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
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
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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