Tumor Biology

, Volume 33, Issue 2, pp 463–474 | Cite as

Utility of serum tumor markers as an aid in the differential diagnosis of patients with clinical suspicion of cancer and in patients with cancer of unknown primary site

  • Rafael Molina
  • Xavier Bosch
  • Josep M. Auge
  • Xavier Filella
  • José M. Escudero
  • Víctor Molina
  • Manel Solé
  • Alfonso López-Soto
Research Article


Cancer may be diagnosed in advanced stages, when the patient has already developed metastasis, with symptoms that can be also observed in benign diseases. The objective of this study was to evaluate tumor marker sensitivity and specificity in the differential diagnosis of patients with suspected signs of cancer. We studied 2.711 consecutive patients admitted to the Internal Medicine Department of our hospital with suspected cancer; 1.240 patients had non-malignant processes and 1.471 had malignant disease. Determinations were considered positive for suspected malignancy when serum levels were carcinoembryonic antigen >15 ng/ml (>20 in patients with renal failure or liver disease), alpha fetoprotein >40 ng/ml (>80 ng/ml in patients with liver diseases), carbohydrate antigen (CA) 19.9 > 200 U/ml (>500 U/ml in patients with liver diseases or gamma glutamyl transpeptidase (GGT) <150 UI/L or effusions; >1.000 U/ml in patients with jaundice or GGT > 150 UI/L), neuron-specific enolase >45 ng/ml (renal failure >50 ng/ml; samples with hemolysis were excluded), prostate-specific antigen > 30 ng/ml (excluding acute prostatitis), tumor-associated glycoprotein-72 >80 U/ml, cytokeratin 19 fragment 21-1 > 7.5 ng/ml (>19 ng/ml in patients with renal failure; >11 ng/ml in patients with liver cirrhosis or jaundice), >3.5 ng/ml for squamous cell carcinoma (excluding patients with renal failure or skin disorders), CA 15.3 >100 U/ml, and CA 125 >350 U/ml (>600 U/ml in patients with pleural effusion and >900 U/ml in those with ascites). There was a specificity of 97.6% in patients without malignancy, 67.4% of sensitivity in patients with malignancy, and 75.4% of sensitivity in the 1,280 patients with epithelial tumors (53.7% in patients with locally advanced tumors and 79.4% in patients with metastases). Sensitivity was 81.4% in patients with cancer of unknown primary site. Tumor markers were useful in the differential diagnosis between epithelial and non-epithelial tumors, brain masses (metastases vs. primary tumors), and between benign or malignant origin of different clinical situations such as wasting syndrome, effusions, liver or bone lesions, and effusions with a positive predictive value higher than 95%. Tumor markers are useful as an aid in the evaluation of the risk of cancer of these patients with suspected cancer and may be useful to reduce the hospitalization time, morbidity, and the number of diagnostic tests required for diagnosis.


Cancer of unknown primary site Tumor markers CEA CA 125 CA 19.9 


Conflicts of interest



  1. 1.
    Brown ML, Lipscomb J, Zinder C. The burden of illness of cancer: economic cost and quality of life. Annu Rev Public Health. 2001;22:91–113.PubMedCrossRefGoogle Scholar
  2. 2.
    Yabroff KR, Lamont EB, Mariotto A, Warren JL, Topor M, Meekins A, Brown ML. Cost of care for elderly cancer patients in the United States. J Natl Canc Inst. 2008;100:630–41.CrossRefGoogle Scholar
  3. 3.
    Kessler LG, Ramsey SD. The forest and the trees: the human costs of cancer. J Natl Canc Inst. 2007;99:2–3.CrossRefGoogle Scholar
  4. 4.
    Greco FA, Hainsworth JD. Cancer of unknown primary site. In: de Vita VT, editor. Cancer principles and practice of oncology. 7th ed. Philadelphia: Lippincott, Williams & Wilkins; 2005. p. 2213–36.Google Scholar
  5. 5.
    Al-Brahim N, Ross C, Carter B, Chorneyko K. The value of postmortem examination in cases of metastases of unknown origin −20 years retrospective data from a tertiary care center. Ann Diagn Pathol. 2005;9:77–80.PubMedCrossRefGoogle Scholar
  6. 6.
    Pavlidis N, Briasoulis E, Hainsworth J, Greco FA. Diagnostic and therapeutic management of cancer of an unknown primary. Eur J Cancer. 2003;39:1990–2005.PubMedCrossRefGoogle Scholar
  7. 7.
    Molina R, Barak V, van Dalen A, Duffy MJ, Einarsson R, Gion M, et al. Tumor markers in breast cancer. European Group on Tumor Markers recommendations. Tumor Biol. 2005;26:281–93.CrossRefGoogle Scholar
  8. 8.
    Duffy MJ, van Dalen A, Haglund C, Hansson L, Holinski-Feder R, Klapdor R, et al. Tumour markers in colorectal cancer: European Group on Tumor Markers (EGTM) guidelines for clinical use. Eur J Cancer. 2007;43:1348–60.PubMedCrossRefGoogle Scholar
  9. 9.
    Duffy MJ, Bonfrer JM, Kulpas J, Rustin GJ, Soletormos G, Torre GC, et al. CA 125 in ovarian cancer: European group on tumor markers guidelines for clinical use. Int J Gynecol Canc. 2005;15:679–91.CrossRefGoogle Scholar
  10. 10.
    Sturgeon CM, Duffy MJ, Stenman UH, Lilja H, Brunner N, Chan DW, et al. National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers. Clin Chem. 2008;54:11–79.CrossRefGoogle Scholar
  11. 11.
    Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol. 2007;25:5287–312.PubMedCrossRefGoogle Scholar
  12. 12.
    Rustin GJ, Quinn M, Thigpen T, du Bois A, Pujade-Lauraine E, Jakobsen A, et al. New guidelines to evaluate the response to treatment in solid tumors (ovarian cancer). J Natl Canc Inst. 2004;96:487–8.CrossRefGoogle Scholar
  13. 13.
    Duffy MH, Sturgeon C, Lamer R, Haglund C, Holubec VL, Klapdor R, et al. Tumor markers in pancreatic cancer: a European Group on Tumor Markers (EGTM) status report. Ann Oncol. 2010;21:441–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Locker GY, Hamilton S, Harris J, Jessup JM, Kemeny N, Macdonald JS, et al. ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol. 2006;24:5313–27.PubMedCrossRefGoogle Scholar
  15. 15.
    Molina R, Filella X, Lejarcegui JA, Pahisa A, Torne A, Rovirosa B, et al. Prospective evaluation of squamous cell carcinoma and carcinoembryonic antigen as prognostic factors in patients with cervical cancer. Tumor Biol. 2003;24:156–64.CrossRefGoogle Scholar
  16. 16.
    Molina R, Zanon G, Filella X, Moreno F, Daniels M, Zanon G, et al. Use of serial carcinoembryonic antigen and CA 15.3 assays in detecting relapses in breast cancer patients. Br Canc Res Treat. 1995;36:41–8.CrossRefGoogle Scholar
  17. 17.
    Choi S, Jang J, Lee J, Roh MH, Kim MC, Lee WS, et al. Role of serum tumor markers in monitoring for recurrence of gastric cancer following radical gastrectomy. Dig Dis Sci. 2006;51:2081–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stelin H, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. Geneva: World Health Organization; 2008.Google Scholar
  19. 19.
    Maurel M, Arustova M, Stansy B, Light RW. Incidence of pleural effusion in a well-defined region: epidemiology study in central Bohemia. Chest. 1993;104:1486–9.CrossRefGoogle Scholar
  20. 20.
    Pass HI. Malignant pleural and pericardial effusions. In: De Vita VT, Hellman S, Rosenberg SA, editors. Cancer principles and practice of oncology. 5th ed. Philadelphia: Lippincott-Raven; 1997. p. 2586–98.Google Scholar
  21. 21.
    Maringola FM, Schwartzentruber DJ. Malignant ascites. In: De Vita VT, Hellman S, Rosenberg SA, editors. Cancer principles and practice of oncology. 5th ed. Philadelphia: Lippincott-Raven; 1997. p. 2598–606.Google Scholar
  22. 22.
    Culine S, Kramar A, Saghatchion M, Bugat R, Lesimple T, Latholary A, et al. Development and validation of a prognostic model to predict the length of survival in patients with carcinomas of an unknown primary site. J Clin Oncol. 2002;20:4679–83.PubMedCrossRefGoogle Scholar
  23. 23.
    Van de Wouw AJ, Jansen RLH, Griffionen AW, Hillen HFP. Clinical and immunohistochemical analysis of patients with unknown primary tumor. A search for prognostic factors in UPT. Anticancer Res. 2004;24:297–302.PubMedGoogle Scholar
  24. 24.
    Molina R, Auge JM, Bosch X, Escudero JM, Marrades R, Viñolas N, et al. Mucins CA 125, CA 199, CA 15.3, and TAG 72.3 as tumor markers in patients with lung cancer: comparison with CYFRA 21-1, CEA, SCC and NSE. Tumor Biol. 2008;29:371–80.CrossRefGoogle Scholar
  25. 25.
    Duraker N, Hot S, Polat Y, Höbek N, Gençler N, Urhan N. CEA, CA 19.9, and CA 125 in the differential diagnosis of benign and malignant pancreatic diseases with or without jaundice. J Surg Oncol. 2007;95:142–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Trape J, Molina R, Sant F. Clinical evaluation of the simultaneous determination of tumor markers in fluid and serum and their ratio in the differential diagnosis of serous effusions. Tumor Biol. 2005;51:219–22.Google Scholar
  27. 27.
    Molina R, Auge JM, Bosch X, Escudero JM, Viñolas N, Marrades R, et al. Usefulness of serum tumor markers, including progastrin-releasing peptide in patients with lung cancer: correlation with histology. Tumor Biol. 2009;30:121–9.CrossRefGoogle Scholar
  28. 28.
    Filella X, Molina R, Jo J, Bedini JL, Joseph J, Ballesta AM. Tumor associated glycoprotein-72 (TAG-72) levels in patients with non-malignant and malignant diseases. Bull Cancer. 1992;79:271–7.PubMedGoogle Scholar
  29. 29.
    Molina R, Filella X, Torres MD, Ballesta AM, Mengual P, Cases A, Balague A. SCC antigen measured in malignant and non malignant diseases. Clin Chem. 1990;36:251–4.PubMedGoogle Scholar
  30. 30.
    Molina R, Filella X, Bruix J, Mengual PJ, Bosch J, Calvet X, et al. Cancer antigen 125 in serum and ascitic fluid of patients with liver diseases. Clin Chem. 1991;37:1379–83.PubMedGoogle Scholar
  31. 31.
    Ohtsuka T, Sato S, Kitajima Y. False positive findings for tumors markers after curative gastrectomy for gastric cancer. Dig Dis Sci. 2008;53:73–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Cases A, Filella X, Molina R, Ballesta AM, Lopez-Revert JL, Revert L. Tumor markers in chronic renal failure and hemodialysis patients. Nephron. 1991;57:183–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Symeonides A, Kouraklis-Symeonides A, Apostolopoulos D, Arvanitopoulou E, Giannakoulas N, Vassilakos P, et al. Increased serum CA 15.3 levels in patients with megaloblastic anemia due to vitamin B12 deficiency. Oncology. 2004;67:359–67.CrossRefGoogle Scholar
  34. 34.
    Porcel JM, Vives M, Esquerda A, Salud A, Perez B, Rodriguez-Panadero F. Use of a panel of tumor markers (carcinoembryonic antigen, cancer antigen 125, carbohydrate antigen 15-3, and cytokeratin 19 fragments) in pleural fluid for the differential diagnosis of benign and malignant effusions. Chest. 2004;126:1757–63.PubMedCrossRefGoogle Scholar
  35. 35.
    Miédougé M, Rouzaud P, Salama G, Pujazon MC, Vincent C, Mauduyl MA, et al. Evaluation of seven tumour markers in pleural fluid for the diagnosis of malignant effusions. Br J Cancer. 1999;81:1059–61.PubMedCrossRefGoogle Scholar
  36. 36.
    El-Rachkidy RG, Young HS, Griffiths CE, Camp RD. Humoral autoimmune responses to the squamous cell carcinoma antigen protein family in psoriasis. J Invest Dermatol. 2008;128:2219–24.PubMedCrossRefGoogle Scholar
  37. 37.
    Yamane Y, Moriyama K, Yasuda C, Miyata S, Aihara M, Ikezawa Z, et al. New horny layer marker proteins for evaluating skin condition in atopic dermatitis. Int Arch Allergy Immunol. 2009;150:89–101.PubMedCrossRefGoogle Scholar
  38. 38.
    Adachi Y, Tsuchihashi J, Shiraishi N, Yasuda K, Etoh T, Kitano S. AFP-producing gastric carcinoma: multivariate analysis of prognostic factors in 270 patients. Oncology. 2003;65:95–101.PubMedCrossRefGoogle Scholar
  39. 39.
    Takahashi Y, Takeuchi T, Sakamoto J, Touge T, Mai M, Ohkura H, et al. The usefulness of CEA and/or CA19-9 in monitoring for recurrence in gastric cancer patients: a prospective clinical study. Gastric Cancer. 2003;6:142–5.PubMedCrossRefGoogle Scholar
  40. 40.
    Yonemori K, Ando M, Shibata T, Katsumata N, Matsumoto K, Yamanaka Y, et al. Tumor-marker analysis and verification of prognostic models in patients with cancer of unknown primary, receiving platinum-based combination chemotherapy. J Canc Res Clin Oncol. 2006;132:635–42.CrossRefGoogle Scholar
  41. 41.
    Currow DC, Findlay M, Cox K, Harnette PR. Elevated germ cell markers in carcinoma of uncertain primary site do not predict response to platinum based chemotherapy. Eur J Cancer. 1996;32:2357–9.CrossRefGoogle Scholar
  42. 42.
    Milovic M, Popov I, Jelic S. Tumor markers in metastatic disease from cancer of unknown primary origin. Med Sci Mon. 2002;8:25–30.Google Scholar
  43. 43.
    Varadhachary GR, Abbruzzesse JL, Lenzi R. Diagnostic strategies for unknown primary cancer. Cancer. 2004;100:1776–85.PubMedCrossRefGoogle Scholar
  44. 44.
    Destombe Cl, Botton E, Le Gal G, Roudaut A, Jousse-Joulin S, Devauchelle-Pensec V, Saraux A. Investigations for bone metastases from an unknown primary. Joint Bone Spine. 2007;74:85–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Light RW. Tumor markers in undiagnosed pleural effusions. Chest. 2004;126:1721–2.PubMedCrossRefGoogle Scholar
  46. 46.
    Lee JH, Chang JH. Diagnostic utility of serum and pleural fluid carcinoembryonic antigen, neuron-specific enolase, and cytokeratin 19 fragments in patients with effusions from primary lung cancer. Chest. 2005;128:2298–303.PubMedCrossRefGoogle Scholar
  47. 47.
    Amoura Z, Duhaut P, Huong DL, Wechsler B, Costedoat-Charlumeau N, Frances C, et al. Tumor antigen markers for the detection of solid cancers in inflammatory myopathies. Canc Epidemiol Biomarkers Prev. 2005;14:1279–82.CrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2011

Authors and Affiliations

  • Rafael Molina
    • 1
  • Xavier Bosch
    • 2
  • Josep M. Auge
    • 1
  • Xavier Filella
    • 1
  • José M. Escudero
    • 1
  • Víctor Molina
    • 3
  • Manel Solé
    • 4
  • Alfonso López-Soto
    • 2
  1. 1.Laboratory of Clinical Biochemistry (Unit for Cancer Research), Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)University of BarcelonaBarcelonaSpain
  2. 2.Department of Internal Medicine, Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)University of BarcelonaBarcelonaSpain
  3. 3.Department of Surgery, Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)University of BarcelonaBarcelonaSpain
  4. 4.Department of Pathology, Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)University of BarcelonaBarcelonaSpain

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