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Lung cancer

In most industrialised countries, lung cancer is the most common cancer in men, and is rapidly approaching the same incidence in women. In the European Community, lung cancer accounts for 29% of all cancer deaths, and 21% of all male cancers. Lung cancer represents the prototype of a tumour induced by chemical carcinogens, and in principle its incidence could be decreased by public health measures. In industrialised countries, the association of lung cancer and cigarette smoking is strong (85%), but in spite of this strong correlation between smoking and lung cancer, only a small proportion of smokers (5-10%) develop lung cancer. Many lung cancers develop without known exposure to a known carcinogen. As well as exogenous physical or chemical carcinogenic influences, an individual genetic pre-disposition to cancer or vulnerability to the effects of carcinogens must therefore be assumed.

diagnosis of lung cancer

At the time of primary diagnosis, almost 50% of patients appear to have operable tumours. However, once diagnostic investigations are complete, it becomes evident that 70% of this group of patients have tumours that cannot be completely resected. The aims of diagnostic tools for lung cancer should therefore be to provide information that

  • Spares patients unnecessary operations or exploratory thoracotomies
  • Encourages early surgical intervention in the 15% of patients for whom surgical intervention is likely to be effective
  • Identifies those patients for whom palliative resection is desirable

As many of these diagnostic procedures are invasive, they should be chosen according to the therapeutic consequences that can be expected, in a stepwise manner, e.g.

  • Basic diagnostic procedures to secure a final histological diagnosis and to identify patients with inoperable tumours
  • Functional tests to determine whether patients are well enough to undergo surgery
  • Diagnostic procedures for TNM classification and staging of malignancy

classification

Most primary lung tumours can be classified into four major histological types:

  • Squamous cell carcinoma
  • Adenocarcinoma
  • Large cell carcinoma
  • Small cell lung cancer (SCLC)

SCLC accounts for 20-25% of the cases of bronchogenic carcinoma and differs clinically and biologically from the other three histological types. However, it has become evident that many tumours have features of more than one histological type of cancer. Thus both SCLC and non-small cell lung cancer (NSCLC) represent heterogeneous groups in which there is considerable overlap among the major histological types of carcinoma of the lung.

Tumour markers

Many different tumour associated antigens have been described and investigated. The most commonly used markers circulating in the blood are neuron specific enolase (NSE), carcinoembryonic antigen (CEA), cytokeratin 19 fragments (CYFRA 21-1), squamous cell carcinoma antigen (SCC), cancer antigen CA 125 (CA 125) and tissue polypeptide antigen (TPA.)

NSE is a glycolytic neurospecific isoenzyme of enolase. It consists of two almost identical polypeptide chains, each with a molecular weight of 39 kD. It is produced in central and peripheral neurons and malignant tumours of neuroectodermal origin (e.g. SCLC, neuroblastomas, intestinal carcinoid). Furthermore, as NSE is also found in erythrocytes, plasma cells and platelets it may be released into serum if separation from red cells does not occur within 60 minutes of venepuncture.

CEA is a glycoprotein of molecular weight of ~180 kD. It is one of the carcinofetal antigens produced during embryonal and fetal development. CEA was one of the first tumour markers to be described, and has relatively high sensitivity for many advanced adenocarcinomas (primarily colon, but also breast, stomach and lung cancer). Sensitivity of CEA measurement is greatest, and serum CEA concentrations are highest, in adenocarcinoma and large cell lung cancer.

SCC is a 48 kD protein with strong homology to the serpin family of protease inhibitors. Serum measurements of SCC have been used in squamous cell carcinomas of the cervix, oesophagus, head, neck and lung. One of the most important applications of SCC measurements in lung cancer is as an aid to histological diagnosis.

CA125 (MW ~200 kD) is the second hybridoma-defined tumour marker. It is a differentiation antigen that arises in fetal tissue from coelomic epithelial derivatives. Serum measurements are mainly used in serous ovarian carcinomas but are sometimes used in breast and lung cancer.

TPA is, like CEA, one of the oldest tumour markers. TPA assays measure a mixture of cytokeratins 8, 18 and 19. Since the development of monoclonal antibody technology, antibodies to cytokeratins and other intermediate filaments of the cell (e.g. vimentin, desmin) have been used in histopathology for the differentiation and classification of pathological tissue. In contrast to cytokeratins themselves, fragments of intermediate filaments are soluble in serum, where they can be detected as aggregates with the aid of monoclonal antibodies.

CYFRA 21.1 is a relatively new tumour marker test which uses two specific monoclonal antibodies against a cytokeratin 19 fragment. Histopathological studies demonstrate that cytokeratin 19 is abundant in carcinomas of the lung. CYFRA 21-1 is especially suitable for NSCLC as it is the most sensitive tumour marker in these histologies including squamous tumours. Since CYFRA 21.1 determines only fragments of cytokeratin 19, the test shows a higher specificity than TPA, which determines a mixture of cytokeratins 8, 18 and 19.

serum tumour markers

Screening and diagnosis
Their lack of organ and tumour specificity means that tumour markers cannot be used for screening of lung cancer in asymptomatic patients or in patients at high risk of malignancy. In general, primary diagnosis and primary therapy of lung cancer is determined by clinical investigations including medical imaging, endoscopy and intra-operative findings.

NSE, however, provides an important marker in immunohistochemistry for histological typing, and its serum determination can help to support a diagnosis of SCLC at the time of primary diagnosis. Similarly, SCC may be useful because patients with SCC >2 m g/L have a 95% probability of having NSCLC and 80% probability of having a squamous tumor. If CA125 is higher than 100 U/mL and CEA is higher than 10 m g/L it is highly likely that the histology will indicate either adenocarcinoma or large cell lung cancer. Although serum concentrations of CYFRA 21.1, TPA, NSE and CEA also show significant correlation with tumour burden, there is no consistent relationship between production of these markers and tumour type. In most cases, high tumour marker concentrations reflect advanced tumour stage and therefore suggest a bad prognosis. However, low or mildly increased marker concentrations never exclude any kind of tumour disease or progression of disease. Despite these limitations, the determination of tumour markers at the time of primary diagnosis is important for several reasons:

  • Tumour associated antigens expressed at the time of primary diagnosis are likely to be the most relevant markers for follow-up monitoring
  • CYFRA 21.1, CEA and CA 125 are independent prognostic factors of high significance in NSCLC, and NSE in SCLC (6,23,24)
  • The rate and extent of decrease of pre-operatively expressed markers after surgery provides useful information about remaining tumour burden and the effectiveness of therapy

Determination of CEA, CYFRA 21.1, and NSE at the time of primary diagnosis may be performed as suggested in Table 1. For lung tumours of unknown origin, NSE can be particularly helpful in differential diagnosis (17). Although tumour associated antigen measurements cannot replace histological results, they can be very helpful in those cases (~20%) where for varied reasons it is not possible to establish a final diagnosis by biopsy (Table 2).

Follow-up and therapy monitoring

An important indication for tumour marker determinations in lung cancer is in assessing the effective of therapy and post-operative follow-up care. As for tumour markers in other carcinomas, the rate of post-operative decrease of the relevant marker provides an indication of patient outcome. Decreasing values after primary surgery corresponding to the half-life period (~2-3 days for CEA, 1 day for NSE and several hours for CYFRA 21.1) is the first sign of curative resection and therefore of good prognosis. Tumour marker concentrations which decrease slowly, and which may not fall to within the reference range, can indicate non-curative surgery and suggest residual tumour. During follow-up care, an increase of tumour marker concentration (including increases within the reference range) may provide the first sign of recurrent disease. Such increases may be observed more than twelve months before detection of progression by medical imaging or clinical symptoms. (18) This lead time may be helpful in early initiation of imaging methods and secondary intervention.

conclusions

NSE and CYFRA 21.1 have high diagnostic capacity in lung cancer. The bad prognosis of lung cancer patients in general, and the lack of satisfactory treatment modalities for recurrent disease, limit the application of tumour marker determinations, especially in follow-up care. Generally, follow-up investigations of any kind are of limited use in the absence of alternative therapy. Nevertheless, tumour markers may provide very helpful diagnostic tools in differential diagnosis (NSE, CYFRA 21.1, SCC, CA 125) and in monitoring the efficacy of therapy (CEA, NSE, CYFRA 21.1 and TPA).

References

  1. Debus E, Moll R, Franke WW, Weber K, Osborn M: Immunohistochemical distinction of human carcinomas by cytokeratin typing with monoclonal antibodies. Am J Pathol 114: 121-130, 1984.
  2. Broers JL, Ramaekers FC, Rot MK, Oostendorp T, Huysmans A, van Muijen GN: Cytokeratins in different types of human lung cancer as monitored by chain-specific monoclonal antibodies. Cancer Res 48: 3221-3229, 1988.
  3. Akoun G, Scarna H, Milleron B, Benichou M, Herman D: Serum neuron-specific enolase. A marker for disease extent and response to therapy for small cell lung cancer. Chest 87: 39-43, 1985.
  4. Ebert W, Hug G, Stabrey A, Bülzebruck H, Drings P: Evaluation of tumor markers NSE and CEA for the diagnosis and follow-up of small cell lung cancer. Ärztl Lab 35: 1-10, 1989.
  5. Stieber P, Hasholzner U, Bodenmüller H, Nagel D, Sunder-Plassmann L, Dienemann H, et al: CYFRA 21-1 - A new marker in lung cancer. Cancer, 72S: 707-713, 1993.
  6. Stieber P: CYFRA 21-1 (Cytokeratin-19-fragments). In: Clinical Laboratory Diagnostics, pp. 966-970 Eds., L. Thomas, TH-Books. Frankfurt/Main, Germany: 1998.
  7. Ebert W, Dienemann H, Fateh-Moghadam A, Scheulen M, Konietzko N, Schleich T, et al: Cytokeratin 19 fragment CYFRA 21-1 compared with carcinoembryonic antigen, squamous cell carcinoma antigen and neuron specific enolase in lung cancer. Results of an international multicentre study. Eur J Clin Chem Clin Biochem, 32: 189-199, 1994.
  8. Molina R, Agusti C, Mane JM, Filella X, Joseph J, Giminez N, et al: CYFRA 21-1 in lung cancer: comparison with CEA, CA 125, SCC and NSE serum levels. Int J Biol Markers, 9: 96-101, 1994.
  9. Paone G, De Angelis G, Munno R, Pallotta G, Bigioni D, Saltini C, et al: Discriminant analysis on small cell lung cancer and non-small cell lung cancer by means of NSE and CYFRA 21-1. Eur Respir J 8: 1136-1140, 1995.
  10. Niklinski J, Furman M, Chyczewska E, Chyczewski L, Rogowski F, Laudanski J: Diagnostic and prognostic value of the new tumour marker CYFRA 21-1 in patients with squamous cell lung cancer. Eur Resp J 8: 291-294, 1995.
  11. Wieskopf B, Demangeat C, Purohit A, Stenger R, Gries P, Kreisman H, et al: CYFRA 21-1 as a biologic marker of non-small cell lung cancer. Chest 108: 163-169, 1995.
  12. Van der Gaast A, Schoenmakers CH, Kok TC, Blijenberg BG, Cornilllie F, Splinter TA: Evaluation of a new tumour marker in patients with non-small-cell lung cancer: CYFRA 21-1. Br J Cancer 69: 525-528, 1994.
  13. Stieber P, Dienemann H, Hasholzner U, Fabricius PG, Schambeck C, Weinzierl M, et al: Comparison of CYFRA 21-1, TPA and TPS in lung cancer, urinary bladder cancer and in benign diseases. Int J Biol Markers 9: pp 82-88, 1994.
  14. Nisman B, Lafair J, Heching N, Lyass O, Baras M, Peretz T, et al: Evaluation of tissue polypeptide specific antigen, CYFRA 21-1, and CEA in non-small cell lung carcinoma. Cancer 82: 1850-1859, 1998.
  15. Pujol JL, Grenier J, Parrat E, Lehmann M, Lafontaine T, Quantin X, et al: Cytokeratins as serum markers in lung cancer: a comparison of CYFRA 21-1 and TPS. Am J Respir Crit Care Med 154: 725-733, 1996.
  16. Scheulen ME, Klanig H, Wiefelspÿtz JK, Kšmper P, Wagner B, Konietzko N, et al: Pre-therapeutic evaluation of cytokeratin fragment 19 (CYFRA 21-1) in 240 patients with lung cancer in comparison to CEA, NSE, SCC-Ag, TPA and TPS. Tumordiagn Ther 18: 14-19, 1997.
  17. Stieber P, Dienemann H, Hasholzner U, Zimmermann A, Hofmann K, Fateh-Moghadam A: Tumour associated antigens in the differential diagnosis of lung tumours of unknown origin. Anticancer Res 15, 2389, 1995.
  18. Stieber P, Zimmermann A, Reinmiedl J, Müller C, Hoffmann, H Dienemann H. CYFRA 21-1 in the early diagnosis of recurrent disease in non-small cell lung carcinomas (NSCLC). Anticancer Res 19: 2665-2668, 1999.
  19. Rapellino M, Pecchio F, Baldi S, Scappaticci E, Cavallo A: Clinical utility of tissue polypeptide antigen determination in lung cancer management. Anticancer Res 15: 1065-1070, 1995.
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  21. Viallat JR, Sauvan R, Rey F, Boutin C, Pasquier J: Contribution de deux biomarqueurs des cytokeratines, le Cyfra 21-1 et le TPA, au diagnostic de mesotheliome pleural malin. Immunoanal Biol Spec 11: 372-378, 1996.
  22. Seregni E, Foa P, Bogni A, Botti C, Cataldo I, Sala M, et al. Evaluation of the soluble fragments of cytokeratin 19 (CK19) in non-small cell lung cancer (NSCLC): Comparison with TPA, CEA, Scc and NSE. Oncol Reports 3: 95-101, 1996.
  23. Molina R, Fuentes R, Bover I, Rifa J, Moreno V, Canals E, et al: Tumour markers (CEA, CA125, CYFRA 21-1, SCC and NSE) in NSCLC patients as aid in histological diagnosis and prognosis: comparison with the main clinical, pathological and anthropomorphic prognostic factors. Submitted to Br J Cancer.
  24. Diez M, Torres A, Maestro ML, Ortega MD, Gomez A, Pollan M, et al: Prediction of survival and recurrence by serum and cytosolic levels of CEA, CA 125 and SCC antigens in resectable non-small cell lung cancer. Br J Cancer 73: 1248-54, 1996.

 

TABLE 1. Tumour markers in lung cancer.

Histology Before therapy Post-therapy follow-up
Unknown CYFRA 21-1, NSE, CEA After surgery: following histology

Without surgery: using the leading marker

Adenocarcinoma CYFRA 21-1 and CEA CYFRA 21-1 or CEA
Squamous cell carcinoma CYFRA 21-1 CYFRA 21-1
Small cell carcinoma NSE and CYFRA 21-1 NSE and CYFRA 21-1
Large cell carcinoma CYFRA 21-1 and CEA CYFRA 21-1 or CEA

TABLE 2. Tumour markers in lung tumours of unknown origin (17)

Tumour marker

Concentrations suggestive of

 

Malignancy

Lung cancer

SCLC

NSE (m g/L)

>25

>25

>100

CYFRA 21-1 (m g/L)

>10

>30

 
CEA (m g/L)

>20

 

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