syndrome
Titulaer, M.J.
Citation
Titulaer, M. J. (2010, November 24). Prediction of small cell lung cancer in the Lambert-Eaton myasthenic syndrome. Department of Neurology, Faculty of Medicine / Leiden University Medical Center (LUMC), Leiden University. Retrieved from https://hdl.handle.net/1887/16174
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CHAPTER 7
Screening for small cell lung cancer.
A follow-up study of 100 patients with Lambert-Eaton myasthenic Syndrome
MJ Titulaer 1, PW Wirtz 1,2, LNA Willems 3, KW van Kralingen 3, PAE Sillevis Smitt 4, JJGM Verschuuren 1
1 Dep. of Neurology, Leiden University Medical Center, Leiden, the Netherlands
2 Dep. of Neurology, Haga Hospital, The Hague, the Netherlands
3 Dep. of Pulmonology, Leiden University Medical Center, Leiden, the Netherlands
4 Dep. of Neurology, Erasmus MC, Rotterdam, the Netherlands
Abstract
Introduction A small cell lung carcinoma (SCLC) is found in 50% of the patients with the Lambert-Eaton myasthenic syndrome (LEMS). We evaluated screening to optimize screening strategy for SCLC. It is important to detect these tumours early in newly diagnosed LEMS patients to offer optimal patient treatment.
Patients and methods A large nationwide cohort study of consecutive Dutch patients, seen between 1990 and 2007, were screened for the presence of a tumour using chest-X-ray, CT-Thorax, FDG-PET, brochoscopy and/or medias- tinoscopy.
Results In 54 patients a SCLC was found, in 46 patients no tumour was found during a median follow-up of 8 years (range 3 - 26). All patients with SCLC had a positive smoking history and 86% were still smoking at diagnosis. SCLC was found in 92% of these patients within 3 months and in 96% within a year. At first screening CT-thorax detected a SCLC in 45 patients (83%), while chest X-ray found the tumour in only 23 patients (51%). A SCLC was found during secondary screening in another nine patients (median 3 months, range 1-41). In six patients a lung tumour was found by CT-thorax or FDG-PET and in three extrapulmonary metastases were found, initially without identifiable tumour mass on CT-thorax.
Conclusions In almost all patients (96%) the SCLC was found within one year of diagnosis. CT-thorax scans detected most of the tumours (93%) and was far more sensitive than chest X-ray (51%). FDG-PET may have additive value in selected cases. We propose a screening protocol based on CT-thorax and FDG-PET.
Introduction
Lung cancer is one of the most frequent types of cancer and is the number one cause of cancer related death in both women and men, as well in the US as in Europe.1, 2 Small cell lung cancer (SCLC), representing 13-20%3, 4 of all lung cancers, is associated with an aggressive clinical course and poor long term outcome.4 A few percent of SCLC patients have a paraneoplastic neurological syndrome, of which the most frequent is Lambert-Eaton myasthenic syndrome (LEMS). LEMS is a disease of the neuromuscular junction, characterized by proximal muscle weakness, areflexia and autonomic dysfunction.5 It is caused by antibodies, directed against P/Q-type voltage gated calcium channels (VGCC) in the presynaptic nerve terminal.6 The same VGCCs are expressed by SCLC, suggesting that autoimmunization by the tumour is causing LEMS .7
Only 1-3% of SCLC patients have LEMS.8, 9 Between 40 to 60% of LEMS patients have a SCLC,10-14 which results in an a priori chance of 50% to carry a SCLC at the moment of diagnosis of LEMS.12, 15 This is a major clinical concern for the patient as well as for the doctor. Smoking and the absence of HLA-B8 are factors associated with a higher risk of having an underlying tumour.16 Most SCLC are found within two years of diagnosis of LEMS. Discovery of a tumour has been described up till more than five years after diagnosis of LEMS.17 One anecdotal case with an interval of even 12 years exists.18
Screening recommendations for SCLC in patients with a paraneoplastic syndrome, like LEMS, consist of repeated radiological imaging, amongst others CT-thorax.19-21 These screening protocols are based on expert opinion and no supporting evidence based on clinical data is available. Recent discussions about screening for lung cancer in risk groups22, 23 have resulted in the start of large randomized controlled trials. The NLST has been started to determine the use of screening by chest X-ray vs CT-thorax24 and the NELSON-trial will compare CT- thorax vs no screening.25
We have determined the outcome of actual screening in a large cohort of LEMS patients with a high a priori risk of carrying a SCLC. Our results apply to patients with LEMS, but could also be helpful for the design of screening protocols for lung cancer in patients in general.
Patients and methods
We included all Dutch LEMS patients with and without SCLC seen in our Neurology outpatient clinic between 1990 and 2006. Our clinic is an university neuromuscular centre with special interest and expertise in disorders of the neuromuscular junction. Nationwide referral and inclusion started from July 1, 1998, as described before.10 In 1998 all patients alive were seen. From this moment all data were collected prospectively.
Diagnostic criteria for LEMS were the presence of VGCC antibodies and characteristic clinical features (proximal muscle weakness, lowered tendon reflexes, autonomic symptoms). Electromyography supported diagnosis if it comprised reduced resting compound muscle action potential amplitude that increased > 100% following high-frequency repetitive nerve stimulation or maximal voluntary contraction.
After obtaining informed consent, we (PW, MT, PSS or JV) interviewed and examined the patients. Of 13 patients who could not be seen in our clinic detailed clinical information was obtained from the hospital records. We recorded demographic and clinical features, including date of onset of LEMS, date of diagnosis of LEMS and date of diagnosis of SCLC and results of diagnostic tests.
As there was no uniform diagnostic screening protocol, our study reflects the results of cancer screening in daily practice in several centres in the Netherlands. A histologic or cytologic diagnosis of SCLC was mandatory. To diagnose a patient as LEMS without a tumour, a follow-up of at least three years after diagnosis of LEMS was necessary. Disease stage was defined as limited if the tumour was confined to one hemithorax and ipsilateral supraclavicular lymph nodes. This is compatible with a TNM/ IASCL stage I through IIIB.26
Patients were considered smokers if they had consumed one or more cigarettes per day for at least half a year or a lifetime consumption of 200 cigarettes or more.
Median values for age were compared using the Mann-Whitney U test.
Contingency tables were analyzed using a Χ2 test.
Results
Characteristics
LEMS was diagnosed in 104 patients. Four patients were excluded, because follow-up after diagnosis was shorter than 3 years. In 54 out of 100 patients a SCLC was found. In 1998 33 patients were still alive (11 patients with a SCLC).
The second, prospective cohort consists of 67 patients, of which 43 had a SCLC.
Median follow-up for non-tumour (NT-LEMS) patients was 8 years (range 3 – 26 years). Table 1 summarizes baseline characteristics. SCLC-LEMS patients differed significantly from NT-LEMS patients: they were older at diagnosis (p = 0.008), more often male (p = 0.034), invariably smokers, at diagnosis and in the past (p <
0.0001). Two-third of patients had a limited stage SCLC, a higher percentage than reported in epidemiological lung cancer reports (40%).3
Primary screening
Complete data about screening were available for all patients. A tumour was found
SCLC-LEMS NT-LEMS
no % no % OR 95% CI p
number of patients 54 46
median age at diagnosis (years, range)
59 (37-77)
54 (24-74)
0.008 §
sex
male 36 67% 21 46% 2.3 (1.03–5.1) 0.034 ‡
female 18 33% 25 54%
smoking ever
yes 54 100% 27 59% 39.3 (2.3–675) 1.5 * 10-7 ‡
No 0 0% 19 41%
smoking only in past *
yes 44 86% 15 33% 11.3 (4.2–30.1) 6.4 * 10-8 ‡
No 7 14% 31 67%
extent of disease **
limited 35 66%
extended 18 34%
Table 1 Baseline characteristics all LEMS patients
* smoking only in past for three patients missing ; ** tumour stage of one patient missing ; § Mann Whitney U test ; ‡ Chi square test
0%
20%
40%
60%
80%
100%
-48 -36 -24 -12 0 12 24 36 48
Cumulative proportion of SCLC cases (%)
Time from diagnosis of LEMS (months)
Figure 1 Time between diagnosis of LEMS and diagnosis of SCLC
before diagnosis of LEMS in only four patients (7%) (Figure 1). A SCLC was found at first screening in an additional 41 patients (76%). In these 45 patients, chest X- ray was abnormal in 23 patients (51%), CT-thorax was abnormal in all 45 patients (100%) (Figure 2).
Follow-up
In the remaining 55 patients, a tumour was found in nine patients either between first and second screening or during repeated screening (Figure 2 and Table 2).
Median time between diagnosis of LEMS and detection of the SCLC in these nine patients was 3 months (range 1-41 months). Regularly, secondary screening was performed after six months.
Between first and second screening (1-6 months)
In five patients the SCLC was already found between first screening and six months. Two tumours were detected because of tumour-related symptoms (patient A and E). In three patients secondary screening was advanced because of high suspicion of a tumour. Patient C had an opsoclonus and cerebellar degeneration, patient D was therapy resistant and on respiratory ventilation and patient B had anti-Hu antibodies. In the first two patients, SCLC was found by CT-thorax, in the third patient only FDG-PET-bodyscan was aberrant.
Figure 2 Flowchart detection SCLC (n=54) in LEMS patients (n=104) PNS paraneoplastic syndrome
LEMS patients (n = 104)
LEMS patients (n = 100)
LEMS patients (n = 96)
Primary screening (≤ 1 month)
Negative 1st screen (n = 55)
Follow-up (1 - 6 months)
LEMS patients (n = 50)
Repeated screening
Remain negative ≥ 3 years (n = 46)
Excluded (n = 4)
• Follow-up < 3 years
• 1st screen negative
SCLC diagnosed before LEMS (n = 4)
• X-thorax 3 positive in 4
• CT-thorax 4 positive in 4
• PET-body 1 positive in 1
SCLC (n = 41)
• X-thorax 20 positive in 41
• CT-thorax 41 positive in 41
• PET-body 8 positive in 8
SCLC (n = 5)
Metastases on CT-abdomen or MRI-brain (n = 2) Ongoing screening because of PNS (n = 3)
• Chest X-ray 0 positive in 2
• CT-thorax 2 positive in 3
• PET-body 1 positive in third patient
SCLC (n = 4)
Brain metastasis on CT-scan (n = 1) Found during screening (n = 3)
• Chest X-ray 0 positive in 3
• CT-thorax 2 positive in 3
• PET-body 2 positive in 2
Repeated screening
By repeated screening a SCLC was found in three more patients, in two by CT- thorax (patient F and H) and in patient G by FDG-PET-bodyscan. The last patient (patient K) with the longest interval of SCLC diagnosis after diagnosis of LEMS (41 months) was diagnosed with a solitary brain metastasis in 1988. Chest X-ray did not detect a tumour in any of the nine patients during follow-up or secondary screening.
Bronchoscopy and mediastinoscopy were valuable procedures to obtain a cytologic or histologic diagnosis. However, if imaging techniques did not reveal any abnormalities, bronchoscopy did not reveal a tumour in any patient, as illustrated in Table 2.
Discussion
In a large cohort of LEMS patients with SCLC we demonstrate that the tumours were detected within three months after diagnosis of LEMS in 91% and in 96%
within one year. Overall, a SCLC was found in 54% of the LEMS patients, which is in line with previous publications.10-14 In only two patients the SCLC was found more than one year after the diagnosis of LEMS (Figure 1). In both patients (patients H and K) initial screening had been probably insufficient as it only consisted of chest X-ray and bronchoscopy (Table 2).
Our study clearly showed that screening by chest X-ray is insufficient.
Overall, chest X-ray was abnormal in only 43%. At secondary screening chest X- ray did not detect any tumour. In 83% first CT-thorax was abnormal and in another 9% follow-up CT-thorax showed a SCLC. The CT-thorax eventually showed a SCLC in 92% of SCLC-LEMS patients. Our study reflects the results of cancer screening in daily practice in several centres in the Netherlands without a pre- existing diagnostic consensus protocol. All centres routinely performed chest X-ray, CT-Thorax and mostly bronchoscopy, but access to FDG-PET scanning was limited. FDG-PET scanning was introduced for patient care in 1998, but only became fairly accessible around 2002 - 2003. Bronchosopy and mediastinoscopy, although indispensable to acquire a cytological or histological diagnosis, were available but of no value if imaging techniques didn’t reveal any abnormalities.
There has been discussion about the value of chest X-ray for the screening for SCLC in the general population. Our study comprises data from a group of patients with an a priori risk over 50% for an undetected SCLC. It offers valuable
1st Screening2nd Screening Patient agesexChest X-rayCT- thoraxPET- bodyMRI/CT- brainbroncho scopyTime since 1st screening *reasonChest X-rayCT- thoraxPET- bodyMRI/CT- brainDecisiveComments A62MNNANn.p. 1plexopathyCT- abdomenPET-body was retrospectively abnormal ; anti-amphiphysin B60FNNn.p. Nn.p. 2progr LEMSn.p. NAn.p. PET-bodyanti-Hu C53MNNn.p. NN2screeningNAn.p. n.p. CT-thoraxcerebellar degeneration ; opsoclonus D73FNNn.p. NN3screeningNAn.p. n.p. CT-thorax E70FNNn.p. n.p. n.p. 4 ICP, ataxiaNAAAMRI-brain F56MNNn.p. Nn.p. 8screeningNAn.p. NCT-thorax G64MNNn.p. n.p. N10screeningNNAn.p. PET-body H58MNn.p. n.p. NN21screeningNAANPET-bodyanti-Hu ; Limbic Encephalitis ; CT-thorax performed after PET-body K41FNn.p. n.p. n.p. N41 ICP, ataxiaNn.p. n.p. ACT-brain
Table 2 Characteristics of nine LEMS-patients in which SCLC was found after an initial negative first screening; M male, F female, N normal, A abnormal, n.p. not performed, * in months, progr progressive, ICP intracranial pressure
information regarding screening efficiency. Although the study group was relatively small compared to the large population based cohorts from the NSLT and the NELSON trial, our group is well characterized and has a long follow-up. In our LEMS-SCLC patients with a relatively high percentage of limited disease, it was shown that chest X-ray is not a sensitive test to detect SCLC in contrast to repeated CT-thorax.
It remains possible that in a few percent of the patients a slow growing tumour can go undetected for years. A time interval over 36 months is very rare, but has been described in a few well-documented cases.17, 27-31 In all these patients onset of symptoms was between 1965 and 1987. Two patients had no lung tumour, but breast cancer28 and a non-Hodgkin lymphoma located in the esophagus.30 No causal relationship was shown in these papers, for example by demonstrating neuroendocrine characteristics or calcium channel expression by the tumour. The four patients having a lung tumour had all been screened only by chest X-ray and bronchoscopy.17, 27, 29, 31
. In our study, screening was more extensive, minimal duration of follow-up was three years and median follow-up was eight years, strongly suggesting that all clinically relevant SCLC were found.
The six SCLC found because of secondary screening were detected by CT- thorax in three and by FDG-PET in the other three (Table 2). Unfortunately, FDG- PET scans were not readily accessible for these patients during first screening. It is possible that some patients would have been diagnosed earlier if FDG-PET scan would have been performed at first screening. The added value of FDG-PET scans has been shown before in patients with paraneoplastic anti-Hu syndrome.19, 20
In the other three patients with a “normal” first screening (patient A, E and K) the SCLC were found later because of metastases related symptoms. Patient A had a plexopathy because of growth into the iliosacral plexus. In retrospect a SCLC metastasis was already visible retroperitoneally on his FDG-PET performed at the time of primary screening. Patients E and K presented with neurological signs and symptoms because of cerebral metastases. Noteworthy is that a simultaneously made CT-thorax in patient E showed no abnormalities. These cases stress the fact that primary screening, especially using FDG-PET scanning, should not only focus on the thorax. As widespread, intracerebral glucose uptake makes FDG-PET scanning less sensitive than MRI for brain metastases, a MRI-brain could be considered in selected cases. Some primary SCLC tumours remain clinically silent and are only detected because of their metastases.
Four of the nine patients, in which the SCLC was found at secondary screening, had additional features at their diagnosis of LEMS suggesting a
Figure 3 Flowchart recommended screening for SCLC in LEMS patients without paraneoplastic disease; N normal, Abn abnormal, NT-LEMS non-tumour, SCLC-LEMS small cell lung cancer
Abn
CT-thorax or FDG-PET each 6 months up to two years No
N N N N
3x yes Abn
Abn
Abn
SCLC-LEMS Ascertain diagnosis
e.g. bronchoscopy
NT-LEMS
SCLC-LEMS Ascertain diagnosis
e.g. bronchoscopy NT-LEMS
Under 45 years?
Never-smoker?
HLA 8.1 haplotype?
CT-thorax or FDG-PET at 6 months Negative 1st screen
FDG-PET CT-thorax LEMS patients
paraneoplastic origin (table 2, patient A, B, C and H). These patients should be screened more regularly than the other LEMS patients.
Based on the data of this study we would like to propose a screening protocol (Figure 3). Primarily the lungs should be screened by CT-thorax. If negative, a total body FDG-PET scan should be performed. Secondary screening should consist of a CT-thorax every six months up to two years after diagnosis.
We suggest performing a FDG-PET scan in all LEMS patients with a negative CT-thorax at primary screening, also if they never smoked. The incidence of LEMS is 0.8 per million or 240 new LEMS patients each year in the USA, of whom 132 (55%) will have a SCLC. Extrapolating our data, 109 (45%) SCLC will be found by the first CT-thorax. Twenty-two more tumours will be found in the remaining 131 patients during follow-up, almost invariably in smokers. Yearly 131 FDG-PET scans will be needed for the whole of the USA. One could argue that only smoking LEMS patients or LEMS patients with a history of smoking should be screened by FDG-PET scan from a cost-benefit perspective. The first CT-scan has reduced the prior probability of 55% to a posterior probability of 17%. In our cohort we have no patients with a SCLC and LEMS who never smoked. Generally, SCLC is almost exclusively related tot tobacco smoking.32 As only around 30% in the general population never smoked, only offering FDG-PET scans to (former) smokers will save a mere 39 FDG-PET scans a year for the whole USA. For a rare disease like LEMS, in our opinion, these costs do not weigh against the risk of missing a SCLC.
We would recommend screening secondarily by CT-thorax every six months up to two years after diagnosis. The decision whether to choose CT-thorax or FDG- PET for secondary screening is based upon easy access to CT in everyday practice and larger experience with sensitivity and specificity of CT. It seems reasonable to reduce screening from four years to two years from diagnosis of LEMS, although our numbers are too low to support stringent recommendations. A recently published expert opinion, not based on patient series, suggested four years.21 A SCLC was detected in our series in only one patient more than two years after diagnosis. In this patient screening by CT-thorax and FDG-PET- scanning had not been performed, suggesting that the tumour could have been detected earlier if screening would have been adequate.
Data are accumulating which suggest that an exception can be made for patients under the age of 45 years, who never smoked and carry the HLA 8.1 haplotype.16, 33 They represent the idiopathic autoimmune form of the disease and no patient with this profile in our series developed a tumour. A second CT-thorax
after six months might be sufficient and it could be considered to stop routine screening afterwards.
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