virally infected cells undergoing malignant transformation. The incidence of many of these tumors, especially Kaposi sarcoma, is decreasing as treatment has improved and patients


Pathology_Robbins

Pathology_Robbins. immunity against virally infected cells undergoing malignant transformation. The incidence of many of these tumors, especially Kaposi sarcoma, is decreasing as treatment has improved and patients have less immune compromise. Nevertheless, HIV-infected individuals remain more susceptible to tumors that occur in the general population, such as lung and skin cancers and certain forms of lymphoma.


Pathology_Robbins

Pathology_Robbins. Kaposi Sarcoma. Kaposi sarcoma (KS), a vascular tumor that is otherwise rare in the United States, is considered an AIDS-defining malignancy. The morphology of KS and its occurrence in patients not infected with HIV are discussed in Chapter 10. At the onset of the AIDS epidemic, up to 30% of infected homosexual or bisexual men had KS, but with use of HAART there has been a dramatic decline in its incidence in recent years. In contrast, in areas of sub-Saharan Africa where HIV infection is both frequent and largely untreated, Kaposi sarcoma is one of the most common tumors. The lesions of KS are characterized by a proliferation of spindle-shaped cells that express markers of both endothelial cells (vascular or lymphatic) and smooth muscle cells. http://ebooksmedicine.net In addition, KS lesions contain chronic inflammatory cell infiltrates. Many of the features of KS suggest that it is not a malignant tumor (despite its ominous name).


Pathology_Robbins

Pathology_Robbins. There is compelling evidence that KS is caused by the KS herpesvirus (KSHV), also called human herpesvirus 8 (HHV8). Exactly how KSHV infection leads to KS is still unclear. Like other herpesviruses, KSHV establishes latent infection, during which several proteins are produced with potential roles in stimulating spindle cell proliferation and preventing apoptosis. These include a viral homologue of the cell cycle regulator cyclin D (an oncogene) and several inhibitors of p53 (a key tumor suppressor gene), both of which have been implicated in tumor development (Chapter 6). The spindle cells produce proinflammatory and angiogenic factors, which recruit the inflammatory and neovascular components of the lesion, and the latter components supply signals that aid in spindle cell survival and growth. However, KSHV infection, while necessary for KS development, is not sufficient, and additional cofactors are needed. In the AIDS-related form, that cofactor is clearly HIV. HIV-mediated immune


Pathology_Robbins

Pathology_Robbins. However, KSHV infection, while necessary for KS development, is not sufficient, and additional cofactors are needed. In the AIDS-related form, that cofactor is clearly HIV. HIV-mediated immune suppression may aid in widespread dissemination of KSHV in the host.


Pathology_Robbins

Pathology_Robbins. Clinically, AIDS-associated KS is quite different from the sporadic form (Chapter 10). In HIV-infected individuals, the tumor is usually widespread, affecting the skin, mucous membranes, gastrointestinal tract, lymph nodes, and lungs. These tumors also tend to be more aggressive than sporadic KS. Lymphomas. Lymphoma occurs at a markedly increased rate in individuals with AIDS, making it another AIDS-defining tumor. Roughly 5% of AIDS patients present with lymphoma, and approximately another 5% develop lymphoma during their subsequent course. Even in the era of anti-retroviral therapy, lymphoma continues to occur in HIV-infected individuals at an incidence that is at least 10-fold greater than the population average. Based on molecular characterization of HIV-associated lymphomas and the epidemiologic considerations above, at least two mechanisms appear to underlie the increased risk for B-cell tumors in HIV-infected individuals.


Pathology_Robbins

Pathology_Robbins. Tumors Induced by Oncogenic Viruses. T-cell immunity is required to restrain the proliferation of B cells latently infected with oncogenic viruses such as EBV and KSHV. With the appearance of severe T-cell depletion in the course of HIV infection, this control is lost, and the infected B cells undergo unchecked proliferation that predispose to mutations and the development of B-cell tumors. As a result, AIDS patients are at high risk for developing aggressive B-cell lymphomas composed of tumor cells infected by oncogenic viruses, particularly EBV. The tumors often occur in extranodal sites, such as the CNS, gut, orbit, and lungs, and elsewhere. AIDS patients also are prone to rare lymphomas that present as malignant effusions (so-called “primary effusion lymphoma”), which are remarkable in that the tumor cells are usually coinfected by both EBV and KSHV, a highly unusual example of cooperativity between two oncogenic viruses.


Pathology_Robbins

Pathology_Robbins. Germinal Center B-Cell Hyperplasia. The majority of the lymphomas that arise in patients with preserved CD4 T-cell counts are not associated with EBV or KSHV. The increased risk for lymphoma in these patients may be related to the profound germinal center B cell hyperplasia that occurs in HIV infection. The high level of proliferation and somatic mutations that occur in germinal center B cells set the stage for chromosomal translocations and mutations involving tumor-causing genes. In fact, the aggressive B-cell tumors that arise outside the setting of severe T cell depletion in HIV-infected individuals, such as Burkitt lymphoma and diffuse large B cell lymphoma, often are associated with mutations in oncogenes such as MYC and BCL6 that bear the molecular hallmarks of “mistakes” during the attempted diversification of immunoglobulin genes in germinal center B cells.


Pathology_Robbins

Pathology_Robbins. Several other EBV-related proliferations also merit mention. Hodgkin lymphoma, an unusual B-cell tumor associated with a pronounced tissue inflammatory response (Chapter 12), also occurs at increased frequency in HIV-infected individuals. In virtually all instances of HIV-associated Hodgkin lymphoma, the characteristic tumor cells (Reed-Sternberg cells) are infected with EBV. Many (but not all) HIV patients with Hodgkin lymphoma have low CD4 counts at the time of disease presentation. EBV infection also is responsible for oral hairy leukoplakia (white projections on the tongue), which results from EBV-driven squamous cell proliferation of the oral mucosa (Chapter 15). Other Tumors. In addition to KS and lymphomas, patients with AIDS also have an increased occurrence of carcinoma of the uterine cervix and of anal cancer. Both of these tumors are highly associated with human papilloma virus infection, which is poorly controlled in the setting of immunosuppression.


Pathology_Robbins

Pathology_Robbins. Involvement of the CNS is a common and important manifestation of AIDS. Ninety percent of patients demonstrate some form of neurologic involvement at autopsy, and 40% to 60% have clinically apparent neurologic dysfunction. Importantly, in some patients, neurologic manifestations may be the sole or earliest presenting feature of HIV infection. Lesions include a self-limited presumed viral meningoencephalitis or aseptic meningitis, vacuolar myelopathy, peripheral neuropathies, and, most commonly, a progressive encephalopathy called HIV-associated neurocognitive disorder (Chapter 23). Effect of Anti-Retroviral Drug Therapy on the Course of HIV Infection


Pathology_Robbins

Pathology_Robbins. Effect of Anti-Retroviral Drug Therapy on the Course of HIV Infection The advent of new drugs that target the viral reverse transcriptase, protease, and integrase enzymes has changed the clinical face of AIDS. When a combination of at least three effective drugs is used in a motivated, compliant patient, HIV replication is reduced to below the threshold of detection (<50 RNA copies/mL) and remains there as long as the patient adheres to therapy. Once the virus is suppressed, the progressive loss of CD4+ T cells is halted, and the peripheral CD4+ T-cell count slowly increases, often returning to a normal level. With the use of these drugs, the annual death rate from AIDS in the United States has decreased from a peak of 16 to 18 per 100,000 individuals in 1995–1996 to less than 4 per 100,000. Many AIDS-associated disorders, such as opportunistic infections with http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. P. jiroveci and Kaposi sarcoma, now are uncommon. Effective anti-retroviral therapy also has reduced the transmission of the virus, especially from infected mothers to newborns.


Pathology_Robbins

Pathology_Robbins. Despite these dramatic improvements, several new complications associated with HIV infection and its treatment have emerged. Some patients with advanced disease who are given anti-retroviral therapy develop a paradoxical clinical deterioration during the period of recovery of the immune system despite increasing CD4+ T-cell counts and decreasing viral load. This disorder, called the immune reconstitution inflammatory syndrome, is not understood but is postulated to be a poorly regulated host response to the high antigenic burden of persistent microbes. Perhaps a more important complication of long-term anti-retroviral therapy pertains to adverse side effects of the drugs. These include lipoatrophy (loss of facial fat), lipoaccumulation (excess fat deposition centrally), elevated lipids, insulin resistance, peripheral neuropathy, and premature cardiovascular, kidney, and liver disease. Finally, non-AIDS morbidity is far more common than classic AIDS-related morbidity in long-term


Pathology_Robbins

Pathology_Robbins. insulin resistance, peripheral neuropathy, and premature cardiovascular, kidney, and liver disease. Finally, non-AIDS morbidity is far more common than classic AIDS-related morbidity in long-term HAART-treated patients. Major causes of morbidity are cancer and accelerated cardiovascular disease. The mechanism for these non-AIDS–related complications is not known, but persistent inflammation and T-cell dysfunction may have a role.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Despite impressive advances in our understanding and treatment of HIV infection, the long-term prognosis of patients with AIDS remains a concern. Although with effective drug therapy the mortality rate has declined in the United States, the treated patients still carry viral DNA in their lymphoid tissues. Truly curative therapy remains elusive. Similarly, although considerable effort has been mounted to develop a protective vaccine, many hurdles remain before this becomes a reality. Molecular analyses have revealed an alarming degree of variation in viral isolates from patients; this renders the task of producing a vaccine extremely difficult. Recent efforts have focused on producing broadly neutralizing antibodies against relatively invariant portions of HIV proteins. At present, therefore, prevention, public health measures, and anti-retroviral drugs remain the mainstays in the fight against AIDS. Progression of disease. HIVinfectionprogressesthroughphases.


Pathology_Robbins

Pathology_Robbins. Progression of disease. HIVinfectionprogressesthroughphases. Acute HIV infection. Manifestationsofacuteviralillness Chronic (latent) phase. Disseminationofvirus,hostimmuneresponse,progressivedestructionofimmunecells. AIDS. Severeimmunedeficiency. Clinical features. Full-blownAIDSmanifestswithseveralcomplications,mostlyresultingfromimmunedeficiency. Tumors,especiallytumorscausedbyoncogenicviruses Antiretroviraltherapyhasgreatlydecreasedtheincidenceofopportunisticinfectionsandtumorsbutalsohasnumerouscomplications.


Pathology_Robbins

Pathology_Robbins. Tumors,especiallytumorscausedbyoncogenicviruses Antiretroviraltherapyhasgreatlydecreasedtheincidenceofopportunisticinfectionsandtumorsbutalsohasnumerouscomplications. Amyloidosis is a condition associated with a number of disorders in which extracellular deposits of fibrillar proteins are responsible for tissue damage and functional compromise. These abnormal fibrils are produced by the aggregation of improperly folded proteins (which are soluble in their normal folded configuration). The fibrillar deposits bind a wide variety of proteoglycans and glycosaminoglycans, which contain charged sugar groups that give the deposits staining characteristics thought to resemble those of starch (amylose). Therefore, the deposits were called amyloid, a name that is firmly entrenched despite the realization that the deposits are unrelated to starch. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Amyloid deposits can occur in a variety of conditions, in each of which the protein composition is different. Although amyloid always has the same morphologic appearance, it is biochemically heterogeneous. In fact, at least 30 different proteins can aggregate to form fibrils with the appearance of amyloid. Regardless of their derivation, all amyloid deposits are composed of nonbranching fibrils, each formed of intertwined polypeptides in a β pleated sheet conformation ( Fig. 5.41 ). Approximately 95% of the amyloid material consists of fibril proteins, the remaining 5% being various glycoproteins. The three most common forms of amyloid are the following: AL (amyloid light chain) amyloid is made up of complete immunoglobulin light chains, the amino-terminal fragments of light chains, or both.


Pathology_Robbins

Pathology_Robbins. The three most common forms of amyloid are the following: AL (amyloid light chain) amyloid is made up of complete immunoglobulin light chains, the amino-terminal fragments of light chains, or both. AA (amyloid-associated) amyloid is composed of an 8500dalton protein derived by proteolysis from a larger precursor in the blood called SAA (serum amyloidassociated) protein, which is synthesized in the liver. β-amyloid protein (Aβ) is a 4000-dalton peptide that is derived by proteolysis from a much larger transmembrane glycoprotein, called amyloid precursor protein. Fig. 5.41 Structureofamyloid.(A)Aschematicdiagramofanamyloidfibershowingfourfibrils(therecanbeasmanyassixineachfiber)woundaroundoneanotherwithregularlyspacedbindingoftheCongoreddye.(B)Congoredstainingshowsapple-greenbirefringenceunderpolarizedlight,adiagnosticfeatureofamyloid.(C)Electronmicrographof7.5-to10-nmamyloidfibrils.(From Merlini G, Bellotti V: Molecular mechanisms of amyloidosis. NEnglJMed349:583–596, 2003.)


Pathology_Robbins

Pathology_Robbins. Many other proteins also can deposit as amyloid in a variety of clinical settings. Some of the most clinically important examples are mentioned in the following section. Amyloidosis results from abnormal folding of proteins, which assume a β pleated sheet conformation, aggregate, and deposit as fibrils in extracellular tissues. Normally, intracellular misfolded proteins are degraded in proteasomes and extracellular protein aggregates are taken up and degraded by macrophages. In amyloidosis, these quality control mechanisms fail and fibrillar proteins accumulate outside of cells. The proteins that form amyloid fall into two general categories ( Fig. 5.42 ): (1) normal proteins that have an inherent tendency to associate and form fibrils, particularly when produced in increased amounts; and (2) mutant proteins that are prone to mis-folding and aggregation. The mechanisms of deposition of different types of amyloid are discussed next along with classification.


Pathology_Robbins

Pathology_Robbins. Because a given form of amyloid (e.g., AA) may be associated with diverse clinical settings, we will follow a classification that takes into account clinical and biochemical features ( Table 5.16 ). Amyloid may be systemic (generalized), involving several organ systems, or it may be localized to a single organ, such as the heart. On clinical grounds, the systemic pattern is subclassified into primary amyloidosis when it is associated with a clonal plasma cell proliferation, or secondary amyloidosis when it occurs as a complication of an underlying chronic inflammatory or tissue-destructive process. Hereditary or familial amyloidosis constitutes a separate, heterogeneous group with several distinctive patterns of organ involvement.


Pathology_Robbins

Pathology_Robbins. Primary Amyloidosis: Plasma Cell Proliferations Associated With Amyloidosis. Amyloid in this category is of the AL type and is usually systemic in distribution. This is the most common form of amyloidosis, with approximately 2000 to 3000 new cases each year in the United States. It is caused by a clonal proliferation of plasma cells that synthesize abnormal Ig molecules. The AL type of systemic amyloidosis occurs in 5% to 15% of individuals with multiple myeloma, a plasma-cell tumor characterized by excessive production of free immunoglobulin light chains (Chapter 12). The free, unpaired κ or λ light chains (referred to as Bence Jones protein) are prone to aggregating and depositing in tissues as amyloid. Since the majority of myeloma patients do not develop amyloidosis, however, it is clear that not all free light chains are equally likely to produce amyloid. For unknown reasons, λ light chains are approximately six times more likely to deposit as amyloid than κ light chains.


Pathology_Robbins

Pathology_Robbins. Most persons with AL amyloid do not have multiple myeloma or any other overt B cell neoplasm; such cases have been traditionally classified as primary amyloidosis, because their clinical features derive solely from the effects of amyloid deposition rather than formation of tumor masses. In virtually all such cases, however, monoclonal immunoglobulins or free light chains, or both, can be found in the blood or urine. Most of these patients also have a http://ebooksmedicine.net (e.g., misfolded protein) Monomers assemble to form ˜-sheet structure PRODUCTION OF NORMAL AMOUNTS OF MUTANT PROTEIN (e.g., transthyretin) Fig. 5.42 Pathogenesisofamyloidosis.(A)Generalmechanismofformationofamyloidfibrils.(B)Formationofamyloidfromexcessiveproductionofproteins pronetomisfolding.(C)Formationofamyloidfrommutantprotein. modest increase in the number of plasma cells in the bone marrow, which presumably secrete the precursors of AL protein.


Pathology_Robbins

Pathology_Robbins. modest increase in the number of plasma cells in the bone marrow, which presumably secrete the precursors of AL protein. Reactive Systemic Amyloidosis. The amyloid deposits in this pattern are systemic in distribution and are composed of AA protein. This category was previously referred to as secondary amyloidosis because it is secondary to an Table 5.16 Classification of Amyloidosis associated inflammatory condition. At one time, tuberculosis, bronchiectasis, and chronic osteomyelitis were the most important underlying conditions, but currently, these conditions frequently resolve with antibiotic treatment and less often lead to amyloidosis. More commonly now, reactive systemic amyloidosis complicates rheumatoid arthritis, other connective tissue disorders such as ankylosing spondylitis, and inflammatory bowel disease, particularly


Pathology_Robbins

Pathology_Robbins. PlasmacellproliferationswithMultiplemyelomaandothermonoclonalALImmunoglobulinlightchains,amyloidosis(primaryamyloidosis)plasmacellproliferations http://ebooksmedicine.net Crohn disease and ulcerative colitis. Among these, the most frequent associated condition is rheumatoid arthritis. Amyloidosis is reported to occur in approximately 3% of patients with rheumatoid arthritis and is clinically significant in one half of those affected. Heroin abusers who inject the drug subcutaneously also have a high occurrence rate of generalized AA amyloidosis. The chronic skin infections, which cause the “skin-popping” associated with injection of narcotics, seem to be responsible for the amyloidosis. Reactive systemic amyloidosis also may occur in association with certain cancers, the most common being renal cell carcinoma and Hodgkin lymphoma.


Pathology_Robbins

Pathology_Robbins. In AA amyloidosis, SAA synthesis by liver cells is stimulated by cytokines such as IL-6 and IL-1 that are produced during inflammation; thus, long-standing inflammation leads to a sustained elevation of SAA levels. While SAA levels are increased in all cases of inflammation, only a small subset get amyloidosis. It seems that in some patients SAA breakdown produces intermediates that are prone to forming fibrils.


Pathology_Robbins

Pathology_Robbins. Heredofamilial Amyloidosis. A variety of familial forms of amyloidosis have been described. Most are rare and occur in limited geographic areas. The most common and best studied is an autosomal recessive condition called familial Mediterranean fever, which is encountered largely in individuals of Armenian, Sephardic Jewish, and Arabic origins. This is an “autoinflammatory” syndrome associated with excessive production of the cytokine IL-1 in response to inflammatory stimuli. It is characterized by attacks of fever accompanied by inflammation of serosal surfaces that manifests as peritonitis, pleuritis, and synovitis. The gene for familial Mediterranean fever encodes a protein called pyrin that is important in dampening the response of innate immune cells, particularly neutrophils, to inflammatory mediators. The amyloid seen in this disorder is of the AA type, suggesting that it is related to the recurrent bouts of inflammation.


Pathology_Robbins

Pathology_Robbins. In contrast to familial Mediterranean fever, a group of autosomal dominant familial disorders is characterized by deposition of amyloid made up of fibrils derived from mutant transthyretin (TTR). TTR is a transporter of the hormone thyroxine. Remarkably, specific TTR mutant polypeptides tend to form amyloid in different organs; thus, in some families, deposits are seen mainly in peripheral nerves (familial amyloidotic polyneuropathies), whereas in others cardiac deposits predominate. The mutated form of the TTR gene that leads to cardiac amyloidosis is carried by approximately 4% of the black population in the United States, and cardiomyopathy has been identified in both homozygous and heterozygous patients. The precise prevalence of patients with this mutation who develop clinically manifest cardiac disease is not known.


Pathology_Robbins

Pathology_Robbins. Hemodialysis-Associated Amyloidosis. Patients on long-term hemodialysis for renal failure can develop amyloid deposits derived from β2-microglobulin. This protein is present in high concentrations in the serum of individuals with renal disease, and in the past it was retained in the circulation because it could not be filtered through dialysis membranes. With new dialysis filters, the incidence of this complication has decreased substantially. The classical features of this form of amyloidosis are the triad of scapulohumeral periarthritis, carpal tunnel syndrome, and flexor tenosynovitis of the hand.


Pathology_Robbins

Pathology_Robbins. Localized Amyloidosis. Sometimes, amyloid deposits are limited to a single organ or tissue without involvement of any other site in the body. The deposits may produce grossly detectable nodular masses or be evident only on microscopic examination. Nodular deposits of amyloid are most often encountered in the lung, larynx, skin, urinary bladder, tongue, and the region about the eye. Frequently, there are infiltrates of lymphocytes and plasma cells associated with these amyloid masses. At least in some cases, the amyloid consists of AL protein and may therefore represent a localized form of plasma cell–derived amyloid.


Pathology_Robbins

Pathology_Robbins. Endocrine Amyloid. Microscopic deposits of localized amyloid may be found in certain endocrine tumors, such as medullary carcinoma of the thyroid gland, islet tumors of the pancreas, pheochromocytomas, and undifferentiated carcinomas of the stomach, and in the islets of Langerhans in individuals with type 2 diabetes mellitus. In these settings, the amyloidogenic proteins seem to be derived either from polypeptide hormones (e.g., medullary carcinoma) or from unique proteins (e.g., islet amyloid polypeptide).


Pathology_Robbins

Pathology_Robbins. Amyloid of Aging. Several well-documented forms of amyloid deposition occur with aging. Senile systemic amyloidosis refers to the systemic deposition of amyloid in elderly patients (usually in their seventies and eighties). Because of the dominant involvement and related dysfunction of the heart, this form was previously called senile cardiac amyloidosis. Those who are symptomatic present with a restrictive cardiomyopathy and arrhythmias (Chapter 11). The amyloid in this form, in contrast to familial forms, is derived from normal TTR.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Other Organs. Nodulardepositionsinthetongue maycausemacroglossia,givingrisetothedesignationtumor-formingamyloidofthetongue.Therespiratory tract maybeinvolvedfocallyordiffuselyfromthelarynxdowntothesmallestbronchioles.Adistinctformofamyloidisfoundinthebrains ofpatientswithAlzheimerdisease.Itmaybepresentinso-called“plaques”aswellasbloodvessels(Chapter23).Amyloidosisofperipheralandautonomicnerves isafeatureofseveralfamilialamyloidoticneuropathies. Fig. 5.43 Amyloidosis.(A)AsectionofliverstainedwithCongoredrevealspink-reddepositsofamyloidinthewallsofbloodvesselsandalongsinusoids. (B)Notetheyellow-greenbirefringenceofthedepositswhenobservedbyapolarizingmicroscope.(B, Courtesy of Dr.Trace Worrell and Sandy Hinton, Department of Pathology,University of Texas Southwestern Medical School,Dallas,Texas.) http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Amyloidosis may be found as an unsuspected anatomic change, having produced no clinical manifestations, or it may cause serious clinical problems and even death. The symptoms depend on the magnitude of the deposits and on the sites or organs affected. Clinical manifestations at first are often entirely nonspecific, such as weakness, weight loss, lightheadedness, or syncope. Somewhat more specific findings appear later and most often relate to renal, cardiac, and gastrointestinal involvement.


Pathology_Robbins

Pathology_Robbins. Renal involvement gives rise to proteinuria that may be severe enough to cause the nephrotic syndrome (Chapter 14). Progressive obliteration of glomeruli in advanced cases ultimately leads to renal failure and uremia. Renal failure is a common cause of death. Cardiac amyloidosis may present insidiously as congestive heart failure. The most serious aspects of cardiac amyloidosis are conduction disturbances and arrhythmias, which may prove fatal. Occasionally, cardiac amyloidosis produces a restrictive pattern of cardiomyopathy and masquerades as chronic constrictive pericarditis (Chapter 11). Gastrointestinal amyloidosis may be asymptomatic, or it may present in a variety of ways. Amyloidosis of the tongue may cause sufficient enlargement and inelasticity to hamper speech and swallowing. Depositions in the stomach and intestine may lead to malabsorption, diarrhea, and disturbances in digestion. Vascular amyloidosis causes vascular fragility that may lead to bleeding, sometimes massive,


Pathology_Robbins

Pathology_Robbins. in the stomach and intestine may lead to malabsorption, diarrhea, and disturbances in digestion. Vascular amyloidosis causes vascular fragility that may lead to bleeding, sometimes massive, that can occur spontaneously or following seemingly trivial trauma. Additionally, in some cases AL amyloid binds and inactivates factor X, a critical coagulation factor, leading to a life-threatening bleeding disorder.


Pathology_Robbins

Pathology_Robbins. The diagnosis of amyloidosis depends on the histologic demonstration of amyloid deposits in tissues. The most common sites biopsied are the kidney, when renal manifestations are present, or rectal or gingival tissues in patients suspected of having systemic amyloidosis. Examination of abdominal fat aspirates stained with Congo red can also be used for the diagnosis of systemic amyloidosis. The test is quite specific, but its sensitivity is low. In suspected cases of AL amyloidosis, serum and urine protein electrophoresis and immunoelectrophoresis should be performed. Bone marrow aspirates in such cases often show a monoclonal population of plasma cells, even in the absence of overt multiple myeloma. Scintigraphy with radiolabeled serum amyloid P (SAP) component is a rapid and specific test, since SAP binds to the amyloid deposits and reveals their presence. It also gives a measure of the extent of amyloidosis and can be used to follow patients undergoing treatment. Mass spectroscopy


Pathology_Robbins

Pathology_Robbins. since SAP binds to the amyloid deposits and reveals their presence. It also gives a measure of the extent of amyloidosis and can be used to follow patients undergoing treatment. Mass spectroscopy is a useful tool for identification of the protein component of amyloid. It can be performed on paraffin embedded tissues.


Pathology_Robbins

Pathology_Robbins. The prognosis for individuals with generalized amyloidosis is poor. Those with AL amyloidosis (not including multiple myeloma) have a median survival of 2 years after diagnosis. Individuals with myeloma-associated amyloidosis have an even poorer prognosis. The outlook for individuals with reactive systemic amyloidosis is somewhat better and depends to some extent on the control of the underlying condition. Resorption of amyloid after treatment of the associated condition has been reported, but this is a rare occurrence. New therapeutic strategies aimed at correcting protein misfolding and inhibiting fibrillogenesis are being developed. Amyloidosisisadisordercharacterizedbytheextracellulardepositsofproteinsthatarepronetoaggregateandforminsolublefibrils. Thedepositionoftheseproteinsmayresultfrom:excessiveproductionofproteinsthatarepronetoaggregation;mutationsthatproduceproteinsthatcannotfoldproperlyandtendtoaggregate;defectiveorincompleteproteolyticdegradationofextracellularproteins.


Pathology_Robbins

Pathology_Robbins. Amyloidosismaybelocalizedorsystemic.Itisseeninassociationwithavarietyofprimarydisorders,includingmonoclonalB-cellproliferations(inwhichtheamyloiddepositsconsistofimmunoglobulinlightchains);chronicinflammatorydiseasessuchasrheumatoidarthritis(depositsofamyloidAprotein,derivedfromanacute-phaseproteinproducedininflammation);Alzheimerdisease(amyloidβ protein);familialconditionsinwhichtheamyloiddepositsconsistofmutatedproteins(e.g.,transthyretininfamilialamyloidpolyneuropathies);andhemodialysis(depositsofβ2-microglobulin,whoseclearanceisdefective). Amyloiddepositscausetissueinjuryandimpairnormalfunctionbycausingpressureoncellsandtissues.Theydonotevokeaninflammatoryresponse. Bonnelykke K, Sparks R, Waage J, et al: Genetics of allergy and allergic sensitization: common variants, rare mutations, Curr Opin Immunol 36:115, 2015. [An update on the genes associated with allergic diseases.]


Pathology_Robbins

Pathology_Robbins. Broderick L, De Nardo D, Franklin BS, et al: The inflammasomes and autoinflammatory syndromes, Annu Rev Pathol 10:395, 2015. [A discussion of the inflammasome and its role in inflammatory diseases.] Chaudhry A, Rudensky AY: Control of inflammation by integration of environmental cues by regulatory T cells, J Clin Invest 123:939– 944, 2013. [A thoughtful discussion of how regulatory T cells control inflammatory responses and maintain homeostasis in the immune system.] Cheng MH, Anderson MS: Monogenic autoimmunity, Annu Rev Immunol 30:393–427, 2012. [An excellent review of autoimmune syndromes caused by single-gene mutations, and what they teach us about pathways of immunologic tolerance.] Conley ME, Casanova JL: Discovery of single-gene inborn errors of immunity by next generation sequencing, Curr Opin Immunol 30:17, 2014. [A review of modern approaches for identifying the genetic basis of immunodeficiency diseases.]


Pathology_Robbins

Pathology_Robbins. Craft JE: Follicular helper T cells in immunity and systemic autoimmunity, Nat Rev Rheumatol 8:337–347, 2012. [A discussion of the properties and generation of follicular helper T cells and their roles in antibody production and autoimmunity.] Douek DC, Roederer M, Koup RA: Emerging concepts in the immunopathogenesis of AIDS, Annu Rev Med 60:471, 2009. [A balanced discussion of the pathogenesis of AIDS, and the still unresolved issues.] Galli SJ: The development of allergic inflammation, Nature 454:445, 2008. [An excellent review of the mechanisms of inflammation in allergic diseases.] Galli SJ: The mast cell-IgE paradox: from homeostasis to anaphylaxis, Am J Pathol 186:212, 2016. [A fascinating discussion of the evolution of mast cell responses and their roles in host defense and disease.] http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Goodnow CC: Multistep pathogenesis of autoimmune disease, Cell 130:25, 2007. [An excellent discussion of the checkpoints that prevent autoimmunity and why these might fail.] Holgate ST: Innate and adaptive immune responses in asthma, Nat Med 18:673–683, 2012. [A comprehensive discussion of the roles of TH2 cells, cytokines, and other cells of the immune system in the development and resolution of asthma.] Jancar S, Sanchez Crespo M: Immune complex–mediated tissue injury: a multistep paradigm, Trends Immunol 26:48, 2005. [A summary of the mechanisms of immune complex–mediated tissue injury.] Jennette JC, Falk RJ, Hu P, et al: Pathogenesis of antineutrophil cytoplasmic autoantibody-associated small-vessel vasculitis, Annu Rev Pathol 8:139–160, 2013. [A comprehensive review of the clinical and pathologic features and pathogenesis of small-vessel vasculitis.]


Pathology_Robbins

Pathology_Robbins. Pandey S, Kawai T, Akira S: Microbial sensing by Toll-like receptors and intracellular nucleic acid sensors, Cold Spring Harb Perspect Biol 7:a016246, 2014. [An excellent review of the receptors used by the innate immune system to sense microbes.] Klein L, Kyewski B, Allen PM, et al: Positive and negative selection of the T cell repertoire: what thymocytes see (and don’t see), Nat Rev Immunol 14:377, 2014. [A discussion of the mechanisms of T cell maturation and central tolerance induced in the thymus.] Lamkanfi M, Dixit VM: Mechanisms and functions of inflammasomes, Cell 157:1013, 2014. [An excellent update on the inflammasome and its role in inflammation and host defense.]


Pathology_Robbins

Pathology_Robbins. Lamkanfi M, Dixit VM: Mechanisms and functions of inflammasomes, Cell 157:1013, 2014. [An excellent update on the inflammasome and its role in inflammation and host defense.] Liu Z, Davidson A: Taming lupus—a new understanding of pathogenesis is leading to clinical advances, Nat Med 18:871–882, 2012. [An excellent review of recent advances in understanding the genetics of lupus and the roles of innate and adaptive immune responses in the disease, and how these advances are shaping the development of novel therapies.] Mahajan VS, Mattoo H, Deshpande V, et al: IgG4-related disease, Annu Rev Pathol 9:315, 2014. [A comprehensive discussion of the features and likely pathogenesis of this recently recognized entity.] Mathis D, Benoist C: Microbiota and autoimmune disease: the hosted self, Cell Host Microbe 10:297–301, 2011. [A review of the evidence that the microbiome influences immune activation and autoimmunity, and the relevance of these findings to human autoimmune diseases.]


Pathology_Robbins

Pathology_Robbins. Mavragani CP, Moustsopoulos HM: Sjögren’s syndrome, Annu Rev Pathol 9:273, 2014. [A review of the pathogenesis and clinical features of Sjögren’s syndrome.] Mitchell RN: Graft vascular disease: immune response meets the vessel wall, Annu Rev Pathol 4:19, 2009. [A review of the mechanisms that lead to vascular disease in chronic graft rejection.] Moir S, Chun TW, Fauci AS: Pathogenic mechanisms of HIV disease, Annu Rev Pathol 6:223, 2011. [A discussion of current concepts of the mechanisms by which HIV causes immunodeficiency.] Nankivell BJ, Alexander SI: Rejection of the kidney allograft, N Engl J Med 363:1451, 2010. [A good review of the mechanisms of recognition and rejection of allografts and the development of new strategies for treating rejection.]


Pathology_Robbins

Pathology_Robbins. O’Shea JJ, Paul WE: Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells, Science 327:1098, 2010. [An excellent review of the development and functions of helper T cell subsets, and the uncertainties in the field.] Ohkura N, Kitagawa Y, Sakaguchi S: Development and maintenance of regulatory T cells, Immunity 38:414–423, 2013. [An excellent review of the molecular mechanisms underlying the generation, maintenance, and stability of regulatory T cells.] Pattanaik D, Brown M, Postlethwaite BC, et al: Pathogenesis of systemic sclerosis, Front Immunol 6:272, 2015. [A discussion of current concepts of the pathogenesis of systemic sclerosis.] Parvaneh N, Casanova JL, Notarangelo LD, et al: Primary immunodeficiencies: a rapidly evolving story, J Allergy Clin Immunol 131:314–323, 2013. [An excellent review of newly described primary immunodeficiency syndromes.]


Pathology_Robbins

Pathology_Robbins. Schwartz RH: Historical overview of immunological tolerance, Cold Spring Harb Perspect Biol 4:a006908, 2012. [A thoughtful summary of the mechanisms of tolerance, the experimental studies behind the elucidation of these mechanisms, and how they may be disrupted to give rise to autoimmunity.] Tsokos GC: Systemic lupus erythematosus, N Engl J Med 365:2110, 2011. [An excellent review of the clinical features and pathogenesis of lupus.] Westermark GT, Fandrich M, Westermark P: AA amyloidosis: pathogenesis and targeted therapies, Annu Rev Pathol 10:321, 2015. [An excellent review of the pathogenesis and clinical features of a major form of amyloidosis.] Victora GD, Nussenzweig MC: Germinal centers, Annu Rev Immunol 30:429–457, 2012. [An excellent review of the properties and formation of germinal centers and their roles in antibody responses and autoimmune diseases.]


Pathology_Robbins

Pathology_Robbins. Voight BF, Cotsapas C: Human genetics offers an emerging picture of common pathways and mechanisms in autoimmunity, Curr Opin Immunol 24:552–557, 2012. [A discussion of the genetic associations with autoimmune diseases and the implications for understanding pathways of autoimmunity.] Weaver CT, Elson CO, Fouser LA, et al: The TH17 pathway and inflammatory diseases of the intestines, lungs, and skin, Annu Rev Pathol 8:477, 2013. [An excellent review of the development and lineage relationships of TH17 cells and their roles in autoimmune and other inflammatory diseases.] Zenewicz L, Abraham C, Flavell RA, et al: Unraveling the genetics of autoimmunity, Cell 140:791, 2010. [An update on susceptibility genes for autoimmune diseases, how these are identified, and their significance.] http://ebooksmedicine.net studentconsult.com Carcinogenesis:AMultistepProcess Insensitivity to Growth Inhibitory Signals:Tumor Evasion of Cell Death Evasion of Immune Surveillance


Pathology_Robbins

Pathology_Robbins. Carcinogenesis:AMultistepProcess Insensitivity to Growth Inhibitory Signals:Tumor Evasion of Cell Death Evasion of Immune Surveillance Tumor-Promoting Inflammation as an Enabler of Malignancy EtiologyofCancer:CarcinogenicAgents Effects of Tumor on Host Grading and Staging of Cancer Laboratory Diagnosis of Cancer


Pathology_Robbins

Pathology_Robbins. Cancer is the second leading cause of death in the United States; only cardiovascular diseases exact a higher toll. Even more agonizing than the associated mortality is the emotional and physical suffering inflicted by neoplasms. Patients and the public often ask, “When will there be a cure for cancer?” The answer to this simple question is difficult, because cancer is not one disease but rather many disorders that share a profound growth dysregulation. Some cancers, such as Hodgkin lymphoma, are highly curable, whereas others, such as cancer of the pancreas, are virtually always fatal. The only hope for controlling cancer lies in learning more about its pathogenesis, and great strides have been made in understanding the molecular basis of cancer. This chapter deals with the basic biology of neoplasia—the nature of benign and malignant neoplasms and the molecular basis of neoplastic transformation. The host response to tumors and the clinical features of neoplasia also are discussed.


Pathology_Robbins

Pathology_Robbins. Before we discuss the features of cancer cells and the mechanisms of carcinogenesis, it is useful to summarize the fundamental and shared characteristics of cancers: • Cancer is a genetic disorder caused by DNA mutations. Most pathogenic mutations are either induced by exposure to mutagens or occur spontaneously as part of aging. In addition, cancers frequently show epigenetic changes, such as focal increases in DNA methylation and alterations in histone modifications, which may themselves stem from acquired mutations in genes that regulate such modifications. These genetic and epigenetic changes alter the expression or function of key genes that regulate fundamental cellular processes, such as growth, survival, and senescence.


Pathology_Robbins

Pathology_Robbins. Genetic alterations in cancer cells are heritable, being passed to daughter cells upon cell division. As a result, cells harboring these alterations are subject to Darwinian selection (survival of the fittest, arguably the most important scientific concept in biology). Cells bearing mutations that provide a growth or survival advantage outcompete their neighbors and thus come to dominate the population. At the time of tumor initiation, these selective advantages are conferred on a single cell, and as a result all tumors are clonal (i.e., the progeny of one cell). However, even beyond the point of initiation, Darwinian selection continues to shape the evolution of cancers by favoring the emergence of genetically distinct subclones with more aggressive characteristics, an important concept referred to as progression and discussed in more detail later in this chapter.


Pathology_Robbins

Pathology_Robbins. Mutations and epigenetic alterations impart to cancer cells a set of properties that are referred to collectively http://ebooksmedicine.net as cancer hallmarks. These properties produce the cellular phenotypes that dictate the natural history of cancers as well as their response to various therapies. The molecular underpinnings of each hallmark of cancer are discussed in later sections. Basic research has elucidated many of the cellular and molecular abnormalities that give rise to cancer and govern its pernicious behavior. These insights are in turn leading to a revolution in the diagnosis and treatment of cancer, an emerging triumph of biomedical science.


Pathology_Robbins

Pathology_Robbins. Neoplasia literally means “new growth.” Neoplastic cells are said to be transformed because they continue to replicate, apparently oblivious to the regulatory influences that control normal cells. Neoplasms therefore enjoy a degree of autonomy and tend to increase in size regardless of their local environment. Their autonomy is by no means complete, however. All neoplasms depend on the host for their nutrition and blood supply. Neoplasms derived from hormone responsive tissues often also require endocrine support, and such dependencies sometimes can be exploited therapeutically. In common medical usage, a neoplasm often is referred to as a tumor, and the study of tumors is called oncology (from oncos, “tumor,” and logos, “study of”). Among tumors, the division of neoplasms into benign and malignant categories is based on a judgment of a tumor’s potential clinical behavior.


Pathology_Robbins

Pathology_Robbins. A tumor is said to be benign when its microscopic and gross characteristics are considered to be relatively innocent, implying that it will remain localized and is amenable to local surgical removal. Affected patients generally survive. Of note, however, benign tumors can produce more than localized lumps, and sometimes they produce significant morbidity or are even lethal. Malignant, as applied to a neoplasm, implies that the lesion can invade and destroy adjacent structures and spread to distant sites (metastasize) to cause death. Malignant tumors are collectively referred to as cancers, derived from the Latin word for “crab”—that is, they adhere to any part that they seize in an obstinate manner, similar to a crab’s behavior. Not all cancers pursue so deadly a course. The most aggressive are also some of the most curable, but the designation malignant constitutes a red flag.


Pathology_Robbins

Pathology_Robbins. All tumors, benign and malignant, have two basic components: (1) the parenchyma, made up of transformed or neoplastic cells, and (2) the supporting, host-derived, non-neoplastic stroma, made up of connective tissue, blood vessels, and host-derived inflammatory cells. The parenchyma of the neoplasm largely determines its biologic behavior, and it is this component from which the tumor derives its name. The stroma is crucial to the growth of the neoplasm, since it carries the blood supply and provides support for the growth of parenchymal cells. Although the biologic behavior of tumors largely reflects the behavior of the parenchymal cells, there has been a growing realization that stromal cells and neoplastic cells carry on a two-way conversation that influences the growth of the tumor.


Pathology_Robbins

Pathology_Robbins. In general, benign tumors are designated by attaching the suffix -oma to the cell type from which the tumor arises. For example, a benign tumor arising in fibrous tissue is a fibroma; a benign cartilaginous tumor is a chondroma. More varied and complex nomenclature is applied to benign epithelial tumors. The term adenoma is generally applied not only to benign epithelial neoplasms that produce glandlike structures, but also to benign epithelial neoplasms that are derived from glands but lack a glandular growth pattern. Thus, a benign epithelial neoplasm arising from renal tubule cells and growing in a glandlike pattern is termed an adenoma, as is a mass of benign epithelial cells that produces no glandular patterns but has its origin in the adrenal cortex. Papillomas are benign epithelial neoplasms, growing on any surface, that produce microscopic or macroscopic fingerlike fronds. A polyp is a mass that projects above a mucosal surface, as in the gut, to form a macroscopically visible


Pathology_Robbins

Pathology_Robbins. neoplasms, growing on any surface, that produce microscopic or macroscopic fingerlike fronds. A polyp is a mass that projects above a mucosal surface, as in the gut, to form a macroscopically visible structure (


Pathology_Robbins

Pathology_Robbins. Fig. 6.1 ). Although this term commonly is used for benign tumors, some malignant tumors also may grow as polyps, whereas other polyps (such as nasal polyps) are not neoplastic but inflammatory in origin. Cystadenomas are hollow cystic masses that typically arise in the ovary. The nomenclature of malignant tumors essentially follows that of benign tumors, with certain additions and exceptions. Malignant neoplasms arising in “solid” mesenchymal tissues or its derivatives are called sarcomas, whereas those arising from the mesenchymal cells of the blood are called leukemias or lymphomas. Sarcomas are designated based on their cell-type composition, which presumably reflects their cell of origin. Thus, a malignant neoplasm comprised of fat-like cells is a liposarcoma, and a malignant neoplasm composed of chondrocyte-like cells is a chondrosarcoma.


Pathology_Robbins

Pathology_Robbins. While the epithelia of the body are derived from all three germ cell layers, malignant neoplasms of epithelial cells are called carcinomas regardless of the tissue of origin. Thus, malignant neoplasms arising in the renal tubular epithelium (mesoderm), the skin (ectoderm), and lining epithelium of the gut (endoderm) are all considered carcinomas. Furthermore, mesoderm may give rise to carcinomas (epithelial), sarcomas (mesenchymal), and hematolymphoid tumors (leukemias and lymphomas). Carcinomas are subdivided further. Carcinomas that grow in a glandular pattern are called adenocarcinomas, and those that produce squamous cells are called squamous cell carcinomas. Sometimes the tissue or organ of origin can be identified, as in the designation of renal cell adenocarcinoma, but it is not uncommon for tumors http://ebooksmedicine.net Fig. 6.1 Colonicpolyp.Thisglandulartumorisseenprojectingintothecoloniclumen.Thepolypisattachedtothemucosabyadistinctstalk.


Pathology_Robbins

Pathology_Robbins. Fig. 6.1 Colonicpolyp.Thisglandulartumorisseenprojectingintothecoloniclumen.Thepolypisattachedtothemucosabyadistinctstalk. to show little or no differentiation. Such tumors are referred to as poorly differentiated or undifferentiated carcinoma. The transformed cells in a neoplasm, whether benign or malignant, usually resemble each other, consistent with their origin from a single transformed progenitor cell. In some unusual instances, however, the tumor cells undergo divergent differentiation, creating so-called “mixed tumors”. Mixed tumors are still of monoclonal origin, but the progenitor cell in such tumors has the capacity to differentiate down more than one lineage. The best example is mixed tumor of salivary gland. These tumors have obvious epithelial components dispersed throughout a fibromyxoid stroma, sometimes harboring islands of cartilage or bone (


Pathology_Robbins

Pathology_Robbins. Fig. 6.2 ). All of these diverse elements are thought to derive from a single transformed epithelial progenitor cell, and the preferred designation for these neoplasms is pleomorphic adenoma. Fibroadenoma of the female breast is another common mixed tumor. This benign tumor contains a mixture of proliferating ductal elements (adenoma) embedded in loose fibrous tissue (fibroma). Unlike pleomorphic adenoma, only the fibrous component is neoplastic, but the term fibroadenoma remains in common usage.


Pathology_Robbins

Pathology_Robbins. Teratoma is a special type of mixed tumor that contains recognizable mature or immature cells or tissues derived from more than one germ cell layer, and sometimes all three. Teratomas originate from totipotential germ cells such as those that normally reside in the ovary and testis and that are sometimes abnormally present in midline embryonic rests. Germ cells have the capacity to differentiate into any of the cell types found in the adult body; not surprisingly, therefore, they may give rise to neoplasms that contain elements resembling bone, epithelium, muscle, fat, nerve, and other tissues, all thrown together in a helterskelter fashion. The specific names of the more common neoplasms are presented in Table 6.1 . Some glaring inconsistencies may be noted. For example, the terms lymphoma, mesothelioma, melanoma, and seminoma are used for malignant neoplasms. Unfortunately for students, these exceptions are firmly entrenched in medical terminology.


Pathology_Robbins

Pathology_Robbins. There also are other instances of confusing terminology: Hamartoma is a mass of disorganized tissue indigenous to the particular site, such as the lung or the liver. While traditionally considered developmental malformations, many hamartomas have clonal chromosomal aberrations that are acquired through somatic mutations and on this basis are now considered to be neoplastic. Choristoma is a congenital anomaly consisting of a heterotopic nest of cells. For example, a small nodule of well-developed and normally organized pancreatic tissue may be found in the submucosa of the stomach, duodenum, or small intestine. The designation -oma, connoting a neoplasm, imparts to these lesions an undeserved gravity, as they are usually of trivial significance.


Pathology_Robbins

Pathology_Robbins. Although the terminology of neoplasms is regrettably complex, an understanding of the nomenclature is important because it is the language by which a tumor’s nature and significance is communicated among physicians in different disciplines involved in cancer care. Fig. 6.2 Mixedtumoroftheparotidgland.Smallnestsofepithelialcellsandmyxoidstromaformingcartilageandbone(anunusualfeature)arepresentinthisfield.(Courtesy of Dr. Vicky Jo, Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts.) http://ebooksmedicine.net More Than One Neoplastic Cell Type—Mixed Tumors, Usually Derived From One Germ Cell Layer TotipotentialcellsingonadsorinembryonicMatureteratoma,dermoidcystImmatureteratoma,teratocarcinomarests


Pathology_Robbins

Pathology_Robbins. More Than One Neoplastic Cell Type—Mixed Tumors, Usually Derived From One Germ Cell Layer TotipotentialcellsingonadsorinembryonicMatureteratoma,dermoidcystImmatureteratoma,teratocarcinomarests There are three fundamental features by which most benign and malignant tumors can be distinguished: differentiation and anaplasia, local invasion, and metastasis. In general, rapid growth also signifies malignancy, but many malignant tumors grow slowly and as a result growth rate is not a reliable discriminator between good and bad actors. Nothing is more important to the patient with a tumor than being told: “It is benign.” Although some neoplasms defy easy characterization, in most instances the determination of benign versus malignant is made with remarkable accuracy using long-established clinical and anatomic criteria.


Pathology_Robbins

Pathology_Robbins. Differentiation refers to the extent to which neoplasms resemble their parenchymal cells of origin, both morphologically and functionally; lack of differentiation is called anaplasia. In general, benign neoplasms are composed of well-differentiated cells that closely resemble their normal counterparts. A lipoma is made up of mature fat cells laden with cytoplasmic lipid vacuoles, and a chondroma is made up of mature cartilage cells that synthesize their usual cartilaginous matrix—evidence of morphologic and functional differentiation. In well-differentiated benign tumors, mitoses are usually rare and are of normal configuration. By contrast, while malignant neoplasms exhibit a wide range of parenchymal cell differentiation, most exhibit morphologic alterations that betray their malignant nature. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. By contrast, while malignant neoplasms exhibit a wide range of parenchymal cell differentiation, most exhibit morphologic alterations that betray their malignant nature. http://ebooksmedicine.net Fig. 6.3 Well-differentiatedsquamouscellcarcinomaoftheskin.Thetumorcellsarestrikinglysimilartonormalsquamousepithelialcells,withintercellularbridgesandnestsofkeratin(arrow). (Courtesy of Dr.Trace Worrell,Department of Pathology, University of Texas Southwestern Medical School, Dallas,Texas.) In well-differentiated cancers, these features may be quite subtle (


Pathology_Robbins

Pathology_Robbins. In well-differentiated cancers, these features may be quite subtle ( Fig. 6.3 ). For example, well-differentiated adenocarcinoma of the thyroid gland may contain normal-appearing follicles, its malignant potential being only revealed by invasion into adjacent tissues or metastasis. The stroma carrying the blood supply is crucial to the growth of tumors but does not aid in the separation of benign from malignant ones. The amount of stromal connective tissue does, however, determine the consistency of a neoplasm. Certain cancers induce a dense, abundant fibrous stroma (desmoplasia), making them hard, so-called “scirrhous tumors”.


Pathology_Robbins

Pathology_Robbins. Tumors composed of undifferentiated cells are said to be anaplastic, a feature that is a reliable indicator of malignancy. The term anaplasia literally means “backward formation”—implying dedifferentiation, or loss of the structural and functional differentiation of normal cells. It is now known, however, that at least some cancers arise from stem cells in tissues; in these tumors, failure of differentiation of transformed stem cells, rather than dedifferentiation of specialized cells, accounts for their anaplastic appearance. Recent studies also indicate that in some cases, dedifferentiation of apparently mature cells occurs during carcinogenesis. Anaplastic cells often display the following morphologic features: Pleomorphism (i.e., variation in size and shape) ( Fig. 6.4


Pathology_Robbins

Pathology_Robbins. Pleomorphism (i.e., variation in size and shape) ( Fig. 6.4 Nuclear abnormalities, consisting of extreme hyperchromatism (dark-staining), variation in nuclear size and shape, or unusually prominent single or multiple nucleoli. Enlargement of nuclei may result in an increased nuclear-to-cytoplasmic ratio that approaches 1:1 instead of the normal 1:4 or 1:6. Nucleoli may attain astounding sizes, sometimes approaching the diameter of normal lymphocytes. Tumor giant cells may be formed. These are considerably larger than neighboring cells and may possess either one enormous nucleus or several nuclei. Atypical mitoses, which may be numerous. Anarchic multiple spindles may produce tripolar or quadripolar mitotic figures ( Fig. 6.5 Loss of polarity, such that anaplastic cells lack recognizable patterns of orientation to one another. Such cells may grow in sheets, with total loss of communal


Pathology_Robbins

Pathology_Robbins. Fig. 6.5 Loss of polarity, such that anaplastic cells lack recognizable patterns of orientation to one another. Such cells may grow in sheets, with total loss of communal Fig. 6.4 Pleomorphicmalignanttumor(rhabdomyosarcoma).Notethemarkedvariationincellandnuclearsizes,thehyperchromaticnuclei,andthepresenceoftumorgiantcells.(Courtesy of Dr. Trace Worrell, Department of Pathology,University of Texas Southwestern Medical School,Dallas,Texas.) structures, such as glands or stratified squamous architecture. Well-differentiated tumor cells are likely to retain the functional capabilities of their normal counterparts, whereas anaplastic tumor cells are much less likely to have specialized functional activities. For example, benign neoplasms and even well-differentiated cancers of endocrine glands frequently elaborate the hormones characteristic of their cell of origin. Similarly, well-differentiated squamous cell carcinomas produce keratin (see


Pathology_Robbins

Pathology_Robbins. Fig. 6.3 ), just as well-differentiated hepatocellular carcinomas secrete bile. In other instances, unanticipated functions emerge. Some cancers may express fetal proteins not produced by comparable cells in the adult. Cancers of nonendocrine origin may produce so-called “ectopic hormones.” For example, certain lung carcinomas may produce adrenocorticotropic hormone (ACTH), parathyroid hormone– like hormone, insulin, glucagon, and others. More is said about these so-called “paraneoplastic” phenomena later. Also of relevance in the discussion of differentiation and anaplasia is dysplasia, referring to disorderly proliferation. Fig. 6.5 High-powerdetailedviewofanaplastictumorcellsshowscellularandnuclearvariationinsizeandshape.Theprominentcellinthecenterfieldhasanabnormaltripolarspindle. http://ebooksmedicine.net


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Dysplastic epithelium is recognized by a loss in the uniformity of individual cells and in their architectural orientation. Dysplastic cells exhibit considerable pleomorphism and often possess abnormally large, hyperchromatic nuclei. Mitotic figures are more abundant than usual and frequently appear in abnormal locations within the epithelium. In dysplastic stratified squamous epithelium, mitoses are not confined to the basal layers, where they normally occur, but may be seen throughout the epithelium. In addition, there is considerable architectural anarchy. For example, the usual progressive maturation of tall cells in the basal layer to flattened squames on the surface may be lost and replaced by a disordered hodgepodge of dark basal-appearing cells. When dysplastic changes are severe and involve the entire thickness of the epithelium, the lesion is referred to as carcinoma in situ, a preinvasive stage of cancer ( Fig. 6.6


Pathology_Robbins

Pathology_Robbins. Fig. 6.6 It is important to appreciate that dysplasia is not synonymous with cancer. Mild to moderate dysplasias that do not involve the entire thickness of the epithelium sometimes regress completely, particularly if inciting causes are removed. However, dysplasia is often noted adjacent to frankly malignant neoplasms (e.g., in cigarette smokers with lung cancer), and in general the presence of dysplasia marks a tissue as being at increased risk for developing an invasive cancer. The growth of cancers is accompanied by progressive infiltration, invasion, and destruction of surrounding tissues, whereas most benign tumors grow as cohesive expansile masses that remain localized to their sites of origin. Because benign tumors grow and expand slowly, they usually develop a rim of compressed fibrous tissue (


Pathology_Robbins

Pathology_Robbins. Figs. 6.7 6.8 ). This capsule consists largely of extracellular matrix that is deposited by stromal cells such as fibroblasts, which are activated by hypoxic damage to parenchymal cells resulting from compression by the expanding tumor. Encapsulation creates a tissue plane that makes the tumor discrete, moveable (non-fixed), and readily excisable by surgical enucleation. However, it is important to recognize that not all benign neoplasms are encapsulated. For example, the leiomyoma of the uterus is discretely demarcated from the surrounding smooth muscle by a zone of compressed and attenuated normal myometrium, but lacks a capsule. A few benign tumors are neither encapsulated nor discretely defined; lack of demarcation is particularly likely in benign vascular neoplasms such as hemangiomas, which understandably may be difficult to excise. These exceptions are pointed out only to emphasize that although encapsulation is the rule in benign tumors, the lack of a capsule does not mean


Pathology_Robbins

Pathology_Robbins. which understandably may be difficult to excise. These exceptions are pointed out only to emphasize that although encapsulation is the rule in benign tumors, the lack of a capsule does not mean that a tumor is malignant. Sadly, because of their uncivilized nature, tumor cells sometimes do not follow the rules set by humans. We will see such deviations many times in this chapter.


Pathology_Robbins

Pathology_Robbins. Fig. 6.7 Fibroadenomaofthebreast.Thetan-colored,encapsulatedsmalltumorissharplydemarcatedfromthewhiterbreasttissue. Fig. 6.8 Microscopicviewoffibroadenomaofthebreastseenin Fig.6.7 .Thefibrouscapsule(right) sharplydelimitsthetumorfromthesurroundingtissue.(Courtesy of Dr.Trace Worrell, Department of Pathology, University of Texas Southwestern Medical School, Dallas,Texas.) http://ebooksmedicine.net Fig. 6.9 Cutsectionofinvasiveductalcarcinomaofthebreast.Thelesionisretracted,infiltratingthesurroundingbreastsubstance,andwasstony-hardonpalpation. Next to the development of metastases, invasiveness is the feature that most reliably distinguishes cancers from benign tumors (


Pathology_Robbins

Pathology_Robbins. Next to the development of metastases, invasiveness is the feature that most reliably distinguishes cancers from benign tumors ( Figs. 6.9 6.10 ). Cancers lack well-defined capsules. There are instances in which a slowly growing malignant tumor deceptively appears to be encased by the stroma of the surrounding host tissue, but microscopic examination reveals tiny crablike feet penetrating the margin and infiltrating adjacent structures. This infiltrative mode of growth makes it necessary to remove a wide margin of surrounding normal tissue when surgical excision of a malignant tumor is attempted. Surgical pathologists carefully examine the margins of resected tumors to ensure that they are devoid of cancer cells (clean margins).


Pathology_Robbins

Pathology_Robbins. Metastasis is defined by the spread of a tumor to sites that are physically discontinuous with the primary tumor and unequivocally marks a tumor as malignant, as by definition benign neoplasms do not metastasize. The invasiveness of cancers permits them to penetrate into blood vessels, lymphatics, and body cavities, providing opportunities for spread ( Fig. 6.11 ). Overall, approximately 30% of patients with newly diagnosed solid tumors (excluding skin cancers other than melanomas) present with Fig. 6.10 Microscopicviewofbreastcarcinomaseenin Fig.6.9 Fig.6.8 ).Notetheabsenceofawell-definedcapsule.(Courtesy of Dr. Susan Lester, Brigham and Women’s Hospital, Boston, Massachusetts.) clinically evident metastases. An additional 20% have occult (hidden) metastases at the time of diagnosis.


Pathology_Robbins

Pathology_Robbins. In general, the more anaplastic and the larger the primary neoplasm, the more likely is metastatic spread, but as with most rules there are exceptions. Extremely small cancers have been known to metastasize; conversely, some large and ominous-looking lesions may not. While all malignant tumors can metastasize, some do so very infrequently. For example, basal cell carcinomas of the skin and most primary tumors of the central nervous system are highly locally invasive but rarely metastasize. It is evident then that the properties of local invasion and metastasis are sometimes separable. A special circumstance involves so-called “blood cancers”, the leukemias and lymphomas. These tumors are derived from blood-forming cells that normally have the capacity to enter the bloodstream and travel to distant sites; as a result, with only rare exceptions, leukemias and lymphomas are taken to be disseminated diseases at diagnosis and are always considered to be malignant.


Pathology_Robbins

Pathology_Robbins. Malignant neoplasms disseminate by one of three pathways: (1) seeding within body cavities, (2) lymphatic spread, or (3) hematogenous spread. Spread by seeding Fig. 6.11 Aliverstuddedwithmetastaticcancer. http://ebooksmedicine.net occurs when neoplasms invade a natural body cavity. This mode of dissemination is particularly characteristic of cancers of the ovary, which often cover the peritoneal surfaces widely. The implants literally may glaze all peritoneal surfaces and yet not invade the underlying tissues. Here is an instance where the ability to reimplant and grow at sites distant from the primary tumor seems to be separable from the capacity to invade. Neoplasms of the central nervous system, such as a medulloblastoma or ependymoma, may penetrate the cerebral ventricles and be carried by the cerebrospinal fluid to reimplant on the meningeal surfaces, either within the brain or in the spinal cord.


Pathology_Robbins

Pathology_Robbins. Lymphatic spread is more typical of carcinomas, whereas hematogenous spread is favored by sarcomas. There are numerous interconnections, however, between the lymphatic and vascular systems, so all forms of cancer may disseminate through either or both systems. The pattern of lymph node involvement depends principally on the site of the primary neoplasm and the natural pathways of local lymphatic drainage. Lung carcinomas arising in the respiratory passages metastasize first to the regional bronchial lymph nodes and then to the tracheobronchial and hilar nodes. Carcinoma of the breast usually arises in the upper outer quadrant and first spreads to the axillary nodes. However, medial breast lesions may drain through the chest wall to the nodes along the internal mammary artery. Thereafter, in both instances, the supraclavicular and infraclavicular nodes may be seeded. In some cases, the cancer cells seem to travel in lymphatic channels within the immediately proximate nodes to be


Pathology_Robbins

Pathology_Robbins. in both instances, the supraclavicular and infraclavicular nodes may be seeded. In some cases, the cancer cells seem to travel in lymphatic channels within the immediately proximate nodes to be trapped in subsequent lymph nodes, producing so-called “skip metastases.” The cells may traverse all of the lymph nodes ultimately to reach the vascular compartment by way of the thoracic duct.


Pathology_Robbins

Pathology_Robbins. A “sentinel lymph node” is the first regional lymph node that receives lymph flow from a primary tumor. It can be identified by injection of blue dyes or radiolabeled tracers near the primary tumor. Biopsy of sentinel lymph nodes allows determination of the extent of spread of tumor and can be used to plan treatment. Of note, although enlargement of nodes near a primary neoplasm should arouse concern for metastatic spread, it does not always imply cancerous involvement. The necrotic products of the neoplasm and tumor antigens often evoke immunologic responses in the nodes, such as hyperplasia of the follicles (lymphadenitis) and proliferation of macrophages in the subcapsular sinuses (sinus histiocytosis). Thus, histopathologic verification of tumor within an enlarged lymph node is required.


Pathology_Robbins

Pathology_Robbins. While hematogenous spread is the favored pathway for sarcomas, carcinomas use it as well. As might be expected, arteries are penetrated less readily than are veins. With venous invasion, the bloodborne cells follow the venous flow draining the site of the neoplasm, with tumor cells often stopping in the first capillary bed they encounter. Since all portal area drainage flows to the liver, and all caval blood flows to the lungs, the liver and lungs are the most frequently involved secondary sites in hematogenous dissemination. Cancers arising near the vertebral column often embolize through the paravertebral plexus; this pathway probably is involved in the frequent vertebral metastases of carcinomas of the thyroid and prostate glands.


Pathology_Robbins

Pathology_Robbins. Certain carcinomas have a propensity to grow within veins. Renal cell carcinoma often invades the renal vein to grow in a snakelike fashion up the inferior vena cava, sometimes reaching the right side of the heart. Hepatocellular carcinomas often penetrate and grow within the radicles of portal and hepatic veins, eventually reaching the main venous channels. Remarkably, such intravenous growth may not be accompanied by widespread dissemination. Many observations suggest that the anatomic localization of a neoplasm and its venous drainage cannot wholly explain the systemic distributions of metastases. For example, prostatic carcinoma preferentially spreads to bone, bronchogenic carcinoma tends to involve the adrenal glands and the brain, and neuroblastoma spreads to the liver and bones. Conversely, skeletal muscles, although rich in capillaries, are rarely sites of tumor metastases. The molecular basis of such tissue-specific homing of tumor cells is discussed later.


Pathology_Robbins

Pathology_Robbins. Thus, numerous features of tumors ( Fig. 6.12 ) usually permit the differentiation of benign and malignant neoplasms. Benignandmalignanttumorscanbedistinguishedfromoneanotherbasedonthedegreeofdifferentiation,rateofgrowth,localinvasiveness,anddistantspread. Benigntumorsresemblethetissueoforiginandarewelldifferentiated;malignanttumorsarepoorlyorcompletelyundifferentiated(anaplastic). Benigntumorstendtobeslowgrowing,whereasmalignanttumorsgenerallygrowfaster. Benigntumorsarewellcircumscribedandhaveacapsule;malignanttumorsarepoorlycircumscribedandinvadethesurroundingnormaltissues. Benigntumorsremainlocalizedtothesiteoforigin,whereasmalignanttumorsarelocallyinvasiveandmetastasizetodistantsites.


Pathology_Robbins

Pathology_Robbins. Study of cancer occurrence in populations has contributed substantially to knowledge about its origins. The now well-established concept that cigarette smoking is causally associated with lung cancer arose primarily from epidemiologic studies. A comparison of the incidence rates for colon cancer and dietary patterns in the Western world and in Africa led to the recognition that dietary fat and fiber content may figure importantly in the causation of this cancer. Major insights into the causes of cancer can be obtained by epidemiologic studies that relate particular environmental, racial (possibly hereditary), and cultural influences to the occurrence of specific neoplasms. Certain diseases associated with an increased risk for developing cancer also provide clues to the pathogenesis of cancer. The following discussion first summarizes the overall incidence of cancer to provide insight into the magnitude of the cancer problem and then reviews factors relating to the


Pathology_Robbins

Pathology_Robbins. pathogenesis of cancer. The following discussion first summarizes the overall incidence of cancer to provide insight into the magnitude of the cancer problem and then reviews factors relating to the http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Large Locally invasive Poorly demarcated Metastatic Rapidly growing with Poorly differentiated Fig. 6.12 Comparisonbetweenabenigntumorofthemyometrium(leiomyoma)andamalignanttumorofsimilarorigin(leiomyosarcoma). patient and the environment that influence the predisposition to cancer.


Pathology_Robbins

Pathology_Robbins. patient and the environment that influence the predisposition to cancer. For the year 2012, the World Health Organization (WHO) estimated that there were about 14.1 million new cancer cases worldwide, leading to 8.2 million deaths (approximately 22,500 deaths per day). Moreover, due to increasing population size, by the year 2035 the WHO projects that the numbers of cancer cases and deaths worldwide will increase to 24 million and 14.6 million, respectively (based on current mortality rates). Additional perspective on the likelihood of developing a specific form of cancer can be gained from national incidence and mortality data. In the United States, it is estimated that the year 2016 will be marked by approximately 1.69 million new cases of cancer and 595,000 cancer deaths. Incidence data for the most common forms of cancer, with the major killers identified, are presented in Fig. 6.13


Pathology_Robbins

Pathology_Robbins. Fig. 6.13 Over several decades, the death rates for many forms of cancer have changed. Since 1995, the incidence of cancer in men and women in the United States has been roughly stable, but the cancer death rate has decreased by roughly 20% in men and 10% in women. Among men, 80% of the decrease is accounted for by lower death rates for cancers of the lung, prostate, and colon; among women, nearly 60% of the decrease is due to reductions in death rates from breast and colorectal cancers. Decreased use of tobacco products is responsible for the reduction in lung cancer deaths, while improved detection and treatment are responsible for the decrease in death rates for colorectal, female breast, and prostate cancers.


Pathology_Robbins

Pathology_Robbins. The last half-century has also seen a sharp decline in death rates from cervical cancer and gastric cancer in the United States. The decrease in cervical cancer is directly attributable to widespread use of the Papanicolaou (PAP) smear test for early detection of this tumor and its precursor lesions. The deployment of the human papillomavirus (HPV) vaccine may nearly eliminate this cancer in coming years. The cause of the decline in death rates for cancers of the stomach is obscure; it may be related to decreasing exposure to unknown dietary carcinogens.


Pathology_Robbins

Pathology_Robbins. Environmental exposures appear to be the dominant risk factors for many common cancers, suggesting that a high fraction of cancers are potentially preventable. This notion is supported by the geographic variation in death rates from specific forms of cancer, which is thought to stem mainly from differences in environmental exposures. For instance, death rates from breast cancer are about four to five times higher in the United States and Europe than in Japan. Conversely, the death rate for stomach carcinoma in men and women is about seven times higher in Japan than in the United States. Liver cell carcinoma is relatively infrequent in the United States but is the most lethal cancer among many African populations. Nearly all the evidence indicates that these geographic differences have environmental rather than genetic origins. For example, Nisei (secondgeneration Japanese living in the United States) have mortality rates for certain forms of cancer that are intermediate between those


Pathology_Robbins

Pathology_Robbins. rather than genetic origins. For example, Nisei (secondgeneration Japanese living in the United States) have mortality rates for certain forms of cancer that are intermediate between those in natives of Japan and in Americans who have lived in the United States for many generations. The two rates come closer with each passing generation.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Men 314,290 Women 281,400 There is no paucity of environmental factors that con-with a modestly increased risk for developing many tribute to cancer. They lurk in the ambient environment, in different cancers. the workplace, in food, and in personal practices. They can • Smoking. Smoking, particularly of cigarettes, has been be as universal as sunlight or be largely restricted to urban implicated in cancer of the mouth, pharynx, larynx, settings (e.g., asbestos) or particular occupations ( esophagus, pancreas, bladder, and, most significantly, 6.2 ). The most important environmental exposures linked the lung, as 90% of lung cancer deaths are related to to cancer include the following: smoking.


Pathology_Robbins

Pathology_Robbins. • Diet. Certain features of diet have been implicated as • Alcohol consumption. Alcohol abuse is an independent predisposing influences. More broadly, obesity, cur-risk factor for cancers of the oropharynx, larynx, esophrently epidemic in the United States, is associated agus, and (due to alcoholic cirrhosis) liver. Moreover, Table 6.2 Occupational Cancers Human Cancers for Agents or Groups Which Reasonable of Agents Evidence Is Available Typical Use or Occurrence ArsenicandarsenicLungcarcinoma,skincarcinomaBy-productofmetalsmelting;componentofalloys,electricalandsemiconductordevices,compounds medicationsandherbicides,fungicides,andanimaldips BenzeneAcutemyeloidleukemiaPrincipalcomponentoflightoil;despiteknownrisk,manyapplicationsexistinprintingandlithography,paint,rubber,drycleaning,adhesivesandcoatings,anddetergents;formerlywidelyusedassolventandfumigant BerylliumandberylliumLungcarcinomaMissilefuelandspacevehicles;hardenerforlightweightmetalalloys,particularlyincompounds


Pathology_Robbins

Pathology_Robbins. BerylliumandberylliumLungcarcinomaMissilefuelandspacevehicles;hardenerforlightweightmetalalloys,particularlyincompounds ChromiumcompoundsLungcarcinomaComponentofmetalalloys,paints,pigments,andpreservatives NickelcompoundsLungandoropharyngealNickelplating;componentofferrousalloys,ceramics,andbatteries;by-productofcarcinomastainless-steelarcwelding ModifiedfromStellmanJM,StellmanSD:Cancerandtheworkplace,CA Cancer J Clin 46:70–92,1996,withpermissionfromLippincottWilliams&Wilkins. http://ebooksmedicine.net alcohol and tobacco smoking synergistically increase the risk for developing cancers of the upper airways and upper digestive tract. Reproductive history. There is strong evidence that lifelong cumulative exposure to estrogen stimulation, particularly if unopposed by progesterone, increases the risk for developing cancers of the endometrium and breast, both of which are estrogen-responsive tissues.


Pathology_Robbins

Pathology_Robbins. Infectious agents. It is estimated that infectious agents cause approximately 15% of cancers worldwide. Thus, there is no escape: it seems that everything people do to earn a livelihood, to subsist, or to enjoy life turns out to be illegal, immoral, or fattening, or—most disturbing— possibly carcinogenic! In general, the frequency of cancer increases with age. Most cancer deaths occur between 55 and 75 years of age; the rate declines, along with the population base, after 75 years of age. The rising incidence with age may be explained by the accumulation of somatic mutations that drive the emergence of malignant neoplasms (discussed later). The decline in immune competence that accompanies aging also may be a factor.


Pathology_Robbins

Pathology_Robbins. Although cancer preferentially affects older adults, it also is responsible for slightly more than 10% of all deaths among children younger than 15 years of age (Chapter 7). The major lethal cancers in children are leukemias, tumors of the central nervous system, lymphomas, and soft-tissue and bone sarcomas. As discussed later, study of several childhood tumors, such as retinoblastoma, has provided fundamental insights into the pathogenesis of malignant transformation. Acquired conditions that predispose to cancer include disorders associated with chronic inflammation, immunodeficiency states, and precursor lesions. Many chronic inflammatory conditions create a fertile “soil” for the development of malignant tumors (


Pathology_Robbins

Pathology_Robbins. Table 6.3 ). Tumors arising in the context of chronic inflammation are mostly carcinomas, but also include mesothelioma and several kinds of lymphoma. By contrast, immunodeficiency states mainly predispose to virus-induced cancers, including specific types of lymphoma and carcinoma and some sarcoma-like proliferations. Precursor lesions are localized disturbances of epithelial differentiation that are associated with an elevated risk for developing carcinoma. They may arise secondary to chronic inflammation or hormonal disturbances (in endocrine-sensitive tissues), or may occur spontaneously. Molecular analyses have shown that precursor lesions often possess some of the genetic lesions found in their associated cancers (discussed later). However, progression to cancer is not inevitable, and it is important to recognize precursor lesions because their removal or reversal lowers cancer risk.


Pathology_Robbins

Pathology_Robbins. Many different precursor lesions have been described; among the most common are the following: Table 6.3 Chronic Inflammatory States and Cancer PancreatitisPancreaticcarcinomaAlcoholism,germlinemutations(e.g.,inthetrypsinogengene) ChroniccholecystitisGallbladdercancerBileacids,bacteria,gallbladderstones Refluxesophagitis,EsophagealGastricacidBarrettesophaguscarcinoma Sjögrensyndrome,MALTlymphomaHashimotothyroiditis Gastritis/ulcersGastricHelicobacter pylori adenocarcinoma,MALTlymphoma AdaptedfromTlstyTD,CoussensLM:Tumorstromaandregulationofcancerdevelopment,Ann Rev Pathol Mech Dis 1:119,2006. Squamous metaplasia and dysplasia of bronchial mucosa, seen in in habitual smokers—a risk factor for lung carcinoma (Chapter 13) Endometrial hyperplasia and dysplasia, seen in women with unopposed estrogenic stimulation—a risk factor for endometrial carcinoma (Chapter 19)


Pathology_Robbins

Pathology_Robbins. Endometrial hyperplasia and dysplasia, seen in women with unopposed estrogenic stimulation—a risk factor for endometrial carcinoma (Chapter 19) Leukoplakia of the oral cavity, vulva, and penis, which may progress to squamous cell carcinoma (Chapters 15, 18, and 19) Villous adenoma of the colon, associated with a high risk for progression to colorectal carcinoma (Chapter 15) In this context it also may be asked, “What is the risk for malignant change in a benign neoplasm?”—or, stated differently, “Are benign tumors precancers?” In general the answer is no, but inevitably there are exceptions, and perhaps it is better to say that each type of benign tumor is associated with a particular level of risk, ranging from high to virtually nonexistent. As cited earlier, adenomas of the colon as they enlarge can undergo malignant transformation in up to 50% of cases; by contrast, malignant change is extremely rare in leiomyomas of the uterus. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Cancer behaves like an inherited trait in some families, usually due to germ line mutations that affect the function of a gene that suppresses cancer (a so-called “tumor suppressor gene,” discussed later). What then can be said about the influence of heredity on sporadic malignant neoplasms, which constitute roughly 95% of the cancers in the United States?


Pathology_Robbins

Pathology_Robbins. While the evidence suggests that sporadic cancers can largely be attributed to environmental factors or acquired predisposing conditions, lack of family history does not preclude an inherited component. It may in fact be difficult to tease out hereditary and genetic contributions because these factors often interact. Such interactions may be particularly complex when tumor development is affected by small contributions from multiple genes. Furthermore, genetic factors may alter the risk for developing environmentally induced cancers. Instances where this holds true often involve inherited variation in enzymes such as components of the cytochrome P-450 system that metabolize procarcinogens to active carcinogens. Conversely, environmental factors can influence the risk for developing cancer, even in individuals who inherit well-defined “cancer genes.” For instance, breast cancer risk in females who inherit mutated copies of the BRCA1 or BRCA2 tumor suppressor genes (discussed later) is


Pathology_Robbins

Pathology_Robbins. even in individuals who inherit well-defined “cancer genes.” For instance, breast cancer risk in females who inherit mutated copies of the BRCA1 or BRCA2 tumor suppressor genes (discussed later) is almost three-fold higher for women born after 1940 than for women born before that year, perhaps because of changes in reproductive behavior or increases in obesity in more recent times.


Pathology_Robbins