A tumor marker is a biochemical indicator for the presence ... Tumor Marker Laboratory at the Pittsburgh. Cancer ...... files.137.138The NMR spectra obtained in.
Tumor Markers in Cancer Diagnosis and Prognosis Mohamed A. Virji, MD Donald W. Mercer, PhD Ronald B. Herberman, MD
Introduction A tumor marker is a biochemical indicator for the presence of a tumor. In clinical usage, the term usually refers to a molecule that can be detected in plasma or other body fluids. Table I summarizes the major concep tual developments in the history of tumor markers. Bence Jones proteins in urine and the serum levels of acid phosphatase have been employed for many years as indica tors for multiple myeloma and prostatic adenocarcinoma, respectively. Although efforts were made in the early decades of this century to identify tumor-specific anti gens, the number of markers in clinical use remained limited, and almost none were available for the more common cancers.
markers. The search has yielded an ever increasing variety of tumor markers with differing tissue specificity and sensitivity. These discoveries have been made in com bination with several developments, most notably those of rapid, highly sensitive, immunoassay techniques to provide reli able quantitation; hybridoma technology for an unlimited supply of monoclonal an tibodies with defined specificities; recom binant DNA methodology for molecular genetic analysis of genomic alteration and expression in cancer cells; and refinements in protein purification and sequencing methods. This overview discusses the currently available tumor markers in cancer diagno sis and prognosis.
The discovery of alpha-feto@@t@Th' (AFP) as a marker for hepatomas, and car cinoembryonic antigen2 (CEA) as a marker for colon carcinoma, provided a fresh im petus for the search for specific tumor Dr. Virji is Director of the Tumor Marker Lab oratory at the Pittsburgh Cancer Institute, Uni versity of Pittsburgh School of Medicine, in Pittsburgh, Pennsylvania. Dr. Mercer is Clinical Associate Director of the Tumor Marker Laboratory at the Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, in Pittsburgh, Pennsylva nia. Dr. Herberman is Director of the Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, in Pittsburgh, Pennsylva nia. 104
Defining a Tumor Marker An ideal tumor marker would be expected to have high sensitivity and specificity for cancer and fulfill certain criteria.3 It would be produced and released primarily by transformed cells or by other tissues in re sponse to the tumor, at levels proportional to the state of differentiation and the mass of tumor cells. A therapeutic response or alteration in the state of the neoplastic tis sue would be reflected in a change in the production of the marker such that tumor ablation or recrudescence would result in an appropriate change in the level of the marker. Furthermore, elevated marker lev els would be seen in patients with small CA-A CANCERJOURNALFORCLINICIANS
amounts of tumor present, so that residual primary or recurrent tumors could be de tected at times appreciably earlier than would be possible by conventional diag nostic procedures. Most of the tumor markers currently
available for clinical use do not fulfill these criteria. The only constant abnormality ex pressed in a cancer cell is that of growth inconsistent with the physiologic needs of the tissue where the tumor originates. This heritable alteration in growth is not accom panied by other consistent expression of eithera singlebiochemicalfactoror a groupofmoleculesthatcouldbe usedasan imprint to distinguish a neoplastic from a normal cell.4 The detection of a molecular marker to serve as an indicator specific for a tumor depends upon the constantproductionof that molecule by the tumor, but not at all, or not above a background level, by non tumor cells. However, the production of the molecule may vary not only between similar tumors from the same organ, but also from the same tumor, since there is cellular heterogeneity within the same tu mor represented by differences in the rate of growth, the stage of differentiation, and, therefore, the expressionof biochemical features that could potentially be consid ered as markers for malignancy.5 The pro duction of such marker molecules may also be increased from normal tissues in re sponse to certain physiologic stimuli, thus further confounding the utility of a mole cule as a specific tumor marker. In practice, therefore, a tumor marker can be defined as a biochemical indicator that is usually found in abnormal concen tration in the presence of a neoplasm. Vir tually no tumor marker, however, has been shown to be specific or sensitive enough to use in the detection of tumors in the general population.
Categories of Tumor Markers Tumor markers can be divided into two broad categories—tumor-derived, mole cules produced by the neoplastic cells: and tumor-associated (or host-response), met abolic and immunologic products of nor VOL 38. NO 2 MARCH/APRIL1988
mal tissues produced in response to the presence of the neoplastic tissue. Both these groups include different types of molecules (Table 2). Tumor-Derived
Markers
Tumor-derived markers that are products of the cancer cell include differentiation antigens (lymphocyte surface markers);' oncofetal antigens (CEA, AFP); isoen zymes (neuron-specific enolase [NSE]; prostatic acid phosphatase [PAP]); hor mones (human chorionic gonadotropin
[HCG]; adrenocorticotropic hormone IACTHI); tissue-specific proteins (alpha
Virtually no tumor marker has been shown to be specific or sensitive enough to use in the detection of tumors in the general population.
lactalbumin, prostate-specific antigen); on cogenes and their products: and mucins and other glycoproteins or glycolipids. Until recently, it was believed that tu mor cells, by virtue of transformation, could acquire the ability to elaborate novel molecules not found in normal cells, and the search for such products was actively pursued in certain cancers. Apparently, uniquemoleculesforvarioushuman tu mors were initially thought to be identified, but rigorous studies revealed that these molecules were present in normal cells at certain stages of development or at low levels of expression.6 Transformed cells may produce sub stances that are not present in the normal differentiated tissues in which the tumor arose (ectopic molecules, ACTH, vaso pressin production by small cell carcino mas of lung), or that are characteristic of normalembryonicdevelopment(oncofetal antigens). 105
Oncofetal antigens are produced by neoplastic cells that are usually derived
antibody
Not only are these molecules not tissue specific, but they are also increased in cer tain benign conditions and are not present
roglobulin, C-reactive acute-phase reactants.
in all the tumors derived from the same
Tumor Markers in Clinical Use
response
to an altered
antigen
originating from the tumor tissue with sub from tissuesin which theseantigensare sequent antigen-antibody complex forma tion. Attempts have been made to isolate expressed normally during fetal develop ment, but they also occur in tumors arising the antigens from immune complexes and from unrelated tissue.78 Thus. AFP pro identify their possible use as tumor duced by hepatoma cells is elaborated by markers.2° the fetal hepatocytes. but it is also produced Other such markers include isoen by lung, testicular, and intestinal cancers.9 zymes. beta2-microglobulin. alpha@-mac
tissue.'°― AFP levels increase in cirrhosis
when cellular regeneration occurs. and in creased serum levels are observed in only
protein,
and other
tumor to therapy; a decline in serum levels follows tumor ablation, and increasing lev
The main function ot' tumor markers in clinical medicine has been as laboratory tests to confirm the diagnosis of a cancer serum or urine electrophoresis to identify a monoclonal peak for the myeloma proteins in multiple myeloma. CEA determination in colon cancer, and serum PAP levels in prostate cancer21.23 Tumor markers are also increasingly being used to determine
els denote failure of therapy or recurrence
the response to therapy and as an indication
up to 70 percent of all hepatomas.'2
These features limit the usefulness of the markers as screening
tests. They can.
however, confirm a diagnosis of cancer and are helpful in following
the response of a
of the disease. In this regard, HCG has proven to be a useful indicator for guiding
of relapse during the follow-up period.24'26 Experience with a range of markers has therapyinchoriocarcinoma and forindicat increased the awareness that both sensitiv ing progno5is.@3To a lesser extent, PAP for ity and specificity of an individual marker prostate cancerand CEA forbreastcancer are important in determining the role of a have providedsimilar information.'4'5 marker for a particular use. Studies designed to provide informa tion for a marker should address several issues: the presence of a pathologic level of Tumor-Associated(Host-Response) the marker as a biochemical indicator ac Markers companying a neoplastic process versus its Tumor-associated markers have been used absence in health: the relationship of the with tumor-derived markers to provide ad marker to benign tumors and other disease ditional information about certain cancers, processes of the same tissue: the relation to determine or confirm the extent of the ship of the marker to different tumor stages disease or its prognosis. and to therefore and histologic variants; the effect of the tumor burden on the concentration of the aid in therapeutic management. Serum fer ritin levels in neuroblastoma, determined marker and the rapidity of a decline or rise together with NSE levels, have been shown in the levels with a decrease or increase in to correlate with both disease stage and tumor mass: and the relationship of the therapeutic response. 16While the elevation marker to other markers of relevance. Al of serum levels of femtin, an acute-phase though such multistep studies could neces reactant producedmainlyintheliver, could sitate a concerted effort for every new tu reflect a response to tumor burden, it could mor marker identified, markers that have also be produced by tumor cells.'7―8 the potential to provide information for Immune complexes are found in the clinical decisions could be readily evalu serum of many patients with cancer, as ated through this process. well as in patients with other diseases.'9 Of the markers available, serum 1-ICG Theirpresenceincancermay indicate an provides information most useful for detec 106
CA-A CANCER JOURNAL FOR CLINICIANS
Year
Investigator(s)
concept
Observation
1846
Bence-Jones
Specific Proteins
Proteins inurine asmarkers for multiple myeloma (immunoglobulin light chains)
1928
Brown
Ectopic Hormones
Ectopic production ofhormones bytumors
1930
Zondek
Humanchorionicgonadotropin
1932
Gushing
Adrenocorticotropic hormone
1933
Gutmanet al
1959
Markert
lsoenzymes
Prostaticacidphosphatase in prostaticcancer lsoenzymesin tissue
differentiation 1960
Newell
1963
Abelev1
Ghromosomal Aberrations
Philadelphia chromosome
Oncofetal
Alpha-fetoprotein in livercarcinoma
Antigens
1965
Garcinoembryonic antigenin coloncancer
Gold and
Freedman2
1969
Huebnerand Todaro1@
Oncogenes
Oncogenes astransforming factors
1975
Kohler and Milstein
Monoclonal Antibodies
Monoclonal production of antibodies ofdefined specificities
VOL.38.NO.2 MARCH/APRIL 1988
107
tion, choice of therapy, and determination of the course of choriocarcinoma.27'28 In familial medullary thyroid carcinoma (MIC), serum calcitonin levels are sensi tive indicators for the presence of the can cer, which is otherwise undetectable by radioisotope scans or palpation; the serum levels of the hormone also correlate with the extent of disease. In individuals at high risk for MIC, regular screening with serum calcitonin is performed for early detection, and then subsequent to therapy, for moni toring response.29 Measurements of serum HCG and AFP in patients with germ cell tumors of the testis have been shown to correlate with the extent of disease. Serial measurements are valuable in following the
prove diagnostic accuracy, as has been at tempted in the diagnosis of ascites due to ovariancancer.4° A special use of immunohistologic techniques for tumor markers is in the diag nosis and classification of leukemias. B and I lymphocytes express cell surface differ entiation antigens during normal matura tion, characteristic of the cell lineage.4'
The disordered or arrested maturation of malignancy is marked by the presence of specific cell surface antigens for which probes in the form of monoclonal antibod ies have been developed.42 In a still evolv ing process, these probes are used for char acterization of leukemias and lymphomas
for cell lineage, maturation state, and alter
response to therapy and in the detection of residual disease and tumor recurrence.3° Other markers, such as CEA, have not ful filled the initial expectations of specificity
ations induced by treatment.43 It has been shown, therefore, that acute lymphoblastic leukemia is heterogeneous, and subgroups consisting of different I- and B-cell matur for colon carcinoma or sensitivity for de ation steps have been defined. tection of early stages of the disease;3―32 Through the use of DNA probes for information from clinical studies, how immunoglobulingenesortheI-cellrecep ever, has shown CEA's utility as a marker tor gene, it has also been shown that both in post-therapy management of patients B-cell and I-cell cancers represent mono withcolonand breast cancers.2233'35 clonal expansion of transformed cells.44 The histopathologic diagnosis of can This has resulted in a correlation between cer has been refined by the introduction of the cancer's cell type and the therapeutic immunochemistry techniques for the detec response observed. With the use of flow tion of tumor markers in tissue biopsies.36 cytometry techniques and monoclonal an The array of monoclonal antibodies of de tibodies, itis now possible to confirm mono fined specificities has aided in the definitive clonalproliferation incaseof relapseand diagnosis of tumors that are otherwise dif to determine appropriate therapeutic strate ficult to diagnose, and has also revealed the gies. This use of cell surface markers is heterogeneity in the distribution of a based on the presence of cellular matura marker within the tumor, indicating the tion and differentiation antigens. A similar nonuniformity of the antigen production in concept has been the basis for attempts at different areasofthesame tumor.37 Mono identifying maturation/differentiation anti clonal antibodies to different epitopes on a gens in other tissues, but has not yet re molecule, as for CEA, have also shown sulted in clinically applicable uses. expression of specific antigenic forms in In the field of radioimmunoimaging, certain tissues.38 The tissue expression of tagged antibodies have found initial appli an antigen determined immunohistologi cations in locating and mapping metastases cally—for example, CEA in colon can or delivering lethal irradiation locally to the cer—does not always correlate with the tumor.45 Although several antibodies have levels found in serum; this is probably due proved useful for imaging small, otherwise to a difference in the functional secretory occult metastatic lesions, the sensitivity mass of the tumor and the total tumor mass limitation remains at about one gm of tu containing the antigen.39 Histopathologic mor, and many radiolabeled antibodies are identification by immunochemistry and tu taken up in considerable amounts in some mor marker levels in serum or other body normal tissues, particularly in the liver or fluids could be used in combination to im spleen. In experimental studies, toxin 108
CA-A CANCERJOURNALFORCLINICIANS
Human chorionic gonadotropin Antidiuretic hormone Parathyroidhormone Calcitonin Insulin-like growth factors Catecholamines and metabolites
Aipha-fetoprotein carcinoembryonic antigen
Prostaticacid phosphatase Neuron-specificenolase Regan ALP isoenzyme LDH.1
ImmunoglobulinsProstate-specific antigenAipha-lactalbuminBeta2-microglobulin
CA-i 25CA-19-9CA-i 5-3,-,c@srcN-mycH-ras
Polyamines
Sialic acid Glycolipids
Ferritin Immunecomplexes Enzymes (LDH, GDH, CK-BB) Acute phase proteins Key:LDH = Lacticdehydrogenase CK-BB= Creatine kinase, BB isoenzyme
VOL.38,NO 2 MARCH/APRIL 1988
GDH = Glutamate dehydrogenase ALP = Alkalinephosphatase
109
tagged
antibodies
against
specific tumor
markers have been found to deliver the toxin at the site of a tumor and result in a decrease in tumor mass upon activation of the toxin.46 These applications are not yet part of routine clinical use, but they do demonstrate the potential for innovative approaches to targeted therapy using tumor markers.
Serum Tumor Markers in Diagnosis and Prognosis Only a few of the tumor markers for which tests have become available are in routine clinical use (Table 3). The most frequent use is as a confirmatory test at the time of initial diagnosis of cancer, together with a batteryof other diagnosticprocedures. Such use, however, if restricted to the time of diagnosis when histopathologic findings are already known, may be inappro
priate.3'47 The tumor markers are most use
@
ful if utilized not only as confirmatory tests, but also as a part of routine follow-up. The sequential estimation of a tumor marker level during the follow-up period and the chronology of the pattern obtained could thenbe correlated withtheresponseinthe patient to tumor therapy or as an indicator of recurrence. In only a few tumors are serum tumor markerlevels currently utilized asa partof routine clinical follow-up studies or as a regular guide to therapeutic decisions. In addition, the markers are usually followed individually rather than used as a selected panel of tumor-derived and tumor-associ
ated markers. The pattern of current tumor marker use is related to the empirical infor mation about a marker, the perceived ease of interpretation of the laboratory result in the clinical setting, and a reliance on other factors tojudgethecourseofthedisease.
trations in the serum and is also present in the semen. The immunochemical methods (counterimmunoelectrophoresis and ra dioimmunoassay [RIA]) are more sensitive analytically than the older enzymatic method, but do not have a greater sensitiv ity for detection of prostate cancer. 23.5ii@52 In adult males, the upper limit of serum concentration of PAP that can be detected with most of the RIA kits available is five ng/ml. Although serum PAP levels become elevated with extracapsular growth of pros tate cancer in 24 to 71 percent of patients. in most patients with early disease the serum concentration is within the normal range, thereby precluding use of the assay
in screening high-risk individuals.3'53'54 The serum levels correlate with the pres ence of metastatic disease, and PAP in bone biopsy samples has been employed for confirming bone-marrow metas tasis.'4'55 PAP, however, is not a sensitive indicator for the response to therapy, be cause only about one half of patients show a correlation between a decrease in serum enzyme concentration and reduction in tu mor mass, and in a small percentage of
patients serum levels do not increase as the disease worsens. 4.23,24.56 A new protein marker for prostate can cer, serum prostate-specific antigen (PSA), has recently become available: its clinical
utility, however, remains to be further evaluated
Human Chorionic Gonadotropin The placental hormone HCG comes closest to being an ideal tumor marker, since it fulfills most of the needed criteria. Its use in both gestational and germ-cell-derived choriocarcinomas
is well established
for
diagnosis of the tumor and estimation of its size and response to treatment, and during follow-up.
Prostatic Acid Phosphatase The prostatic isoenzyme of acid phospha tase is assayed by enzymatic methods or @
immunochemically The low pH, phosphoric monoester hydrolase from ly sosomes is normally found in low concen 110
HCG is produced by syncytiotropho blasts in the placenta during normal gesta tion and forms the basis for pregnancy tests for urine or serum samples; it is first de tected in plasma at five days and reaches a peak at eight to 10 weeks.6° l-ICG is a glycoprotein hormone of 45.000 molecular CA-A CANCER JOURNAL FOR CLINICIANS
Alpha-Fetoprotein
Liver, Testis
Carcinoembryonic Antigen
Colon, Lung, Breast
Human Chorionic Gonadotropin
Trophoblastic Tumors, Germ Cell Tumors of Testis
Calcitonin
Medullary Cancer of Thyroid
Prostatic Acid Phosphatase
Prostate
CA-i25
Ovary
Immunoglobulins
Multiple Myeloma
weight, is composed of two peptide sub units, and is structurally similar to thyroid stimulating hormone (TSH), follicle-stim ulating hormone (FSH), and luteinizing hormone (LH) from the anterior pituitary. The alpha-subunits of the hormones have structural homology, but the beta-subunits have unique carboxyl terminals.6163 Anti bodies directed against the beta-subunits have replaced the older immunoassays for laboratory determination of HCG, since these antibodies detect only HCG and should have no significant cross-reactivity with the other related hormones. To deter mine the analytic specificity for HCG, however, it is nonetheless important to de termine the information about cross-reac tivity of a new antibody. Using the beta subunit specific assays, the normal serum concentration of HCG in the nonpregnant state is less than one ng/ml. The half-life of
HCG is approximately 24 hours.26'@°'62 HCG is produced by all tumors contain ing syncytiotrophoblastic tissue, as well as by several other cancers—carcinomas of VOL.38.NO.2 MARCH/APRIL 1988
the lung, gastrointestinal tract, breast, and ovary; melanoma; and lymphoproliferative disorders.M67 Unlike the situation in preg nancy, tumor production of HCG is accom panied by varying degrees of release of free subunits.59'62'63 Less than 30 percent of the nontrophoblastic tumors produce HCG, and these tumors usually produce smaller amounts of the hormone. HCG levels are also increased in some non-neoplastic dis eases.62 There is a linear relationship between the trophoblastic tumor mass and the serum HCG level,68 and serial HCG measure ments are used in high-risk patients with hydatidiform mole to identify those whose disease has progressed to cancer. 3,26,69 HCG's value in screening for nonsemi nomatous testicular tumors, however, is limited by a lower sensitivity of detection for early disease.70'7' Persistent high or ris ing levels of serum HCG following re moval of a hydatidiform mole indicate a need for further therapeutic interven tion.26,27 111
The serum levels of HCG usually fall rapidly following successful treatment, and a plateauing at high levels or increases dur ing therapy may indicate drug resistance with a need for reevaluation of the treat ment regimen. Some patients with chorio
carcinoma may show a paradoxical rise of HCG initially
following
treatment and clin
ical response.27-72 This is believed to be due to the differentiation of some previ ously nonproductive tumor cells to hor mone-producing cells and may also be due to cell lysis with release of the hormone; it does not necessarily reflect treatment fail ure. Serial measurements of HCG are therefore important in determining re sponse 27.28 Serum levels of HCG are also of prog nostic value. Circulating levels above 8,000 ng/ml are usually associated with a poor prognosis unless the patient receives intensive therapy.3.26.27.73
seen in approximately two thirds of patients with hepatomas and germ cell tumors of the testis.9'@2-77Cholangiocarcinomas do not
show any increase in serum AFP, and ele vations occur in less than 25 percent of patients with gastrointestinal, pancreatic, and lung cancers.77'8°Non-neoplastic dis eases of the liver—cirrhosis, hepatocellu lar necrosis, and hepatitis—can also cause increased levels ofAFP, and some patients with metastatic liver disease also show in creased serum levels. 10.81.82 AFP levels decline rapidly following surgical resection of hepatocellular carci nomas or treatment of testicular germ cell
tumors. Serial measurements are of value in determining the presence of residual dis ease or relapse.77-82'83 AFP is measured se rially together with HCG in patients with testicular germ cell tumors to provide a sensitive index of response to therapy and disease recurrence 30
Alpha-Fetoprotein
Carcinoembryonic
The discoveryin 1963by Abelevand col leagues of a novel protein in the sera of adult mice bearing hepatomas led to re newed interest in the identification of tumor markers.―74 The protein, AFP, is normally present in fetal mice. Initial studies using a relatively insensitive immunodiffusion technique showed the presence of AFP in most of the patients with clinically apparent hepatocellular carcinomas 75,76 AFP is a single-chain glycoprotein of 70,000 molecular weight.77 It has sequence homology with albumin and is the major plasma protein in the fetus.78 AFP is pro duced in the yolk sac, liver, and gastroin testinal tract of the fetus and reaches a peak serum concentration of three ng/ml at 12 weeks of gestation. The levels decline after birth and reach the adult levels of one to 25 ng/ml by age one.9-77'78 AFP's plasma half life is approximately six days. Although increases in serum AFP are found in patients with hepatomas, the use of AFP determinations with sensitive ana lytic techniques to screen for hepatomas in high-risk patients provides only a relatively low yield of early, treatable tumors.'2'79 AFP increases (greater than 40 ng/ml) are
CEA,
112
a cell
Antigen surface
glycoprotein
of
200,000 molecular weight,@ was identified in 1965 by Gold and Freedman by immu nizing rabbits with an extract of human colon carcinoma.2'85 CEA is present in em bryonic tissues in the gastrointestinal tract, pancreas, and liver during the first two trimesters of gestation. Adult tissues were initially thought to be devoid of the anti gen, but very sensitive assays utilizing an tibodies to specific epitopes on the mole cule have shown expression of the antigen
on cells of normal colonic mucosa, as well as on other tissues. 38.86-88The diversity of epitopes to which the antibodies are di rected also makes it difficult to compare the serum concentrations determined by differ ent antibodies or to switch between kit methods, although the commonly used RIAs set the upper limit at 2.5 ng/ml.89 The half-life of the molecule is variable, but following removal of a tumor source of CEA, the levels should return to normal in six weeks.9° Increases in serum CEA levels also oc cur in many benign diseases—inflamma tory bowel disease, benign liver diseases, renal disease, pulmonary inflammatory CA-ACANCER JOURNAL FORCLINICIANS
disease,and collagendisorders—and in heavy smokers.31'3The levelsin these situations are usually below 10 ng/ml.91'92 CEA elevations are associated with many cancers, including carcinomasofthe liver, lung, breast, and pancreas.93'@ Pa tients with colorectal polyps have a 20 per cent incidence of increased levels.3' Pre
operative CEA levels have a bearing on prognosis,
since they correlate
with the
Dukes' grading of colon cancer, with stages progressing from A2 to D showing increases in 25 to 80 percent of pa tients.22'97 Well-differentiated colon can cers produce CEA, but poorly differen tiated tumors lack CEA. Screening for
colon cancer with CEA is not useful be cause of the low sensitivity for early dis ease and the association of increased levels with nonmalignant diseases.3133 In pa tients with recurrent colonic polyps, how ever, serial determinations of CEA are used in clinical follow-up in conjunction with
other investigations.
clinical use. Some of these new markers are discussed below.
Prostate-Specific Antigen PSA is@a biochemically and' immunologi cally distinct molecule isolated in 1979 from the prostate gland.'°3 It has a molec ular weight of 33,000 and is a glycosylated single-chain peptide.'°3―°5 Itsfunctionin
the normal gland is unknown. Although the molecule is prostate specific. it is not pros tate tumor specific. In adult males, the nor mal serum levels measured with an enzy matic immunoassay are less than four
ng/ml.'°6 Investigations haveshown thatpatients with benign prostatic hyperplasia or stage A malignant disease have similar slight ele vations (mean of 4.8 ng/ml), but patients with stage B and more widespread disease have levels more than twice the upper limit of normal.'03 A combination of PAP ‘¿and PSA determination has been reported to improve the sensitivity for detecting the disease. 03107 It appears, however, that
In patients with CEA-positive colorec talcancers, post-therapy serial serumCEA determinations are indicative of residual PSA could be most useful in monitoring diseaseifthelevelsdo notdeclineby six therapy and disease progressions. 03. OR
weeks.25'39'9° Recurrence is also indicated
Lower pretreatment levels of PSA are also
by a rising CEA level, with the tumor marker increases preceding clinically de tectable disease, sometimes by months.98 False-positive elevations due to inflamma
correlated with a better prognosis. 103
tory disease are also seen, however, as are false negatives in .a few cases of recurrence
Neuron-Specific
Enolase
NSE is the brain neuronal form of the gly
enolase. It is present in or nonresponse to therapy. peripheral and central neuroendocrine CEA levelsin breastcancercorrelate cells.'°'@ Increases in serum levels have with thetumor stageand with metastatic been found in 69 percent of .94 newly diag disease; most patients have increased levels nosed patients with small cell carcinoma of
(greater than five ng/ml).'5'@ Following re section of the tumor and successful chemo therapy, CEA levels fall in breast cancer patients.34'35 The serial follow-up of CEA
level has been useful as an indicator of tumor recurrence. IS.OO@ 02
colytic enzyme
the lung, and it may be useful in monitoring treatment.@°―@ NSE levels in neuroblas toma, a childhood tumor arising in the sym pathetic ganglia or adrenal medulla, show a correlation with the stage of the disease and also provide a prognostic and therapeu
tic guide. 16.112114Very high levels are cor New Tumor Markers for Specific Cancers Many new tumor markers, primarily tu mor-derived, have recently become avail able (Table 4). Most of these have yet to be fully evaluated and introduced into routine VOL.38,NO 2 MARCH/APRIL 1988
related with advanced stage and poor prog nosis. In stages III and IV neuroblastoma,
both serum NSE and femtin are markedly increased) 12.115There is experimental evi dence that the ferritin in neuroblastoma
may be derived from the neoplastic cells. 18.116 113
Prostate-Specific Antigen
Prostate
Tumor-Associated Antigen (TA-4)
Uterine Cervix
CA-i9-9
Pancreas, Colon
CA-i5-3
Breast
NSE
Small Cell Carcinoma of the Lung, Neuroblastoma
CK-BB
Lung, Breast, Prostate
LD-1
Testis
Key: NSE = Neuron-specificenolase CK-BB= Creatine kinase, BB isoenzyme
CA-125 CA-l25 is a cell-surface glycoprotein as sociated with cells of ovarian carcinoma. but is not found in normal adult ovarian cells.''7 Serum CA-l25 levels in healthy adults are less than 65 U/I. Serum CEA levels are increased in less than 25 percent of patients with ovarian carcinomas. CA-125. however. may provide the sensi tivity needed: according to the results of one study. 75 percent of patients with ovar ian cancers were reported to have elevated levels of CA-l25.''@ Increases in serum CA-l25 also occur during menstruation and pregnancy. with values up to 140 U/mI 114
LD-1 = Lactate dehydrogenase-1
during the first and second trimesters. I 9 Serum CA-125 may also be elevated (greater than 4(X) U/ml) in patients with liver cirrhosis. When used together with serum CEA assay. CA- 125 improves the positive identification of ovarian carcino mas. The half-life of the marker in plasma is about six days. In a recent report, CA-125 determina tion in malignant effusions and ascites was used with cytologic findings to diagnose ovarian cancer.4―20 The utility of CA- 125 for monitoring therapy and prognosis is not fully determined, but initial studies suggest that the levels correlate with tumor size and recurrence. CA-A CANCER JOURNAL FOR CLINICIANS
CA- 125 is present in normal fallopian tubes, in the endometrium, and in ovarian surface epithelium involved in the inflam matory process. The mesothelium and res piratory epithelium also show the presence of the antigen.
New Tumor-Associated (Host-Response) Markers The presence of neoplastic cells triggers
varying degreesofhostresponse, including the activation of the immune system, with participation of lymphocytes and macro phages. A number of molecules produced by these cells have recently been identified. CA 19-9 These molecules—lymphokines and cyto CA 19-9isa glycolipid antigen, probably kines—modulate the immune response. the Lewisa blood group hapten, originally
isolated from a human colorectal carci noma cell line.'2' Although CA 19-9 serum levels have a concordance with CEA con centration, some gastrointestinal tumors
that are positive for CEA do not have de tectable levels of CA 19-9. The marker's value in colorectal cancer, when used in conjunction with CEA, remains to be deter mined, but increases in CA 19-9 in inflam matory bowel disease and biliary disease
may limit its use. In recent studies, CA 199 has been shown to be useful in the diag nosis of pancreatic cancer, since blood lev
els can help differentiate pancreatitis from cancer. 122.123In this group
of patients,
however, other inflammatory bowel dis ease needs to be ruled out as the cause of
abnormal levels.
Tumor-Associated
lnterleukin-2
Receptors
Interleukin-2 (IL-2 or T-cell growth factor) is a 15,000 molecular weight glycoprotein
secreted by activated T cells that exerts its effects on other T cells by binding to spe cific cell surface receptors.43 These recep tors are also induced by cell activation and
have been identified as a 55,000 molecular weightglycoprotein. The receptor protein is shed by the cells into circulation and can be detected by an immunoassay tech
nique.'28 The levels of soluble receptor in plasma could potentially be used as an in dicator of the host response to tumors and be helpful in monitoring therapy. IL-2 re ceptors are also found on activated B cells, and their presence on the cell surface has been used for immunocytochemical identi fication of hairy cell leukemia.
Antigen
Tumor-associated antigen (TA-4) was pur ified by Kato et al from human uterine
Tumor Necrosis Factor
cervical mucosa in 1977, and preliminary
Tumor necrosis factor (TNF), or cachectin,
studies indicate that the serum levels cor
is produced by endotoxin or gamma-inter
relate with the stage of cervical squamous
feron-activated macrophages. TNF is a 17,000 molecular weight polypeptide cy tokine that binds to specific cell receptors. TNF induces hemorrhagic necrosis of tu mors and has many other effects, both sys temic and immunoregulatory. It appears to
carcinoma.'24―25In a follow-up study, ele vated post-therapy serum levels were found in patients with short survival.'26
An immunoassay for a subfraction of the TA-4 antigen, called squamous cell car cinoma-associated antigen (SCC-antigen), has also been developed. In a study of pa tients with head and neck squamous cell carcinoma, TA-4 was found to be elevated in 45 percent of the patients before treat ment. Following treatment, disease recur rence was associated with elevated levels in 92 percent of the patients with initially abnormal values.'27 VOL.38, NO.2 MARCH/APRIL 1988
be a mediatorofgeneral inflammation, and recombinant TNF hasbeenusedinclinical trials toaugmentthehostimmune response in cancer patients.'29-'3° Sensitive assays for serum TNF levels are only now becom ing available for investigational use, and
the role of TNF as a marker for host re sponse in cancer patients remains to be established. 115
Neoptenn
Neopterin is a metabolite formed in macro phages and lymphocytes, from guanosine triphosphate.
Activated and rapidly prolif
erating cells produce increased amounts of neopterin, which can be detected in plasma and urine. It has been suggested that neop tern levels could be used as an additional marker for the immunologic response in the host to the tumor, but its clinical utility has
not been fully evaluated.'3' IL-2 receptors (soluble), TNF, and neopterin are all indicators of immune (lymphocyte and macrophage) activation. Since the activation may be in response to a tumor or a nontumorigenic stimulus, these indicators are not specific for re sponse to cancer. Tumor Markers of General Applicability Periodically, reports have appeared pur porting to show that a biochemical deter mination
is indicative
of the presence of
cancer, regardless of the type of tumor and clinical stage.'32'35 In some cases, the data are inadequate to fully evaluate the value of such a marker, but considering the tissue heterogeneity of tumors, the extent of clin ical stage, and the variation in individual responses to the presence of a cancer, such tests would have to overcome several hur dles. Many of these tests have been shown in rigorous
studies to lack the specificity
that would allow their use as general tumor markers. Tests of recent interest in this category are outlined below. Information
on other tests has appeared in a review by Klavins. 132 Nuclear Magnetic Resonance Plasma Lipids
of
Fossel et al recently described the applica tion of the technique of water-suppressed proton nuclear magnetic resonance (NMR) spectroscopy for the analysis of spectral patterns of plasma samples from patients with malignant and benign tumors, from normal controls, from patients without tu mors, and from women with normal preg 116
nancies.'36 This technique was selected on the basis of previous reports that cancer patients have changes in plasma lipid pro files. 137.138 The NMR spectra obtained in the study group were analyzed for lipopro tein line widths.
The data obtained in the study showed that healthy controls and patients with be nign tumors and non-neoplastic diseases had similar spectral line widths that were different from those obtained from plasma samples from patients with untreated can cers, including breast, gastrointestinal, genitourinary, hematologic, and lung can cers, and lymphomas. However, plasma from pregnant subjects and samples from patients with benign prostatic hyperplasia had NMR spectral features similar to those found in the group with cancer. In a sepa rate group of patients who had already undergone treatment for cancer, the line width data had a wide scatter. The reported NMR spectral informa tion is tantalizing and needs to be pursued further to answer the questions about the biochemical basis for the observations, the effect of therapy on the spectral changes, the findings in chronic inflammatory dis ease, and the replicability of the findings by other investigators. This technique of identifying “¿oncolipids― may have other limitations due to the highly sophisticated and expensive means of analysis; these lim itations could possibly be overcome by identification of the molecular basis for the
observed differences between the groups and by developing a biochemical tech nique, if feasible. Oncogenes and Their Products Oncogenes are viral genes that have the potential to induce neoplastic transforma tion in cells. The existence of oncogenes was initially postulated by Huebner and Todaro to explain the mechanism of viral transformation of cells.'39 Viral oncogenes of RNA-containing retroviruses cause neo plastic transformation in susceptible host cells.'39 It is believed that the retroviruses may have acquired these genetic elements from mammalian cells originally, during viral infection and replication, where these CA-A CANCERJOURNALFORCLINICIANS
U, Co
(-. ui_i_ I -
0. (3 C')
C
Co
. .
--
u
H.
I
0) > 0) C
:@.
-@
I II
.0
C
z
z
0)—
0)C0 32 CQ) Oc >0)
H' fl
It II .@Co
o
VOL. 38, NO.2
MARCH/APRIL1988
117
Oncogene
Product FunctIon
Cancer
sis
Growth Factor'
SimianSarcoma
erb-B
CellSurface Receptors'*
ChickenErythroblastosis
neu
Rat Neuroblastoma
mos
MouseMaloneySarcoma
HER-2/neu
HumanBreast Cancer
src
ProteinKinase
ChickenRousCarcinoma HumanCML Lymphosarcoma
abi
MouseAbelson Leukemia
yes
ChickenSarcoma
H-rae
GTPBinding
Rat,Harvey Sarcoma HumanCarcinoma Sarcoma
K-ras myc
HumanLeukemia Lymphoma DNABinding
ChickenMyelomatosis HumanCarcinoma,Sarcoma, Leukemia
N-myc
HumanNeuroblastoma
myb
ChickenMyelomatosis
cit-A
Undefined
Chicken Erythroblastoma
B Iym-1
HumanLymphoma
met
Human Osteosarcoma
Oncogenes are given a three-letter, lower-case designation indicatingthe tumor and/or species in which they were initiallyidentified.An upper-case preceding letter is a modifierto distinguishsimilarlydesignated but differentoncogenes.
•¿ Homologous to platelet-derived growth factor. •¿ ‘¿The oncogene product is similar to the intracellular-activated portion of the cell surface receptor for epidermal growth factor.
CML = Chronic myelogenous leukemia
118
GTP
Guanosine 5'-triphosphate
CA-ACANCER JOURNAL FORCLINICIANS
Cancer/Site
MarkerS'
Breast
CEA, CA 15-3, Alpha-Lactalbumin,
Colorectal
CEA, CA 19-9, Beta-HCG
Lung (Small Cell)
AFP, CEA, NSE, Antidiuretic Hormone,ACTH
Neuroblastoma
NSE, HVA, VMA (Urine), Plasma-Catecholamines
Prostate
PAP, PSA, Gamma-Seminoprotein
Regan ALP lsoenzyme
‘¿Only tumor-derived markers are indicated. Selected tumor-associated (host-response) markers (ferritin, immune complexes, and acute phase proteins) could also be included in the panels.
ACTH = Adrenocorticotropichormone
HVA = Homovallinicacid
AFP ALP CEA CK-BB
NSE PAP PSA VMA
= = = =
Alpha-fetoprotein Alkaline phosphatase Carcinoembryonic antigen Creatine kinase, BB isoenzyme
genes served regulatory functions in the cellular genome. ‘¿@‘ Genetic elements sim ilar to viral oncogenes have been identified in eukaryotic cells. This plausible mecha nism of evolutionary acquisition of regula tory mammalian genes is therefi@re sup ported by the observations that the oncogenes bear a close similarity to certain mammalian genes, that they code for prod ucts that are regulatory cellular compo nents, and that the oncogenes in the retro viruses are in some cases incomplete copies of similar cellular genes or are incorporated in the middle of other genetic compo nents. 41.142 The cellular counterparts of
VOL 38, NO 2
MARCH/APRIL 1988
= = = =
Neuron-specific enolase Prostatic acid phosphatase Prostate-specific antigen Vanillylmandelic acid
the viral oncogenes are known as proto oncogenes. These are believed to be ac tivated in cancers due to mutational or chromosomal rearrangement events (see figure). Table 5 summarizes information about many of the oncogenes that have been iden tified to date. Oncogene activation has been detected in some cancers. and their proba ble products have also been identified.'4@ The oncogenes are not specific for a partic ular cancer. Tests have been developed to detect oncogenes in human cancer tissues and for some of their products in body fluids. 43 u Panels composed of such tests 119
fordetection of theoncogeneproductsin
plasma or other body fluids may be poten tially useful for the detection of oncogene associated cancers in high-risk groups. Strategies for Use of Serum Tumor Markers
@
The clinical usesofindividual serumtumor markers available' in routine laboratory use are well established and fall into the follow ing categories: confirmation of clinical diagnosis, indication of response to ther
apy, .early or confirmatory indication of tumor recurrence as part of follow-up as sessment,
and assessment
of prognosis.
Screening in high-risk groups for tumors using tumor-derived markers like CEA has been shown to be unproductive.
Tumor Marker Test Panels Tumor marker test panels have been de vised, composed of tumor-derived and tu mor-associated markers; statistical criteria have been formulated for interpretation of the combination used and to guide the se lection most appropriate for a particular cancer. 145-147Such an approach is effort
intensiveiind although it is notwidely ac cepted, there are indications that it can be useful, as has been shown in studies on patients with lung and prostate can Experience is necessary, how ever, to determine if such an approach is clinically useful in patients being prospec
tively ‘¿followed for the more common forms of cancer. Such panelsforspecific cancersmight be composed of primary, tumor-derived markersas wellas selected tumor-associ
ated markers (Table 6). The individual panels could be evaluated for the selected tumor, at the time of diagnosis, before ther apeutic intervention, in comparison with benign and nonmalignant
conditions,
and
in different tumor stages. A panel tested in this preliminary setting could then be fur ther evaluated for changes attributable to
therapeutic response, prognostic value, The use ofThesemarkersinscreening for and disease recurrence, as well as for fac specific tumors,even inhigh-risk groups, tors not primarily related to the cancer being'studiecl, but -which could affect the is limited due to a lack of appropriate speci ficity and sensitivity. The newer tumor test result.
markers that are becoming available are for tumors for which markers were either pre viously unavailable or considered inade quate in some regard. In the latter case, such as for PAP in prostate cancer, there
Better Use of Currently Available Markers
are indications thatthe use of measure
More appropriate use could be made of individual markers already available. the clinical utility of the markers by en Screening in high-risk groups for tumors abling earlier stages of .the cancer to be using tumor-derived markers like CEA has detected.103 None of the markers that ‘¿have'been shown to be ‘¿unproductive. Most beenclaimedininitial studies tobe general markers do have a place in following thera indicators forcancerhave yetfoundappli peutic response, assessing prognosis, and cability, because of either a lack of sensi detecting relapse. Most of theseusesrely tivity for detection of early tumors or non on serial measurements of the marker with specificity due to pathologic alterations in analytic methods that provide consistent non-neoplastic diseases. results. Rather than simply utilizing a tu Strategies to increase the sensitivity mor marker test during the initial eval and specificity of tumor marker tests are uation of cancer, following the levels of discussed below. tumor markers serially against the back
ments of both PAP and PSA could increase
120
- CA-ACANCERJOURNALFORCLINICIANS
ground
of clinical
and other diagnostic
findings will enhance the value of the tumor marker in providing information that could be used in therapeutic decisions and evalu
ation of prognosis. This has clearly been shown to be the case for HCG in choriocar cinoma, and shows promise for other mark ers for specific tumors.
ReferenCes 1.Abelev01,PerovaSD, KhramkovNI,etal: Production of -embryonal alphaglobulin by transplantable mouse hepatomas. Transplanta tion1:174—180, 1963. 2. Gold P, Freedman SO: Demonstration of tu mor-specific antigens in human colonic carci nomataby immunologic tolerance andabsorp tion techniques. J Exp Med 121:439—462,1965. 3. Coombes RC, Neville AM: Significance of tumor-index-substances in management, in Stoll BA (ed): Secondary
Spread in Breast Can
cer. Chicago, William Heinemann Medical ‘¿Books, 1977, pp 113—138. 4. Harris H: Neoplasia, in Weatherall DJ, Led ingham JOG, Worrell DA (eds): The Oxford Textbook of Medicine. United Kingdom, Ox fordUniversity Press, 1983,pp4—46. 5. Farber E: The multistep nature of cancer de velopment.
Cancer Res 44:4217—4223, 1984.
13. Bagshawe KD: Risk and prognostic factors in trophoblastic neoplasia. Cancer 38:1373— 1385, 1976. 14.Richards B,Sylvester R,dePauw M, etal: The clinical value of the serum acid phosphatase in carcinoma
of the prostate,
in Pavone-Maca
luso M, Smith PH (eds): Cancer of the Prostate and Kidney. New York, Plenum Publishing, 1981, pp 167—177. 15. Palazzo 5, Liguori V. Molinari B, Ctal:The role of carcinoembryonic antigen in the post mastectomy follow-up of primary breast cancer and in-theprognostic evaluation of disseminated breast cancer. Tumori 70:57—59,1984. 16. Hann H-WL, Stahlhut MW, Evans AE: Is ofcrritins and prognosis of neuroblastoma: The immunological role of acidic isofemtins, in Al bertini A, et al (eds): Femtins
and Isofemtins
and Biochemical Markers. Amsterdam, Neth 6. Houghton AN, EisingerM, Albino AP, et al: erlands, Elsevier Scientific PubI By, l984, pp Surface antigens of melanocytes and melano 171—180. -mas:-Markers of melanocyte differentiation and 17.Crichton RR: Femtin: Structure, synthesis melanomasubsets. JExp Med 156:1755—1766, and function. N EngI J Med 284:1413—1422, 1982. 1971. 7. Waldmann TA, Mclntire KR: The use of a 18. Hann HW, Stahlhut MW, Millman I: Hu radioimmunoassay for alpha-fetoprotein in the diagnosis of malignancy. Cancer 34:1510— man femtins present in the sera of nude mice transplanted with human neuroblastoma or 1515, 1974. 8. Gold P, Shuster J, Freedman SO: Carci hepatocellular carcinoma. Cancer Res 44: 3898—3901,1984. noembryonic antigen (CEA) in clinical mcdi 19. Baldwin RW, Robbins RA: Circulating im cine@Historical perspectives, pitfalls and projec mune complexes in cancer, in Sell S (ed): Can tions. Cancer42:1399—1405, 1978. cer Markers: Diagnostic and Developmental 9. Wepsic HT: Alpha-fetoprotein: Its quantita tion and relationship to neoplastic disease, in Significance. Clifton, NJ, The Humana Press Kirkpattrick AM, NakamuraRM (eds): Alpha Inc., 1980, pp 507—531. 20. -Theofilopoulos AN, Dixon FJ: Immune fetoprote.in. Laboratory Procedures and Clinical Applications. New York, Masson, 1981, pp complexes associated with neoplasia, in Herber man RB, Mclntire KR (eds): Immunodiagnosis 115—129. Inc., 10. Furukawa R, Tajima H, Nakata K, et al: of'Cancer. New York, Marcel ‘¿Dekker 1979, pp 896—937. Clinical significance ofserumalpha-fetoprotein inpatients withliver cirrhosis. Tumour Biol 21. Paredes JM, Mitchell BS: Multiple mye loma: Current concepts in diagnosis and man 5:327—338,1984. 11. Zamcheck N: Carcinoembryonicantigen: agement. Med Clin North Am 64:729—742, 1980. Quantitative variations in circulating levels in 22. Wolmark N, Fisher B, Wieand HS, et al: benign and malignant digestive tract diseases. Theprognostic significance ofpreoperative car Mv Intern Med 19:413—433,1974. cinoembryonic antigen leveis in colorectal can 12. ‘¿Trichopoulos D, Sizaret P. Tabor E, etal: Alphafetoprotein levels ofliver cancer patientscer: Results. from NSABP (National Surgical andcontrols ina Europeanpopulation. Cancer Adjuvant Breast and Bowel Project) clinical trials. Ann Surg l99@375—382, 1984. 46:736—740,1980. VOL. 38. NO.2
MARCH/APRIL1988
121
23. Pontes JE: Biological markers in prostate cancer.JUrol 130:1037—1047,1983. 24. Johnson DE. Prout OR. Scott WW. et al: Clinical significance of serum acid phosphatase levels in advanced prostatic carcinoma. Urology 8:123—126.1976. 25. Martin EW Jr. Minton JP. Carey LC: CEA directed second-look surgery in the asympto matic patient after primary resection of colorec
tal carcinoma. Ann Surg 202:310—317.1985. 26. ZárateA. MacGregor C: Beta-subunit hCG and the control of trophoblastic disease. Semin Oncol9:187—l90, 1982. 27. Bagshawe KD: Trophoblastic disease, in Caplan
RM, Sweeney
Wi (eds): Advances
in
Obstetrics and Gynecology. Baltimore. Wil liams & Wilkins. 1978. pp 225—237. 28. Lokich ii: Tumor markers: Hormones, an tigens. and enzymes in malignant disease. On cology 35:54—57.1978. 29. Wells SA Jr. Baylin SB. Oann DS. et al: Medullary thyroid carcinoma: Relationship of method of diagnosis to pathologic staging. Ann Surg 188:377—383.1978. 30. Newlands ES. Begent RHJ. Rustin GJS. et al: Further advances in the management of ma lignant teratomas of the testis and other sites. Lancet 1:948—951,1983.
40. Pinto MM. Bernstein LH. Brogan DA. et al: Carcinoembryonic antigen in effusions: A diagnostic adjunct to cytology. Acta Cytol 31:113—118. 1987.
41. Foon KA. Todd RF 3d: Immunologic clas sification of leukemia and lymphoma. Blood 68:1—31.1986. 42. Vodinelich L. Greaves MF: Monoclonal antibodies to human leukemia antigens. in Wright GL ir (ed): Monoclonal Antibodies and Cancer. New York. Marcel Dekker. Inc. 1984.
pp 209—240. 43. Freedman
AS. Nadler
LM: Cell surface
markers in hematologic malignancies. Semin Oncol l4:l93—2l2, 1987. 44. Desforges
iF: T-cell receptors.
N EngI J
Med 3 13:576—577.1985. 45. Pateisky N. Philipp K. Skodler D. et al: Radioimmunoscintigraphy of the lymphatic sys tem versus intravenous
application
of tumour
associated monoclonal antibodies: Indications and clinical
usefulness
in the management
of
cancer patients. NucI Med Commun 5:540—541. 1984 (Abstract).
46. Myers CD. Thorpe PE. Ross WCJ. et al: An immunotoxin with therapeutic potential in T cell leukemia: WTI-ricin A. Blood 63: 1178—I 185. 1984. 31 - Fletcher RH: Carcinoembryonic antigen. 47. Herberman RB: Summary of discussion on Ann Intern Med 104:66—73.1986. general assays for immunodiagnosis of human 32. Stevens DP. Mackay lR, Cullen KJ: Carci cancer. in Herberman RB ted): Compendium of noembryonic antigen in an unselected elderly Immunodiagnostic Assays for Cancer. New population. A four-year followup. Br J Cancer York. Elsevier/North-Holland Publishing Co. 32: 147—151.1975. 1979. pp 3—5. 33. Beatty JD. Romero C. Brown PW. et al: 48. Sudhof H. Meuniann 0. Oloffs i: Alpha Clinical value of carcinoembryonic antigen: Naphthylphosphat als substrat zur erfassung der Diagnosis, prognosis. and follow-up of patients sauren phosphatase prostatischer Herkuntt. with cancer. Arch Surg 114:563—567.1979. Deutsch Med Wschr 89:217—219.1964. 34. Coombes RC. Dearnaley DP. Ellison ML. 49. Cooper iF: The radioimmunochemical et al: Markers in breast and lung cancer. Ann measurement of prostatic acid phosphatase: Clin Biochem 19:263—268.1982. Current state of the art. Urol Clin North Am 35. Caftier H. Brandau H: Serum tumor mark 7:653—665.1980. ers in metastatic breast cancer and course of 50. Griftiths JC: Prostate-specific acid phos disease. Cancer Detect Prey 6:451—457.1983. phatase: Re-evaluation of radioimmunoassay in 36. Triche Ti: Morphologic tumor markers. diagnosing prostatic disease. Clin Chem SeminOncol 14:139—172.1987. 26:433—436.1980. 37. Lee SH: Cancer cell estrogen receptor of 51. Foti AG. Herschman H, Cooper IF: A human mammary carcinoma. Cancer 44:1—12. solid-phase radioimmunoassay for human 1979. prostatic acid phosphatase. Cancer Res 38. Reynoso 0. Keane M. Reynoso MA: Mon 35:2446—2452.1975. oclonal carcinoembryonic antigen antibodies, in 52. Chu TM. Wang MC. Scott WW. ci al: Sell S. Reisfeld RA (eds): Monoclonal Antibod Immunochemical detection of serum prostatic ies in Cancer. Clifton. Ni. The Humana Press acid phosphatase: Methodology and clinical Inc. 1985. pp 19—40. evaluation. Invest Urol l5:3l9—323, 1978. 39. Ravry M. Moertel CO. Schutt AJ. et al: 53. Bruce AW. Mahan DE. Belville WD: The Usefulness of serial serum carcinoembryonic role of the radioimmunoassay for prostatic acid antigen (CEA) determinations during anticancer phosphatase in prostatic carcinoma. Urol Clin therapy or long-term follow-up of gastrointes North Am 7:645—652.1980. tinal carcinoma. Cancer 34: 1230—1234.1974. 54. Watson RA. Tang DB: The predictive value 122
CA-ACANCER JOURNAL FORCLINICIANS
of pro@taticacid phosphatase as a screening test for prostatic cancer. N EngI J Med 303: 497—499.1980. 55. Belville WD. Mahan DE. Sepulveda RA. ci al: Bone marrow acid phosphatase by ra dioimmunoassay: 3 years of experience. i Urol 125:809—811.1981.
56. Ahmann FR. Schifman RB: Prospective comparison between serum monoclonal prostate specific antigen and acid phosphatase measure ments in metastatic prostatic cancer. i Urol 137:431—434,l987. 57. Kuriyama M. Wang MC. Papsidero LD. et al: Quantitation of prostate-specific antigen in serum by a sensitive enzyme immunoassay. Cancer Res 40:4658—4662.1980. 58. Kuriyama M. Wang MC. Lee Cl. et al: Use
68. Searle F. Boden J. Lewis JC. et al: A human choriocarcinoma xenograft in nude mice: A model for the study of antibody localization. Br iCancer44:137—l44. 1981. 69. Bagshawe KD. Lawler SD: Unmasking moles. Br J Obstet Gynaecol 89:255—257.1982. 70. Norgaard-Pedersen B. Schultz HP. Arends J. et al: Tumour markers in testicular germ cell tumours: Five-year experience from the DATECA Study 1976—1980.Acta Radiol lOncoll 23:287—294. 1984.
71. Peckham Mi. Barrett A. Husband JE. et al: Orchidectomy alone in testicular stage I non seminomatous germ-cell tumours. Lancet 2:678—680.1982. 72. Browne P. Bagshawe KD: Enhancement ot' human chorionic gonadotrophin production by of human prostate-specificantigen in monitor antimetabolites. Br I Cancer 46:22—29.1982. ing prostate cancer. Cancer Res 41:3874—3876. 73. Bagshawe KD: Risk and prognostic factors 1981. in trophoblastic neoplasia. Cancer 38: 1373— 1385. 1976. 59. KillianCS. YangN. EmrichU. et al: Prog nostic importance of prostate-specific antigen 74. Abelev GI: Alpha-fetoprotein as a model for monitoring patients with stages B2 to TI for studying reexpression of embryonic antigens prostate cancer. Cancer Res 45:886—891.1985. in neoplasia. in Herberman RB. Mclntire KR 60. Anderson T. Waldmann TA. Javadpour N. (eds): Immunodiagnosis of Cancer. New York. Inc.1979.pp76—101. et al: Testicular germ cell neoplasms: Recent MarcelDekker. advances in diagnosis and therapy. Ann Intern 75. Tatarinovlu 5: Obnaruzhenie embriospetsi Med 90:373—385. 1979. ficheskogo alpha-globulina v syvoroike krovi bolnogo pervichnym rakom pecheni. (Detec 61. Rosen SW, Weintraub DB, Vaitukaitis IL, et al: Placental proteins and their subunits as tion of embryo-specific alpha-globulin in the blood serum of a patient with primary hepatic tumor markers.Ann InternMed 82:71—83. cancer.) Vopr Med Khim 10:90—91.1964. 1975. 62. Vaitukaitis IL. Braunstein GD. Ross GT: A 76. The Coordinating Group for the Research radioimmunoassay which specifically measures of Liver Cancer, Peoples Republic of China: humanchorionic gonadotrophin inthepresence Application of serum alpha-fetoprotein assay in of human luteinizing hormone. Am J Obstet mass survey of primary carcinoma of liver. Am IChinMed 2:241—245, 1974. Gynaecol 113:751—758.1972. 77. Masseyeff R: Human alpha-feto-protein. 63. Vaitukaitus JL, Ross 01. Braunstein GD. Biol20:703—725. 1972. et al: Gonadotropins and their subunits: Basic Pathol and clinical studies. Recent Prog Horm Res 78. Egan ML, Engvall E, Ruoslahti EL. et al: 32:289—331,1976. Detection of circulating tumor antigens. Cancer 40:458—466.1977. 64. Tormey DC. WaalkeslP, Simon RM: Bio 79. Chen DS. Sung JL, Sheu JC, et al: Serum logical markers in breast carcinoma: II. Clinical alpha-fetoprotein in the early stage of human correlations with human chorionic gonadotro phin. Cancer 39:2391—2396,1977. hepatocellular carcinoma. Gastroenterology 65. Anderson1,WaldmannTA. Javadpour N, 86:1404—1409,1984. et al: Testicular germ cell neoplasms. Recent 80. Bloomer JR. Waldmann TA, Mclntire KR. innonneoplastic hepatic advances in diagnosis and therapy. Ann Intern etal:Alpha-fetoprotein disorders. JAMA 233:38—41.1975. Med 90:373—385,1978. 66. Gailani S. Chu TM, Nussbaum A. et al: 81. Lehmann FG: Prognostic significance of Human chorionic gonadotrophins (hCG)innon alpha-l-fetoprotein in liver cirrhosis: Five year trophoblastic neoplasms: Assessment of abnor prospective study. in Fishman WH. Sell S feds): malities of hCG and CEA in bronchogenic and Oncodevelopmental Gene Expression. Orlando. digestive neoplasms. Cancer 38:1684—1686. Academic. 1976. pp407—415. 1976. 82. Medical Research Council Working Party Tumours:Prognostic factors in 67. Bagshawe KD, Wass M. Searle F: Markers on Testicular advanced nonseminomatous germ-cell testicular in gynaecological cancer. Arch Gynecol tumours: Results ofa multicentre study. Lancet 229:303—310.1980. VOL.38.NO 2 MARCH/APRIL 1988
123
1:8—Il,1985. 83. Catalona WI: Tumor markers in testicular cancer. Urol Clin North Am 6:613—628,1979. 84. Fuks A. Banjo C, Shuster 1. et al: Carcino embryonic antigen (CEA): Molecular biology and clinical significance. Biochem Biophys Acta4I7:123—152, 1975. 85. Gold P. Freedman SO: Specific carcino embryonic antigens of the human digestive sys tem.JExpMed 122:467—481.1965. 86. Vrba R. Alpert E. Isselbacher KJ: Immuno logical heterogeneity of serum carcino embryonic
antigen
(CEA).
Immunochemistry
therapy of colonic and pancreatic cancer. Clin Gastroenterol
5:625—638. 1976.
99. Laurence Di, Stevens U. Bettelheim R, et al: Role of plasma carcinoembryonic antigen in diagnosis
of gastrointestinal,
mammary.
and
bronchial carcinoma. Br Med 1 3:605—609. 1972.
100. Wang DY, Bulbrook RD. Hayward JL. et al: Relationship between plasma carcino embryonic antigen and prognosis in women with breast cancer. EurJ Cancer 11:615—618, 1975.
101. Falkson HC. Falkson U. Portugal MA, et al: Carcinoembryonic
antigen
as a marker
in
13:87—89.1976. 87. NiloffiM. KIug TL. Schaetzl E. et al: Ele vation of serum CA 125 in carcinomas of the fallopian tube. endometrium and endocervix. Am J Obstet Gynecol 148:1057—1058,1984. 88. Laurence DI. Neville AM: Foetal antigens and their role in the diagnosis and clinical man agement of human neoplasms: A review. Br I Cancer 26:335—355,1972.
patients with breast cancer receiving post surgical adjuvant chemotherapy. Cancer 49:1859—1865,1982. 102. Lang BA. Ko@entA. NekulováM, et al: Three-year follow-up of carcinoembryonal an tigen levels in the serum of patients with breast cancer. Neoplasma 31:79—87,1984. 103. Chu TM. Murphy UP: What@snew in tu
89. Fleisher M, Nisselbaum IS, Loftin L, et al: Roche RIA and Abbot EIA carcinoembryonic antigens assays compared. Clin Chem 30:200—
27:487—491.1986. 104. Wang MC. Valenzuela LA. Murphy UP. et al: Purification of a human prostate specific antigen. Invest Urol 17:159—163.1979. 105. Frankel AE. Rouse RV. Wang MC, et al: Monoclonal antibodies to a human prostate an tigen. Cancer Res 42:3714—3718. 1982.
205, 1984. 90. Mach IP. Vienny H. Jaeger P. et al: Long term follow-up of colorectal carcinoma patients by repeated
CEA radioimmunoassay.
Cancer
42:1439—1447.1978. 91. Lowenstein MS. Zamchek N: Carcino embryonic antigen (CEA) levels in benign gas trointestinal disease states. Cancer 42:1412— 1418. 1978. 92. Stevens DP. Mackay IR: Increased carcino embryonic antigen in heavy cigarette smokers. Lancet2:1238—1239. 1973. 93. Jalanko H, Kuusela P. Roberts P. et al: Comparison of a new tumour marker. CA 19-9. with alpha-fetoprotein and carcinoembryonic antigen in patients with upper gastrointestinal diseases. I Clin Pathol 7:218—222. 1984. 94. Dent PB. McCuIIoch PB, Wesley-James 0. et al: Measurement of carcinoembryonic antigen in patients with bronchogenic carcinoma. Can cer42: 1484—1491, 1978.
95. Myers RE. Sutherland DJ. Meakin 1W. et al: Carcinoembryonic antigen in breast cancer. Cancer 42:1S20—1526.1978. 96. Rochman H: Tumor associated markers in clinical diagnosis. Ann Clin Lab Sci 8:167—175. 1978. 97. Wanebo Hi. Rao B. Pinsky CM. et al: Pre operative carcinoembryonic antigen level as a prognostic indicator in colorectal cancer. N EngI
I Med 299:448—45 I, 1978. 98. Zamcheck N: The present status of carcino embryonic antigen (CEA) in diagnosis. detec tion of recurrence, prognosis and evaluation of 124
mor
markers
for prostate
cancer'!
Urology
106. Kuriyama M. Wang MC. Lee Cl. et al: Multiple marker evaluation in human prostate
cancer with the use of tissue-specific antigens. JNCI 68:99—105,1982. 107. Killian CS. Emrich Li. Vargas FP. et al: Relative reliability of five serially measured markers for prognosis of progression in prostate cancer. INCI 76:179—185. 1986.
108. Stamey TA. Yang N. Hay AR. et al: Prostate-specific adenocarcinoma
antigen as a serum marker for of the prostate. N EngI I Med
317:909—916,1987. 109. Marangos P1:Clinical studies with neuron specific enolase. Prog Clin Biol Res 175: 285—294. 1985.
110. Carney DN. Marangos PL. lhde DC. et al: Serum neuron-specific enolase: A marker for disease extent and response to therapy of small cell lung cancer. Lancet 1:583—585.1982. Ill. Johnson DH. Marangos P1. Forbes iT, et al: Potential
utility of serum
neuron-specific
enolase levels in small cell carcinoma of the lung. Cancer Res 44:5409—5414. 1984. 112. Zeltzer PM. Marangos P1. Parma AM. et al: Raised neuron-specific
enolase in serum of
children with metastatic neuroblastoma: A re port from the Children's Cancer Study Group. Lancet 2:361—363. 1983. 113. Ishiguro Y. Kato K. Ito T. et al: Nervous system-specific enolase in serum as a marker for CA-A CANCERJOURNALFORCLINICIANS
neuroblastoma. Pediatrics 72:696—700,1983. 114. Zeltzer PM, Marangos P1, Sather H, et al: Prognostic importance of serum neuron specific
SCC RIA in the diagnosis of squamous cell
carcinoma of the head and neck: A preliminary report, in press. enolase in local and widespread neuroblastoma. 128. Rubin LA, Kurman CC, Fritz ME, et al: Soluble interleuken 2 receptors are released ProgClin Biol Res 175:319—329, 1985. 115. Hann HW, Evans AE, Siegel SE, et al: from activated human lymphoid cells in vitro. Prognostic importance of serum ferritin in pa I Immunol 135:3172—3177,1985. 129. Beutler B, Cerami A: Cachectin: More tients with Stages III and IV neuroblastoma: The Childrens Cancer Study Group experience. Can than a tumor necrosis factor. N EngI I Med 316:379—385,1987. cer Res 45:2843—2848,1985. 116. Hann HW, Stahlhut MW, Chung LC: In 130.BlickM, SherwinSA, RosenblumM, et hibitory effects of isoferritins from tumour and al: Phase I study of recombinant tumor necrosis non-tumour tissues on E-rosette formation. Lan factor in cancer patients. Cancer Res 47:2986— cet 1:43, 1984. 2989, 1987. 131. Werner ER, Bichler A, Daxenbichler G, 117. Bast RC Jr. Feeney M, Lazarus H, et al: et al: Determination of neopterin in serum and Reactivity of a monoclonal antibody with hu man ovarian carcinoma. I Clin Invest 68: urine. Clinical Chem 33:62—66.1987. 1331—1337.1981. 132. Klavins IV: Types of tumor markers, in 118. Bast RC Jr. KIug TL. St John E, et al: A Klavins IV (ed): Tumor Markers in Clinical and radioimmunoassay using a monoclonal antibody Laboratory Studies. New York. Alan R Liss, to monitor the course of epithelial ovarian can Inc. 1985, pp3—28. cer. N EngIJ Med 309:883—887, 1983. 133. Hams H: The CA antigen: Structure, 119. Niloff IM, Knapp RC, Schaetzl E. et al: function and clinical application, in Daar AS CA 125 antigen levels in obstetric and gyneco (ed): Tumor Markers in Clinical Practice: Con logic patients. Obstet Gynecol 64:703—707, cepts and Applications. Boston, Blackwell Sci 1984. entific Publications, 1987, pp 115—128. 120. Pinto MM. Bernstein LH, Brogan DA. et 134. Bucovaz ET: An assessment of serological al: Immunoradiometric assay of CA 125 in ef testing for cancer and the Beta-protein assay. fusions: Comparison with carcinoembryonic an IRCSMedSci 11:1—4.1983. tigen. Lab Invest 54:50A, 1986 (Abstract). 135. Mross KB, Wolfrum Dl, Rauschecker H: 121. Magnani IL, Steplewski Z. Koprowski H, Determination of tissue polypeptide antigen et al: Identification of the gastrointestinal and (TPA) levels in different cancer types and con pancreatic cancer-associated antigen detected trols. Oncology 42:288—295,1985. by monoclonal antibody 19-9 in the sera of pa 136. Fossel ET. CarrIM, McDonagh I: Detec tients as a mucin. Cancer Res 43:5489—5492, tion of malignant tumors: Water-suppressed 1983. proton nuclear magnetic resonance spectros 122. Staab HI. Brummendorf T, Hornung A, copy of plasma. N EngI I Med 315:1369—I376. et al: The clinical validityof circulatingtumor 1986. 137. Nydegger UE. Butler RE: Serum lipopro associated antigens CEA and CA 19-9 in pri mary diagnosis and follow-up of patients with tein levels in patients with cancer. Cancer Res 32:1756—1760.1972. gastrointestinal malignancies. KIm Wochenschr 138. Spiegel Ri, Schaefer Ei, Magrath IT. et 63:106—IIS. 1985. 123.Satake K, KanazawaU, Kho I,etal: Eval al: Plasma lipid alterations in leukemia and lym phoma. Am I Med 72:775—782,1982. uation of serum pancreatic enzymes, carbohy 139. Huebner RI, Todaro GI: Oncogenes of drate antigen 19-9, and carcinoembryonicanti RNA tumor viruses as determinants of cancer. gen in various pancreatic diseases. Am I Proc NatI Acad Sci USA 64:1087—1094.1969. Gastroenterol 80:630—636,1985. 140. Aaronson SA, Robbins KC, Tronick SR: 124. Kato H. Morioka H, Aramaki S. et al: Human proto-oncogenes. growth factors, and Prognostic significance of the tumor antigen TA-4 in squamous cell carcinoma of the uterine cancer, in Ford Ri, Maizel AL (eds): Mediators in Cell Growth and Differentiation. New York, cervix. Am I Obst Gynecol 145:350—354, 1983. Raven Press, 1985, pp 24 1—255. 125. Kato H, Torigoe T: Radioimmunoassay 141. Bishop IM: Viral oncogens. Cell 42:23— for tumor antigen of human cervical squamous 38, 1985. cell carcinoma. Cancer 56:302—308,1985. 142. Willecke K, Schafer R: Human onco 126. Kato H. Tamai K, Morioka H, et al: Tumor-antigenTA-4 in the detection of recur genes. Hum Genet 66:132—142,1984. 143. Brodeur GM, Seeger RC, Schwab M. et rence in cervical squamous cell carcinoma. Can at: Amplification of N-myc in untreated human cer54:l544—1546, 1984. 127. Johnson IT, Wagner RL. Eibling DE: neuroblastomas correlates with advanced dis VOL 38,NO 2 MARCH/APRIL 1988
125
ease stage. Science224:1121—1124. 1984. 144. Niman HL: Detection of oncogene-relaied proteins with site-directed monoclonal antibody probes. I Clin Lab Anal 1:28-41, 1987. 145. Mclntire KR: Use of multiple immunoas says for circulating tumor markers, in Herber man R, Mclntire KR (eds): lmmunodiagnosis of Cancer. New York, Marcel Dekker, Inc. 1979, pp 52 1—539. 146. Mercer DW. Talamo TS: Multiple mark ers of malignancy in sera of patients with cob
rectal carcinoma: Preliminary clinical studies. ClinChem3l:1824—1828, 1985. 147. Gail MH, Muenz L, Mclntire KR, ci al: Multiple markers for lung cancer diagnosis: Val idation of models for advanced lung cancer. JNCI 76:805—8 16, 1986. 148.Siddall 1K. ShettySD. Cooper EH: Measurements ofserumgamma-seminoprotein and prostate specific antigen evaluated for mon itoring carcinoma of the prostate. Clin Chem 32:2040—2043,1986.
Erratum: Author'sCorrection Dr. Alex Ferenczy, author of the article, “¿Laser Treatment of Patients with Condylomata and Squamous Carcinoma Precursors of the Lower Female Genital Tract,― published in the November/December 1987 issue (Ca 37:334—347.1987), has informed us that there was an error in the labeling of Tables 6 and 7, which appear on page 345. In both tables, the Failure Rates were inadvertently labeled Cure Rates. Thus, in Table 6, “¿Laser Treatment Results for Vulvar Intraepithelial Neoplasia (Multifocal Le sions),―for the 17 patients with laser margins of less than 5 mm, the failure rate (not the cure rate) was 23.5 percent; and for the 9 patients with laser margins of 10—20mm, the failure rate was 11.0 percent. Similarly, in Table 7, “¿Laser Treatment Results for Condylomata Acuminata of the Vulva and/or Anal/Perianal Regions,― for the 105 patients with laser margins of less than 5 mm, the failure rate was 20 percent; and for the 55 patients with laser margins of 10—20mm, the failure rate was 7 percent. However, in TableS, “¿Laser Treatment Results for Vaginal lntraepithelial Neoplasia,― which appears on the same page, the data are presented correctly, as cure rates. Thus, in Table 5, for the 5 patients with a single lesion, the cure rate is 100 percent; for the 15 patients with multifocal
lesions, the cure rate is 75 percent; and for the total of 20 patients, the cure rate is 80 percent.
126
CA-ACANCER JOURNAL FORCLINICIANS