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Survival and treatment of lung cancer is clearly related to the histological type involved. Neuron specific enolase (nse) has been the tumour marker of choice in SCLC. Nse levels that are double the cut-off values highly suggest SCLC or neuroendocrine tumours.
Survival and treatment of lung cancer is clearly related to the histological type involved. Neuron specific enolase (nse) has been the tumour marker of choice in SCLC. Nse levels that are double the cut-off values highly suggest SCLC or neuroendocrine tumours.
Survival and treatment of lung cancer is clearly related to the histological type involved. Neuron specific enolase (nse) has been the tumour marker of choice in SCLC. Nse levels that are double the cut-off values highly suggest SCLC or neuroendocrine tumours.
Ra f a e l Mol i na , Xa v i e r F i l e l l a and J os e p M Aug
Oncobiology Unit, Laboratory of Biochemistry and Genetics, IDIBAPS Hospital Clinic Survival and treatment of lung cancer is clearly related to the histological type involved. Non-small cell lung cancer (NSCLC) is comprised of three major histological subtypes: adenocarcinoma, squamous cell carcinoma and large cell carcinoma in which surgery is the only chance for cure (stages IIIIA). SCLC is an aggressive neoplasm of rapid growth, with metastatic diseases in regional lymph nodes or distant organs at the time of diagnosis, but with high sensitivity to chemotherapy and radiotherapy. 1 Unfortunately, however, the disease is usually diagnosed late in most patients. 2 Patients with lung cancer, particularly in the early stages, often do not exhibit specific symptoms: dyspnoea, cough, thoracic pain, symptoms frequently found in smokers. Radiotherapy is mainly palliative and the role of chemotherapy in the therapeutic management of patients with advanced NSCLC is still debatable since only modest improvement in survival has been obtained. 2 T umour Ma r ke r s i n L ung Ca nc e r The most commonly used tumour markers in lung cancer are discussed below. Ne ur on S pe c i f i c Enol as e Neuron specific enolase (NSE) has been the tumour marker of choice in SCLC. 37 NSE is present in platelets and erythrocytes making it necessary to exclude samples with haemolysis. Moderate elevations of NSE serum levels are found in about 1020% of NSCLC as well as in a small proportion of patients with benign lung diseases or in malignancies other than in the lung (pancreas, gastric, breast). 48 In contrast, NSE levels that are double the cut-off values highly suggest SCLC or neuroendocrine tumours. 48 The sensitivity of NSE in SCLC ranges from 5080%, in relation to the tumour extension. 39 Different publications have demonstrated NSE values to be an independent prognostic factor in both SCLC and NSCLC. 412 Likewise, NSE is useful in therapy monitoring as well as in the detection of recurrent disease of SCLC after primary therapy. 37 Pr o- g as t r i n- r e l e as i ng Pe pt i de Pro-gastrin-releasing peptide (ProGRP) is a precursor of the gastrin-releasing peptide (GRP) gut hormone, which is the mammalian counterpart of amphibian bombesin. ProGRP specificity is high and only renal failure may produce significantly high serum levels of this tumour marker. 710 Excluding renal failure, fewer than 5% of patients with benign or malignant diseases, except for lung cancer or neuroendocrine tumours, had ProGRP levels higher than 50pg/ml. 911 ProGRP serum levels are clearly related to the histology of the lung cancer, with significantly higher levels in SCLC. 3,4,7,1012 Slightly high ProGRP serum levels (95% <150pg/ml) may be found in 518% of NSCLC, mainly in squamous tumours. 712 The sensitivity of ProGRP ranges from 4060% in intrathoracic SCLC and from 7585% in extrathoracic SCLC. 38,1012 Most publications indicate a higher sensitivity with ProGRP than with NSE, mainly in SCLC patients with limited disease (LD). Likewise, the absence of ProGRP false positive results with haemolysis, in addition to the greater differences between the normal range and the levels found in SCLC patients with ProGRP than with NSE, support ProGRP as marker of choice. 10,1315 However, NSE is a complementary marker for SCLC, and the combination of the two markers increases the sensitivity as well as facilitates greater precision in the histological diagnosis, prognosis, follow-up and early diagnosis of recurrence. 6,7 Car c i noe mbr y oni c Ant i g e n Carcinoembryonic antigen (CEA) is a glycoprotein with a molecular weight of 180kDa. It is one of the carcinofoetal antigens produced during embryonal and foetal development. Slightly high CEA concentrations, habitually lower than 10ng/ml, are found in 510% of smoker patients and in various benign pathologies including liver and renal diseases (<20ng/ml). 1621 CEA is a tumour marker used in many solid adenocarcinomas, mainly in gastrointestinal tumours. The sensitivity of this tumour marker ranges from Tumour Mar ker s i n Lung Cancer Reference Section E U R OP E A N ON C OL OG I C A L D I S E A S E 2 0 0 6 1 4070% in NSCLC and from 3065% in SCLC. 8,14,1720 The highest CEA sensitivity and serum concentrations are found in adenocarcinomas and large cell lung cancer with the lowest values being seen in squamous tumours. CEA may provide prognostic information in NSCLC, particularly in lung adenocarcinomas. 8,2124 Likewise, as with other tumour markers, the utility of CEA in the early diagnosis of recurrence and in therapy monitoring has been clearly established. 25,26 Cy t ok e r at i n- 19 F r ag me nt CYFRA 21-1 is a water soluble cytokeratin-19 fragment. Histopathological studies have demonstrated that cytokeratin-19 is abundant in carcinomas of he lung. 8,1822,26,27 Abnormal serum levels (>3.3ng/ml) of this tumour marker have been found in several benign diseases, including liver pathologies and renal failure. 78 Likewise, CYFRA 21-1 is increased in several malignancies other than lung cancer, including most gynaecological or gastrointestinal tumours, mesotheliomas and urological malignancy. 8,2 However, the highest CYFRA 21-1 concentrations are found in lung cancer, mainly in NSCLC. On comparing different tumour markers, different authors reported that CYFRA 21-1 is the most sensitive tumour marker in lung cancer, with the highest concentrations in squamous tumours. The sensitivity of CYFRA ranges from 3075% in NSCLC and from 2060% in SCLC. 29 Since CYFRA 21-1 determines only fragments of cytokeratin-19, the test shows a higher specificity than tissue-polypeptide antigen (TPA), which determines a mixture of cytokeratins 8, 18 and 19. 3032 The utility of CYFRA as an aid in the diagnosis, prognosis (mainly in NSCLC), early diagnosis of recurrence and therapy monitoring has been clearly indicated. 8,1922,2528,30,3335 S quamous Ce l l Car c i noma Ant i g e n Squamous cell carcinoma antigen (SCC) is a 48kDa protein with strong homology to the serpin family of protease inhibitors. Its main clinical application is in squamous tumours of different origin: uterine cervix, oesophagus, head, neck and lung. The main sources of SCC false positive results are renal failure and dermatological disorders in which very high levels up to 3040 times higher than the cut-off values may be found. 16,21 The sensitivity of SCC in lung cancer ranges from 2560% in NSCLC, but is rarely found in SCLC (<5%). 78,1718,21,27,32 The highest sensitivity of this tumour marker is observed in squamous tumours, but it is possible to find abnormal levels in other NSCLC. One of the most important utilities of SCC in lung cancer is its aid in establishing histological diagnosis. 7,8,33,1719,36,37 Several articles have reported the potential utility of SCC as a prognostic factor in the early diagnosis of recurrence and in the follow-up of NSCLC, mainly in squamous tumours. 8,36,37 Cl i ni c a l Ut i l i t y of T umour Ma r ke r s Di ag nos i s and Ear l y Di ag nos i s There are no reports on the utility of tumour markers in the early diagnosis of lung cancer in asymptomatic populations. The sensitivity obtained in the early stages of lung cancer clearly suggests that tumour makers are not useful for these purposes. However, tumour markers, alone or in combination, show considerable sensitivity in lung cancer. 710 In the authors experience, with the use of three tumour markers in NSCLC (CEA, CYFRA 21-1 and SCC) and in SCLC (ProGRP, NSE and CEA or CYFRA 21-1) it is possible to obtain a sensitivity higher than 80% in stage IIII patients or LD and 90% in stage IV or extensive disease (ED). 7,8 It is known than some benign diseases may produce false positive results in this group of patients. 7,8,16,21 However, when these pathologies are excluded, the specificity increases significantly (>90%). 710 In summary, there are no ideal tumour markers in lung cancer, but the sensitivity and specificity obtained with them is higher than that achieved with other tumour markers in other malignancies, such as prostate serum antigen (PSA) in prostate cancer. Tumour markers in lung cancer may be useful as an aid in patients suspected of having this malignancy. 4,78,1721,26,38,39 Hi s t ol og i c al Di ag nos i s The most important point in lung cancer is to distinguish NSCLC and SCLC. ProGRP and NSE are useful parameters to suggest SCLC. 411,20 The higher the levels of NSE and/or ProGRP, the higher the probability of SCLC (see Table 1). The highest efficiency in the diagnosis of SCLC is obtained using both tumour markers simultaneously (see Table 1). 412,33 There are no specific tumour markers for NSCLC, but some of them show a clear relationship with the histological type. 20,21 Abnormal SCC serum levels suggest a probability higher than 95% of NSCLC (75% probability, squamous). Significantly higher concentrations of CEA and mucins (CA 15.3 and TAG) are found in adenocarcinomas. 17,18,24,29,40 It is interesting to point out that it is very infrequent to find abnormal levels of some tumour markers such as CEA or CYFRA 21-1 with normal NSE or ProGRP. Table 2 shows some combinations of tumour markers to help in the histological diagnosis. Reference Section 2 E U R OP E A N ON C OL OG I C A L D I S E A S E 2 0 0 6 Tumour Mar ker s i n Lung Cancer In summary, pathological evaluation is the gold standard in diagnosis, but the use of tumour markers may be of aid when biopsy is not available or in certain specific situations. Pr og nos t i c Val ue Numerous studies have been published regarding the utility of tumour markers in the prognosis, on univariate and multivariate analysis, in SCLC (CEA, CYFRA 21-1, NSE and ProGRP) as well as in NSCLC (CEA, CYFRA 21-1, NSE, SCC, CA 125). 48,1726,34,35,40,41 The authors group compared the most important clinical and pathological prognostic factors and tumour markers in a prospective evaluation of 211 NSCLC patients and, on multivariate analysis, found that some clinical (stage, histology, Karnofsky Index, thoracic pain), therapeutical (surgery, chemotherapy) and biological (CA 125 or CEA, NSE or LDH and SCC) parameters were independent prognostic factors. However, as occurs with most prognostic factors, the clinical utility remains to be demonstrated. Moreover, serum tumour markers have potential advantages, as they are readily performed and can be standardised and quality controlled. NSE has also been suggested as a prognostic factor in NSCLC. 22,33,42,43 The hypothesis to explain these results may be that NSE is a predictive factor, selecting the patients with neuroendocrine differentiation and with higher response to chemotherapy. The use of NSE and other parameters such as LDH or chromogranin A as predictive factors in SCLC has also been suggested. 310 Ear l y Di ag nos i s of Re c ur r e nc e Following curative resection, tumour markers, depending on the half-life of each tumour marker, may decrease, reaching normal values within a short period of time. Patients with an elevated plateau or with increased tumour marker levels in serial determinations are indicative of the presence of residual tumour cells. 44 However, to suspect recurrence, possible sources of false positive results such as in liver diseases or renal failure must be excluded. Tumour marker sensitivity as well as the lead time are related to the tumour marker used. Increasing serial SCC levels have been reported as the first sign of recurrence in 79% of squamous tumours. 26 The sensitivity of CYFRA 21-1 was found to be similar in NSCLC with a lead time of between two and 15 months. 26,45,46 CEA and TPS have also been reported as relevant tumour markers for detecting recurrent disease. 24,25,4547 The simultaneous use of ProGRP and NSE is useful in the early diagnosis of recurrence in more than 80% of patients with SCLC recurrence. 38,10,15 The r apy Moni t or i ng The main interest of tumour marker evaluation in serum is in patient follow-up, mainly in those with abnormal values. 715,21,28,34,4043 Patients in remission usually have a substantial reduction in marker levels, while those with progressive disease generally have increased levels. Tumour markers in patients treated with chemotherapy should be determined before every chemotherapy course, since certain treatments may cause transient increases in serum marker levels. ProGRP is the most sensitive tumour marker in SCLC but the addition of NSE as complementary tumour marker, mainly in patients with LD, provides additional information. 36,15,48 The tumour marker used in NSCLC differs according to the histological type. CYFRA 21-1 is the most sensitive tumour marker in NSCLC and its use in therapy evaluation, mainly in the detection of progression, has been reported. 26,32,43,49 E U R OP E A N ON C OL OG I C A L D I S E A S E 2 0 0 6 3 Table 2: Probability of NSCLC According to Tumour Extension and Tumour Markers in 384 Patients with Lung Cancer Criteria NSCLC/total lung Stage IIII/total lung Stage IV/total cancer cancer Mo lung cancer M1 SCC > 2ng/ml 84/85 (98.8%) 47/48 (97.9%) 36/36 (100%) CEA > 5ng/ml, 157/161 (97.5%) 70/71 (98.6%) 87/90 96.7% NSE < 26ng/ml and ProGRP < 50pg/ml CYFRA > 3.3ng/ml 223/231 (96.5%) 118/121 (97.5%) 105/110 (95.5%) NSE < 36ng/ml PROgrp < 150pg/ml CA 125 > 100U/ml 76/80 (95%) 22/23 (95.7%) 54/57 (94.7%) NSE < 36ng/ml and ProGRP < 150pg/ml Table 1: Probability of SCLC According to Tumour Stage and NSE and/or ProGRP Serum Levels in 533 Patients with Lung Cancer Criteria SCLC/total lung LD/total stage IIII ED/total stage IV cancer NSE > 25ng/ml 98/135 (72.6%) 38/57 (66.7%) 60/78 (76.9%) NSE > 35ng/ml 76/79 (96.2%) 24/24 (100%) 52/55 (94.5%) NSE > 40ng/ml 68/70 (97.1%) 20/20 (100%) 48/50 (96%) ProGRP 95/113 (84.1%) 36/44 (81.8%) 59/69 (85.5%) > 100pg/ml ProGRP 87/95 (91.6%) 31/32 (96.8%) 56/63 (88.9%) > 150pg/ml ProGRP 82/86 (95.3%) 29/29 (100%) 53/57 (93%) > 200pg/ml NSE > 40ng/ml 109/114 (95.6%) 40/40 (100%) 69/74 (93.2%) and/or ProGRP > 200pg/ml NSE > 35ng/ml 116/126 (92%) 44/45 (97.8%) 72/81 (87.7%) and/or ProGRP > 150pg/ml In our experience, the best combination of tumour markers in disease monitoring is CYFRA 21-1 and CEA in all NSCLC, also including SCC in squamous tumours and one mucin (CA 15.3, TAG) in adenocarcinoma or SCLC. 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