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Tumor Markers in Lung Cancer

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Tumor Markers in Lung Cancer Onkologie Redaktion: Petra Stieber Tumor Markers in Lung Cancer Tumormarker beim Bronchialkarzinom A. Schalhorn1'4, H. Fürst2, Petra Stieber3 Summary: Among the many tumor-associated anti- kann festgestellt werden, daß jegliche Art von Verlauf- gens and substances described and evaluated, NSE, suntersuchungen ohne das Vorhandensein therapeutis- ProGRP, CYFRA 21-1 and CEA proved to be relevant cher Möglichkeiten von begrenztem Nutzen sind. Über tumor markers for lung cancer with high diagnostic ca- diese Einschränkungen hinaus stellen jedoch Tumor- pacity. Nevertheless, due to the lack of sensitivity in marker als nicht invasive, reproduzierbare, schnelle early stages of lung cancer and also the lack of organ und kostengünstige Untersuchungsmethode hilfreiche - as well as tumor specificity none of these tumor diagnostische Maßnahmen in der Differentialdiagnos- markers should be used for screening purposes in tik sowie zur Überwachung der Therapieeffizienz dar. asymptomatic persons or in patients at high risk of ma- lignancy (smokers). Schlüsselwörter: Tumormarker; Bronchialkarzinom: The bad prognosis of lung cancer patients in gener- NSCLC; SCLC; CEA; NSE; CYFRA 21-1; ProGRP. al and the lack of satisfactory treatment modalities for recurrent disease limit the application of tumor mark- er determination, especially in follow-up care. Gener- n most industrialised countries, lung cancer is the ally, follow-up investigations of any kind are of limit- Imost common cancer in men and is rapidly ap- ed use in the absence of alternative therapy. But apart proaching the same incidence in women. Despite from these limitations, tumor markers as non invasive, worldwide efforts in diagnosis and therapy of lung reproducible, fast and not expensive methods provide cancer, the five-year survival rate could not be im- very helpful diagnostic tools in differential diagnosis proved significantly over the past 25 years and is and in monitoring the efficacy of therapy. nowadays around 13 %. Lung cancer represents the prototype of a tumor in- Keywords: tumor markers; lung cancer; NSCLC; duced by chemical carcinogens, and in principle its in- SCLC: CEA; NSE; CYFRA 21-1; ProGRP. cidence could be decreased by public health measures. In industrialised countries, the association of lung can- Zusammenfassung: Unter vielen in der Literatur be- cer and cigarette smoking is strong (85 %), but as well schriebenen tumorassoziierten Antigenen und Substan- as exogenous physical or chemical carcinogenic influ- zen haben sich NSE, ProGRP, CYFRA 21-1 und CEA ences (asbestos, urane), an individual genetic pre-dis- als für das Bronchialkarzinom relevante Tumormarker position to cancer or vulnerability to the effects of car- mit einer hohen diagnostischen Aussagekraft heraus- cinogens must be assumed. kristallisiert. Aufgrund einer ungenügenden Empfind- lichkeit für frühe Stadien des Bronchialkarzinoms Diagnosis of Lung Cancer sowie insbesondere -in- Anbetracht der fehlenden Organ- und Tumorspezifität ist keiner dieser Tumor- At the time of primary diagnosis, almost 50 % of pa- marker weder für die Screeningsituation noch für eine tients appear to have operable tumors. However, once Überwachung von Risikopatienten wie Rauchern ge- diagnostic investigations are complete, it becomes ev- eignet. ident that 70 % of this group of patients have tumors Die schlechte Prognose von Patienten mit einem that cannot be completely resected. The aims of diag- Bronchialkarzinom im Allgemeinen und das Fehlen nostic tools for lung cancer should therefore be to pro- zufriedenstellender therapeuti scher Möglichkeiten vide information that zum Zeitpunkt der Rezidivierung schränken von vorn- • Spares patients unnecessary operations or ex- herein die Anwendung von Tumormarkern ein, dies ploratory thoracotomies gilt insbesondere für die Nachsorgesituation. Generell • Encourages early surgical intervention in the 15% of patients for whom surgical intervention is likely 1 Medical Department III, to be effective Department of Surgery, • Identifies those patients for whom palliative resec- 3lnst. of Clinical Chemistry, University of Munich. Germany tion is desirable 4Corresponding author: Prof. Dr. med. Andreas Schalhorn Med- ical Department III, University Hospital Munich-Großhadern, Mar- chioninistr. 15, 81366 Munich, Germany. Fax: +49-89-7095-2250, As many of these diagnostic procedures are invasive, E-mail: [email protected] they should be chosen according to the therapeutic © 2001 Blackwell Wissenschafts-Verlag, Berlin J Lab Med 2001; 25 (9/10): 353-361 353 Onkologie consequences that can be expected, in a stepwise man- I). Histopathological studies demonstrate that cytoker- ner, e.g. atin 19 is abundant in carcinomas of the lung [121. • Basic diagnostic procedures to secure a final histo- CYFRA 21-1 is especially suitable for NSCLC as it is logical diagnosis and to identity patients with inop- the most sensitive tumor marker in these histologies erable tumors including squamous tumors [4, 5, 7, 8, 10, II, 13, 14]. » Functional tests to determine whether patients are Since CYFRA 21-1 determines only fragments of cy- well enough to undergo surgery tokeratin 19, the test shows a higher specificity than • Diagnostic procedures for TNM classification and TPA, which determines a mixture of cytokeratins 8. 18 staging of malignancy and 19 [9, 15]. ProGRP (Pro Gastrin Releasing Peptide) is the more stable precursor of the gut hormone gastrin re- Classification leasing peptide (GRP) originally isolated from porcine Most primary lung tumors can be classified into four stomach. GRP is the mammalian counterpart to the major histological types: amphibian bombesin being well known for years for • Squamous cell carcinoma the histopathological classification of lung tissues. • Adenocarcinoma Due to a good overall profile of specificity and sensi- • Large cell carcinoma tivity, ProGRP has become a reliable marker for small • Small cell lung cancer (SCLC) cell lung cancer within a short period of time [16, 17, SCLC accounts for 20-25 % of the cases of bron- 18, 19]. chogenic carcinoma and differs clinically and biologi- cally from the other three histological types. However, Further frequently described markers in lung cancer it has become evident that many tumors have features SCC is a 48 kD protein with strong homology to the ser- of more than one histological type of cancer. Thus pin family of protease inhibitors. Serum measurements of both SCLC and non-small cell lung cancer (NSCLC) SCC have been used in squamous cell carcinomas of the represent heterogeneous groups in which there is con- cervix, oesophagus, head, neck and lung [20]. One of the siderable overlap among the major histological types most important applications of SCC measurements in of carcinoma of the lung. lung cancer is as an aid to histological diagnosis [8]. Being significantly less sensitive in non small cell lung cancer SCC has been replaced by CYFRA 21-1 as the Tumor Markers marker of first choice [4, 5, 7, 9, 11]. Many different tumor-associated antigens have been CA125 (MW -200 kD) is the second hybridoma- described and investigated in lung cancer. Depending defined tumor marker. It is a differentiation antigen on the clinical indication the following markers circu- that arises in fetal tissue from coelomic epithelial de- lating in the blood proved to possess a superior profile rivatives. Serum measurements are mainly used in of specificity and sensitivity: neuron specific enolase serous ovarian carcinomas but are sometimes used in (NSE), carcinoembryonic antigen (CEA), cytokeratin breast and lung cancer [21]. 19 fragments (CYFRA 21-1) and Progastrin Releasing NCAM soluble neural cell adhesion molecule = Peptide (ProGRP). cluster 1 SCLC-Antigen. NSE is a glycolytic neurospecific isoenzyme of NCAM was desribed to be a relevant marker espe- enolase. It consists of two almost identical polypeptide cially for small cell lung cancer, but up to now there is chains, each with a molecular weight of 39 kD. It is no investigation available showing significant superior produced in central and peripheral neurons and malig- or additional information in comparison to markers nant tumors of neuroectodermal origin (e.g. SCLC, like NSE, a comparison to ProGRP has not yet been neuroblastomas, intestinal carcinoid) [1, 2]. Further- performed. more, as NSE is also found in erythrocytes, plasma Chromogranin A is an acidic, soluble protein of cells and platelets it may be released into serum if sep- 49,000 D which was initially recognized as the major aration from red cells does not occur within 60 min- soluble protein in the core of the adrenal medullary utes of venepuncture [3]. catecholamine storage vesicles, the chromaffin vesi- • CEA is a glycoprotein of molecular weight of ~180 cles. This analyte nas been widely used for years in kD. It is one of the carcinofetal antigens produced dur- immunohistochemistry for neuroendocrine tumors in- ing embryonal and-fetal development. CEA was one of cluding SCLC. For serum determinations, some au- the first tumor markers to be described and has rela- thors found small advantages as compared to NSE tively high sensitivity for many advanced adenocarci- [22], others not [23]. There is only one recent investi- nomas (primarily colon, but also breast, stomach and gation comparing Chromogranin A, NSE and ProGRP lung cancer). Sensitivity of CEA measurement is [24], and according to these results, Chromogranin is greatest, and serum CEA concentrations are highest in clearly inferior to
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