a report by

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.
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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.
Conc l us i on
Tumour markers are not habitually used in patients
with lung cancer because the clinical advantages of
their use are not clear. In this review it is shown
that the sensitivity and specificity of tumour
markers in lung cancer are high or are at least
similar to the values obtained in other malignancies.
The use of tumour markers is closely related to
treatment and lung cancer is habitually diagnosed
late with short curative possibilities. Nevertheless,
tumour markers may provide very helpful aid in
diagnosis, prognosis, early diagnosis of recurrence
and therapy monitoring.
Reference Section
4 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
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