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Lung tumor markers fall into several categories including oncofetal proteins, structural proteins and their fragments, enzymes, membrane antigens, peptide and non-peptide hormones. Cytokeratins (CK) are well known structural proteins whose degradation gives rise to soluble fragments, measurable in the blood of patients and capable of cancer marking. Among them, Tissue Polypeptide Antigen (TPA), Tissue Polypeptide-Specific Antigen (TPS) and Cytokeratin-19-Fragments (Cyfra 21-1) are the most studied CK fragments' complexes. This article will review biological characteristics and clinical properties of these substances, emphasizing as their concentration in the peripheral blood might reflect the mass of tumor, the rate of cancer cell lysis, and other potentially unfavorable tumor characteristics. Assaying the concentration of CK fragments in the blood is an easy and effective way to assess lung cancer and monitor its clinical evolution.

The tissue polypeptide antigen (TPA) is a protein produced and released by proliferating cells that possesses several characteristics for an ideal tumor marker. Our purpose was to define the clinical yield of TPA in the follow-up of patients with lung cancer (LC). Three hundred and forty-one new LC patients underwent an extensive pre-treatment staging evaluation (UICC 1987 classification) and a TPA serum measurement. We restaged them at regular times by: 1, clinical history and physical examination, routine lab tests, chest X-rays, and any other examination as suggested by the prior baseline evaluation, and 2, the serum level of TPA. We evaluated a total of 1513 assays (including 1172 posttreatment measurements). Individual values of TPA correlated significantly with treatment response and disease status. Patients with small-cell lung cancer showed the lowest correlation indexes between clinical parameters and the marker. Each objective response to treatment or disease progression was almost always associated to consistent changes of TPA (P < 0.0001, by the Wilcoxon's test). A 50% reduction under the prior TPA value was 30% sensitive, 90% specific, and 88% accurate in the diagnosis of response to treatment. The same percent reduction was 18% sensitive, 92% specific, and 88% accurate in predicting a future response. A 100% increase over the prior level of TPA permitted to recognize tumor relapses with sensitivity, specificity, and accuracy of 30%, 93%, and 80% (diagnosis of progression), and 18%, 92%, and 78% (prediction of progression). Similar diagnostic yields were observed using progressively increasing or progressively decreasing changes of the marker level. In lung cancer, the diagnosis (and even the anticipation) of disease status is often possible using appropriate threshold value of TPA.

Tissue polypeptide antigen (TPA) is a protein produced and released by proliferating cells that has been shown to possess several characteristics for an ideal tumor marker. Our purpose was to determine the yield of TPA in the pretreatment assessment of non-small cell lung cancer (NSCLC), in comparison with a baseline clinical evaluation and multiorgan computed tomography (CT) assumed to be the gold standard for presurgical staging. One hundred four patients with NSCLC underwent thoracotomy, mediastinoscopy, or biopsy of suspected metastatic deposits, in addition to an extensive noninvasive evaluation of their stage of disease. We restaged retrospectively (UICC 1987 classification) these patients, on the basis of the following: (1) clinical history and physical examination, routine laboratory tests, bronchoscopy, chest radiographs, and any other examination as indicated by the prior baseline evaluation (BE stage); (2) the serum level of TPA (TPA stage); (3) the reading of a CT scan of brain, thorax, and abdomen obtained with no limitation to clinical information (CT stage); and (4) pathologic findings (RE stage). The TPA stage was calculated using 20 threshold values ranging from 45 U/L to 450 U/L. On the basis of the RE stage, sensitivity, specificity, accuracy, and predictive capabilities of BE, CT, and TPA were determined for stage I and II (full operability, FO), stage IIIa (possible operability, PO), and stage IIIb and IV (full inoperability, FI). The TPA thresholds were 110 U/L for detecting FO with the highest rate of success, and 160 U/L for detecting FI. Using these thresholds BE, CT, and TPA showed a diagnostic accuracy of, respectively, 75%, 79%, and 68% for FO; 87%, 69%, and 77% for PO; 87%, 77%, and 76% for FI. The accuracy of BE, CT, and TPA for both FO and FI was, respectively, 85%, 69%, and 69%. Of 74 patients classified operable by BE, 6 had a serum concentration of TPA less than 50 U/L and all 6 were confirmed in stage I or II at the subsequent thoracotomy; 15 others, out of 26 patients judged to have inoperable conditions by BE, had a TPA test result above 135 U/L and all 15 were pathologically classified in stage IIIb or IV. Using appropriate threshold values of TPA, it should be possible to predict NSCLC resectability with a diagnostic accuracy similar to that routinely achieved by CT.

Multivariate models of survival have been established for both small cell and non-small cell lung cancers. So far, no study has focussed on squamous cell types. Previous demonstrations of the prognostic value of the tissue polypeptide antigen (TPA) and, partially, of the carcinoembryonic antigen (CEA) are based on univariate analyses of survival. These analyses do not account for the other prognostic factors. In the present study, we report the combined influence of various clinical and biological characteristics on the survival duration of 360 patients with a newly diagnosed squamous cell carcinoma of the lung. The study comprised 29 variables, including age, sex, smoking habit (SH), symptoms at diagnosis, the Karnofsky performance status (KPS), weight loss (WL), radiological findings, various disease extent parameters (DEP), CEA and TPA. Preliminary univariate analyses showed that 20 variables were survival-related. The Cox proportional hazards regression analysis selected stage of disease, KPS, TPA, WL, the existence of bone metastases, and SH as independent factors of prognosis (global chi-square: 122.40, P = 0.0000). A second multivariate analysis, performed with the same covariates but excluding DEP, revealed previous pulmonary diseases and CEA to be, in addition to KPS, TPA, SH, and WL the next most influential prognostic determinants. Also in squamous cell lung cancer, classifications based on the Cox's prediction equation may improve individual counseling and patient selection for therapeutic trials. In this malignancy, TPA shows an independent and strong prognostic significance while CEA shares informations of diverse other prognostic factors and seems to be less important.

The prognostic impact of TPA was evaluated by assaying the marker in the serum of 563 patients with a newly diagnosed bronchogenic carcinoma. The group included patients with squamous cell cancers and others with tumors of diverse or undefined histologies. Raised levels of TPA were clearly associated with a shortened survival, even adjusting for the stage of disease. A Cox's proportional hazards regression analysis, incorporating all major prognostic factors, selected TPA as an independent survival predictor. In the regression model, however, TPA was less important than disease extent, KPS and weight loss. Another multivariate analysis was made in a subgroup of 121 patients who, because of poor KPS or advanced age, had undergone a limited staging workup; TPA came out as the first most important factor. This study shows that TPA is an important prognostic factor and that it should be included among laboratory data evaluated in lung cancer studies.

A study of tissue polypeptide antigen (TPA) serum levels was conducted in patients with various cell types of bronchial carcinoma. A total of 548 assays (226 pretreatment) were evaluated. In all, the sensitivity of the test at diagnosis was 61 percent. It varied considerably in relation to the extent and site of disease. Individual pretreatment values of TPA correlated significantly with the stage of disease. Similarly, posttreatment TPA values related to disease evolution. In small cell carcinoma, eight of the 29 meaningful changes in follow-up levels of TPA preceded clinical recognition of disease status variations. Raised pretreatment values of TPA were significantly associated with a shortened survival. These results indicate that TPA may contribute to staging, monitoring, and prognosis of lung cancer.

One hundred six patients with histologically proven bronchogenic carcinoma were tested for carcinoembryonic antigen (CEA), tissue polypeptide antigen (TPA), and carbohydrate antigenic determinant 19-9 (CA19-9). A total of 349 CEAs, 350 TPAs, and 317 CA19-9s were measured. In addition, sera were assayed from 57 patients with pulmonary benign diseases and their CEA, TPA, and CA19-9 levels were used as negative controls for specificity and accuracy. One hundred twenty healthy subjects provided our normal CA19-9 reference value. Sensitivity, specificity, and accuracy were obtained for CEA, TPA, and CA19-9, respectively. Significant intermarker correlations were found both at diagnosis and during follow-up, CEA and CA19-9 being the most closely related substances. The percentage of patients with elevated levels of TPA increased significantly according to tumor load. Individual values of TPA related significantly to the stage of disease. Concentrations of CEA, TPA, and CA19-9 varied significantly during the course of the illness in relation to treatment response; however, TPA showed the closest relationship to the clinical status assessments of the follow-up period. Abnormal pretreatment levels of TPA were significantly associated with a poor outcome. Biomarker combinations were clinically evaluated by calculating the mean of the percentage of the reference value for each combined marker. Using this method, any association of TPA with CEA and/or CA19-9 revealed neither a greater diagnostic accuracy nor a more reliable predictive capacity for the above clinical variables than TPA evaluated on its own. The authors believe that a single TPA assay should be added to the initial and subsequent clinical assessments of patients with bronchogenic carcinoma.