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Surgery_Schwartz. mutations are also increased in several rare inher-ited diseases, such as Fanconi anemia, ataxia telangiectasia, and xeroderma pigmentosum, which are associated with increased risks of cancer.40,41 The rest of the somatic mutations in a can-cer cell have been acquired after the cancer cell already shows phenotypic evidence of neoplastic change. Whether the somatic AdulthoodEarly clonalexpansionBenigntumorEarly invasivecancerLate invasivecancerChemotherapy-resistantrecurrenceFertilized eggIntrinsicmutation processesPassenger mutationDriver mutationChemotherapyresistance mutationEnvironmentaland lifestyle exposures10s–1,000s of mitosesdepending on the organ10s–100s of mitosesdepending on the cancer10s–100,000 of morepassenger mutationsMutatorphenotypeChemotherapy1–10 or moredriver mutationsGestationInfancyChildhoodFigure 10-9. Accumulation of somatic mutations acquired by the cancer cell. Mutations may be acquired while the cell lineage is phenotypi-cally normal, reflecting intrinsic


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Surgery_Schwartz. 10-9. Accumulation of somatic mutations acquired by the cancer cell. Mutations may be acquired while the cell lineage is phenotypi-cally normal, reflecting intrinsic mutations acquired during normal cell division as well as the effects of exogenous mutagens. Other processes such as example DNA repair defects may contribute to the mutational burden. Passenger mutations do not have any effect on the cancer cell, but driver mutations cause clonal expansion. Relapse after chemotherapy can be associated with resistance mutations that may predate the initiation of treatment. (Reproduced with permission from Stratton MR, Campbell PJ, Futreal PA. The cancer genome, Nature. 2009 Apr 9;458(7239):719-724.)Brunicardi_Ch10_p0305-p0354.indd 31822/02/19 2:14 PM 319ONCOLOGYCHAPTER 10mutation rate is always higher during this part of the lineage is controversial. This is clearly the case for some cancers. For instance, colorectal and endometrial cancers with defective DNA mismatch repair due to


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Surgery_Schwartz. always higher during this part of the lineage is controversial. This is clearly the case for some cancers. For instance, colorectal and endometrial cancers with defective DNA mismatch repair due to abnormalities in genes such as MLH1 and MSH2, exhibit increased rates of single nucleotide changes and small insertions/deletions at repetitive noncoding polynucleotide tracts known as microsatellites.42 It has been proposed that one early step in tumor progression is the development of a “mutator phenotype” that is the result of mutations in genes that normally function in the maintenance of genetic stability. This hypothesis was formulated in order to account for the disparity between the low frequency of spontaneous mutations in normal cells as com-pared to the large number of mutations seen in human tumors.To date about 300 genes that have been reported to be mutated and causally implicated in cancer development.43 Ninety percent of cancer genes are mutated at the somatic or tumor


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Surgery_Schwartz. seen in human tumors.To date about 300 genes that have been reported to be mutated and causally implicated in cancer development.43 Ninety percent of cancer genes are mutated at the somatic or tumor level, 20% show germline mutations, and 10% show both. The most common class of genomic alterations among the known cancer genes is a chromosomal translocation that creates a chi-meric gene. Many more cancer genes have been found in leuke-mias, lymphomas, and sarcomas than in other types of cancer; and these genes are usually altered by chromosomal transloca-tion. The most common cancer genes are protein kinases. Several domains that are involved in DNA binding and transcriptional regulation are also common in proteins encoded by cancer genes. Somatic mutations in a cancer genome may be classified according to its consequences for cancer development. “Driver” mutations confer a growth advantage to the cells carrying them and have been positively selected during the evolution of the cancer.


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Surgery_Schwartz. according to its consequences for cancer development. “Driver” mutations confer a growth advantage to the cells carrying them and have been positively selected during the evolution of the cancer. The remainder of mutations are “bystanders” or “pas-sengers” that do not confer growth advantage. It is likely that most somatic mutations are passenger mutations. Each tumor may have dozens to hundreds of genomic alterations, making it critical to determine which alterations are indeed drivers, and potentially better therapeutic targets.There have been many recent advancements in large-scale databases and tools to catalogue and interpret genomic vari-ants in cancer patient populations. Currently, the NCI Genomic Data Commons provides a unified data repository, The Cancer Genome Atlas (TCGA), the NCI Center for Cancer Genomics (CCG), and the childhood cancer initiative entitled Therapeu-tically Applicable Research to Generate Effective Treatments (TARGET), as well as a suite of tools for


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Surgery_Schwartz. the NCI Center for Cancer Genomics (CCG), and the childhood cancer initiative entitled Therapeu-tically Applicable Research to Generate Effective Treatments (TARGET), as well as a suite of tools for users to interact with the GDC data and provide their own data. Other cancer genome repositories include the Catalogue of Somatic Mutations in Can-cer (COSMIC) and the International Cancer Genome Consor-tium (ICGC).44 The Precision Medicine Initiative launched in 2016 that includes the All of Us Research Program, which will collect genetic data, biologic samples, and other clinical informa-tion from at least 1 million volunteer participants. To facilitate the clinical and biologic interpretation of genomic variants in cancer genomes, several open-access tools have been developed and expanded, including MuSiC, MutSigCV, and OncodriveFM. Other curated database resources used to annotate clinical pheno-types to variants observed in cancer genomes include ClinVAR, Clinical Interpretation of


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Surgery_Schwartz. including MuSiC, MutSigCV, and OncodriveFM. Other curated database resources used to annotate clinical pheno-types to variants observed in cancer genomes include ClinVAR, Clinical Interpretation of Variants in Cancer (CiVic), and the Precision Medicine Knowledgebase (PMKB). These resources and tools are being utilized to conduct pan-cancer analyses to characterize genomic variation and other molecular aberra-tions observed across tumors to define cancer drivers, clinically actionable targets, and prognostic and predictive signatures. This information is being integrated into clinical practice in many UnknownKIF5B-RETROS1 fusionsNRASMAP2K1AKT1PIK3CABRAFHER2ALKfusionsKRASEGFRFigure 10-10. Molecular subsets of lung adenocarcinoma. Pie chart shows the percentage of tumors with each potentially action-able alteration. (Reproduced with permission from Pao W, Hutchinson KE. Chipping away at the lung cancer genome, Nat Med. 2012 Mar 6;18(3):349-351.)Hereditary:Nonhereditary:TumorTumorFigure


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Surgery_Schwartz. action-able alteration. (Reproduced with permission from Pao W, Hutchinson KE. Chipping away at the lung cancer genome, Nat Med. 2012 Mar 6;18(3):349-351.)Hereditary:Nonhereditary:TumorTumorFigure 10-11. Tumor heterogeneity. A. Patients with tumors with similar histologies may differ in genetic mutation status and other molecular features B. Cells within the primary tumor can acquire or lose genomic alterations in different metastatic sites. C. Intra-tumoral spatial heterogeneity: common initiating genomic events usually exist in all tumor cells but additional spatially separated heterogeneous somatic mutations or copy number changes may accumulate within an individual tumor. (Reproduced with permis-sion from Knudson AG: Two genetic hits (more or less) to cancer, Nat Rev Cancer. 2001 Nov;1(2):157-162.)tumor types, such as lung cancer, where molecular drivers are being taken into consideration when selecting systemic therapies (Fig. 10-10). TCGA data was recently leveraged in a study


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Surgery_Schwartz. types, such as lung cancer, where molecular drivers are being taken into consideration when selecting systemic therapies (Fig. 10-10). TCGA data was recently leveraged in a study to identify TRK fusions in tumors from six different cancer types, which led to the development of novel TRK inhibitor therapies.Tumor Heterogeneity and Molecular EvolutionThere is increasing recognition that tumors are heterogeneous; this represents an important challenge to utilizing genomic alterations to personalize cancer therapy (Fig. 10-11).45 First, Brunicardi_Ch10_p0305-p0354.indd 31922/02/19 2:14 PM 320BASIC CONSIDERATIONSPART Ithere may be significant heterogeneity between cancer patients, such that patients with tumors that seem similar histologically, may differ in genomic alterations and in malignant potential.46-48 Second, during cancer progression, subclones frequently arise, resulting in differences in the proportion and pattern of genomic alterations between the primary tumor and the


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Surgery_Schwartz. potential.46-48 Second, during cancer progression, subclones frequently arise, resulting in differences in the proportion and pattern of genomic alterations between the primary tumor and the metastases or local-regional recurrences.45 Third, there may also be signifi-cant heterogeneity within any one tumor deposit, with spatially separated heterogeneous somatic mutations and chromosomal imbalances.49 Such spatial heterogeneity of subclones within the primary tumor or metastases provides an additional challenge, as it has been proposed that sequencing of a biopsy specimen or only a portion of the tumor could miss therapeutically rel-evant genomic alterations. The genomic alterations found in a tumor can also change under the selective pressure of a targeted therapy, adding to the challenge of implementing genomically informed personalized therapy.Genes Associated With Hereditary Cancer RiskMost of our information on human cancer genes has been gained from hereditary cancers. In the


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Surgery_Schwartz. of implementing genomically informed personalized therapy.Genes Associated With Hereditary Cancer RiskMost of our information on human cancer genes has been gained from hereditary cancers. In the case of hereditary cancers, the individual carries a particular germline mutation in every cell. To date, over 70 genes have been associated with hereditary cancers (Table 10-3).43 A few of these hereditary cancer genes are oncogenes, but most are tumor-suppressor genes. Although hereditary cancer syndromes are rare, somatic mutations that occur in sporadic cancer have been found to disrupt the cellular pathways altered in hereditary cancer syndromes, which sug-gests that these pathways are critical to normal cell growth, cell cycle, and proliferation. Recently, the results of a genome-wide association study of breast cancer in over 120,000 cases and 100,000 controls identified 65 new loci that are associated with overall breast cancer risk.50The following factors may suggest the presence of


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Surgery_Schwartz. study of breast cancer in over 120,000 cases and 100,000 controls identified 65 new loci that are associated with overall breast cancer risk.50The following factors may suggest the presence of a hereditary cancer51:1. Tumor development at a much younger age than usual2. Presence of bilateral disease3. Presence of multiple primary malignancies4. Presentation of a cancer in the less affected sex (e.g., male breast cancer)5. Clustering of the same cancer type in relatives6. Occurrence of cancer in association with other conditions such as mental retardation or pathognomonic skin lesionsIt is crucial that all surgeons caring for cancer patients be aware of hereditary cancer syndromes, because a patient’s genetic background has significant implications for patient and family counseling, planning of surgical therapy, and cancer screening and prevention. Some of the more commonly encoun-tered hereditary cancer syndromes are discussed here.rb1Gene. The retinoblastoma gene rb1 was the first


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Surgery_Schwartz. of surgical therapy, and cancer screening and prevention. Some of the more commonly encoun-tered hereditary cancer syndromes are discussed here.rb1Gene. The retinoblastoma gene rb1 was the first tumor sup-pressor to be cloned. The rb1 gene product, the Rb protein, is a regulator of transcription that controls the cell cycle, differen-tiation, and apoptosis in normal development.52 Retinoblastoma has long been known to occur in hereditary and nonhereditary forms. Interestingly, although most children with an affected parent develop bilateral retinoblastoma, some develop unilateral retinoblastoma. Furthermore, some children with an affected parent are not affected themselves but then have an affected child, which indicates that they are rb1 mutation carriers. These findings led to the theory that a single mutation is not sufficient for tumorigenesis. Alfred Knudson hypothesized that hereditary retinoblastoma involves two mutations, of which one is germ-line and one somatic, whereas


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Surgery_Schwartz. that a single mutation is not sufficient for tumorigenesis. Alfred Knudson hypothesized that hereditary retinoblastoma involves two mutations, of which one is germ-line and one somatic, whereas nonhereditary retinoblastoma is due to two somatic mutations (Fig. 10-12).53 Thus, both heredi-tary and nonhereditary forms of retinoblastoma involve the same number of mutations, a hypothesis known as Knudson’s “two-hit” hypothesis. A “hit” may be a point mutation, a chro-mosomal deletion referred to as allelic loss, or a loss of hetero-zygosity, or silencing of an existing gene. Approximately 40% of retinoblastomas are hereditary and due to germline mutations in the RB1 gene. Children with hereditary RB are also at risk for developing a midline intracranial tumor, most commonly pineoblastoma.p53 and Li-Fraumeni Syndrome. Li-Fraumeni syndrome (LFS) was first defined on the basis of observed clustering of malignancies, including early-onset breast cancer, soft tissue sarcomas, brain tumors,


Surgery_Schwartz

Surgery_Schwartz. and Li-Fraumeni Syndrome. Li-Fraumeni syndrome (LFS) was first defined on the basis of observed clustering of malignancies, including early-onset breast cancer, soft tissue sarcomas, brain tumors, adrenocortical tumors, and leukemia.54 Criteria for classic LFS in an individual (the proband) include: (a) a bone or soft tissue sarcoma when younger than 45 years, (b) a first-degree relative with cancer before age 45 years, and (c) another firstor second-degree relative with either a sar-coma diagnosed at any age or any cancer diagnosed before age 45 years.55 Approximately 70% of LFS families have been shown to have germline mutations in the tumor-suppressor gene p53.56 Breast carcinoma, soft tissue sarcoma, osteosarcoma, brain tumors, adrenocortical carcinoma, Wilms’ tumor, and phyllodes tumor of the breast are strongly associated; pancre-atic cancer is moderately associated; and leukemia and neuro-blastoma are weakly associated with germline p53 mutations.57 Mutations of p53 have not


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Surgery_Schwartz. of the breast are strongly associated; pancre-atic cancer is moderately associated; and leukemia and neuro-blastoma are weakly associated with germline p53 mutations.57 Mutations of p53 have not been detected in approximately 30% of LFS families, and it is hypothesized that genetic alterations in other proteins interacting with p53 function may play a role in these families.Of the known genes in human cancer, p53 is the most commonly mutated within cancer cells. The p53 protein regu-lates cell-cycle progression as well as apoptotic cell death as part of stress response pathways after exposure to ionizing or ultraviolet (UV) irradiation, chemotherapy, acidosis, growth factor deprivation, or hypoxia. When cells are exposed to stress-ors, p53 acts as a transcription factor for genes that induce cell-cycle arrest or apoptosis. A majority of p53 mutations are found within a central DNA recognition motif and disrupt DNA bind-ing by p53. Families with germline missense mutations in the


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Surgery_Schwartz. induce cell-cycle arrest or apoptosis. A majority of p53 mutations are found within a central DNA recognition motif and disrupt DNA bind-ing by p53. Families with germline missense mutations in the DNA-binding domain show a more highly penetrant phenotype than families with other p53 mutations.58 Furthermore, proband cancers are linked with significantly younger age at diagnosis in patients with missense mutations in the DNA-binding domain.58 It has become apparent that children and adults with LFS will benefit from intensive surveillance aimed at early detection of cancers and a modified version of the “Toronto protocol” that includes a combination of physical exams, blood tests, and imaging is recommended.BRCA1, BRCA2, and Hereditary Breast-Ovarian Cancer Syndrome. It is estimated that 5% to 10% of breast cancers are hereditary. Of women with early-onset breast cancer (age 40 years or younger), nearly 10% have a germline mutation in one of the breast cancer genes BRCA1 or BRCA2.59


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Surgery_Schwartz. 5% to 10% of breast cancers are hereditary. Of women with early-onset breast cancer (age 40 years or younger), nearly 10% have a germline mutation in one of the breast cancer genes BRCA1 or BRCA2.59 Mutation carriers are more prevalent among women who have a firstor second-degree relative with premenopausal breast cancer or ovarian cancer at any age. The likelihood of a BRCA mutation is higher in patients who belong to a population in which founder Brunicardi_Ch10_p0305-p0354.indd 32022/02/19 2:14 PM 321ONCOLOGYCHAPTER 10Table 10-3Selected genes associated with hereditary cancerSYMBOLNAMETUMOR TYPES (GERMLINE MUTATIONS)CANCER SYNDROMEALKanaplastic lymphoma kinase (Ki-1)NeuroblastomaFamilial neuroblastomaAPCadenomatous polyposis of the colon geneColorectal, pancreatic, desmoid, hepatoblastoma, glioma, other CNSAdenomatous polyposis coli; Turcot syndromeATMataxia telangiectasia mutatedLeukemia, lymphoma, medulloblastoma, gliomaAtaxia-telangiectasiaBLMBloom syndromeLeukemia,


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Surgery_Schwartz. hepatoblastoma, glioma, other CNSAdenomatous polyposis coli; Turcot syndromeATMataxia telangiectasia mutatedLeukemia, lymphoma, medulloblastoma, gliomaAtaxia-telangiectasiaBLMBloom syndromeLeukemia, lymphoma, skin squamous cell, other cancersBloom syndromeBMPR1Abone morphogenetic protein receptor, type IAGastrointestinal polypsJuvenile polyposisBRCA1familial breast/ovarian cancer gene 1Breast, ovarianHereditary breast/ovarian cancerBRCA2familial breast/ovarian cancer gene 2Breast, ovarian, pancreaticHereditary breast/ovarian cancerBRIP1BRCA1 interacting protein C-terminal helicase 1AML, leukemia, breastFanconi anemia J, breast cancer susceptibilityBUB1BBUB1 budding uninhibited by benzimidazoles 1 homolog beta (yeast)RhabdomyosarcomaMosaic variegated aneuploidyCDH1cadherin 1, type 1, E-cadherin (epithelial) (ECAD)Gastric, lobular cancerFamilial gastric carcinomaCDK4cyclin-dependent kinase 4MelanomaFamilial malignant melanomaCDKN2Acyclin-dependent kinase inhibitor 2A (p16[INK4a])


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Surgery_Schwartz. E-cadherin (epithelial) (ECAD)Gastric, lobular cancerFamilial gastric carcinomaCDK4cyclin-dependent kinase 4MelanomaFamilial malignant melanomaCDKN2Acyclin-dependent kinase inhibitor 2A (p16[INK4a]) geneMelanoma, pancreaticFamilial malignant melanomaCDKN2a(p14)cyclin-dependent kinase inhibitor 2A– p14ARF proteinMelanoma, pancreaticFamilial malignant melanomaCHEK2CHK2 checkpoint homolog (S pombe)BreastFamilial breast cancerCYLDfamilial cylindromatosis geneCylindromaFamilial cylindromatosisDDB2damage-specific DNA binding protein 2Skin basal cell, skin squamous cell, melanomaXeroderma pigmentosum (E)DICER1dicer 1, ribonuclease type IIIPleuropulmonary blastomaFamilial pleuropulmonary blastomaEGFRepidermal growth factor receptor (erythroblastic leukemia viral [v-erb-b] oncogene homolog, avian)NSCLCFamilial lung cancerERCC2, 3, 4, 5excision repair cross-complementing rodent repair deficiency, complementation groupSkin basal cell, skin squamous cell, melanomaXeroderma pigmentosum (D, B, F,


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Surgery_Schwartz. lung cancerERCC2, 3, 4, 5excision repair cross-complementing rodent repair deficiency, complementation groupSkin basal cell, skin squamous cell, melanomaXeroderma pigmentosum (D, B, F, G)EXT1multiple exostoses type 1 geneexostoses, osteosarcomaexostoses, osteosarcomaFANCA, C, D2, E, F, GFanconi anemia, complementation groupAML, leukemiaFanconi anemia A, C, D2, E, F, GFHfumarate hydrataseleiomyomatas, renalHereditary leiomyomatosis and renal cell cancerGPC3glypican 3Wilms’ tumorSimpson-Golabi-Behmel syndromeHRASv-Ha-ras Harvey rat sarcoma viral oncogene homologv-Ha-ras Harvey rat sarcoma viral oncogene homologCostello syndromeHRPT2Hyperparathyroidism 2 (parafibromin)parathyroid adenoma, multiple ossifying jaw fibromaHyperparathyroidism-jaw tumor syndrome(Continued)Brunicardi_Ch10_p0305-p0354.indd 32122/02/19 2:14 PM 322BASIC CONSIDERATIONSPART ITable 10-3Selected genes associated with hereditary cancerSYMBOLNAMETUMOR TYPES (GERMLINE MUTATIONS)CANCER SYNDROMEKITv-kit


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Surgery_Schwartz. 32122/02/19 2:14 PM 322BASIC CONSIDERATIONSPART ITable 10-3Selected genes associated with hereditary cancerSYMBOLNAMETUMOR TYPES (GERMLINE MUTATIONS)CANCER SYNDROMEKITv-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homologGIST, epitheliomaFamilial gastrointestinal stromal tumorMADH4Homolog of Drosophila Mothers Against Decapentaplegic 4 geneGastrointestinal polypsJuvenile polyposisMEN1multiple endocrine neoplasia type 1 geneParathyroid adenoma, pituitary adenoma, pancreatic islet cell, carcinoidParathyroid adenoma, pituitary adenoma, pancreatic islet cell, carcinoidMLH1E coli MutL homolog geneColorectal, endometrial, ovarian, CNSHereditary nonpolyposis colorectal cancer, Turcot syndromeMPLmyeloproliferative leukemia virus oncogene, thrombopoietin receptorMPDFamilial essential thrombocythemiaMSH2mutS homolog 2 (E coli)colorectal, endometrial, ovarianHereditary non-polyposis colorectal cancerMSH6mutS homolog 6 (E coli)colorectal, endometrial, ovarianHereditary non-polyposis


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Surgery_Schwartz. thrombocythemiaMSH2mutS homolog 2 (E coli)colorectal, endometrial, ovarianHereditary non-polyposis colorectal cancerMSH6mutS homolog 6 (E coli)colorectal, endometrial, ovarianHereditary non-polyposis colorectal cancerMUTYHmutY homolog (E coli)ColorectalAdenomatous polyposis coliNBS1Nijmegen breakage syndrome 1 (nibrin)NHL, glioma, medulloblastoma, rhabdomyosarcomaNijmegen breakage syndromeNF1neurofibromatosis type 1 geneNeurofibroma, gliomaNeurofibromatosis type 1NF2neurofibromatosis type 2 geneMeningioma, acoustic neuromaNeurofibromatosis type 2PALB2partner and localizer of BRCA2Wilms tumor, medulloblastoma, AML, breastFanconi anemia N, breast cancer susceptibilityPHOX2Bpaired-like homeobox 2bNeuroblastomaFamilial neuroblastomaPMS1PMS1 postmeiotic segregation increased 1 (S cerevisiae)Colorectal, endometrial, ovarianHereditary non-polyposis colorectal cancerPMS2PMS2 postmeiotic segregation increased 2 (S cerevisiae)Colorectal, endometrial, ovarian, medulloblastoma, gliomaHereditary


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Surgery_Schwartz. endometrial, ovarianHereditary non-polyposis colorectal cancerPMS2PMS2 postmeiotic segregation increased 2 (S cerevisiae)Colorectal, endometrial, ovarian, medulloblastoma, gliomaHereditary nonpolyposis colorectal cancer, Turcot syndromePRKAR1Aprotein kinase, cAMP-dependent, regulatory, type I, alpha (tissue specific extinguisher 1)Myxoma, endocrine, papillary thyroidCarney complexPTCHHomolog of Drosophila Patched geneSkin basal cell, medulloblastomaNevoid basal cell carcinoma syndromePTENphosphatase and tensin homolog geneHamartoma, glioma, prostate, endometrialCowden syndrome, Bannayan-Riley-Ruvalcaba syndromeRB1retinoblastoma geneRetinoblastoma, sarcoma, breast, small cell lungFamilial retinoblastomaRECQL4RecQ protein-like 4Osteosarcoma, skin basal and squamous cellRothmund-Thompson syndromeRETret proto-oncogeneMedullary thyroid, papillary thyroid, pheochromocytomaMultiple endocrine neoplasia 2A/2BSBDSShwachman-Bodian-Diamond syndrome proteinAML, MDSSchwachman-Diamond


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Surgery_Schwartz. syndromeRETret proto-oncogeneMedullary thyroid, papillary thyroid, pheochromocytomaMultiple endocrine neoplasia 2A/2BSBDSShwachman-Bodian-Diamond syndrome proteinAML, MDSSchwachman-Diamond syndrome(Continued)(Continued)Brunicardi_Ch10_p0305-p0354.indd 32222/02/19 2:14 PM 323ONCOLOGYCHAPTER 10Table 10-3Selected genes associated with hereditary cancerSYMBOLNAMETUMOR TYPES (GERMLINE MUTATIONS)CANCER SYNDROMESDH5chromosome 11 open reading frame 79ParagangliomaFamilial paragangliomaSHD, B, Dsuccinate dehydrogenase complexParaganglioma, pheochromocytomaFamilial paragangliomaSMARCB1SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1Malignant rhabdoidRhabdoid predisposition syndromeSTK11serine/threonine kinase 11 gene (LKB1)Jejunal hamartoma, ovarian, testicular, pancreaticPeutz-Jeghers syndromeSUFUsuppressor of fused homolog (Drosophila)MedulloblastomaMedulloblastoma predispositionTCF1transcription factor 1, hepatic (HNF1)Hepatic adenoma,


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Surgery_Schwartz. testicular, pancreaticPeutz-Jeghers syndromeSUFUsuppressor of fused homolog (Drosophila)MedulloblastomaMedulloblastoma predispositionTCF1transcription factor 1, hepatic (HNF1)Hepatic adenoma, hepatocellular carcinomaFamilial Hepatic AdenomaTP53tumor protein p53Breast, sarcoma, adrenocortical carcinoma, glioma, multiple other tumor typesLi-Fraumeni syndromeTSC1tuberous sclerosis 1 geneHamartoma, renal cellTuberous sclerosis 1TSC2tuberous sclerosis 2 geneHamartoma, renal cellTuberous sclerosis 2TSHRthyroid stimulating hormone receptorThyroid adenoma VHLvon Hippel-Lindau syndrome geneRenal, hemangioma, pheochromocytomavon Hippel-Lindau syndromeWRNWerner syndrome (RECQL2)Osteosarcoma, meningioma, othersWerner syndromeWT1Wilms’ tumor 1 geneWilms’Denys-Drash syndrome, Frasier syndrome, Familial Wilms tumorXPA, Cxeroderma pigmentosum, complementation groupSkin basal cell, skin squamous cell, melanomaXeroderma pigmentosum (A C)A = amplification; AEL = acute eosinophilic leukemia; AL = acute


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Surgery_Schwartz. Wilms tumorXPA, Cxeroderma pigmentosum, complementation groupSkin basal cell, skin squamous cell, melanomaXeroderma pigmentosum (A C)A = amplification; AEL = acute eosinophilic leukemia; AL = acute leukemia; ALCL = anaplastic large-cell lymphoma; ALL = acute lymphocytic leukemia; AML = acute myelogenous leukemia; AML = acute myelogenous leukemia (primarily treatment associated); APL = acute promyelocytic leukemia; B-ALL = B-cell acute lymphocytic leukemia; B-CLL = B-cell lymphocytic leukemia; B-NHL = B-cell non-Hodgkin’s lymphoma; CLL = chronic lymphatic leukemia; CML = chronic myeloid leukemia; CMML = chronic myelomonocytic leukemia; CNS = central nervous system; D = large deletion; DFSP = dermatofibrosarcoma protuberans; DLBL = diffuse large B-cell lymphoma; DLCL = diffuse large-cell lymphoma; Dom = dominant; E = epithelial; F = frameshift; GIST = gastrointestinal stromal tumor; JMML = juvenile myelomonocytic leukemia; L = leukemia/lymphoma; M = mesenchymal; MALT =


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Surgery_Schwartz. large-cell lymphoma; Dom = dominant; E = epithelial; F = frameshift; GIST = gastrointestinal stromal tumor; JMML = juvenile myelomonocytic leukemia; L = leukemia/lymphoma; M = mesenchymal; MALT = mucosa-associated lymphoid tissue lymphoma; MDS = myelodysplastic syndrome; Mis = Missense; MLCLS = mediastinal large cell lymphoma with sclerosis; MM = multiple myeloma; MPD = myeloproliferative disorder; N = nonsense; NHL = non-Hodgkin’s lymphoma; NK/T = natural killer T cell; NSCLC = non-small cell lung cancer; O = other; PMBL = primary mediastinal B-cell lymphoma; pre-B All = pre-B-cell acute lymphoblastic leukemia; Rec = recessive; S = splice site; T = translocation; T-ALL = T-cell acute lymphoblastic leukemia; T-CLL = T-cell chronic lymphocytic leukemia; TGCT = testicular germ cell tumor; T-PLL = T-cell prolymphocytic leukemia.Adapted with permission from Futreal PA, Coin L, Marshall M, et al. A census of human cancer genes. Nat Rev Cancer. 2004 Mar;4(3):177-183.(Continued)mutations


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Surgery_Schwartz. T-PLL = T-cell prolymphocytic leukemia.Adapted with permission from Futreal PA, Coin L, Marshall M, et al. A census of human cancer genes. Nat Rev Cancer. 2004 Mar;4(3):177-183.(Continued)mutations may be prevalent, such as in the Ashkenazi Jewish population. For a female BRCA1 mutation carrier, the cumula-tive risks of developing breast cancer and ovarian cancer by age 70 have been estimated to be 87% and 44%, respectively.60 The cumulative risks of breast cancer and ovarian cancer by age 70 in families with BRCA2 mutation have been estimated to be 84% and 27%, respectively.61 Although male breast cancer can occur with either BRCA1 or BRCA2 mutation, the majority of families (76%) with both male and female breast cancer have mutations in BRCA2.61 Besides breast and ovar-ian cancer, BRCA1 and BRCA2 mutations may be associated with increased risks for several other cancers. BRCA1 mutations confer a fourfold increased risk for colon cancer and threefold increased risk for prostate


Surgery_Schwartz

Surgery_Schwartz. BRCA1 and BRCA2 mutations may be associated with increased risks for several other cancers. BRCA1 mutations confer a fourfold increased risk for colon cancer and threefold increased risk for prostate cancer.60 BRCA2 mutations confer a fivefold increased risk for prostate cancer, sevenfold in men younger than 65 years.62 Furthermore, BRCA2 mutations confer Brunicardi_Ch10_p0305-p0354.indd 32322/02/19 2:14 PM 324BASIC CONSIDERATIONSPART Ia fivefold increased risk for gallbladder and bile duct cancers, fourfold increased risk for pancreatic cancer, and threefold increased risk for gastric cancer and malignant melanoma.62BRCA1 was the first breast cancer susceptibility gene identi-fied and has been mapped to 17q21. BRCA2, mapped to 13q12.3, was reported shortly afterward. BRCA1 and BRCA2 encode large nuclear proteins, 208 kDa and 384 kDa, respectively, that have been implicated in processes fundamental to all cells, including DNA repair and recombination, checkpoint control of the


Surgery_Schwartz

Surgery_Schwartz. encode large nuclear proteins, 208 kDa and 384 kDa, respectively, that have been implicated in processes fundamental to all cells, including DNA repair and recombination, checkpoint control of the cell cycle, and transcription.63 Although early studies suggested that the two proteins function together as a complex, subsequent data demonstrated that they have distinct functions.64,65 In fact, breast cancers arising from BRCA1 or BRCA2 mutations are different at the molecular level and have been found to have distinct gene expression profiles.66 BRCA1-associated tumors are more likely to be estrogen receptor negative, whereas BRCA2-associated tumors are more likely to be estrogen receptor positive. Cur-rently, studies are ongoing to determine whether BRCA1 and BRCA2 status can be used to guide systemic therapy choices for breast cancer. Some targeted therapies are showing activity in BRCA mutation carriers with breast cancer such as PARP poly(ADP-ribose) polymerase-inhibitors.APC Gene


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Surgery_Schwartz. systemic therapy choices for breast cancer. Some targeted therapies are showing activity in BRCA mutation carriers with breast cancer such as PARP poly(ADP-ribose) polymerase-inhibitors.APC Gene and Familial Adenomatous PolyposisPatients affected with familial adenomatous polyposis (FAP) characteristically develop hundreds to thousands of polyps in the colon and rectum. The polyps usually appear in adolescence and, if left untreated, progress to colorectal cancer. FAP is asso-ciated with benign extracolonic manifestations that may be use-ful in identifying new cases, including congenital hypertrophy of the retinal pigment epithelium, epidermoid cysts, and osteo-mas. In addition to colorectal cancer, patients with FAP are at risk for upper intestinal neoplasms (gastric and duodenal pol-yps, duodenal and periampullary cancer), hepatobiliary tumors (hepatoblastoma, pancreatic cancer, and cholangiocarcinoma), thyroid carcinomas, desmoid tumors, and medulloblastomas.The product of the


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Surgery_Schwartz. duodenal and periampullary cancer), hepatobiliary tumors (hepatoblastoma, pancreatic cancer, and cholangiocarcinoma), thyroid carcinomas, desmoid tumors, and medulloblastomas.The product of the adenomatous polyposis coli tumor-sup-pressor gene (APC) plays an important role in cell-cell interac-tions, cell adhesion, regulation of β-catenin, and maintenance of cytoskeletal microtubules. Alterations in APC lead to dys-regulation of several physiologic processes that govern colonic epithelial cell homeostasis, including cell-cycle progression, migration, differentiation, and apoptosis. Mutations in the APC have been identified in FAP and in 80% of sporadic colorectal cancers.67 Furthermore, APC mutations are the earliest known genetic alterations in colorectal cancer progression, which emphasizes its importance in cancer initiation. The germline mutations in APC may arise from point mutations, insertions, or deletions that lead to a premature stop codon and a truncated, functionally


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Surgery_Schwartz. its importance in cancer initiation. The germline mutations in APC may arise from point mutations, insertions, or deletions that lead to a premature stop codon and a truncated, functionally inactive protein. The risk of developing specific manifestations of FAP is correlated with the position of the FAP mutations, a phenomenon referred to as genotype-phenotype correlation. For example, desmoids usually are associated with mutations between codons 1403 and 1578.68,69 Mutations in the extreme 5′ or 3′ ends of APC, or in the alternatively spliced region of exon 9, are associated with an attenuated version of FAP. Better understanding of the genotype-phenotype correla-tions may assist in patient counseling and therapeutic planning.Mismatch Repair Genes and Hereditary Nonpolyposis Colorectal Cancer. Hereditary nonpolyposis colorectal cancer (HNPCC), also referred to as Lynch syndrome, is an autoso-mal dominant hereditary cancer syndrome that predisposes to a wide spectrum of cancers,


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Surgery_Schwartz. Cancer. Hereditary nonpolyposis colorectal cancer (HNPCC), also referred to as Lynch syndrome, is an autoso-mal dominant hereditary cancer syndrome that predisposes to a wide spectrum of cancers, including colorectal cancer without polyposis. Some have proposed that HNPCC consists of at least two syndromes: Lynch syndrome 1, which entails hereditary predisposition for colorectal cancer with early age of onset (approximately age 44 years) and an excess of synchronous and metachronous colonic cancers; and Lynch syndrome 2, featur-ing a similar colonic phenotype accompanied by a high risk for carcinoma of the endometrium, transitional cell carcinoma of the ureter and renal pelvis, and carcinomas of the stomach, small bowel, ovary, and pancreas.70 The diagnostic criteria for HNPCC are referred to as the Amsterdam criteria, or the 3-2-1-0 rule. The classic Amsterdam criteria were revised to include other HNPCC-related cancers (Table 10-4).71 These criteria are met when three or more family


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Surgery_Schwartz. to as the Amsterdam criteria, or the 3-2-1-0 rule. The classic Amsterdam criteria were revised to include other HNPCC-related cancers (Table 10-4).71 These criteria are met when three or more family members have histologically ver-ified, HNPCC-associated cancers (one of whom is a first-degree relative of the other two), two or more generations are involved, at least one individual was diagnosed before age 50 years, and no individuals have FAP.71During DNA replication, DNA polymerases may intro-duce single nucleotide mismatches or small insertion or deletion loops. These errors are corrected through a process referred to as mismatch repair. When mismatch repair genes are inactivated, DNA mutations in other genes that are critical to cell growth and proliferation accumulate rapidly. In HNPCC, germline mutations have been identified in several genes that play a key role in DNA nucleotide mismatch repair: hMLH1 (human mutL homologue 1), hMSH2 (human mutS homologue 2), hMSH6, A


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Surgery_Schwartz. In HNPCC, germline mutations have been identified in several genes that play a key role in DNA nucleotide mismatch repair: hMLH1 (human mutL homologue 1), hMSH2 (human mutS homologue 2), hMSH6, A Heterogeneity among patientsB Heterogeneity betweenprimary and metastatic sitesC Intratumoral spatialheterogeneityFigure 10-12. “Two-hit” tumor formation in both hereditary and nonhereditary cancers. A “one-hit” clone is a precursor to the tumor in nonhereditary cancer, whereas all cells are one-hit clones in hereditary cancer. (Reproduced with permission from Meric-Bernstam F, Mills GB. Overcoming implementation challenges of personalized cancer therapy, Nat Rev Clin Oncol. 2012 Sep;9(9):542-548.)Brunicardi_Ch10_p0305-p0354.indd 32422/02/19 2:14 PM 325ONCOLOGYCHAPTER 10and hPMS1 and hPMS2 (human postmeiotic segregation 1 and 2), of which hMLH1 and hMSH2 are the most common.72-77 The hallmark of HNPCC is microsatellite instability, which occurs on the basis of unrepaired mismatches and


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Surgery_Schwartz. postmeiotic segregation 1 and 2), of which hMLH1 and hMSH2 are the most common.72-77 The hallmark of HNPCC is microsatellite instability, which occurs on the basis of unrepaired mismatches and small inser-tion or deletion loops. Microsatellite instability can be tested by comparing the DNA of a patient’s tumor with DNA from adja-cent normal epithelium, amplifying the DNA with polymerase chain reaction (PCR) using a standard set of markers, compar-ing the amplified genomic DNA sequences, and classifying the degree of microsatellite instability as high, low, or stable. Such microsatellite instability testing may help select patients who are more likely to have germline mutations. An analysis of patients with early-onset colorectal cancer (age less than 50) showed that 8% had an unsuspected germline mutation in a mismatch repair gene and could be considered as having Lynch syndrome. Thus, genetic counseling and testing with a multigene panel should be considered for such patients.78PTEN


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Surgery_Schwartz. germline mutation in a mismatch repair gene and could be considered as having Lynch syndrome. Thus, genetic counseling and testing with a multigene panel should be considered for such patients.78PTEN and Cowden DiseaseSomatic deletions or mutations in the tumor-suppressor gene PTEN (phosphatase and tensin homologue deleted on chromosome 10) have been observed in a number of glioma breast, prostate, and renal carcinoma cell lines and several primary tumor specimens.79PTEN encodes a 403-amino-acid protein, tyrosine phos-phatase. PTEN negatively controls the PI3K signaling pathway for the regulation of cell growth and survival by dephosphory-lating phosphoinositol 3,4,5-triphosphate; thus, mutation of PTEN leads to constitutive activation of the PI3K/Akt signaling pathway. The “hot spot” for PTEN mutations has been identi-fied in exon 5. Forty-three percent of CD mutations have been identified in this exon, which contains the tyrosine phosphatase core domain. This suggests that the PTEN


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Surgery_Schwartz. PTEN mutations has been identi-fied in exon 5. Forty-three percent of CD mutations have been identified in this exon, which contains the tyrosine phosphatase core domain. This suggests that the PTEN catalytic activity is vital for its biologic function. PTEN was identified as the sus-ceptibility gene for the autosomal dominant syndrome Cowden disease (CD) or multiple hamartoma syndrome.80 Trichilem-momas, benign tumors of the hair follicle infundibulum, and mucocutaneous papillomatosis are pathognomonic of CD. Other common features include thyroid adenomas and multinodular goiters, breast fibroadenomas, and hamartomatous GI polyps. The diagnosis of CD is made when an individual or family has a combination of pathognomonic major and/or minor criteria pro-posed by the International Cowden Consortium.81 CD is associ-ated with an increased risk of breast and thyroid cancers. Breast cancer develops in 25% to 50% of affected women.81p16 and Hereditary Malignant Melanoma. The gene p16, also


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Surgery_Schwartz. CD is associ-ated with an increased risk of breast and thyroid cancers. Breast cancer develops in 25% to 50% of affected women.81p16 and Hereditary Malignant Melanoma. The gene p16, also known as INK4A, CDKN1, CDKN2A, and MTS1, is a tumor suppressor that acts by binding CDK4 and CDK6 and inhibit-ing the catalytic activity of the CDK4-CDK6/cyclin D complex that is required for phosphorylation of Rb and subsequent cell-cycle progression. Studies suggest that germline mutations in p16 can be found in 20% of melanoma-prone families.82 Muta-tions in p16 that alter its ability to inhibit the catalytic activity of the CDK4-CDK6/cyclin D complex not only increase the risk of melanoma by 75-fold but also increase the risk of pancre-atic cancer by 22-fold.83 Interestingly, p16 mutations that do not appear to alter its function increase the risk of melanoma by 38-fold and do not increase the risk of pancreatic cancer.83 Genomic characterization of primary tumors has revealed that p16 is


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Surgery_Schwartz. do not appear to alter its function increase the risk of melanoma by 38-fold and do not increase the risk of pancreatic cancer.83 Genomic characterization of primary tumors has revealed that p16 is inactivated through point mutation, promoter methyla-tion, or deletion in a significant portion of sporadic tumors, including cancers of the pancreas, esophagus, head and neck, stomach, breast, and colon, as well as melanomas.E-cadherin and Hereditary Diffuse Gastric Cancer. E-cadherin is a cell adhesion molecule that plays an important role in nor-mal architecture and function of epithelial cells. The adhesive function of E-cadherin is dependent on interaction of its cyto-plasmic domain with βand γ-catenins and may be regulated by phosphorylation of β-catenin.Hereditary diffuse gastric carcinoma is an autosomal domi-nant cancer syndrome that results from germline mutations in the E-cadherin gene, CDH1. Carriers of CDH1 mutations have a 70% to 80% chance of developing gastric cancer.84


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Surgery_Schwartz. is an autosomal domi-nant cancer syndrome that results from germline mutations in the E-cadherin gene, CDH1. Carriers of CDH1 mutations have a 70% to 80% chance of developing gastric cancer.84 Furthermore, mutations of CDH1 have been described in sporadic cancers of the ovary, endometrium, breast, and thyroid. However, frequent mutations have been identified in only two particular tumors: dif-fuse gastric carcinomas and lobular breast carcinomas. Invasive lobular breast carcinomas often show inactivating mutations in combination with a loss of heterozygosity of the wild-type CDH1 allele.85 Interestingly, in gastric carcinomas the predominant mutations are exon skipping causing in-frame deletions, whereas most mutations identified in lobular breast cancers are premature stop codons; this suggests a genotype-phenotype correlation.RET Proto-Oncogene and Multiple Endocrine Neoplasia Type 2The RET (rearranged during transfection) gene encodes for a transmembrane receptor tyrosine kinase


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Surgery_Schwartz. suggests a genotype-phenotype correlation.RET Proto-Oncogene and Multiple Endocrine Neoplasia Type 2The RET (rearranged during transfection) gene encodes for a transmembrane receptor tyrosine kinase that plays a role in pro-liferation, migration, and differentiation of cells derived from the neural crest. Gain-of-function mutations in the RET gene are associated with medullary thyroid carcinoma in isolation or mul-tiple endocrine neoplasia type 2 (MEN2) syndromes. MEN2A is associated with medullary thyroid carcinoma and pheochro-mocytoma (in 50%) or parathyroid adenoma (in 20%), whereas MEN2B is associated with medullary thyroid carcinoma, mar-fanoid habitus, mucosal neuromas, and ganglioneuromatosis of the gastrointestinal tract.86 RET mutations lead to uncontrolled growth of the thyroid C cells, and in familial medullary cancer, C-cell hyperplasia progresses to bilateral, multicentric medul-lary thyroid cancer. Mutations in the RET gene have also been identified in half of sporadic


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Surgery_Schwartz. C cells, and in familial medullary cancer, C-cell hyperplasia progresses to bilateral, multicentric medul-lary thyroid cancer. Mutations in the RET gene have also been identified in half of sporadic medullary thyroid cancers.Genetic Modifiers of Risk. Individuals carrying identi-cal germline mutations vary in regard to cancer penetrance (whether cancer will develop or not) and cancer phenotype (the tissues involved). It is thought that this variability may be due to environmental influences or, if genetic, to genetic modifiers Table 10-4Revised criteria for hereditary nonpolyposis colon cancer (HNPCC) (Amsterdam criteria II)Three or more relatives with an HNPCC-associated cancer (colorectal cancer, endometrial cancer, cancer of the small bowel, ureter, or renal pelvis), one of whom is a first-degree relative of the other twoAt least two successive generations affectedAt least one case diagnosed before age 50 yFamilial adenomatous polyposis excludedTumors verified by pathologic


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Surgery_Schwartz. is a first-degree relative of the other twoAt least two successive generations affectedAt least one case diagnosed before age 50 yFamilial adenomatous polyposis excludedTumors verified by pathologic examinationReproduced with permission from Vasen HF, Watson P, Mecklin JP, et al: New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology. 1999 Jun;116(6):1453-1456.Brunicardi_Ch10_p0305-p0354.indd 32522/02/19 2:14 PM 326BASIC CONSIDERATIONSPART Iof risk. Similarly, genetic modifiers of risk also can play a role in determining whether an individual will develop cancer after exposure to carcinogens.Chemical CarcinogensThe first report indicating that cancer could be caused by envi-ronmental factors was by John Hill, who in 1761 noted the association between nasal cancer and excessive use of tobacco snuff.87 Currently, approximately 60% to 90% of cancers are thought to be due


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Surgery_Schwartz. factors was by John Hill, who in 1761 noted the association between nasal cancer and excessive use of tobacco snuff.87 Currently, approximately 60% to 90% of cancers are thought to be due to environmental factors. Any agent that can contribute to tumor formation is referred to as a carcinogen and can be a chemical, physical, or viral agent. Chemicals are clas-sified into three groups based on how they contribute to tumor formation. The first group of chemical agents, the genotoxins, can initiate carcinogenesis by causing a mutation. The second group, the cocarcinogens, by themselves cannot cause cancer but potentiate carcinogenesis by enhancing the potency of geno-toxins. The third group, tumor promoters, enhances tumor for-mation when given after exposure to genotoxins.The International Agency for Research on Cancer (IARC) maintains a registry of human carcinogens that is available through the World Wide Web (http://www.iarc.fr). The compounds are categorized into five groups based


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Surgery_Schwartz. Agency for Research on Cancer (IARC) maintains a registry of human carcinogens that is available through the World Wide Web (http://www.iarc.fr). The compounds are categorized into five groups based on an analysis of epidemio-logic studies, animal models, and short-term mutagenesis tests. Group 1 contains what are considered to be proven human carcinogens, based on formal epidemiologic studies among workers who were exposed for long periods (several years) to the chemicals.88 Group 2A contains what are considered to be probable human carcinogens. Suggestive epidemiologic evidence exists for compounds in this group, but the data are insufficient to establish causality. There is evidence of carcinogenicity, however, from animal studies carried out under conditions relevant to human exposure. Group 2B contains what are considered to be possible carcinogens because these substances are associated with a clear statistically and biologically significant increase in the incidence of


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Surgery_Schwartz. exposure. Group 2B contains what are considered to be possible carcinogens because these substances are associated with a clear statistically and biologically significant increase in the incidence of malignant tumors in more than one animal species or strain. Group 3 agents are not classifiable, and Group 4 agents are prob-ably not carcinogenic to humans. Selected substances that have been classified as proven carcinogens (group 1) by the IARC in an expert panel review are listed in Table 10-5.89Physical CarcinogensPhysical carcinogenesis can occur through induction of inflam-mation and cell proliferation over a period of time or through exposure to physical agents that induce DNA damage. Foreign bodies can cause chronic irritation that can expose cells to carci-nogenesis due to other environmental agents. In animal models, for example, subcutaneous implantation of a foreign body can lead to the development of tumors that have been attributed to chronic irritation from the foreign


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Surgery_Schwartz. environmental agents. In animal models, for example, subcutaneous implantation of a foreign body can lead to the development of tumors that have been attributed to chronic irritation from the foreign objects. In humans, clinical sce-narios associated with chronic irritation and inflammation such as chronic nonhealing wounds, burns, and inflammatory bowel syn-drome have all been associated with an increased risk of cancer. H pylori infection is associated with gastritis and gastric cancer, and thus, its carcinogenicity may be considered physical carci-nogenesis. Infection with the liver fluke Opisthorchis viverrini similarly leads to local inflammation and cholangiocarcinoma.The induction of lung and mesothelial cancers by asbes-tos fibers and nonfibrous particles such as silica are other examples of foreign body-induced physical carcinogenesis.90 Animal experiments have demonstrated that the dimensions and durability of the asbestos and other fibrous minerals are the key determinants


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Surgery_Schwartz. examples of foreign body-induced physical carcinogenesis.90 Animal experiments have demonstrated that the dimensions and durability of the asbestos and other fibrous minerals are the key determinants of their carcinogenicity.91 Short fibers can be inactivated by phagocytosis, whereas long fibers (>10 μm) are cleared less effectively and are encompassed by proliferat-ing epithelial cells. The long fibers support cell proliferation and have been shown to preferentially induce tumors. Asbestosassociated biologic effects also may be mediated through reactive oxygen and nitrogen species. Furthermore, an inter-action occurs between asbestos and silica and components of cigarette smoke. Polycyclic aromatic hydrocarbons (PAHs) in cigarette smoke are metabolized by epithelial cells and form DNA adducts. If PAH is coated on asbestos, PAH uptake is increased.90 Both PAH and asbestos impair lung clearance, potentially increasing uptake further. Therefore, physical car-cinogens may be synergistic


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Surgery_Schwartz. If PAH is coated on asbestos, PAH uptake is increased.90 Both PAH and asbestos impair lung clearance, potentially increasing uptake further. Therefore, physical car-cinogens may be synergistic with chemical carcinogens.Radiation is the best-known agent of physical carcinogens and is classified as ionizing radiation (X-rays, gamma rays, and alpha and beta particles) or nonionizing radiation (UV). The car-cinogenic potential of ionizing radiation was recognized soon after Wilhelm Conrad Roentgen’s discovery of X-rays in 1895. Within the next 20 years, a large number of radiation-related skin cancers were reported. Long-term follow-up of survivors of the atomic bombing of Hiroshima and Nagasaki revealed that virtually all tissues exposed to radiation are at risk for cancer.Radiation can induce a spectrum of DNA lesions that includes damage to the nucleotide bases and cross-linking, and DNA singleand double-strand breaks (DSBs). Misrepaired DSBs are the principal lesions of importance in


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Surgery_Schwartz. a spectrum of DNA lesions that includes damage to the nucleotide bases and cross-linking, and DNA singleand double-strand breaks (DSBs). Misrepaired DSBs are the principal lesions of importance in the induction of chromosomal abnormalities and gene mutations. DSBs in irradiated cells are repaired primarily by a nonhomologous end-joining process, which is error prone; thus, DSBs facilitate the production of chromosomal rearrangements and other large-scale changes such as chromosomal deletions. It is thought that radiation may initiate cancer by inactivating tumor-suppressor genes. Activation of oncogenes appears to play a lesser role in radiation carcinogenesis.Although it has been assumed that the initial genetic events induced by radiation constitute direct mutagenesis from radiation, other indirect effects may contribute to carcinogenesis. For exam-ple, radiation induces genomic instability in cells that persists for at least 30 generations after irradiation. Therefore, even if


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Surgery_Schwartz. other indirect effects may contribute to carcinogenesis. For exam-ple, radiation induces genomic instability in cells that persists for at least 30 generations after irradiation. Therefore, even if cells do not acquire mutations at initial irradiation, they remain at risk for developing new mutations for several generations. Moreover, even cells that have not been directly irradiated appear to be at risk, a phenomenon referred to as the bystander effect.Nonionizing UV radiation is a potent DNA-damaging agent and is known to induce skin cancer in experimental ani-mals. Most nonmelanoma human skin cancers are thought to be induced by repeated exposure to sunlight, which leads to a series of mutations that allow the cells to escape normal growth control. Patients with inherited xeroderma pigmentosum lack one or more DNA repair pathways, which confers susceptibility to UV-induced cancers, especially on sun-exposed body parts. Patients with ataxia telangiectasia mutated syndrome also have


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Surgery_Schwartz. lack one or more DNA repair pathways, which confers susceptibility to UV-induced cancers, especially on sun-exposed body parts. Patients with ataxia telangiectasia mutated syndrome also have a radiation-sensitive phenotype.Viral CarcinogensOne of the first observations that cancer may be caused by trans-missible agents was by Peyton Rous in 1910 when he demon-strated that cell-free extracts from sarcomas in chickens could transmit sarcomas to other animals injected with these extracts.92 This was subsequently discovered to represent viral transmission of cancer by the Rous sarcoma virus. At present, several human viruses are known to have oncogenic properties, and several Brunicardi_Ch10_p0305-p0354.indd 32622/02/19 2:14 PM 327ONCOLOGYCHAPTER 10Table 10-5Group 1 chemical carcinogens and evidence for carcinogenicity in humans and for genotoxicity as the main mechanism TUMOR SITES OR TYPES WITH SUFFICIENT EVIDENCE IN HUMANSEVIDENCE OF GENOTOXICITY AS THE MAIN


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Surgery_Schwartz. chemical carcinogens and evidence for carcinogenicity in humans and for genotoxicity as the main mechanism TUMOR SITES OR TYPES WITH SUFFICIENT EVIDENCE IN HUMANSEVIDENCE OF GENOTOXICITY AS THE MAIN MECHANISM4-AminobiphenylUrinary bladderStrongBenzidineUrinary bladderStrongDyes metabolized to benzidine⋅⋅Stronga4,4’-Methylenebis(2-chloroaniline)⋅⋅Stronga2-NapthylamineUrinary bladderStrongOrtho-toluidineUrinary bladderModerateAuramine productionUrinary bladderWeak/lack of databMagenta productionUrinary bladderWeak/lack of databBenzo[α]pyrene⋅⋅StrongaSoot (chimney sweeping)Skin, lungModerateCoal gasificationLungStrongCoal-tar distillationSkinStrongCoke productionLungStrongCoal-tar pitches (paving, roofing)LungStrongAluminum productionLung, urinary bladderWeak/moderateb,cAflatoxinsHepatocellular carcinomaStrongBenzeneANLLStrongBis (chloromethyl)ether/chloromethyl methyletherLungModerate/strong1,3-ButadieneHaematolymphatic organsStrongDioxin (2,3,7,8-TCDD)All cancers combinedaSee


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Surgery_Schwartz. carcinomaStrongBenzeneANLLStrongBis (chloromethyl)ether/chloromethyl methyletherLungModerate/strong1,3-ButadieneHaematolymphatic organsStrongDioxin (2,3,7,8-TCDD)All cancers combinedaSee textd2,3,4,7,8-Pentachlorodibenzofuran⋅⋅See texta,d3,3’,4,4’,5-Pentachlorobiphenyl (PCB-126)⋅⋅See texta,dEthylene oxide⋅⋅StrongaFormaldehydeNasopharynxLeukemiagStrongModerateSulfur mustardLungStrongVinyl chlorideHepatic angiosarcoma, hepatocellular carcinomaStrongIron and steel foundingLungWeak/moderateIsopropyl alcohol manufacture using strong acidsNasal cavityWeak/lack of dataMineral oilsSkinWeak/lack of dataOccupational exposure as a painterLung, urinary bladder, pleural mesotheliomaStrongcRubber-manufacturing industryLeukaemia, lymphoma,g urinary bladder, lung,g stomachgStrongcShale oilsSkinWeak/lack of dataStrong inorganic acid mistsLarynxWeak/lack of dataANLL = acute nonlymphocytic leukemia; ALL = acute lymphocytic leukemia; CLL = chronic lymphocytic leukemia; MM = multiple myeloma; NH =


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Surgery_Schwartz. of dataStrong inorganic acid mistsLarynxWeak/lack of dataANLL = acute nonlymphocytic leukemia; ALL = acute lymphocytic leukemia; CLL = chronic lymphocytic leukemia; MM = multiple myeloma; NH = non-Hodgkin lymphoma; STS = soft-tissue sarcoma.aAgents classified in Group 1 on the basis of mechanistic information.bWeak evidence in workers, but strong evidence for some chemicals in this industry.cDue to the diversity and complexity of these exposures, other mechanisms may also be relevant.dStrong evidence for an aryl hydrocarbon receptor (AhR)-mediated mechanism.eParticularly myeloid leukemia.fAfter maternal exposure (before or during pregnancy, or both).gNew epidemiological findings.Reproduced with permission from Baan R, Grosse Y, Straif K, et al. A review of human carcinogens–part F: chemical agents and related occupations, Lancet Oncol. 2009 Dec;10(12):1143-1144.Brunicardi_Ch10_p0305-p0354.indd 32722/02/19 2:14 PM 328BASIC CONSIDERATIONSPART ITable 10-6Selected viral


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Surgery_Schwartz. F: chemical agents and related occupations, Lancet Oncol. 2009 Dec;10(12):1143-1144.Brunicardi_Ch10_p0305-p0354.indd 32722/02/19 2:14 PM 328BASIC CONSIDERATIONSPART ITable 10-6Selected viral carcinogensaVIRUSPREDOMINANT TUMOR TYPEbEpstein-Barr virusBurkitt’s lymphoma Hodgkin’s disease Immunosuppression-related lymphoma Sinonasal angiocentric T-cell lymphoma Nasopharyngeal carcinomaHepatitis B virusHepatocellular carcinomaHepatitis C virusHepatocellular carcinomaHIV type 1Kaposi’s sarcoma Cervical cancer Non-Hodgkin’s lymphomaHuman herpes virus 8Kaposi’s sarcomaHuman papillomavirus 16 and 18 Cervical cancerVulvar and vaginal cancer Penile cancer Oropharyngeal cancer (commonly base of tongue and tonsil) Anal cancerHuman T-cell lymphotropic virusesAdult T-cell leukemia/lymphomaMerkel cell polyoma virusMerkel cell carcinomaaData based on information in the International Agency for Research on Cancer monographs.bOnly tumor types for which causal relationships are established are


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Surgery_Schwartz. cell polyoma virusMerkel cell carcinomaaData based on information in the International Agency for Research on Cancer monographs.bOnly tumor types for which causal relationships are established are listed. Other cancer types may be linked to the agents with a lower frequency or with insufficient data to prove causality.have been causally linked to human cancers (Table 10-6).88 It is estimated that 15% of all human tumors worldwide are caused by viruses.93Viruses may cause or increase the risk of malignancy through several mechanisms, including direct transformation, expression of oncogenes that interfere with cell-cycle check-points or DNA repair, expression of cytokines or other growth factors, and alteration of the immune system. Oncogenic viruses may be RNA or DNA viruses. Oncogenic RNA viruses are retro-viruses and contain a reverse transcriptase. After the viral infec-tion, the single-stranded RNA viral genome is transcribed into a double-stranded DNA copy, which is then


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Surgery_Schwartz. RNA viruses are retro-viruses and contain a reverse transcriptase. After the viral infec-tion, the single-stranded RNA viral genome is transcribed into a double-stranded DNA copy, which is then integrated into the chromosomal DNA of the cell. Retroviral infection of the cell is permanent; thus, integrated DNA sequences remain in the host chromosome. Oncogenic transforming retroviruses carry onco-genes derived from cellular genes. These cellular genes, referred to as proto-oncogenes, usually are involved in mitogenic signal-ing and growth control, and include protein kinases, G proteins, growth factors, and transcription factors (Table 10-7).93Integration of the provirus upstream of a proto-oncogene may produce chimeric virus-cell transcripts and recombination during the next round of replication that could lead to incorpo-ration of the cellular gene into the viral genome.93 Then again, many retroviruses do not possess oncogenes but can cause tumors in animals regardless. This occurs


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Surgery_Schwartz. that could lead to incorpo-ration of the cellular gene into the viral genome.93 Then again, many retroviruses do not possess oncogenes but can cause tumors in animals regardless. This occurs by integration of the provirus near a normal cellular proto-oncogene and activation of the expression of these genes by the strong promoter and enhancer sequences in the integrated viral sequence.Unlike the oncogenes of the RNA viruses, those of the DNA tumor viruses are viral, not cellular, in origin. These genes are required for viral replication using the host cell machinery. In permissive hosts, infection with an oncogenic DNA virus may result in a productive lytic infection, which leads to cell death and the release of newly formed viruses. In nonpermis-sive cells, the viral DNA can be integrated into the cellular chromosomal DNA, and some of the early viral genes can be synthesized persistently, which leads to transformation of cells to a neoplastic state. The binding of viral oncoproteins


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Surgery_Schwartz. into the cellular chromosomal DNA, and some of the early viral genes can be synthesized persistently, which leads to transformation of cells to a neoplastic state. The binding of viral oncoproteins to cellu-lar tumor-suppressor proteins p53 and Rb is fundamental to the carcinogenesis induced by most DNA viruses, although some target different cellular proteins.Like other types of carcinogenesis, viral carcinogenesis is a multistep process. Some retroviruses contain two cellular onco-genes, rather than one, in their genome and are more rapidly tumorigenic than single-gene transforming retroviruses, which emphasizes the cooperation between transforming genes. Further-more, some viruses encode genes that suppress or delay apoptosis.Although immunocompromised individuals are at ele-vated risk, most patients infected with oncogenic viruses do not develop cancer. When cancer does develop, it usually occurs sev-eral years after the viral infection. It is estimated, for example, that the risk


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Surgery_Schwartz. most patients infected with oncogenic viruses do not develop cancer. When cancer does develop, it usually occurs sev-eral years after the viral infection. It is estimated, for example, that the risk of hepatocellular carcinoma (HCC) among individu-als infected with hepatitis C virus is 1% to 3% after 30 years.94 There may be synergy between various environmental factors and viruses in carcinogenesis.Recognition of a viral origin for some tumors has led to the pursuit of vaccination as a preventive strategy. The use of childhood hepatitis B vaccination has already translated into a decrease in liver cancer incidence in the East Asia.5 Similarly, it is recognized that cervical cancer and its obligate precursors, cervical intraepithelial neoplasia grades 2 and 3, and adenocar-cinoma in situ, are caused by oncogenic human papillomavirus (HPV); administration of HPV vaccine to HPV-naive women, substantially reduces the incidence of HPV16/18-related cervi-cal precancers and cervical


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Surgery_Schwartz. situ, are caused by oncogenic human papillomavirus (HPV); administration of HPV vaccine to HPV-naive women, substantially reduces the incidence of HPV16/18-related cervi-cal precancers and cervical cancer.95 Studies suggest that HPV vaccination may also reduce oral HPV infections that are a risk factor for the development of oropharyngeal cancer.96 The American Cancer Society recommends routine HPV vaccina-tion for girls and boys starting at age 11 or 12. The vaccination series can be started as early as age 9. HPV vaccination is also recommended for females 13 to 26 years old and for males 13 to 21 years old who have not started the vaccines, or who have started but have not completed the series. Males 22 to 26 years old may also be vaccinated. HPV vaccination is also recom-mended up until age 26 for men who have sex with men and for people with weakened immune systems (including people with HIV infection), if they have not previously been vaccinated. It is important for patients to


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Surgery_Schwartz. age 26 for men who have sex with men and for people with weakened immune systems (including people with HIV infection), if they have not previously been vaccinated. It is important for patients to know that vaccination at older ages is less effective in lowering cancer risk.97CANCER RISK ASSESSMENTCancer risk assessment is an important part of the initial evalua-tion of any patient. A patient’s cancer risk not only is an impor-tant determinant of cancer screening recommendations but also Brunicardi_Ch10_p0305-p0354.indd 32822/02/19 2:14 PM 329ONCOLOGYCHAPTER 10Table 10-7Selected cellular oncogenes in retrovirusesONCOGENEVIRUS NAMEORIGINPROTEIN PRODUCTablAbelson murine leukemia virusMouseTyrosine kinasefesST feline sarcoma virusCatTyrosine kinasefpsFujinami sarcoma virusChickenTyrosine kinasesrcRous sarcoma virusChickenTyrosine kinaseerbBAvian erythroblastosis virusChickenEpidermal growth factor receptorfmsMcDonough feline sarcoma virusCatColony-stimulating factor


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Surgery_Schwartz. kinasesrcRous sarcoma virusChickenTyrosine kinaseerbBAvian erythroblastosis virusChickenEpidermal growth factor receptorfmsMcDonough feline sarcoma virusCatColony-stimulating factor receptorkitHardy-Zuckerman 4 feline sarcoma virusCatStem cell factor receptormilAvian myelocytoma virusChickenSerine/threonine kinasemosMoloney murine sarcoma virusMouseSerine/threonine kinaserafMurine sarcoma virus 3611MouseSerine/threonine kinasesisSimian sarcoma virusMonkeyPlatelet-derived growth factorH-rasHarvey murine sarcoma virusRatGDP/GTP bindingK-rasKirsten murine sarcoma virusRatGDP/GTP bindingerbAAvian erythroblastosis virusChickenTranscription factor (thyroid hormone receptor)etsAvian myeloblastosis virus E26ChickenTranscription factorfosFBJ osteosarcoma virusMouseTranscription factor (AP1 component)junAvian sarcoma virus 17ChickenTranscription factor (AP1 component)mybAvian myeloblastosis virusChickenTranscription factormycMC29 myelocytoma virusChickenTranscription factor (NF-κB family)AP1 =


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Surgery_Schwartz. sarcoma virus 17ChickenTranscription factor (AP1 component)mybAvian myeloblastosis virusChickenTranscription factormycMC29 myelocytoma virusChickenTranscription factor (NF-κB family)AP1 = activator protein 1; FBJ = Finkel-Biskis-Jinkins; GDP = guanosine diphosphate; GTP = guanosine triphosphate; NF-κB = nuclear factor κB.Data from Coffin JM, Hughes SH, Varmus HE: Retroviruses. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 1997.may alter how aggressively an indeterminant finding will be pursued for diagnosis. A “probably benign” mammographic lesion, for example, defined as one with <2% probability of malignancy (American College of Radiology category III) is usually managed with a 6-month follow-up mammogram in a patient at baseline cancer risk, but obtaining a tissue diagnosis may be preferable in a patient at high risk for breast cancer.98Cancer risk assessment starts with taking a complete his-tory that includes history of environmental exposures to potential


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Surgery_Schwartz. diagnosis may be preferable in a patient at high risk for breast cancer.98Cancer risk assessment starts with taking a complete his-tory that includes history of environmental exposures to potential carcinogens and a detailed family history. Risk assessment for breast cancer, for example, includes obtaining a family history to determine whether another member of the family is known to carry a breast cancer susceptibility gene; whether there is famil-ial clustering of breast cancer, ovarian cancer, thyroid cancer, sarcoma, adrenocortical carcinoma, endometrial cancer, brain tumors, dermatologic manifestations, leukemia, or lymphoma; and whether the patient is from a population at increased risk, such as individuals of Ashkenazi Jewish descent. Patients who have a family history suggestive of a cancer susceptibility syn-drome such as hereditary breast-ovarian syndrome, Li-Fraumeni Syndrome, or Cowden’s Disease would benefit from genetic counseling and possibly genetic testing.There are


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Surgery_Schwartz. of a cancer susceptibility syn-drome such as hereditary breast-ovarian syndrome, Li-Fraumeni Syndrome, or Cowden’s Disease would benefit from genetic counseling and possibly genetic testing.There are several models that can estimate risk based on complex family histories and assist clinicians in estimat-ing breast cancer risk or the likelihood that a BRCA mutation is present, including the Claus model, Tyrer-Cuzick model, BRCAPRO model, and the Breast and Ovarian Analysis of Dis-ease Incidence and Carrier Estimation Algorithm (BOADICEA) model.99-102 Patients who do have a strong hereditary component of risk can be evaluated on the basis of their age, race, per-sonal history, and exposures. One of the most commonly used models for risk assessment in breast cancer is the Gail model.103 Gail and colleagues analyzed the data from 2852 breast cancer cases and 3146 controls from the Breast Cancer Detection and Demonstration Project, a mammography screening project conducted in the 1970s,


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Surgery_Schwartz. and colleagues analyzed the data from 2852 breast cancer cases and 3146 controls from the Breast Cancer Detection and Demonstration Project, a mammography screening project conducted in the 1970s, and developed a model for project-ing breast cancer incidence. The model uses risk factors such as an individual’s age, age at menarche, age at first live birth, number of first-degree relatives with breast cancer, number of previous breast biopsy specimens, and whether the biopsy speci-men results revealed atypical ductal hyperplasia (Table 10-8).103 This model has led to the development of a breast cancer risk assessment tool, which is available on the World Wide Web.104 This tool incorporates the risk factors used in the Gail model, as well as race and ethnicity, and allows a health professional to project a woman’s individualized estimated risk for invasive breast cancer over a 5-year period and over her lifetime (to age 90 years). Notably, these risk projections assume that the woman


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Surgery_Schwartz. to project a woman’s individualized estimated risk for invasive breast cancer over a 5-year period and over her lifetime (to age 90 years). Notably, these risk projections assume that the woman is undergoing regular clinical breast examinations and screen-ing mammograms. Also of note is that this program underes-timates the risk for women who have already had a diagnosis of invasive or noninvasive breast cancer and does not take into account specific genetic predispositions such as mutations in BRCA1 or BRCA2. However, risk assessment tools such as this have been validated and are now in widespread clinical use. Similar models are in development or are being validated for Brunicardi_Ch10_p0305-p0354.indd 32922/02/19 2:14 PM 330BASIC CONSIDERATIONSPART ITable 10-8Assessment of risk for invasive breast cancerRISK FACTORRELATIVE RISK (%)Age at menarche (years) >141.00 12–131.10 <121.21Age at first live birth (years) Patients with no first-degree relatives with


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Surgery_Schwartz. of risk for invasive breast cancerRISK FACTORRELATIVE RISK (%)Age at menarche (years) >141.00 12–131.10 <121.21Age at first live birth (years) Patients with no first-degree relatives with cancer <201.00 20–241.24 25–29 or nulliparous1.55 ≥301.93Patients with one first degree-relative with cancer <201.00 20–242.64 25–29 or nulliparous2.76 ≥302.83Patients with ≥2 first-degree relatives with cancer <206.80 20–245.78 25–29 or nulliparous4.91 ≥304.17Breast biopsies (number) Patients aged <50 y at counseling 01.00 11.70 ≥22.88Patients aged ≥50 y at counseling 01.00 11.27 ≥21.62Atypical hyperplasia No biopsies1.00 At least 1 biopsy, no atypical hyperplasia0.93 No atypical hyperplasia, hyperplasiastatus unknown for at least 1 biopsy1.00 Atypical hyperplasia in at least 1 biopsy1.82Modified with permission from Gail MH, Brinton LA, Byar DP, et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually, J Natl Cancer


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Surgery_Schwartz. with permission from Gail MH, Brinton LA, Byar DP, et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually, J Natl Cancer Inst. 1989 Dec 20;81(24):1879-1886.as presence or absence of single nucleotide polymorphisms which each may confer low or intermediate cancer risk. Risk models that include biologic as well as environmental factors may accurately predict cancer risk, providing better guidance as to which patients should undergo more intensive screening (e.g., screening with magnetic resonance imaging of the breast, computerized tomography screening of the lung), and should be considered for preventive strategies.CANCER SCREENINGEarly detection is the key to success in cancer therapy. Screen-ing for common cancers using relatively noninvasive tests is expected to lead to early diagnosis, allow more conservative surgical therapies with decreased morbidity, and potentially improve surgical cure rates and overall


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Surgery_Schwartz. using relatively noninvasive tests is expected to lead to early diagnosis, allow more conservative surgical therapies with decreased morbidity, and potentially improve surgical cure rates and overall survival rates. Key factors that influence screening guidelines are how prevalent the cancer is in the population, what risk is associated with the screening measure, and whether early diagnosis actually affects outcome. The value of a widespread screening measure is likely to go up with the prevalence of the cancer in a population, which often determines the age cutoffs for screening and explains why screening is done only for common cancers. The risks asso-ciated with the screening measure are a significant consider-ation, especially with more invasive screening measures such as colonoscopy. The consequences of a false-positive screening test result also need to be considered. For example, when 1000 screening mammograms are taken, only 2 to 4 new cases of cancer will be identified; this


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Surgery_Schwartz. The consequences of a false-positive screening test result also need to be considered. For example, when 1000 screening mammograms are taken, only 2 to 4 new cases of cancer will be identified; this number is slightly higher (6 to 10 prevalent cancers per 1000 mammograms) for initial screen-ing mammograms.106 However, as many as 10% of screening mammograms may be potentially suggestive of an abnormal-ity, which requires further imaging (i.e., a 10% recall rate). Of those women with abnormal mammogram findings, only 5% to 10% will be determined to have a breast cancer. Among women for whom biopsy specimen is recommended, 25% to 40% will have a breast cancer. A false-positive screening result is likely to induce significant emotional distress in patients, leads to unnecessary biopsy specimens, and has cost implications for the health care system.American Cancer Society guidelines for the early detec-tion of cancer are listed in Table 10-9.96 These guidelines are updated periodically to


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Surgery_Schwartz. and has cost implications for the health care system.American Cancer Society guidelines for the early detec-tion of cancer are listed in Table 10-9.96 These guidelines are updated periodically to incorporate emerging technologies and new data on the efficacy of screening measures. Besides the American Cancer Society, several other professional bodies make recommendations for screening. Although the screening guidelines differ somewhat, most organizations do not empha-size one screening strategy as superior to another, but all empha-size the importance of age-appropriate screening.Screening guidelines are developed for the general base-line-risk population. These guidelines need to be modified for patients who are at high risk. For example, more intensive colorectal cancer screening is recommended for individuals at increased risk because of a history of adenomatous polyps, a personal history of colorectal cancer, a family history of either colorectal cancer or colorectal adenomas


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Surgery_Schwartz. recommended for individuals at increased risk because of a history of adenomatous polyps, a personal history of colorectal cancer, a family history of either colorectal cancer or colorectal adenomas diagnosed in a first-degree relative before age 60 years, a personal history of inflam-matory bowel disease of significant duration, or a family history or genetic test result indicating FAP or HNPCC. For some dis-eases, in higher risk populations, both the screening modality and the screening intensity may be altered. For example, breast magnetic resonance imaging is recommended as an adjunct to other cancers. For example, a lung cancer risk prediction model, which includes age, sex, asbestos exposure history, and smoking history, has been found to predict risk of lung cancer.105 There is now growing interest in using each individuals genotype, such Brunicardi_Ch10_p0305-p0354.indd 33022/02/19 2:14 PM 331ONCOLOGYCHAPTER 10Table 10-9American Cancer Society recommendations for early


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Surgery_Schwartz. now growing interest in using each individuals genotype, such Brunicardi_Ch10_p0305-p0354.indd 33022/02/19 2:14 PM 331ONCOLOGYCHAPTER 10Table 10-9American Cancer Society recommendations for early detection of cancer in average-risk, asymptomatic individualsCANCER SITEPOPULATIONTEST OR PROCEDUREFREQUENCYBreastWomen age 40 and aboveMammographyWomen with an average risk of breast cancer should undergo regular screening mammography starting at age 45 years. Women age 45 to 54 years should be screened annually. Women 55 years and older should transition to biennial screening or have the opportunity to continue screening annually. Women should continue screening mammography as long as their overall health is good and they have a life expectancy of 10 years or longer. The ACS does not recommend clinical breast examination for breast cancer screening among average-risk women at any age.CervixWomen, age 21–65 yPap test and HPV DNA testCervical cancer screening should begin at age 21 y.


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Surgery_Schwartz. clinical breast examination for breast cancer screening among average-risk women at any age.CervixWomen, age 21–65 yPap test and HPV DNA testCervical cancer screening should begin at age 21 y. For women age 21–29 y, screening should be done every 3 y with conventional or liquid-based Pap tests. For women age 30–65 y, screening should be done every 5 y with both the HPV test and the Pap test (preferred), or every 3 y with the Pap test alone (acceptable). Women age >65 y who have had ≥3 consecutive negative Pap tests or ≥2 consecutive negative HPV and Pap tests within the last 10 y, with the most recent test occurring within the last 5 y, and women who have had a total hysterectomy should stop cervical cancer screening.ColorectalMen and women age ≥50 ygFOBT, or FIT, or sDNA with a high sensitivity for cancerAnnual, starting at age 50 y. FSIG, orEvery 5 y, starting at age 50 y. FSIG can be performed alone, or consideration can be given to combining FSIG performed every 5 y with a


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Surgery_Schwartz. sensitivity for cancerAnnual, starting at age 50 y. FSIG, orEvery 5 y, starting at age 50 y. FSIG can be performed alone, or consideration can be given to combining FSIG performed every 5 y with a highly sensitive guaiac-based FOBT or FIT performed annually. DCBE, orEvery 5 y, starting at age 50 y. ColonoscopyEvery 10 y, starting at age 50 y. CT colonographyEvery 5 yr, starting at age 50 y.EndometrialWomen, at menopause At the time of menopause, women at average risk should be informed about the risks and symptoms of endometrial cancer and strongly encouraged to report any unexpected bleeding or spotting to their physicians.LungCurrent or former smokers age 50–74 in good health with at least a 30 pack/year historyLDCTClinicians with access to high-volume, high-quality lung cancer screening and treatment centers should initiate a discussion about lung cancer screening with apparently healthy patients age 55–74 y who have at least a 30 pack-y smoking history, and who currently smoke


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Surgery_Schwartz. and treatment centers should initiate a discussion about lung cancer screening with apparently healthy patients age 55–74 y who have at least a 30 pack-y smoking history, and who currently smoke or have quit within the past 15 y. A process of informed and shared decision-making with a clinician related to the potential benefits, limitations, and harms associated with screening for lung cancer with LDCT should occur before any decision is made to initiate lung cancer screening. Smoking cessation counseling remains a high priority for clinical attention in discussions with current smokers, who should be informed of their continuing risk of lung cancer. Screening should not be viewed as an alternative to smoking cessation.(Continued)Brunicardi_Ch10_p0305-p0354.indd 33122/02/19 2:14 PM 332BASIC CONSIDERATIONSPART ITable 10-9American Cancer Society recommendations for early detection of cancer in average-risk, asymptomatic individualsCANCER SITEPOPULATIONTEST OR


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Surgery_Schwartz. 2:14 PM 332BASIC CONSIDERATIONSPART ITable 10-9American Cancer Society recommendations for early detection of cancer in average-risk, asymptomatic individualsCANCER SITEPOPULATIONTEST OR PROCEDUREFREQUENCYProstateMen, age ≥50 yDRE and PSAMen who have at least a 10-y life expectancy should have an opportunity to make an informed decision with their health care provider about whether to be screened for prostate cancer, after receiving information about the potential benefits, risks, and uncertainties associated with prostate cancer screening. Prostate cancer screening should not occur without an informed decision-making process. Men at average risk should receive this information beginning at age 50 years. Men in higher risk groups should receive this information before age 50 years. Men should either receive this information directly from their health care providers or be referred to reliable and culturally appropriate sources. Patient decision aids are helpful in preparing men to


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Surgery_Schwartz. should either receive this information directly from their health care providers or be referred to reliable and culturally appropriate sources. Patient decision aids are helpful in preparing men to make a decision whether to be tested.Cancer-related checkupMen and women age ≥20 y On the occasion of a periodic health examination, the cancer-related checkup should include examination for cancers of the thyroid, testicles, ovaries, lymph nodes, oral cavity, and skin, as well as health counseling about tobacco, sun exposure, diet and nutrition, risk factors, sexual practices, and environmental and occupational exposures.ACS = American Cancer Society; BSE = breast self-examination; CBE = clinical breast examination; Pap = Papanicolaou; HPV = human papillomavirus; gFOBT = guaiac-based fecal occult blood test; FIT = fecal immunochemical test; sDNA, stool DNA; DRE = digital rectal examination; FSIG = flexible sigmoidoscopy; DCBE = double-contrast barium enema; CT = computed tomography; LDCT =


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Surgery_Schwartz. blood test; FIT = fecal immunochemical test; sDNA, stool DNA; DRE = digital rectal examination; FSIG = flexible sigmoidoscopy; DCBE = double-contrast barium enema; CT = computed tomography; LDCT = low-dose helical CT; PSA = prostate-specific antigen.Reproduced with permission from Smith RA, Brooks D, Cokkinides V, et al: Cancer screening in the United States, 2013: a review of current American Cancer Society guidelines, current issues in cancer screening, and new guidance on cervical cancer screening and lung cancer screening, CA Cancer J Clin. 2013 Mar-Apr;63(2):88-105.mammography for breast cancer screening in BRCA mutation carriers, first-degree relatives of carriers, and women with a life-time breast cancer risk of 20% to 25% or higher.107The National Lung Screening Trial demonstrated a 20% reduction in lung cancer deaths in adults age 55 to 74 years who were at high risk of lung cancer and randomized to low-dose helical computed tomography (LDCT) screening compared with screening


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Surgery_Schwartz. a 20% reduction in lung cancer deaths in adults age 55 to 74 years who were at high risk of lung cancer and randomized to low-dose helical computed tomography (LDCT) screening compared with screening with annual CXR.108 In 2013, the American Cancer Society updated their lung cancer screening recommendations to emphasize that clinicians with access to high-volume, high-quality lung cancer screening and treatment centers should ascertain the smoking history of their patients 55 to 74 years of age, and should discuss lung cancer screening with those who have at least a 30 pack per year smoking history, currently smoke, or have quit within the past 15 years, and who are in relatively good health.109 It is recommended that this discussion include the benefits, uncertainties, and harms associated with screening for lung cancer with LDCT.CANCER DIAGNOSISThe definitive diagnosis of solid tumors is obtained by perform-ing a biopsy specimen of the lesion. Biopsy findings determine the tumor


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Surgery_Schwartz. with screening for lung cancer with LDCT.CANCER DIAGNOSISThe definitive diagnosis of solid tumors is obtained by perform-ing a biopsy specimen of the lesion. Biopsy findings determine the tumor histology and grade and thus, assist in definitive ther-apeutic planning. Biopsy specimens of mucosal lesions usually are obtained endoscopically (e.g., via colonoscope, broncho-scope, or cystoscope). Lesions that are easily palpable, such as those of the skin, can either be excised or sampled by punch biopsy specimen. Deep-seated lesions can be localized with computed tomographic (CT) scan or ultrasound guidance for acquisition of a biopsy specimen.A sample of a lesion can be obtained with a needle or with an open incisional or excisional biopsy specimen. Fine-needle aspiration is easy and relatively safe, but has the disad-vantage of not giving information on tissue architecture. For example, fine-needle aspiration biopsy specimen of a breast mass can make the diagnosis of malignancy but


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Surgery_Schwartz. safe, but has the disad-vantage of not giving information on tissue architecture. For example, fine-needle aspiration biopsy specimen of a breast mass can make the diagnosis of malignancy but cannot dif-ferentiate between an invasive and noninvasive tumor. There-fore core-needle biopsy specimen is more advantageous when the histologic findings will affect the recommended therapy. Core biopsy specimen, like fine-needle aspiration, is relatively safe and can be performed either by direct palpation (e.g., a breast mass or a soft tissue mass) or can be guided by an imag-ing study (e.g., stereotactic core biopsy specimen of the breast). Core biopsy specimens, like fine-needle aspirations, have the disadvantage of introducing sampling error. For example, 19% to 44% of patients with a diagnosis of atypical ductal hyperpla-sia based on core biopsy specimen findings of a mammographic abnormality are found to have carcinoma upon excision of the entire lesion.110 It is crucial to ensure that


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Surgery_Schwartz. of atypical ductal hyperpla-sia based on core biopsy specimen findings of a mammographic abnormality are found to have carcinoma upon excision of the entire lesion.110 It is crucial to ensure that the histologic find-ings are consistent with the clinical scenario and to know the appropriate interpretation of each histologic finding. A needle biopsy specimen for which the report is inconsistent with the clinical scenario should be either repeated or followed by an open biopsy procedure.Open biopsy specimens have the advantage of providing more tissue for histologic evaluation and the disadvantage of being an operative procedure. Incisional biopsy specimens are (Continued)Brunicardi_Ch10_p0305-p0354.indd 33222/02/19 2:14 PM 333ONCOLOGYCHAPTER 10reserved for very large lesions in which a definitive diagnosis cannot be made by needle biopsy specimen. Excisional biopsy specimens are performed for lesions for which either core biopsy specimen is not possible or the results are


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Surgery_Schwartz. which a definitive diagnosis cannot be made by needle biopsy specimen. Excisional biopsy specimens are performed for lesions for which either core biopsy specimen is not possible or the results are nondiagnostic. Excisional biopsy specimens should be performed with curative intent, that is, by obtaining adequate tissue around the lesion to ensure negative surgical margins. Marking of the orientation of the margins by sutures or clips by the surgeon and inking of the specimen margins by the pathologist will allow for determina-tion of the surgical margins and will guide surgical reexcision if one or more of the margins are positive for microscopic tumor or are close. The biopsy specimen incision should be oriented to allow for excision of the biopsy specimen scar if repeat opera-tion is necessary. Furthermore, the biopsy specimen incision should directly overlie the area to be removed rather than tun-neling from another site, which runs the risk of contaminating a larger field.


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Surgery_Schwartz. is necessary. Furthermore, the biopsy specimen incision should directly overlie the area to be removed rather than tun-neling from another site, which runs the risk of contaminating a larger field. Meticulous hemostasis during a biopsy specimen is essential because a hematoma can lead to contamination of the tissue planes and can make subsequent follow-up with physical examinations much more challenging.In the case where an enlarged lymph node is being inves-tigated due to a suspicion of lymphoma, it will usually be nec-essary for the surgeon to remove an entire lymph node through an open biopsy in order to permit an analysis of lymph node architecture and provide sufficient tissue for molecular and flow cytometric analyses.CANCER STAGINGCancer staging is a system used to describe the anatomic extent of a malignant process in an individual patient. Staging sys-tems may incorporate relevant clinical prognostic factors such as tumor size, location, extent, grade, and dissemination to


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Surgery_Schwartz. extent of a malignant process in an individual patient. Staging sys-tems may incorporate relevant clinical prognostic factors such as tumor size, location, extent, grade, and dissemination to regional lymph nodes or distant sites. Accurate staging is essen-tial in designing an appropriate treatment regimen for an indi-vidual patient. Staging of the lymph node basin is considered a standard part of primary surgical therapy for most surgical procedures and is discussed later in this chapter. Cancer patients who are considered to be at high risk for distant metastasis usu-ally undergo a preoperative staging work-up. This involves a set of imaging studies of sites of preferential metastasis for a given cancer type. For a patient with breast cancer, for example, a staging work-up would include a chest radiograph, bone scan, and liver ultrasound, or CT scans to evaluate for lung, bone, and liver metastases, respectively. A distant staging work-up usually is performed only for patients


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Surgery_Schwartz. a chest radiograph, bone scan, and liver ultrasound, or CT scans to evaluate for lung, bone, and liver metastases, respectively. A distant staging work-up usually is performed only for patients likely to have metastasis based on the characteristics of the primary tumor; for example, a staging work-up for a patient with ductal carcinoma in situ of the breast or a small invasive breast tumor is likely to be low yield and not cost effective.Recently there also is increased usage of molecular imag-ing with positron emission tomography (PET) scanning, or PET/CT, for cancer staging. Most commonly PET scanning is performed with fluorine 18 incorporated into fluorodeoxy-glucose (FDG). FDG PET assesses the rate of glycolysis. FDG uptake is increased in most malignant tissues but also in benign pathologic conditions such as inflammatory disorders, trauma, infection, and granulomatous disease. PET/CT combines a PET scanner and an X-ray CT scanner in a single gantry, in order to acquire


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Surgery_Schwartz. pathologic conditions such as inflammatory disorders, trauma, infection, and granulomatous disease. PET/CT combines a PET scanner and an X-ray CT scanner in a single gantry, in order to acquire sequential images from both devices in the same ses-sion. These separate images are combined into a single coreg-istered image that gives information on the size and shape of abnormal masses in conjunction with their metabolic activity. It has been especially useful in the staging and management of lymphoma, lung cancer, and colorectal cancer. The role of PET in evaluating many other cancers is evolving, and additional molecular tracers, such as 3′-deoxy-3′ (18F)-fluorothymidine, used to assess proliferation, are being actively pursued.A PET scan can be useful in staging a cancer that poten-tially can be treated radically, such as small cell lung cancer. In the case of some cancers such as GIST, a PET scan can be used to establish baseline staging before commencing targeted therapy and


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Surgery_Schwartz. can be treated radically, such as small cell lung cancer. In the case of some cancers such as GIST, a PET scan can be used to establish baseline staging before commencing targeted therapy and assessing the overall response to therapy. Another use for PET scanning is the evaluation of an indeterminate lesion as in the case of a solitary pulmonary nodule that is suspected to be malignant in nature. In testicular cancer (seminoma) and lymphoma, this imaging modality has been shown to be effec-tive in assessing suspected disease recurrence, relapse, and/or residual disease. Finally, PET scans have been effective in guid-ing biopsies in the setting of mesothelioma. Standardization of staging systems is essential to allow comparison of results from different studies from different institutions and worldwide. The staging systems proposed by the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer (International Union Against Cancer, or UICC) are among the


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Surgery_Schwartz. and worldwide. The staging systems proposed by the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer (International Union Against Cancer, or UICC) are among the most widely accepted staging systems. Both the AJCC and the UICC have adopted a shared tumor, node, and metastasis (TNM) staging system that defines the cancer in terms of the anatomic extent of disease and is based on assessment of three components: the size of the primary tumor (T), the presence (or absence) and extent of nodal metastases (N), and the presence (or absence) and extent of distant metastases (M).The TNM staging applies only to tumors that have been microscopically confirmed to be malignant. Standard TNM staging (clinical and pathologic) is completed at initial diag-nosis. Clinical staging (cTNM or TNM) is based on informa-tion gained up until the initial definitive treatment. Pathologic staging (pTNM) includes clinical information and information obtained from pathologic