OHO-05(49-62) 11/16/02 10:51 AM Page 52 etiology OF CANCER 52 Hepatitis C (HCV) is a single-stranded RNA virus and primary infection results in acute hep atitis C infection. HCV infection is linked to the development of HCC. Herpes viruses Epstein \200\223Barr virus is an endemic lymphotrophic herpes virus. Primary infection of the oropharyngeal epithelium produces pharyn- gitis and subsequent B lymphocy te in \201ltration. Infection results in lifelong latent infection within lymphoid tissue and B-lymphocytes. A number of EBV encoded proteins have oncogenic potential (EBNA 1 and LM P 1). T-cell surveillance restricts the ability of these proteins to deregulate cell growth /apoptosis with consequent emergence of a lymphoproliferative disorder. EBV is associated with a number of human tumors including: (cid:2) Endemic Burkitt \200\231s lymphoma (BL). (cid:2) Non-endemic/sporadic BL. (cid:2) U ndifferentiated nasopharyngeal carcinoma (NPC). (cid:2) Hodgkin \200\231s disease. (cid:2) Lymphoproliferative disease and immunoblastic lymphomas, in immunocompromised host. Endemic Burkitt \200\231s lymphoma (BL) The majority of tumors in endemic form of BL contai n EBV DNA sequences. In addition, malaria P. falciparum infection occurs co- incidentally. Malaria infection is thought to depress cytotoxic T-cell function, thus rendering the patie nt relatively cytotoxic T-cell de \201cient and allowing the EBV infection to escape T-cel l surveillance. The role of EBV in non-endemic and AIDS-related BL is complex and less de \201nitive. EBV DNA is detectable in only 10 \200\22315% of patients with non-endemic BL an d 50% of patients with AIDS-related BL. Immunoblastic lym- phomas associated with chronic i mmunosuppression in allograft recipi- ents or AIDS patients and undifferentiated NPC invari ably contain EBV DNA sequences. In Hodgkin \200\231s disease, 50% of tumors contain EBV-inf ected cells and, in addition, the EBV genome has been demon- strated in the Reed \200\223St ernberg cells of Hodgkin \200\231s disease. Kaposi \200\231s sarcoma (KS) Kaposi \200\231s sarcoma (KS) is commonly associated with AID S, but was originally described in elderly men of Mediterranean, Middle Eastern, or Eastern European ethnic origin \200\224so-called \200\230classic \200\231 KS. It has also been do cumented in chronically immunosuppressed organ transplant recipients. Within the HIV-infect ed population, variations in develop- ment of KS exists; the risk of KS is highest in HIV-i nfected homo- sexual/bisexual men, compared with only a minority of HIV-infected OHO-05(49-62) 11/16/02 10:51 AM Page 53 VIRAL ONCOGENESIS 53 hemophiliacs, thus supporting the role of a sexually transmitted agent in the development o f KS. Using PCR, herpes-like DNA sequences have been demonstrated in AIDS-associated KS lesions. These sequences have been shown to be non-human and closely related to gamma herpes viruses , EBV, and the simian herpes virus (HVS). These herpes-like DNA sequences have been identi \201ed in all KS tissue and are thought to represent a new herpes virus, HHV 8 or KS-assoc iated herpes virus (KSHV). This supports earlier epidemiological data suggesting an infecti ve agent in the development of this tumor. Like EBV, HHV8 is lymphotrophic and has also bee n identi \201ed in peripheral blood mononuclear cells and two lymphoproliferative conditio ns, the rare body cavity lymphoma and in multicentric Castleman \200\231s disease. Retroviruses Sero-epidemiological and molecular data have established a causal role for HTL V-1 in adult T-cell leukemia (ATL). ATL presents with either a leukaemic or non-Hodgkin \200\231s T-cell lymphoma type picture, characterized by malignant organ in \201ltration, immunode \201ciency, lymphadenopathy, and hypercalcaemia. HTLV-1 is also associated with a chronic non-malignant disorder, tropical spastic paraparesis. HTLV-1 is trophic for CD4+ h uman T-cells, resulting in transforma- tion of infected cells. Human immunode \201ciency virus A number of speci \201c tumors are associated with HIV in fection and are AIDS-de \201ning. However, this association is not due to a direct oncogen ic effect of the HIV virus, but is the result of chronic immunosuppression. A long natural history of virus-associated tumors is accelerated in HIV-infected patients, again the resul t of failure of immune surveillance. OHO-05(49-62) 11/16/02 10:51 AM Page 54 etiology OF CANCER 54 Chemical carcinogenesis Chemical carcinogens are a principal cause of cancer and can be induced by certain lifestyl es e.g. smoking tobacco, exposure to chemi- cals in the community or workplace, some drug t aking. Chemical car- cinogenesis is a multi-stage process. Initiation and promotion When cells are initially exposed to a carcinogenic agent, genetic car- cinogens interact with DNA to form an adduct or to induce chemical alterations of DNA. DNA adducts may result in damage by inducing point mutations, deletions, or chromosomal tr anslocations. When changes are induced in genes involved in cell growth regulation or diffe rentiation (e.g. oncogenes and tumor suppressor genes), cell transformation can result. The majority of chemical carcinogens are metabolically activated, leading to the formation of reactive species \200\224the ultimate carcinogen. Metabolism is frequently mediated by c ytochrome P450 but in tissues and organs with low levels of cytochrome P450, the peroxidase component of prostaglandin synthetase or lipozygenase can activate. Metabolism involves en zymes mainly in the body \200\231s entry routes \200\224 respiratory tract, gastrointestina l tract, and liver \200\224though metabolism may occur elsewhere, leading to organ-speci \201c tumors. Cytochrome P450 exists as a number of isoforms, each having a dif- ferent substrate selecti vity. Activity and substrate speci \201city of both activating and detoxifying enzymes var ies from organ to organ, indi- vidual to individual, and species to species, resulting in o rgan- and species-speci \201c carcinogencity. If the affected cell neither dies nor revert s to a normal cell through error-free DNA repair, initiation becomes irreversible after the cell undergoes replication. The initiated tumor cell, with altered genotype and phenotype, may remain dormant for a lon g time before becoming a tumor, in the presence of a promoter, which may be one of a wide v ariety of chemicals. Promotion is reversible, so for an initiated cell to continue to repli cate, it must be exposed to a promoter more or less continu- ously. Carbon tetrachloride is a well-known example of a promoter resulting in liver cancer in animal studies. Hormones c an also act as promoters e.g. thyroid hormone is a promoter of thyroid cancer. Like initiat ion, progression is an irreversible process. Epigenetic carcinogens Epigenetic carcinogens do not damage DNA, but act at a later stage t hrough non-genotoxic mechanisms. They are frequently promoters. OHO-05(49-62) 11/16/02 10:51 AM Page 55 CHEMICAL CARCINOGENESIS 55 Excretion, with or without EXCRETED CHEMICAL CHEMICAL metabolism Intermediary metabolites (Proximate carcinogen) Bioactivation Covalent binding with REACTIVE METABOLITE (Ultimate carcinogen) CONJUGATED CHEMICAL nucleophiles e.g. reduced glutathione Covalent binding to macromolecules ALTERED GENETIC MATERIAL REPAIRED GENETIC MATERIAL (NORMAL CELL) Replication INITIATED tumor CELLS Promotion DIFFERENTIATED NEOPLASM Conversion and progression CANCER Genotoxic carcinogens and induction of cancer. Their mode of action is based on induction of cell division. They may be mitogenic agents, cytotoxic agents, or immunosuppressive agents. Peroxisome proliferators are an interesting class of epigenetic carcinogens, a chemically h eterogeneous group of compounds, OHO-05(49-62) 11/16/02 10:51 AM Page 56 etiology OF CANCER 56 including the lipid-lowering \201brate drugs and plasticizers such as di-(2-ethylhexyl)ph thalate and di-(2-ethylhexyl)adipate. They induce an increase in the number of peroxisomes in hepatocytes, and also increase liver DNA synthesis and cell proliferation in the rat, bu t the effect is not seen in man, possibly due to a lower expression of peroxisome prolifera tor-activated receptor (PPAR). Exposure Workers at risk from industrial chemical exposure include: (cid:2) Dye and textile workers (naphythylamines) \200\224bladder tumors. (cid:2) Chemical, rubber workers (benzen e) \200\224marrow tumors. (cid:2) Plastics, pesticide workers. (cid:2) Asbestos workers \200\224lung cancer, mesothelioma. Cancers resulting from lifestyle factors account for at least two-thirds of chemical induction of cancer. Tobacco smoke contains a broad range of c arcinogens. The risk of neoplasia increases dose dependent, in particular for lung, throat, esophagus, and urinary bladder cancer. Cigarette smoking has an important synergistic effe ct on the develop- ment of neoplasms caused by other carcinogens, for example in asbestosis , or miners exposed to radioactive elements. In food, pyrrolysis can result in the formation of polycyclic hydrocarbons and heterocyclic amines. 2-Amino-3,8-dimethyl- imidazol[4,5-f]auinoxaline (MeIQx) and 2-amino-1-methyl- 6-p henylimidaxzo[4,5-b]pyridine (PhiP) are potent genotoxic chemicals formed at parts per bill ion levels when meat is cooked. A \202atoxin B1 is a potent hepatocarcinogen in rodents; i n areas of extensive contamination of foodstuffs with A. Flavus there is a high incidence o f human liver cancer. Therapeutic drug use Chemical carcinogenesis can also result from the therapeutic use of dr ugs. An early example was the use of high dose of diethylstilbesterol, where a small percen tage of female offspring of mothers treated dur- ing pregnancy developed clear cell carcino ma of the vagina. Alkylating agents used to treat a number of neoplasms are carcinogenic. T he development of second neoplasms after chemotherapy is striking; N-acetyltransferase (NAT ) is a conjugating enzyme involved in the deactivation of aromatic amines. In a group of arylamine-exposed workers, slow acetylators were found to be at increased ris k compared with rapid acetylators. NAT2 rapid acetylation and fried meat intake represent a combined risk factor for colorectal cancer. The most widely expressed glutathione transferase gene, GSTM1, is polymorphic, with four co mmon phenotypes. About 45% of most pop- ulations are homozygous for deleted GSTM1*0 allele and do not express OHO-05(49-62) 11/16/02 10:51 AM Page 57 CHEMICAL CARCINOGENESIS 57 GST \200\224this value differs between countries and ethnic groups. GSTM1*0 homozygotes are more susceptible to several malignancies; in the case of lung cancer susceptibility, this is seen only in light smokers, pointing to the interactions between genetic and environment al factors. Chemoprevention (cid:2) Selenium. (cid:2) Anti-oxidative vitamins (e.g. vitamin E). (cid:2) Diet. (cid:2) D erivatives of indoles, \202avores, structurally related compounds of the brassia family. (cid:2) Green tea. OHO-05(49-62) 11/16/02 10:51 AM Page 58 etiology OF CANCER 58 Radiation carcinogenesis and radiosensitivity syndromes Ionizing radiation damages cellular contents, speci \201cally DNA, by interacting with mol ecular cellular components like water, iron, and oxygen to generate free radicals. These th en react with DNA leading to double- and single-strand breaks, base loss, and base mutation . Consequences of non-repair of these lesions are: (cid:2) Failure of transcription. (cid:2 ) Production of mutant or truncated proteins. (cid:2) Cell cycle arrest. (cid:2) Cell death . Effects to the organism as a whole include: (cid:2) Ageing. (cid:2) Carcinogenesis. (cid: 2) Organ dysfunction. Repair of induced damage is essential for cellular integrity and func - tion. De \201ciencies in cellular response to DNA damage result in a series of character istic syndromes called genomic instability disorders. They share common phenotypes like ear ly predisposition to cancer, immunode \201ciencies, and sensitivity to DNA-damaging agents such as ionizing radiation and alkylating agents. Radiation carcinogenesis Cancers after atomic bomb explosions include: (cid:2) Leukemia. (c id:2) Breast. (cid:2) Stomach. (cid:2) Lung. (cid:2) Thyroid. (cid:2) Skin. At a molecular level, the initiating factor is felt to be an induced mutation in a tumor su ppressor or proto-oncogene, with conse- quent aberrant loss or gain of function. Certain ge netic syndromes (e.g. hereditary retinoblastoma) are associated with increased risk of seco nd malignancies within the radiation \201eld. OHO-05(49-62) 11/16/02 10:51 AM Page 59 RADIATION CARCINOGENESIS AND RADIOSENSITIVITY SYNDROMES 59 Radiosensitivity syndromes Ataxia-telangiectasia (AT) AT is an autosomal recessive disorder characterized by: (cid:2) Development of telangiectasia (particularly on the bulbar conjunc- tiva). (cid:2) Progressive cerebellar ataxia. (cid:2) Premature ageing. (cid:2) Variable immunode \201ciencies. Patients develop cancer (usually lymphoma and leukemia) at an early age and show a hypersensitive response to therapeutic treatment with ionizing radiation. The defective gene responsible, ATM (AT mutated), has been iden- ti \201ed and cloned. It lies on chromosome 11q22.23, is approximately 150 kb in length and contains 66 exons. The g ene encodes a 3056 amino acid protein with molecular weight of 350 kDa. The protein is thou ght to function in the detection of oxidative DNA damage and DNA damage signal transduction . Nijmegen breakage syndrome (NBS) NBS is a very rare disorder characterized phenotypically b y: (cid:2) Presence of \200\230bird-like \200\231 facies. Immunode \201ciency. (cid:2) Growth retardation. (cid:2) Early development of cancer. The NBS gene has been cloned and lies on chromosome 8q21. It encodes an 85 kDa protein known as p95 or nibrin that has an essen- tial role in homologous recombination, which is important in double- strand break repair. (cid:2) Bloom \200\231s syndrome (BS) BS is characterized by: (cid:2) Growth retardation. Immunode \201ciency. (cid:2) (cid:2) Early development of cancer. Cells from BS show cytogenetic abnormalities character ized by an increased number of sister chromatid exchanges and in vitro sensitiv- ity to alk ylating agents and ionizing radiation. The BS gene has been cloned and lies at chromosome 15.q26.1. It encodes a 150 kDa protein t hat has structural motifs suggesting a function as a DNA helicase (protein essential for DN A replication, recombination, and repair). OHO-05(49-62) 11/16/02 10:51 AM Page 60 etiology OF CANCER 60 Fanconi \200\231s anemia (FA) Although not strictly a syndrome of radiosensitivity, FA is i mportant because cells show sensitivity to DNA cross-linking and alkylating agents. FA is d iagnosed by the presence of chromosomal aberrations when cells are exposed to mitomycin-C. Phenotypically, a number of characteristics may be seen: (cid:2) Absent thumbs and radius. (cid:2) Growth retardation. (cid:2) Bone marrow failure. (cid:2) Early susceptibility to ca ncer. Five different complementation groups of FA have been described; genes for two \200 \224groups FAA and FAC \200\224have been cloned. Individ- ually, both lie within cytoplasm but combine to form a complex of unknown function in nucleus. Others A number of other syndromes have been described in which sensitivi- ty to some form of DNA-damaging agent is seen: (cid:2) Gorlin \200\231s syndrome. (cid:2) Tuberose sclerosi s. (cid:2) Usher \200\231s syndrome. (cid:2) Gardner \200\231s syndrome. The relevance of c linical observation of sensitivity to the underlying genetic defect is still unclear. Perha ps a more interesting group of individuals are those (around 2 \200\2233%) who show undue s ensitivity to conventional doses of ionizing radiation without any obvious pre- treatment p henotype apart from the presence of cancer. It is probable that the same individuals are al so sensitive to chemotherapy that induces DNA damage. Investigation of such individuals has shown a variety of differing defects in DNA repair, cell cycle, and DNA dam- age signal tr ansduction. Given this heterogeneity, it is likely that pre-treatment predictive tests will be developed at cellular \200\224not molecular \200\224level. Treatment Clinically obvious cases of AT, FA, NBS, or BS who develop cancer should be treat ed, if possible, with agents that do not cause DNA dam- age. If necessary, it is possible t o assess cellular radiosensitivity before treatment and adjust doses accordingly, as normal radiosensitivity is re \202ected to tumor sensitivity. OHO-05(49-62) 11/16/02 10:51 AM Page 61 HORMONES IN THE etiology OF CANCER 61 Hormones in the etiology of cancer Different hormones and their related growth factors play a variety of roles in carcinogenes is in a number of malignancies, including cancer of the: (cid:2) Breast. (cid:2) Endometriu m. (cid:2) Prostate. (cid:2) Ovary. (cid:2) Thyroid. (cid:2) Bone. (cid:2) Testis. In these sites the cancer results from excessive hormonal stimulation of relevant target cells. The se effects occur independently of other aetiological agents like chemical carcinogens or io nizing radiation. In the 1960s, daughters of women treated with diethylstilbestrol (DES) during pregnancy wer e found to develop vaginal adenocarci- noma as they reached menarche, an indication that ho rmones could be both directly carcinogenic and involved in tumor promotion. Now it seems DE S causes persistence of Mullerian duct remnants in the vagina, and these are activated with the hormonal changes of puberty. There is some evidence that exposure of the male fetus to high levels of oestrogens can also have carcinogenic effects later in life, with increased risk of maldescent and testicular cancer. The role of hormones in promoting cancer is further shown by the fact that women whose ovar ies never secrete steroid hormones do not develop breast cancer. Hormonal factors associate d with an increased risk of breast cancer are: (cid:2) Early menarche. (cid:2) Late menopau se. (cid:2) Nulliparity. (cid:2) Late age at \201rst pregnancy. As with breast cancer, an increased risk of ovarian cancer is associat- ed with nulliparity . It is thought that promoters of ovarian cancer are growth factors that control normal rep air after ovulation (the fewer numbers of ovulations, the less risk of ovarian cancer). In endometrial cancer the risk of disease is related to exposure of the endometrium to oestrog ens, unopposed by the effects of progesterone (HRT, obesity, sequential oral contraceptives , late menopause). OHO-05(49-62) 11/16/02 10:51 AM Page 62 etiology OF CANCER 62 In laboratory animals, prostate cancer can be produced by exposure to large doses of exogen ous testosterone; in man, castration at an early age provides lifelong protection from this common tumor. However, circulating testosterone levels have not shown consistent differenc es between prostate cancer cases and controls, and studies of alteration in androgen recept ors have so far been inconclusive. Pimentel, E. (1987) Hormones, grown factors and oncogenes. Chapman and Hall, London. Hodges, G.M., Rowlatt, C. (1993) Developmental biology and cancer. Chapman and Hall, London. OHO-06(63-80) 11/16/02 11:07 AM Page 63 Chapter 6 Staging of cancer Imaging in the oncology patient 64 Biochemical markers 67 Germ cell tumors 69 Gastrointesti nal tumors 72 Ovarian cancer 73 Prostate cancer 75 Breast cancer 76 Other cancers 77 TNM st aging of cancer 78 Performance status 80 OHO-06(63-80) 11/16/02 11:07 AM Page 64 STAGING OF CANCER 64 Imaging in the oncology patient The radiologist is involved at every stage from the initial diagnosis through staging, radi otherapy planning, patient management, and follow-up. He/she participates in: (cid:2) Recur rence detection (cid:2) Re-staging (cid:2) Assessing complications of the disease and its t reatment Interventional procedures both curative and palliative (cid:2) (cid:2) Terminal care techniques including pain relief Common tumors such as those of the l ung, breast, and colon are often initially diagnosed by imaging (chest X-ray, mammography, and barium enema), to be con \201rmed by cytology or histology. Further imaging will depen d on tumor type, methods of spread, and the abil- ity of the diagnostic and interventional radiologist to help manage a particular patient. The primary tumor The radiological diagnosis of a primary tumor depends partly on the size and site of tumor and mode of clinical presentation. For example, a small pituitary gland t umor may be only just visible on high-resolution magnetic resonance (MR) imaging yet be cli nically obvious, whereas an asymptomatic 10 cm pulmonary carcinoma may only be discovered a ccidentally on a chest X-ray performed prior to anesthesia. The appearance of primary tumor s on imaging may be characteristic but only cytology and histology give de \201nitive proo f of tumor type. Tumors may produce their clinical effects by: (cid:2) Size (cid:2) Site (cid:2) Spread (cid:2) Paraneoplastic effects Spread of tumor Tumors may spread by: (cid:2) Local invasion (cid:2) Lymphatic and vascular channels (cid:2) Transcoelomic dissemination Local spread may affect clinical presentation , staging, management, and prognosis. For example, a tumor in the apex of a lung (Pancoast tumor) may spread into the chest wall and into the brachial plexus, OHO-06(63-80) 11/16/02 11:07 AM Page 65 IMAGING IN THE ONCOLOGY PATIENT 65 causing characteristic pain and neurological de \201cit. Where tumors abut tissue planes, imaging will often not indicate if the tumor has crossed such a plane. Pleural involvement by a peripheral lung carci- noma, for instance, will only be apparent at operation. Transcoelomic spread is often seen in colorectal and ovarian carci- nomas. Neither CT nor M R are good at showing peritoneal plaque disease, although both can readily demonstrate asci tic \202uid and bulk of a tumor. While imaging may suggest that ascites is due to periton eal disease, cytological proof will be necessary. Tumors may show characteristic spread via lymphatics e.g. bronchial carcinoma to mediastina l nodes, melanoma to regional nodes, and testicular tumors to para-aortic nodes. Other tumo rs (e.g. lung and breast carcinomas) spread by haematogenous means to the liver, brain, bon e, lung, and adrenal glands. The liver is a favorite site for spread from primary tumors in the gastrointestinal tract via the portal venous system. It acts as a venous \201lter wi th tumor emboli lodging and growing in the capillary bed. Contrast-enhanced CT will detect 90% of metastases greater than 1 cm, although solitary les ions require biopsy to con \201rm their nature. Monitoring treatment The primary tumor and any metastatic spread may be monitored by serial examination using the most appropriate technique. Such exam- inations allow measurement of tumor response to radiotherapy, chemotherapy, or other intervention. Recurrence of primary tumor after surgery can also be assessed by serial monitoring, though there may be dif \201culty in differentiating post-operative haematoma, \201brosis, and tumor. Modern tech niques, including Gadolinium- enhanced MR, are becoming more reliable and speci \201c. Interventional procedures These include:- (cid:2) Percutaneous \201ne-needle or core biop sy for cytology or histology under imaging control (U/S, CT) (cid:2) Embolization of vascular tumors pre-operatively (cid:2) Placement of intravenous and intra-arterial chemotherapy catheters Insertion of stents into malignant strictures e.g. gut, bile duct (cid:2) (cid:2) Laser surgery (cid:2) Pain relief Screening for cancer Mammographic screening of women aged >50 years is widely accept- ed an d improves the detection rate for early tumors and reduces OHO-06(63-80) 11/16/02 11:07 AM Page 66 STAGING OF CANCER 66 breast cancer mortality. Such screening programs necessitate high standards of quality assu rance and quality control, in particular the use of skilled radiologists. Radiotherapy planning The basic principles include de \201ning: (cid:2) Tumor volume, ofte n by CT or MR (cid:2) Target volume, which is tumor volume plus a margin of healthy tissue (cid:2) Treatment volume to achieve desired effect while avoiding radio- sensitive areas such as the spinal cord All aspects of such planning require imaging to ensure accurate and appropriate tumor irrad iation Radionuclide imaging Technetium 99m is an ideal diagnostic imaging radionuclide because of its photon energy, short half life of 6 hours, easy production, and ability to attach to a wide variety of radiopharmaceuticals. Some tumors have characteristic properties lending th emselves to imaging with such agents. Neuroendocrine and carcinoid tumors concentrate MIBG (meta-iodo-benzyl-guanidine) and thus can be used both for diagnostic and therapeutic purpo ses. Medullary carcinoma of the thy- roid has a high uptake of Technetium 99m DMSA (dimecap to-succinic acid). Cyclotron-generated isotopes used dynamically in PET (positron emission tomography) scanning show potential in certain areas including pancreatic and lung tumors w ith lymph node spread. OHO-06(63-80) 11/16/02 11:07 AM Page 67 BIOCHEMICAL MARKERS 67 Biochemical markers Tumor markers are detectable substances present in a concentration suggestive of a tumor. A tumor marker is not tumor-speci \201c, but may be secreted or shed into blood and other b ody \202uids or expressed at the cell surface in larger quantities by malignant cells tha n by non- malignant cells. Tumor markers can be assayed either by measuring the concentrati on of marker in body \202uids (usually by immunoassay) or by detecting the marker \200 \231s presence on the cell surface in paraf \201n section or fresh biopsies (by immunohist ochemistry). The potential clinical uses of tumor marker estimation are: (cid:2) Screening (cid:2) Diagnosis (cid:2) Prognosis (cid:2) Monitoring response to therap y (cid:2) Early diagnosis of relapse Gestational trophoblastic tumors Diagnosis and screening Elevated levels of human chorionic gonadotrophin (HCG) are always s een in choriocarcinoma, but can also be found in normal pregnancy, ectopic pregnancy, in so me patients with germ cell tumors, and, occasionally, in patients with non-germ cell tumors . Following diag- nosis and evacuation of a hydatidiform mole, patients are followed using serial HCG measurements in blood or urine. Screening allows patients with persistent tropho blastic disease to be detected on the basis of plateauing or rising tumor markers before cl inical evidence of a tumor develops. Prognosis/monitoring response to treatment The level of HCG at presentation is a major fact or in deciding if a patient falls into a good or poor prognostic group. Serial HCG estima- tion is used to monitor response to chemotherapy and to detect devel- opment of drug resist ance. It has a serum half-life of 18 \200\22336 hours. Plateauing or rising of HCG values d uring a course of chemotherapy indicates the development of drug resistance and the need to change chemotherapy. Detection of recurrence Serial measurement of HCG will detect any recurrence of tropho- bla stic tumor with 100% sensitivity. Accurate measurement of HCG OHO-06(63-80) 11/16/02 11:07 AM Page 68 STAGING OF CANCER 68 in urine increases the ease of monitoring and obviates the need for frequent hospital visit s. A rise in HCG is not, however, diagnostic of recurrent disease and a new pregnancy must always be considered and ruled out by ultrasound examination. OHO-06(63-80) 11/16/02 11:07 AM Page 69 GERM CELL tumors 69 Germ cell tumors Alpha-feto protein (AFP) and HCG are elevated, either singly or in combination, in more tha n 80% of patients with disseminated non- seminomatous germ cell tumors (NSGCT) and in about 60% of patients with stage 1 disease prior to orchidectomy. Another marker useful in patie nts with germ cell tumors is lactate dehydrogenase (LDH). Placental alkaline phosphatase (P LAP), although elevated in about 50% of patients with seminomas, is also raised by cigarett e smoking, and adds little to clinical management. Diagnosis All patients suspected of having a germ cell tumor should have a baseline tumor m arker estimation before excision of the primary tumor. Patients whose clinical status could be compromised by biop- sy should be considered for an NSGCT if disease distribution is co m- patible with such a tumor and there is gross elevation of either HCG or AFP. An elevated HCG can be found in patients with pure semino- ma but a patient with an elevated AFP shoul d never be considered to have a pure seminoma, regardless of histological \201ndings. Failure of tumor marker levels to fall to normal post-operatively indicates the presence of occult metastatic disease. Prognosis and staging Patients should be classi \201ed according to the risk factors shown in the table. Monitoring response to treatment Successful chemotherapy is invariably accompanied by a fal l in serial HCG and AFP levels. The serum half-life of AFP is 5 \200\2237 days. An initial rise in tumor marker levels may occur soon after starting the \201rst course of chemother apy, due to tumor lysis. Occasionally, a plateau or even a rise in AFP levels may occur, de spite evidence of response from all other investigations. This is due to AFP production by the liver in response to toxicity, most commonly after hepatotoxic drugs such as methotrexa te and ifosfamide. Early recurrence detection All patients with germ cell tumors should continue to have seria l tumor marker estimation after completion of chemotherapy to detect relapse early. Serial marker estimation is also invaluable as part of the surveillance program of patients with s tage 1 disease O H O 7 0 0 6 ( 6 3 8 0 ) 1 1 / 1 6 / 0 2 Table 6.1 Assessment of prognosis by marker in germ cell tumors 1 LDH (cid:2) upper limit normal 1 AFP ng/ml HCG IU/L : 0 <1.5 \227 upper limit normal 1.5 \200\22310 \227 upper limit normal >10 \227 upper limit normal and and <500 Good risk >1000 7 1000 \200\22310 000 or 5000 \200\22350 000 or Intermediate A M or or >50 000 Poor risk >10 000 P a g e 7 0 OHO-06(63-80) 11/16/02 11:07 AM Page 71 GERM CELL tumors 71 following orchidectomy. Because tumor markers can double rapidly, it is important that they are measured at least monthly, and more fre- quently if raised. OHO-06(63-80) 11/16/02 11:07 AM Page 72 STAGING OF CANCER 72 Gastrointestinal tumors The most widely used serum marker for colorectal cancer is carci- noembryonic antigen (CEA) . CA 19.9 has an epitope structurally identical to the sialylated Lewis A antigen and is el evated in 75 \200\22390% of patients with pancreatic carcinoma. Diagnosis and screening Serum CEA is elevated in about 65% of patients with distant metas- tases, in 44% of Dukes \200\231 stage C, about 25% of Dukes \200\231 stage B, and fewer tha n 5% of patients with Dukes \200\231 stage A colorectal cancer. CEA can also be elevated in : (cid:2) Severe benign liver disease In \202ammatory lesions, especially of the gastrointestinal tract (cid:2) (cid:2) Trauma Infection (cid:2) (cid:2) Collagen disease (cid:2) Renal impairment (cid:2) Smoking A low incidence of high s erum CEA levels in early disease and its poor speci \201city explain its lack of value in screening normal populations for colorectal cancer. A low sensitivity precludes it being us eful for screening patients even in high-risk groups such as ulcerative colitis or familial polyposis coli. Monitoring treatment Serum CEA levels should fall to normal within 4 \200\2236 weeks of com plete resection of a colorectal carcinoma. Levels usually rise with disease and fall with r esponse to chemotherapy or radiotherapy. Failure of CEA to fall during radiotherapy usually indicates the presence of a tumor outside the radiation \201eld. Several studies have sh own that survival is longer in patients with a fall in serum CEA level during chemotherapy than in those in whom there is no change or an increased level. Follow-up and detection of relapse In about 65% of patients with recurrent colorectal cance r, a rise in ser- ial serum CEA values predicts recurrence, on average 11 months before it becomes clinically apparent. OHO-06(63-80) 11/16/02 11:07 AM Page 73 OVARIAN CANCER 73 Ovarian cancer CA 125 is the most commonly used tumor marker for ovarian cancer and is found in derivative s of coelomic epithelium, including pleura, pericardium, and peritoneum, but not in normal ovarian tissue. Diagnosis CA 125 is elevated in >95% of patients with advanced (stage III or IV) ovarian ca ncer, but in <50% of patients with stage I disease. Levels >30 IU ml \200\2231 are frequent ly seen during the \201rst trimester of pregnancy in patients with endometriosis or cirrh osis, especially if ascites is pre- sent. It is elevated in >40% of patients with advanced non-ovarian intra-abdominal malignancies and in 1% of healthy controls. Screening Apart from women at high risk of familial ovarian cancer, screening for ovarian c ancer should not be offered to women outside a clinical trial. CA 125 has no proven value i n screening for ovarian cancer. Prognosis and response to treatment Very high CA 125 levels prior to surgery are associated with a worse prognosis. In women with stage I disease a pre-operative level >65 U/ml is a powerful adverse prognostic indicator, and such patients are candidates for chemotherapy ra ther than surveillance. Elevated CA 125 levels after one, two, or three courses of chemo- t herapy are important adverse prognostic factors for survival. Serial changes in CA 125 are recognized as one of the best methods for monitoring therapy. A persistently elevated CA 125 after oophorectomy for suspected stage I disease is evidence of residual tumor. A biological response based on CA 125 has been de \201ned as either a 50% or a 75% reducti on in CA 125 levels. To reduce the chance of falsely predicting a response, the 50% CA 125 response de \201nition requires four CA 125 levels \200\224two initial elevated samples, a nd the sample showing a 50% decrease requires con \201rmation by a fourth sample. The 75% CA 125 response de \201nition requires only three CA 125 levels, with a serial decrease of at least 75%. In both 50% and 75% response de \201nitions, the \201nal sample has to be at least 28 days after the previous sample. Detection of progression or relapse A serial rise of CA 125 of >25% is the most accurate me thod of predicting progression of ovarian cancer during therapy. There is OHO-06(63-80) 11/16/02 11:07 AM Page 74 STAGING OF CANCER 74 controversy however over the role of serial CA 125 measurements during follow-up. However, if relapse is suspected, a con \201rmed dou- bling from the upper limit of normal during f ollow-up predicts relapse with almost 100% speci \201city. OHO-06(63-80) 11/16/02 11:07 AM Page 75 PROSTATE CANCER 75 Prostate cancer Prostate-speci \201c antigen (PSA) has superseded prostatic acid phos- phatase as a marker , as it is elevated in a higher proportion of men with prostate cancer. Diagnosis, screening, and staging Elevated levels of PSA (>4 ng ml \200\2231) occur in abou t 53% of men with intracapsular microscopic and 77% of men with intracapsular macro- scopic prostatic cancer, but can also occur in 30 \200\22350% of men with benign prostatic hypert rophy (BPH). A combination of PSA and digi- tal rectal examination, followed by prostatic u ltrasound in patients with abnormal \201ndings, is commonly used for screening in US but is not recommended in the UK. As yet, there is no de \201nite evidence of survival bene \201t from screen detection of early prostate cancer. About 40% of patients with PSA levels of 4.0 \200\2239.9 ng ml \200\2231 at screening will already have tumor spread outside the prostate. The ratio of free to total PSA is being used to improve diagnostic speci \201city \200\224 more of the PSA is protein-bound in patients with prostate cancer compared with BPH. The ra tio of free to total PSA is low (about 10%) in prostate cancer compared to >16% in BPH and prostatitis. Bone or lymph node metastases are usually, but not always, associated with an elevated PSA. Prognosis/monitoring response/recurrence detection A high pre-treatment PSA is associated w ith a poor prognosis. PSA levels fall rapidly to undetectable levels after complete removal of a tumor by radical prostatectomy. The rate of fall is slower and the nadir higher after successful radiotherapy or endocrine therapy. A ser- ial rise in PSA frequently precedes o ther evidence of disease progres- sion in the patient with a past history of prostate cance r. Development of bone pain in the presence of an elevated PSA level suggests the developme nt of bone metastases. OHO-06(63-80) 11/16/02 11:07 AM Page 76 STAGING OF CANCER 76 Breast cancer The most widely investigated mucin marker in breast cancer is CA 15-3. Diagnosis and screening Although elevated levels of CA 15-3 are found in 55 \200\223100% of patients with advanced breast cancer, serum CA 15-3 is raised in only 10 \200\22346% of pa tients with primary breast cancer and in about 10% of patients with early (T1-2NoMo) operab le disease, as well as 2 \200\22320% of patients with benign breast disease. Prognosis/monitoring response to treatment Elevated pre-operative levels of CA 15-3 are ass ociated with a poorer prognosis. Although tumor marker levels can fall with reduction in tu mor burden following system therapy, the variation between patients makes this tumor marker unreliable for assessing response. Early detection of relapse The observation that over 60% of patients who develop recurrent breast cancer have raised levels of CA 15-3 suggests potential value in early detection of recurrence. OHO-06(63-80) 11/16/02 11:07 AM Page 77 OTHER CANCERS 77 Other cancers (cid:2) Serum AFP is elevated at presentation in 50 \200\22380% of UK patients with hepatoc ellular carcinoma and may be used in screening of high-risk populations. (cid:2) Neuron-speci \201c enolase (NSE) is elevated in many patients with advanced small- cell lung cancers and in children with neuroblas- toma. (cid:2) Paraprotein levels are very important in the management of patients with myeloma, w here B2-micro-globulin may be of prog- nostic value. (cid:2) Carcinoid tumors can be monitored by urine levels of 5-hydroxy- indole acetic acid (5HIAA), and polypeptides such as gastrin or glucagon are useful in the management of rare gastrointestinal tumors. (cid:2) Squamous cell carcinomas are associated with elevated levels of squamous cell carci noma antigen (SCC) as well as cytokeratin frag- ments. SCC and CA 125 give valuable prognos tic information in patients with cervical carcinoma and may indicate relapse before scans. (cid:2) Calcitonin and calcitonin-related peptide are used in diagnosis and screening for medullary thyroid carcinoma. (cid:2) Serum S-100 and reverse transcriptase polymerase chain reaction to detect mRNA of t yrosinase on circulating melanoma cells are being studied for staging and follow-up of pati ents with melanoma. OHO-06(63-80) 11/16/02 11:07 AM Page 78 STAGING OF CANCER 78 TNM staging of cancer Staging is the assessment of a patient \200\231s tumor burden. It rises from the observatio n that survival rates are higher for cases in which disease is localized rather than dissem inated. It is performed prior to therapy and can be subdivided into clinical, radiological, and pathological.