Tumour Markers in Lung Cancer

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					                                                                                Reference Section

                                                                         Tumour Markers in Lung Cancer

        a report by
        R a f a e l M o l i n a , X a v i e r F i l e l l a and J o s e p M A u g é

        Oncobiology Unit, Laboratory of Biochemistry and Genetics, IDIBAPS Hospital Clinic

Survival and treatment of lung cancer is clearly related          Pro-gastrin-releasing Peptide
to the histological type involved. Non-small cell lung
cancer (NSCLC) is comprised of three major                        Pro-gastrin-releasing peptide (ProGRP) is a
histological subtypes: adenocarcinoma, squamous cell              precursor of the gastrin-releasing peptide (GRP)
carcinoma and large cell carcinoma in which surgery               gut hormone, which is the mammalian counterpart
is the only chance for cure (stages I–IIIA). SCLC is an           of amphibian bombesin. ProGRP specificity is high
aggressive neoplasm of rapid growth, with metastatic              and only renal failure may produce significantly
diseases in regional lymph nodes or distant organs at             high serum levels of this tumour marker.7–10
the time of diagnosis, but with high sensitivity to               Excluding renal failure, fewer than 5% of patients
chemotherapy and radiotherapy.1 Unfortunately,                    with benign or malignant diseases, except for lung
however, the disease is usually diagnosed late in most            cancer or neuroendocrine tumours, had ProGRP
patients.2 Patients with lung cancer, particularly in the         levels higher than 50pg/ml.9–11 ProGRP serum
early stages, often do not exhibit specific symptoms:             levels are clearly related to the histology of the lung
dyspnoea, cough, thoracic pain, symptoms frequently               cancer, with significantly higher levels in
found in smokers. Radiotherapy is mainly palliative               SCLC.3,4,7,10–12 Slightly high ProGRP serum levels
and the role of chemotherapy in the therapeutic                   (95% <150pg/ml) may be found in 5–18% of
management of patients with advanced NSCLC is                     NSCLC, mainly in squamous tumours.7–12
still debatable since only modest improvement in
survival has been obtained.2                                      The sensitivity of ProGRP ranges from 40–60% in
                                                                  intrathoracic SCLC and from 75–85% in
Tumour Markers in Lung Cancer                                     extrathoracic SCLC.3–8,10–12 Most publications
                                                                  indicate a higher sensitivity with ProGRP than with
The most commonly used tumour markers in lung                     NSE, mainly in SCLC patients with limited disease
cancer are discussed below.                                       (LD). Likewise, the absence of ProGRP false positive
                                                                  results with haemolysis, in addition to the greater
Neuron Specific Enolase                                           differences between the normal range and the levels
                                                                  found in SCLC patients with ProGRP than with
Neuron specific enolase (NSE) has been the tumour                 NSE, support ProGRP as marker of choice.10,13–15
marker of choice in SCLC.3–7 NSE is present in                    However, NSE is a complementary marker for
platelets and erythrocytes making it necessary to                 SCLC, and the combination of the two markers
exclude samples with haemolysis. Moderate                         increases the sensitivity as well as facilitates greater
elevations of NSE serum levels are found in about                 precision in the histological diagnosis, prognosis,
10–20% of NSCLC as well as in a small proportion                  follow-up and early diagnosis of recurrence.6,7
of patients with benign lung diseases or in
malignancies other than in the lung (pancreas,                    Carcinoembryonic Antigen
gastric, breast).4–8 In contrast, NSE levels that are
double the cut-off values highly suggest SCLC or                  Carcinoembryonic antigen (CEA) is a glycoprotein
neuroendocrine tumours.4–8 The sensitivity of NSE                 with a molecular weight of 180kDa. It is one of the
in SCLC ranges from 50–80%, in relation to the                    carcinofoetal antigens produced during embryonal and
tumour extension.3–9                                              foetal development. Slightly high CEA concentrations,
                                                                  habitually lower than 10ng/ml, are found in 5–10% of
Different publications have demonstrated NSE                      smoker patients and in various benign pathologies
values to be an independent prognostic factor in both             including liver and renal diseases (<20ng/ml).16–21
SCLC and NSCLC.4–12 Likewise, NSE is useful in                    CEA is a tumour marker used in many solid
therapy monitoring as well as in the detection of                 adenocarcinomas, mainly in gastrointestinal tumours.
recurrent disease of SCLC after primary therapy.3–7               The sensitivity of this tumour marker ranges from

EUROPEAN ONCOLOGICAL DISEASE 2006                                                                                            1
                    Reference Section

    40–70% in NSCLC and from 30–65% in                         important utilities of SCC in lung cancer is its aid in
    SCLC.8,14,17–20 The highest CEA sensitivity and serum      establishing histological diagnosis.7,8,33,17–19,36,37
    concentrations are found in adenocarcinomas and large      Several articles have reported the potential utility of
    cell lung cancer with the lowest values being seen in      SCC as a prognostic factor in the early diagnosis of
    squamous tumours.                                          recurrence and in the follow-up of NSCLC, mainly
                                                               in squamous tumours.8,36,37
    CEA may provide prognostic information in
    NSCLC, particularly in lung adenocarcinomas.8,21–24        Clinical Utility of Tumour Markers
    Likewise, as with other tumour markers, the utility
    of CEA in the early diagnosis of recurrence and in         Diagnosis and Early Diagnosis
    therapy monitoring has been clearly established.25,26
                                                               There are no reports on the utility of tumour markers
    Cytokeratin-19 Fragment                                    in the early diagnosis of lung cancer in asymptomatic
                                                               populations. The sensitivity obtained in the early
    CYFRA 21-1 is a water soluble cytokeratin-19               stages of lung cancer clearly suggests that tumour
    fragment. Histopathological studies have demonstrated      makers are not useful for these purposes. However,
    that cytokeratin-19 is abundant in carcinomas of he        tumour markers, alone or in combination, show
    lung.8,18–22,26,27 Abnormal serum levels (>3.3ng/ml) of    considerable sensitivity in lung cancer.7–10 In the
    this tumour marker have been found in several benign       authors’ experience, with the use of three tumour
    diseases, including liver pathologies and renal            markers in NSCLC (CEA, CYFRA 21-1 and SCC)
    failure.7–8 Likewise, CYFRA 21-1 is increased in           and in SCLC (ProGRP, NSE and CEA or CYFRA
    several malignancies other than lung cancer, including     21-1) it is possible to obtain a sensitivity higher than
    most gynaecological or gastrointestinal tumours,           80% in stage I–III patients or LD and 90% in stage IV
    mesotheliomas and urological malignancy.8,2                or extensive disease (ED).7,8 It is known than some
    However, the highest CYFRA 21-1 concentrations             benign diseases may produce false positive results in
    are found in lung cancer, mainly in NSCLC. On              this group of patients.7,8,16,21 However, when these
    comparing different tumour markers, different authors      pathologies are excluded, the specificity increases
    reported that CYFRA 21-1 is the most sensitive             significantly (>90%).7–10 In summary, there are no
    tumour marker in lung cancer, with the highest             ideal tumour markers in lung cancer, but the
    concentrations in squamous tumours. The sensitivity        sensitivity and specificity obtained with them is higher
    of CYFRA ranges from 30–75% in NSCLC and from              than that achieved with other tumour markers in
    20–60% in SCLC.29                                          other malignancies, such as prostate serum antigen
                                                               (PSA) in prostate cancer. Tumour markers in lung
    Since CYFRA 21-1 determines only fragments of              cancer may be useful as an aid in patients suspected of
    cytokeratin-19, the test shows a higher specificity        having this malignancy.4,7–8,17–21,26,38,39
    than tissue-polypeptide antigen (TPA), which
    determines a mixture of cytokeratins 8, 18 and             Histological Diagnosis
    19.30–32 The utility of CYFRA as an aid in the
    diagnosis, prognosis (mainly in NSCLC), early              The most important point in lung cancer is to
    diagnosis of recurrence and therapy monitoring has         distinguish NSCLC and SCLC. ProGRP and NSE are
    been clearly indicated.8,19–22,25–28,30,33–35              useful parameters to suggest SCLC.4–11,20 The higher
                                                               the levels of NSE and/or ProGRP, the higher the
    Squamous Cell Carcinoma Antigen                            probability of SCLC (see Table 1). The highest
                                                               efficiency in the diagnosis of SCLC is obtained using
    Squamous cell carcinoma antigen (SCC) is a 48kDa           both tumour markers simultaneously (see Table 1).4–12,33
    protein with strong homology to the serpin family
    of protease inhibitors. Its main clinical application is   There are no specific tumour markers for NSCLC,
    in squamous tumours of different origin: uterine           but some of them show a clear relationship with the
    cervix, oesophagus, head, neck and lung. The main          histological type.20,21 Abnormal SCC serum levels
    sources of SCC false positive results are renal failure    suggest a probability higher than 95% of NSCLC
    and dermatological disorders in which very high            (75% probability, squamous). Significantly higher
    levels up to 30–40 times higher than the cut-off           concentrations of CEA and mucins (CA 15.3 and
    values may be found.16,21 The sensitivity of SCC in        TAG) are found in adenocarcinomas.17,18,24,29,40 It is
    lung cancer ranges from 25–60% in NSCLC, but is            interesting to point out that it is very infrequent to
    rarely found in SCLC (<5%).7–8,17–18,21,27,32 The          find abnormal levels of some tumour markers such as
    highest sensitivity of this tumour marker is observed      CEA or CYFRA 21-1 with normal NSE or
    in squamous tumours, but it is possible to find            ProGRP. Table 2 shows some combinations of
    abnormal levels in other NSCLC. One of the most            tumour markers to help in the histological diagnosis.

2                                                                          EUROPEAN ONCOLOGICAL DISEASE 2006
                                                                             Tumour Markers in Lung Cancer

In summary, pathological evaluation is the gold              Table 1: Probability of SCLC According to Tumour Stage and NSE and/or
standard in diagnosis, but the use of tumour markers         ProGRP Serum Levels in 533 Patients with Lung Cancer
may be of aid when biopsy is not available or in
certain specific situations.                                 Criteria            SCLC/total lung       LD/total stage I–III      ED/total stage IV
Prognostic Value                                             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%)
Numerous studies have been published regarding the           NSE > 40ng/ml     68/70 (97.1%)           20/20   (100%)            48/50   (96%)
utility of tumour markers in the prognosis, on               ProGRP            95/113 (84.1%)          36/44   (81.8%)           59/69   (85.5%)
univariate and multivariate analysis, in SCLC (CEA,          > 100pg/ml
CYFRA 21-1, NSE and ProGRP) as well as in                    ProGRP            87/95 (91.6%)           31/32 (96.8%)             56/63 (88.9%)
NSCLC (CEA, CYFRA 21-1, NSE, SCC, CA                         > 150pg/ml
125).4–8,17–26,34,35,40,41 The authors’ group compared the   ProGRP            82/86 (95.3%)           29/29 (100%)              53/57 (93%)
most important clinical and pathological prognostic          > 200pg/ml
factors and tumour markers in a prospective evaluation       NSE > 40ng/ml     109/114 (95.6%)         40/40 (100%)              69/74 (93.2%)
of 211 NSCLC patients and, on multivariate analysis,         and/or
found that some clinical (stage, histology, Karnofsky        ProGRP > 200pg/ml
Index, thoracic pain), therapeutical (surgery,               NSE > 35ng/ml     116/126 (92%)           44/45 (97.8%)             72/81 (87.7%)
chemotherapy) and biological (CA 125 or CEA, NSE             and/or
or LDH and SCC) parameters were independent                  ProGRP > 150pg/ml
prognostic factors. However, as occurs with most
prognostic factors, the clinical utility remains to be       Table 2: Probability of NSCLC According to Tumour Extension and Tumour
demonstrated. Moreover, serum tumour markers have            Markers in 384 Patients with Lung Cancer
potential advantages, as they are readily performed and
can be standardised and quality controlled.                  Criteria              NSCLC/total lung     Stage I–III/total lung       Stage IV/total
                                                                                   cancer               cancer Mo                  lung cancer M1
NSE has also been suggested as a prognostic factor in        SCC > 2ng/ml          84/85 (98.8%)        47/48 (97.9%)               36/36 (100%)
NSCLC.22,33,42,43 The hypothesis to explain these            CEA > 5ng/ml,         157/161 (97.5%)      70/71 (98.6%)                87/90 96.7%
results may be that NSE is a predictive factor,              NSE < 26ng/ml and
selecting the patients with neuroendocrine                   ProGRP < 50pg/ml
differentiation and with higher response to                  CYFRA > 3.3ng/ml      223/231 (96.5%)      118/121 (97.5%)          105/110 (95.5%)
chemotherapy. The use of NSE and other parameters            NSE < 36ng/ml
such as LDH or chromogranin A as predictive factors          PROgrp < 150pg/ml
in SCLC has also been suggested.3–10                         CA 125 > 100U/ml      76/80 (95%)          22/23 (95.7%)               54/57 (94.7%)
                                                             NSE < 36ng/ml and
Early Diagnosis of Recurrence                                ProGRP < 150pg/ml

Following curative resection, tumour markers,                Therapy Monitoring
depending on the half-life of each tumour marker,
may decrease, reaching normal values within a short          The main interest of tumour marker evaluation in
period of time. Patients with an elevated plateau or         serum is in patient follow-up, mainly in those with
with increased tumour marker levels in serial                abnormal values.7–15,21,28,34,40–43 Patients in remission
determinations are indicative of the presence of             usually have a substantial reduction in marker levels,
residual tumour cells.44 However, to suspect                 while those with progressive disease generally have
recurrence, possible sources of false positive results       increased levels. Tumour markers in patients treated
such as in liver diseases or renal failure must be           with chemotherapy should be determined before
excluded. Tumour marker sensitivity as well as the           every chemotherapy course, since certain treatments
lead time are related to the tumour marker used.             may cause transient increases in serum marker levels.
Increasing serial SCC levels have been reported as           ProGRP is the most sensitive tumour marker in
the first sign of recurrence in 79% of squamous              SCLC but the addition of NSE as complementary
tumours.26 The sensitivity of CYFRA 21-1 was                 tumour marker, mainly in patients with LD, provides
found to be similar in NSCLC with a lead time of             additional information.3–6,15,48
between two and 15 months.26,45,46 CEA and TPS
have also been reported as relevant tumour markers           The tumour marker used in NSCLC differs
for detecting recurrent disease.24,25,45–47 The              according to the histological type. CYFRA 21-1 is
simultaneous use of ProGRP and NSE is useful in              the most sensitive tumour marker in NSCLC and
the early diagnosis of recurrence in more than 80% of        its use in therapy evaluation, mainly in the
patients with SCLC recurrence.3–8,10,15                      detection of progression, has been reported.26,32,43,49

EUROPEAN ONCOLOGICAL DISEASE 2006                                                                                                                     3
                      Reference Section

    In our experience, the best combination of tumour                their use are not clear. In this review it is shown
    markers in disease monitoring is CYFRA 21-1 and                  that the sensitivity and specificity of tumour
    CEA in all NSCLC, also including SCC in                          markers in lung cancer are high or are at least
    squamous tumours and one mucin (CA 15.3, TAG)                    similar to the values obtained in other malignancies.
    in adenocarcinoma or SCLC.                                       The use of tumour markers is closely related to
                                                                     treatment and lung cancer is habitually diagnosed
    Conclusion                                                       late with short curative possibilities. Nevertheless,
                                                                     tumour markers may provide very helpful aid in
    Tumour markers are not habitually used in patients               diagnosis, prognosis, early diagnosis of recurrence
    with lung cancer because the clinical advantages of              and therapy monitoring. ■


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EUROPEAN ONCOLOGICAL DISEASE 2006                                                                                                   5

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