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Neuroendocrine tumors of the lung: A five-year retrospective experience of Egyptian NCI (2010–2014)
Journal of the Egyptian National Cancer Institute xxx (xxxx) xxx
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Neuroendocrine tumors of the lung: A five-year retrospective experience of Egyptian NCI (2010–2014) Magdy Saber a, Yahia Ismail a, Nelly Alieldin b, Iman Loay c, Mohamed El Zawahry a,⇑ a
Department of Medical Oncology, National Cancer Institute, Cairo University, Egypt Department of Cancer Epidemiology and Biostatistics, National Cancer Institute, Cairo University, Egypt c Department of Pathology, National Cancer Institute, Cairo University, Egypt b
a r t i c l e
i n f o
Article history: Received 22 August 2018 Received in revised form 29 October 2018 Accepted 31 October 2018 Available online xxxx Keyword: Neuroendocrine tumors- lung-prognosissurvival-NCI-Egypt
a b s t r a c t Background: The spectrum of lung neuroendocrine tumors (NETs) encompasses low grade typical carcinoid (TC), intermediate grade atypical carcionid (AC) and high grade, both large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC), with extreme differences in management and survival. Objective: To study clinicopathologic and prognostic factors affecting survival of lung NETs. Patients and methods: This is a retrospective study evaluating 35 patients with primary lung NETs treated at National Cancer Institute of Egypt (NCI-E) between January 2010 and December 2014. Pathological diagnosis depended on definite morphology and positivity to at least one of the neuroendocrine markers by immunohistochemistry. Results: The mean age of the patients was 53 ± 11.2 years with male predominance. Performance status (PS) I was encountered in 48.6%. SCLC was the prevalent histology in 68.6%, followed by LCNEC & TC in 20 & 11.4%, respectively. Curative surgery was employed in 100 & 57% of TC & LCNEC patients, respectively. Stage IV was anticipated in 87.5 & 43% of SCLC & LCNEC, respectively. For the entire cohort, the median event-free survival (EFS) and overall survival (OS) were 8.0 and 13.7 months, respectively, whereas the 3year EFS and OS were 17.8 & 20%, respectively. SCLC patients showed significantly the worst OS compared to other NETs (p = 0.001). Patients who presented with stage IV and PS > I demonstrated significantly shorter OS than those with locoregional and PS I (p = 0.00001 & p = 0.002, respectively). Conclusions: SCLC subtype, stage IV and initial PS > I are poor prognostic factors for lung NETs associated with shorter survival. This conclusion needs to be confirmed by larger studies. Ó 2018 National Cancer Institute, Cairo University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction The neuroendocrine (NE) cells are a group of specific cells normally present in the lung; they are characterized by their secretory products, distinguished staining characteristics, and their ability to uptake and decarboxylate the amine precursors [1]. Lung tumors originating from these cells are called neuroendocrine tumors (NETs) that roughly account for 25% of all primary lung neoplasms with the remaining majority (75%) composed mainly of non–small cell lung cancer (NSCLC) and other few rare tumors [2].
Peer review under responsibility of The National Cancer Institute, Cairo University. ⇑ Corresponding author at: Medical Oncology and malignant hematology Department, National Cancer Institute, Fom Al-khaleeg Sq., Kasr Al-eny St., Cairo 11796, Egypt. E-mail addresses: [email protected] (M. Saber), [email protected]. eg (Y. Ismail), [email protected] (N. Alieldin), [email protected] (I. Loay), [email protected] (M. El Zawahry).
The incidence of NETs as a whole entity was extremely low in the National Cancer Institute of Egypt (NCI-E) as reported in the ten-year period cancer pathology registry (2000–2009), constituting 0.86% of total malignancies, 0.71% of primary malignancies and 3.3% of metastatic tumors. The most affected system was the respiratory system reported in 38.5% of all NET cases with the lung being the dominant primary site in 68% of cases. The small cell subtype was the prevalent histology (92.7%) in lung NETs [3]. The 2015 WHO classification of lung tumors provided diagnostic criteria for lung NETs based on the histological features, including cell size, morphology, mitotic index, growth patterns, and the presence of necrosis. Four pathologic variants of lung NETs were described, low grade typical carcinoid (TC), intermediate grade atypical carcinoid (AC) and the high-grade large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC) [4] with an estimated incidence of 2, 0.2, 3 and 20% of primary lung tumors, respectively [2]. Ki-67 labeling index as a marker for proliferation is not currently used for the grading of lung NETs, but the
https://doi.org/10.1016/j.jnci.2018.10.005 1110-0362/Ó 2018 National Cancer Institute, Cairo University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article as: M. Saber, Y. Ismail, N. Alieldin et al., Neuroendocrine tumors of the lung: A five-year retrospective experience of Egyptian NCI (2010–2014), Journal of the Egyptian National Cancer Institute, https://doi.org/10.1016/j.jnci.2018.10.005
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M. Saber et al. / Journal of the Egyptian National Cancer Institute xxx (xxxx) xxx
use of IHC for confirming diagnosis is recommended [5]. For example, carcinoids show strong and diffuse positivity for NE markers (most commonly used: synaptophysin, chromogranin A, and CD56), but in a minor fraction of these tumors -especially in ACnot all NE markers may be expressed, and therefore a panel approach is recommended [6]. Unlike carcinoids, reactivity for synaptophysin and chromogranin A is typically weak in SCLC with approximately 25% of cases being negative for both markers. Although CD56 is considered to be the most sensitive NE marker for SCLC, still around 10% of cases are negative for all 3 commonly used NE markers [7,8]. LCNEC demonstrates coexpression of both synaptophysin and chromogranin A in almost 70% of the cases [9]. Concerning diagnostic imaging, CT is usually used for the detection, localization, and staging of lung NETs, whereas MRI is preferred for detecting and characterizing bone or liver metastases. Functional imaging like somatostatin receptor scintigraphy (octreoscan) has been shown to be sensitive for the localization of lung carcinoids and their metastases, given that the majority (80–90%) of patients with low grade TCs or the intermediate grade ACs express somatostatin receptors, whereas FDG PET scan is most useful in the high grade LCNECs and SCLCs [10]. Each of the lung NET subtypes has its distinct clinical features, behavior, treatment approach and prognosis, which highlight the importance of accurate pathologic diagnosis. Lung carcinoids present with hypersecretion and carcinoid syndrome in less than 2% of the patients compared to 10% of gastroenteropancreatic (GEP) carcinoids [11], and are found in around 5% of patients with multiple endocrine neoplasia syndrome type 1 (MEN-1) [12]. The primary treatment modality is surgical resection which offers the best chance for long-term cure [2] with TC patients experiencing an excellent 5-year survival (>87%) [13,14]. Regional lymph node metastases occur in 10–15% of TC patients and distant metastases (most commonly to liver and bone) in an additional 3–5% [15]. ACs are significantly more aggressive than TCs, with higher frequency of nodal and distant metastases in an average of 50 and 20% of the cases, respectively [15,16] together with a reported lower 5year survival of 60% [6]. The majority (95%) of small cell carcinomas of the body originate in the lung as a primary site, whereas extra pulmonary small cell carcinomas arising from other locations (e.g. esophagus, bladder, cervix and prostate) are extremely rare [17]. It is invariably associated with positive smoking history to the extent that the diagnosis in a nonsmoker is considered exceptional and should be carefully re-evaluated [2]. Most of the patients present with hilar nodal metastases and almost two-thirds with distant metastases (typical sites are brain, liver, adrenal, bone, and bone marrow) [18]. SCLC presenting as a solitary mass without evidence of metastasis is a rare occurrence in <5% of the patients [19]. Ectopic hormone production and paraneoplastic syndromes are frequent clinical findings in SCLC, including the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and Cushing syndrome due to ectopic ACTH secretion [2]. It is a rapidly fatal disease with dismal median survival- still measured in months- and long-term survival is highly unlikely (5-year survival is <5%) [20]. SCLC is generally considered a nonsurgical disease, but is extremely sensitive to chemotherapy (cisplatin plus etoposide is a standard regimen) and radiation therapy. Evidence is emerging that surgical resection may indeed extend the survival of a rare group of patients (<5%) in whom the disease presents as a solitary mass without extra-thoracic spread [21,22]. A unique clinical feature of SCLC is its tendency for brain metastases, which develop in about 50–80% of patients; that is why prophylactic cranial irradiation (PCI) is indicated for this disease, but not for other lung NETs or NSCLC [22]. LCNEC, being a high grade tumor, is also considered a highly aggressive disease with a reported wide range of survival (15–57%) with a weighted mean of 34%
[23]. In some reports, the prognosis of LCNEC is as poor as that of SCLC [24]. The objective of the current study is to evaluate the clinicopathologic characteristics and prognostic factors affecting survival in patients with different lung NETs who presented to NCI-E during a five-year period.
Patients and methods This is a retrospective cohort study for evaluating patients with the diagnosis of lung NETs, who presented to NCI-E during a 5-year period between January 2010 and December 2014. The inclusion criteria were adult patients of both genders aged 18 years with definite pathological diagnosis of a primary lung NET by morphological criteria and positivity of at least one of the neuroendocrine (NE) markers [synaptophysin, chromogranin A (CgA), neuron specific enolase (NSE) and CD56] by immunohistochemistry (IHC); all disease stages were included. Tumors which showed negative reactions to all previously mentioned NE markers were excluded from this study. By searching the NCI-E database for this diagnosis, thirty five cases were found fulfilling the inclusion criteria during the specified period. Archived files of these cases were retrieved from the medical records and all available data extracted, including patient demographics (age, gender, residence, smoking history, co-morbidities and family history of cancer), clinical profile including date of diagnosis, presenting symptoms, ECOG performance status (PS), tumor location in the lung, TNM stage (according to the 8th edition of the AJCC cancer staging system [25]), metastases and their site if present initially, date of relapse after curative surgery and its site (either loco-regional or distant), disease progression in initially advanced or metastatic cases and its date, as well as status at last follow up (alive or dead) and its date. The methods of diagnosis included different imaging modalities, bronchoscopy, surgical biopsy and fine needle aspiration cytology (FNAC). Management included surgery (date and type), neoadjuvant, adjuvant or palliative chemotherapy and radiotherapy. Each line of chemotherapy was assessed regarding date of start, number of cycles, and response.
Pathology review All the archived hematoxylin & edosin (H & E) slides and paraffin blocks of the 35 cases were retrieved from the pathology department and revised by the pathologist in charge of this study. Typing of the tumors was done according to the WHO classification [4]. SCLC was diagnosed on appreciation of small blue cells arranged in sheets (less than the diameter of 3 times that of a resting lymphocyte) with undefined cell borders, scanty cytoplasm, high nuclear cytoplasmic ratio, granular chromatin and no or inconspicuous nucleoli with commonly extensive necrosis with a high mitotic rate (average 80/2 mm2). LCNEC shows histological neuroendocrine features, the cells are generally large, with moderate to abundant cytoplasm. The nucleoli are frequent, prominent and their presence facilitates distinction from SCLC. Mitotic counts are typically > 10 (average 75/2 mm2). Carcinoid tumours are characterized by growth patterns (organoid, trabecular, insular, palisading, ribbon, rosette-like arrangements) that suggest neuroendocrine differentiation with uniform cytologic features and moderate eosinophilic, finely granular cytoplasm, and nuclei with a finely granular chromatin pattern. TC are larger than 0.5 cm displaying < 2 mitoses/2 mm2 with absence of necrosis. None of the cases had the pathology of AC. Positivity of at least one of the NE markers (NSE, Cg A, synaptophysin, CD56) was revised and documented for each case.
Please cite this article as: M. Saber, Y. Ismail, N. Alieldin et al., Neuroendocrine tumors of the lung: A five-year retrospective experience of Egyptian NCI (2010–2014), Journal of the Egyptian National Cancer Institute, https://doi.org/10.1016/j.jnci.2018.10.005
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M. Saber et al. / Journal of the Egyptian National Cancer Institute xxx (xxxx) xxx
Statistical methods All analyses were done using SPSSÒ (Statistical Package for Social Sciences) software, version 12.0.1, Chicago, USA. Quantitative data were presented as mean, standard deviation, median and range as appropriate. Qualitative data were presented as frequency and percentage. Survival analysis was done using KaplanMeier method; comparison between two survival curves was done using log rank test. All tests were two-tailed. A p-value 0.05 was considered significant. Overall survival (OS) was measured from the date of diagnosis to date of death or date of last follow up. Event-free survival (EFS) was measured from the date of first treatment to the date of relapse, progression, death or last follow up. Ethical issues Being a retrospective study, there were no additional risks to the patients. Data collection and presentation were anonymous and both privacy and confidentiality were protected to the maximum possible standards. The study was initiated after getting the approval of the Institutional Review Board (IRB) of NCI-E. Results A total of 35 cases of lung NETs who presented between January 2010 and December 2014 were retrieved from the database of NCIE. The mean age of the patients was 52 ± 11.2 years (median 54, range: 24–76). There was male predominance with male to female ratio 7.75:1. More than three quarters of the patients (83%) gave history of smoking. Nearly half of the cases (48.6%) had ECOG PS I on initial presentation, PS II and III were reported in 37.1 and 14.3%, respectively. Shortness of breath was the most common presenting complaint reported by more than half of the patients (54.3%), followed by chest pain and cough in 34 and 28.6%, respectively. The right lung was the dominant primary tumor location in 77% of the cases and the mean tumor size was 7.2 ± 2.7 cm (median 7.5, range 2–16 cm). SCLC was the prevalent histology depicted in almost two thirds of the cases (68.6%), followed by LCNEC and TC tumors in 20 and 11.4%, respectively. Stage IV at initial presentation was found in 21 cases out of 24 patients with SCLC (87.5%) and in 3 cases out of the 7 with LCNEC (43%). The liver was the most common metastatic site in 45.8% of cases, followed by pleural effusion and brain metastasis in 33.3 and 20.8%, respectively (Table 1). All cases tested positive to at least one of the NE markers with synaptophysin positivity encountered in the majority of cases (62.8%) (Figs. 1a, 1b, 2a, 2b, 3a, 3b). With respect to the treatment employed, none of the 24 cases of SCLC underwent surgery, as all the patients presented with inoperable or stage IV disease. Three patients (12.5%) presented with limited stage disease and received concomitant chemoradiation (CCRT) with a platinum/etoposide regimen followed by prophylactic cranial irradiation (PCI) in two of them who showed good partial response. Palliative chemotherapy was administered in 20 (83.3%) of the metastatic patients (platinum-based), the remaining patient did not receive chemotherapy due to poor PS and received only palliative radiotherapy. As for the seven patients with LCNEC, four of them (57%) underwent curative surgery with chemotherapy employed preoperatively in two cases and postoperatively in the other two. The remaining three patients who presented with stage IV received palliative chemotherapy, also platinum-based. On the contrary, curative surgery was carried out in all 4 (100%) TC patients; none of them received chemotherapy (Table 2). Regarding survival analysis, the median follow up period was 12.3 months (range 1.3–65). At the end of this period, 27 patients (24 SCLC and 3 LCNEC) were dead. For the entire cohort, the med-
Table 1 Demographics and clinicopathological profile of 35 lung NETs cases. Item
Number (n = 35)
Percent (%)
Age (years) Mean ± SD (52 ± 11.2)
Median (54)
Range (24–76)
Gender Male Female
31 4
88.6 11.4
Method of diagnosis Computed tomography Others
30 5
85.7 14.3
History of smoking Positive Negative
29 6
83.0 17.0
Presenting complaint* Dyspnea Chest pain Cough Hemoptysis Swelling Change of voice Mediatinal syndrome
19 12 10 5 2 1 1
54.3 34.3 28.6 14.3 5.7 2.9 2.9
ECOG PS at initial presentation I II III
17 13 5
48.6 37.1 14.3
Laterality Right lung Left lung
27 8
77.1 22.9
Anatomical site of primary tumor Upper lobe Middle lobe Lower lobe Hilar Others Tumor size (Mean ± SD 7.2 ± 2.7)
16 1 4 11 3 (Median 7.5)
45.7 2.9 11.4 31.4 8.6 (range 2–16.5)
Pathology SCLC LCNEC TC Grade High Low
24 7 4
68.6 20 11.4
31 4
88.6 11.4
TNM Stage at presentation I II III IV
2 4 5 24
5.7 11.4 14.3 68.6
Stage IV at presentation per pathology (n = 24) SCLC 21 LCNEC 3 TC 0
87.5 12.5 0
Positive neuroendocrine markers** Synaptophysin NSE CgA CD56
22 7 13 10
62.8 20 37 28.5
LN involvement on imaging Positive Negative
29 6
82.9 17.1
Site of metastasis*** (n = 24) Liver Pleural effusion Brain Bone Adrenal
11 8 5 4 2
45.8 33.3 20.8 16.7 8.3
CgA: chromogranin A ECOG: Eastern Cooperative Oncology Group LCNEC: large cell neuroendocrine carcinoma LN: lymph node NSE: neuron specific enolase PS: performance status SCLC: small cell lung cancer SD: standard deviation TC: typical carcinoid TNM: tumor, node, metastasis. * Fifteen patients reported more than one complaint. ** Ninteen patients showed positivity to > one marker. *** Seven patients had > one site of metastasis.
Please cite this article as: M. Saber, Y. Ismail, N. Alieldin et al., Neuroendocrine tumors of the lung: A five-year retrospective experience of Egyptian NCI (2010–2014), Journal of the Egyptian National Cancer Institute, https://doi.org/10.1016/j.jnci.2018.10.005
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M. Saber et al. / Journal of the Egyptian National Cancer Institute xxx (xxxx) xxx
Fig. 3a. LCNEC [H&Ex400]. Fig. 1a. TC (low grade) [H&Ex200].
Fig. 3b. LCNEC with strong synaptophysin positivity [IHCx400]. Fig. 1b. TC with strong synaptophysin positivity [IHCx200].
Fig. 2a. SCLC [H&Ex200].
and p = 0.001, respectively, Figs. 5a and 5b). The median EFS and OS for SCLC cases were 5.4 and 7.7 months, respectively, whereas the cumulative OS at 1 and 3 years were 45 and 0%, respectively. On the other hand, the cumulative OS at 3 years for LCNEC and TC were 57 and 100%, respectively. Analysis of survival according to the patients’ initial ECOG PS revealed that patients who presented with PS I demonstrated significantly higher EFS (p = 0.0021) and OS (p = 0.002) in comparison to patients with PS II and III (Figs. 6a and 6b). With respect to gender, there was no significant impact on EFS, but females-despite their small number- showed significantly higher OS than males (P = 0.035) (Figs. 7a and 7b). Comparison of survival according to the stage of the disease showed a significant EFS and OS survival difference in favor of locoregional disease versus metastatic disease (P = 0.0001 and P = 0.00001, respectively) (Figs. 8a and 8b). Age showed no significant impact on EFS or OS (Table 3).
Discussion
Fig. 2b. SCLC with strong CD56 positivity [IHCx200].
ian EFS and OS were 8.0 and 13.7 months, respectively, whereas the cumulative EFS and OS at 3 years were 17.8 and 20%, respectively (Figs. 4a and 4b). Analysis of survival in relation to different prognostic factors (Table 3) revealed that the histological subtype had significant impact on survival as SCLC patients showed significantly worse EFS and OS than LCNEC and TC patients (p = 0.009
The results of this retrospective analysis of 35 patients with lung NETs showed male predominance (88.6%) with M: F ratio of 7.75:1. A similar gender distribution with male predominance was reported by other authors, Mokhtar et al. (83.8% males) [3] and Asamura et al. (79.3% males) [26]. Although there were only 4 cases of TC with M: F ratio 1:1, other studies that included larger numbers of patients reported female predominance in this histological subtype as García-Yuste et al. [27], Simbolo et al. [28] and Chong et al. [29]. The mean age of the patients was 52 years which is almost 10 years younger than that reported in the studies of Mokhtar et al. (mean 62.3 years) [3] and Simbolo et al. (mean 61.6 years) [28]. This finding might be due to the relatively small number of the cases in the current study in comparison to other studies. The prevalent histology in the current study was SCLC (68.6%), followed by LCNEC (20%) then TC (11.4%). This predominance of SCLC between lung NETs goes with the worldwide incidence being
Please cite this article as: M. Saber, Y. Ismail, N. Alieldin et al., Neuroendocrine tumors of the lung: A five-year retrospective experience of Egyptian NCI (2010–2014), Journal of the Egyptian National Cancer Institute, https://doi.org/10.1016/j.jnci.2018.10.005
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M. Saber et al. / Journal of the Egyptian National Cancer Institute xxx (xxxx) xxx Table 2 Treatments employed according to histology for 35 lung NET cases. SCLC (n = 24)
LCNEC (n = 7)
Number of patients NACT Curative Surgery
Treatment given
0 0
*
CCRT PCI** ACT
3 2 0
ART PCT***
0 20
PRT
8
PE + RT
PE CE TC Vinorelbine Gemcitabine Irinotecan
TC (n = 4)
Number of patients
Treatment given
Number of patients
2 4
GCis Lobectomy
0 0 1 1 1 3
CE VC
0 2 2 0 0 0
Treatment given Lobectomy Pneumonectomy
0 0
TC GC VC CE
0
0
1.0
1
0.8
0.8
Cummulative Survival
Cummulative Survival
ACT: adjuvant-chemotherapy ART: adjuvant radiotherapy CCRT: concomitant chemo-radiation CE:carboplatin/etoposide GC: gemcitabine/carboplatin GCis: gemcitabine/cisplatin NACT: neoadjuvant chemotherapy. PCI: prophylactic cranial irradiation PCT:palliative chemotherapy PE:plationl/etoposide PRT: palliative radiotherapy RT: radiotherapy TC: taxol/carboplatin VC: vinorelbine/carboplatin. * For three patients with limited stage disease. ** For two patients with limited stage disease who showed good partial response after CCRT. *** Nine patients received more than one line of chemotherapy.
0.6
0.4
0.2
0.6
0.4
0.2
0.0 0
0
12
24
36
48
60
72
EFS (months) Fig. 4a. EFS of 35 Lung NETs cases.
the most common subtype reported [2]. Mokhtar et al. also previously reported that SCLC was the predominant histological subtype of lung NETs among NCI-E patients (92.8%) during a 10-year period (2000–2009) [3],whereas LCNEC was the dominant histological subtype in the studies of Iyoda et al. [23] and Asamura et al. [26]. TC was the most common subtype in the studies of GarcíaYuste et al. [27] and Simbolo et al. [28]. None of the current cases presented with the pathology of atypical carcinoid (AC). Rekhtman [2] reported the strong association of SCLC with smoking to the extent that the diagnosis in a patient with negative smoking history is considered exceptional and should be carefully reevaluated. This statement was typically confirmed in the current study where positive smoking history was documented in 29 (83%) cases, with SCLC patients representing the major fraction (24 cases) of this population.
0
12
24
36
48
60
72
OS (months) Fig. 4b. OS of 35 Lung NETs cases.
Concerning the management employed, radical curative surgery was offered to approximately one fifth (23%) of the cases only (4 TC and 4 LCNEC), which is relatively low compared to other reports [23,26,27] where all the patients included in these studies were treated surgically. This finding could be explained by the predominance of SCLC cases (68.5%) in the current study with the majority of these patients being inoperable and advanced at time of presentation (87.5% stage IV). A similar finding was reported in the work of Elliott et al. [18] who documented that most patients with SCLC had hilar nodal metastases at the time of initial presentation and distant metastases in two-thirds of them. SCLC are exquisitely sensitive to chemotherapy (cisplatin plus etoposide is a standard regimen) and radiation therapy [22]. In the current study, the commonest chemotherapy regimen used, whether with concomitant radiation or in a palliative setting, was cisplatin/eto-
Please cite this article as: M. Saber, Y. Ismail, N. Alieldin et al., Neuroendocrine tumors of the lung: A five-year retrospective experience of Egyptian NCI (2010–2014), Journal of the Egyptian National Cancer Institute, https://doi.org/10.1016/j.jnci.2018.10.005
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Table 3 Analysis of the prognostic factors affecting survival in the 35 lung NET cases. Number (n)
Event free survival
1 year
3 years
All cases
35
28
23.7
Histopathology SCLC LCNEC Typical Carcinoid
24 7 4
24 3 1
Performance status I 17 II&III 18 Gender Males Females
Number of events
Over all survival
Survival probability (%) at
Median EFS (months)
P value
Number of events
1 year
3 years
17.8
8
NA
27
53.4
8.3 57 67
0 57 67
5.4 Not reached Not reached
0.0092
24 3 0
10 18
44 6
38 0
11 1.8
0.0021
31 4
26 2
20 50
13.4 50
6.2 8
Stage Locoregional Metastatic
11 24
4 24
71 4
61 0
Age 50 <50
23 12
18 10
18.4 33.3
18.4 16.7
P value
20
13.7
NA
45 57 100
0 57 100
7.7 Not reached Not reached
0.0012
9 18
76 33.3
44 6
18.6 5.8
0.002
0.1812
26 1
47.2 NA
12.7 75
11.2 Not reached
0.0349
Not reached 2
0.0001
3 24
91 37.5
71 4
Not reached 7.1
0.00001
5.4 8.3
0.6145
18 9
46 66.7
18.4 22
11.2 14.7
0.4951
TC
0.4
P=0.0092
0.2
LCNECcensored TC-censored
0.8
Cummulative Survival
0.6
Pathology LCNEC SCLC
1.0
LCNEC SCLC TC LCNECcensored TC-censored
0.8
Cummulative Survival
Median OS (months)
Pathology
1.0
Survival probability (%) at
0.6
P=0.0012 0.4
0.2
0.0
0.0 0
12
24
36
48
60
0
72
12
36
48
60
72
Fig. 5b. OS of Lung NETs patients according to different histologies.
Fig. 5a. EFS of Lung NETs patients according to different histologies.
PS 1 2&3 1-censored
1.0
0.8
Cummulative Survival
poside similar to the studies of Chong et al. [29] and Veronesi et al. [30]. In terms of prognosis, the pathological subtype of the lung NETs demonstrated a powerful and significant impact on survival in the current study cohort. Merrill et al. [20] previously reported that the typical survival for SCLC patients was measured in months, and long-term survival was highly unusual (5-year survival is <5%). This conclusion was typically depicted in the current study as SCLC cases showed significantly the worst and poorest survival in comparison to TC and LCNEC (p = 0.001), with a median survival of 7.7 months and a 3-year survival of 0%. However, other studies that reported survival rates at 5 years showed higher figures; Travis et al. (9%) [13], García-Yuste et al. (14%) [27], Iyoda et al. (16.4%) [23] and Asamura et al. (35.7%) [26], This discrepancy in reported survival might be due to the fact that none of the SCLC cases of the current study were operable while most of the patients included in the other studies underwent surgery with curative intent. On the other end of the spectrum, TC patients showed the
24
OS (months)
EFS (months)
0.6 P=0.0021 0.4
0.2
0.0 0
12
24
36
48
60
72
EFS (months)
Fig. 6a. EFS according the patients’ initial PS.
Please cite this article as: M. Saber, Y. Ismail, N. Alieldin et al., Neuroendocrine tumors of the lung: A five-year retrospective experience of Egyptian NCI (2010–2014), Journal of the Egyptian National Cancer Institute, https://doi.org/10.1016/j.jnci.2018.10.005
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M. Saber et al. / Journal of the Egyptian National Cancer Institute xxx (xxxx) xxx
PS 1 2&3 1-censored
1.0
0.8
Cummulative Survival
Cummulative Survival
0.8
0.6
P=0.002 0.4
0.2
0.6 P=0.0001 0.4
0.2
0.0
0.0
0
12
24
36
48
60
72
0
OS (months)
12
24
36
48
60
72
EFS (months)
Fig. 6b. OS according the patients’ initial PS.
Fig. 8a. EFS difference of lung NETs cases according to stage at presentation.
gendre F M F-censored M-censored
1.0
0.6
0.4 P=0.1812
Stage 1,2,3 4 1,2,3-censored
1.0
0.8
Cummulative Survival
0.8
Cummulative Survival
Stage 1,2,3 4 1,2,3-censored
1.0
0.6 P=0.00001 0.4
0.2
0.2
0.0
0.0 0
0
12
24
36
48
60
12
24
36
48
60
72
OS (months)
72
EFS (months)
Fig. 8b. OS difference of lung NETs cases according to stage at presentation. Fig. 7a. EFS difference of lung NETs cases according to gender.
gendre F M F-censored M-censored
1.0
Cummulative Survival
0.8
0.6 P=0.0349 0.4
0.2
0.0 0
12
24
36
48
60
72
OS (months)
Fig. 7b. OS difference of lung NETs cases according to gender.
highest cumulative 3-year OS (100%); this excellent survival rate is exactly similar to what was reported by Iyoda et al. [23], whereas it was 96% in both Asamura et al. [26] and García-Yuste et al. [27]. It was lower, but still excellent (87%), in the study of Travis et al. [13]. This astonishing survival for the TC patients may be explained by the fact that all patients underwent curative surgery and the native indolent behavior of this low grade tumor.
Concerning the LCNEC patients, the 3-year OS rate was 57%. Takei et al. [9] reported exactly the same rate but at 5 years; however, other studies reported lower 5-year survival rates for this pathological entity like García-Yuste et al. (21%) [27] Travis et al. (27%) [13], Iyoda et al. (32%) [23], Asamura et al. (40%) [26] and Veronesi et al. (43%) [30]. In an attempt to explore the reasons for these reported low survival rates for this lung NET subtype, Asamura et al. [26] directly compared the 5-year OS of LCNEC vs. SCLC patients. They did not find a significant difference (p = 0.9) and concluded that LCNEC showed almost the same prognosis as SCLC. The latter finding was similarly reported by others; Travis et al. [13], Iyoda et al. [23] and García-Yuste et al. [27]. Also, the results of the study of Takei et al. showed that the prognosis of LCNEC was poor, even for early stage disease as the survival of stage I was poorer than the same stage of other NSCLCs; they concluded that because of its aggressive clinical behavior and poor prognosis, LCNEC should be recognized as one of the poorest prognostic subgroups among primary lung cancers [9]. In the current study, LCNEC patients showed a significantly higher OS than SCLC (p = 0.01); this contradictory finding to the aforementioned studies could be explained by two reasons; firstly because almost all SCLC cases had stage IV at presentation whereas 57% of the LCNEC cases underwent curative surgery and, secondly, due to the small number of LCNEC cases included in the current study in comparison to SCLC (7 vs. 24, respectively). Another prognostic factor that displayed significant correlation with survival in this study was the patients’ ECOG PS at time of
Please cite this article as: M. Saber, Y. Ismail, N. Alieldin et al., Neuroendocrine tumors of the lung: A five-year retrospective experience of Egyptian NCI (2010–2014), Journal of the Egyptian National Cancer Institute, https://doi.org/10.1016/j.jnci.2018.10.005
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presentation. Patients who presented with PS I had significantly higher EFS and OS (p = 0.002 for both) than those with PS II and III. Similar to this finding, Kawahara et al. reported the impact of initial PS on survival in a study that included only SCLC patients; they found significantly higher OS (p = 0.0001) in patients who presented with PS 0/I than PS II/III [31]. Paesmans et al. also demonstrated the effect of PS as a prognostic factor in SCLC, but they used the Karnofsky score instead of ECOG; they found that patients with Karnofsky score 80 had significantly better survival (p = 0.001) compared to those with 70 [32]. The authors could not depict from the literature other studies that evaluated PS as a prognostic factor in relation to different subtypes of lung NETs. The authors admit to the limitations of the current study, firstly being a retrospective one, secondly the relatively small number of the whole cohort and within the subgroups, and thirdly the absence of one of the basic four subtypes of lung NETs (atypical carcinoid) for analysis. The study describes one of the less common entities in cancer, so retrospectivity is mostly the appropriate method of research in the literature, and being limited to a specified period (2010–14), the limitations of the sample size and missing one subtype were absolutely unavoidable events. Conclusions This retrospective analysis showed that in NCI-E, the commonest histological subtype of lung NETs is SCLC which corresponds to the worldwide incidence and almost all the cases of this pathology presented with advanced or metastatic stage that predicted dismal survival. The pathological subtype of lung NET, stage and initial PS are prognostic factors significantly affecting survival. This conclusion needs to be confirmed by larger studies. References [1] Pearse AG. The cytochemistry and ultrastructure of polypeptide hormone producing cells of the APUD series and the embryologic, physiologic and pathologic implications of the concept. J Histochem Cytochem 1969;17 (5):303–13. [2] Rekhtman N. Neuroendocrine tumors of the lung: an update. Arch Pathol Lab Med 2010;134(11):1628–38. [3] Mokhtar N, Salama A, Badawy O. Neuroendocrine tumors. In: Mokhtar N, Asmaa S, Badawy O, Khorshed E, Mohamed G, Ibrahim M, editors. Cancer pathology registry 2000–2011. Cairo, Egypt: Cairo Press; 2016. p. 220–5. [4] Travis WD, Brambilla E, Burke AP, Marx A, Nicolson AG, editors. World Health Organization Classification of Tumours. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: IARC Press; 2015. [5] Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB, et al. The 2015 world health organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol 2015;10:1243–60. [6] Beasley MB, Thunnissen FB, Brambilla E, Hasleton P, Steele R, Hammar SP, et al. Pulmonary atypical carcinoid: predictors of survival in 106 cases. Hum Pathol 2000;31(10):1255–65. [7] Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC, editors. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: IARC Press; 2004. [8] Travis WD. Neuroendocrine lung tumors. Pathol Case Rev 2006;11(6):235–42. [9] Takei H, Asamura H, Maeshima A, Suzuki K, Kondo H, Niki T, et al. Large cell neuroendocrine carcinoma of the lung: a clinicopathologic study of eightyseven cases. J Thorac Cardiovasc Surg 2002;124:285–92.
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Please cite this article as: M. Saber, Y. Ismail, N. Alieldin et al., Neuroendocrine tumors of the lung: A five-year retrospective experience of Egyptian NCI (2010–2014), Journal of the Egyptian National Cancer Institute, https://doi.org/10.1016/j.jnci.2018.10.005
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Neuroendocrine tumors of the lung: A five-year retrospective experience of Egyptian NCI (2010–2014) Magdy Saber a, Yahia Ismail a, Nelly Alieldin b, Iman Loay c, Mohamed El Zawahry a,⇑ a
Department of Medical Oncology, National Cancer Institute, Cairo University, Egypt Department of Cancer Epidemiology and Biostatistics, National Cancer Institute, Cairo University, Egypt c Department of Pathology, National Cancer Institute, Cairo University, Egypt b
a r t i c l e
i n f o
Article history: Received 22 August 2018 Received in revised form 29 October 2018 Accepted 31 October 2018 Available online xxxx Keyword: Neuroendocrine tumors- lung-prognosissurvival-NCI-Egypt
a b s t r a c t Background: The spectrum of lung neuroendocrine tumors (NETs) encompasses low grade typical carcinoid (TC), intermediate grade atypical carcionid (AC) and high grade, both large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC), with extreme differences in management and survival. Objective: To study clinicopathologic and prognostic factors affecting survival of lung NETs. Patients and methods: This is a retrospective study evaluating 35 patients with primary lung NETs treated at National Cancer Institute of Egypt (NCI-E) between January 2010 and December 2014. Pathological diagnosis depended on definite morphology and positivity to at least one of the neuroendocrine markers by immunohistochemistry. Results: The mean age of the patients was 53 ± 11.2 years with male predominance. Performance status (PS) I was encountered in 48.6%. SCLC was the prevalent histology in 68.6%, followed by LCNEC & TC in 20 & 11.4%, respectively. Curative surgery was employed in 100 & 57% of TC & LCNEC patients, respectively. Stage IV was anticipated in 87.5 & 43% of SCLC & LCNEC, respectively. For the entire cohort, the median event-free survival (EFS) and overall survival (OS) were 8.0 and 13.7 months, respectively, whereas the 3year EFS and OS were 17.8 & 20%, respectively. SCLC patients showed significantly the worst OS compared to other NETs (p = 0.001). Patients who presented with stage IV and PS > I demonstrated significantly shorter OS than those with locoregional and PS I (p = 0.00001 & p = 0.002, respectively). Conclusions: SCLC subtype, stage IV and initial PS > I are poor prognostic factors for lung NETs associated with shorter survival. This conclusion needs to be confirmed by larger studies. Ó 2018 National Cancer Institute, Cairo University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction The neuroendocrine (NE) cells are a group of specific cells normally present in the lung; they are characterized by their secretory products, distinguished staining characteristics, and their ability to uptake and decarboxylate the amine precursors [1]. Lung tumors originating from these cells are called neuroendocrine tumors (NETs) that roughly account for 25% of all primary lung neoplasms with the remaining majority (75%) composed mainly of non–small cell lung cancer (NSCLC) and other few rare tumors [2].
Peer review under responsibility of The National Cancer Institute, Cairo University. ⇑ Corresponding author at: Medical Oncology and malignant hematology Department, National Cancer Institute, Fom Al-khaleeg Sq., Kasr Al-eny St., Cairo 11796, Egypt. E-mail addresses: [email protected] (M. Saber), [email protected]. eg (Y. Ismail), [email protected] (N. Alieldin), [email protected] (I. Loay), [email protected] (M. El Zawahry).
The incidence of NETs as a whole entity was extremely low in the National Cancer Institute of Egypt (NCI-E) as reported in the ten-year period cancer pathology registry (2000–2009), constituting 0.86% of total malignancies, 0.71% of primary malignancies and 3.3% of metastatic tumors. The most affected system was the respiratory system reported in 38.5% of all NET cases with the lung being the dominant primary site in 68% of cases. The small cell subtype was the prevalent histology (92.7%) in lung NETs [3]. The 2015 WHO classification of lung tumors provided diagnostic criteria for lung NETs based on the histological features, including cell size, morphology, mitotic index, growth patterns, and the presence of necrosis. Four pathologic variants of lung NETs were described, low grade typical carcinoid (TC), intermediate grade atypical carcinoid (AC) and the high-grade large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC) [4] with an estimated incidence of 2, 0.2, 3 and 20% of primary lung tumors, respectively [2]. Ki-67 labeling index as a marker for proliferation is not currently used for the grading of lung NETs, but the
https://doi.org/10.1016/j.jnci.2018.10.005 1110-0362/Ó 2018 National Cancer Institute, Cairo University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article as: M. Saber, Y. Ismail, N. Alieldin et al., Neuroendocrine tumors of the lung: A five-year retrospective experience of Egyptian NCI (2010–2014), Journal of the Egyptian National Cancer Institute, https://doi.org/10.1016/j.jnci.2018.10.005
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use of IHC for confirming diagnosis is recommended [5]. For example, carcinoids show strong and diffuse positivity for NE markers (most commonly used: synaptophysin, chromogranin A, and CD56), but in a minor fraction of these tumors -especially in ACnot all NE markers may be expressed, and therefore a panel approach is recommended [6]. Unlike carcinoids, reactivity for synaptophysin and chromogranin A is typically weak in SCLC with approximately 25% of cases being negative for both markers. Although CD56 is considered to be the most sensitive NE marker for SCLC, still around 10% of cases are negative for all 3 commonly used NE markers [7,8]. LCNEC demonstrates coexpression of both synaptophysin and chromogranin A in almost 70% of the cases [9]. Concerning diagnostic imaging, CT is usually used for the detection, localization, and staging of lung NETs, whereas MRI is preferred for detecting and characterizing bone or liver metastases. Functional imaging like somatostatin receptor scintigraphy (octreoscan) has been shown to be sensitive for the localization of lung carcinoids and their metastases, given that the majority (80–90%) of patients with low grade TCs or the intermediate grade ACs express somatostatin receptors, whereas FDG PET scan is most useful in the high grade LCNECs and SCLCs [10]. Each of the lung NET subtypes has its distinct clinical features, behavior, treatment approach and prognosis, which highlight the importance of accurate pathologic diagnosis. Lung carcinoids present with hypersecretion and carcinoid syndrome in less than 2% of the patients compared to 10% of gastroenteropancreatic (GEP) carcinoids [11], and are found in around 5% of patients with multiple endocrine neoplasia syndrome type 1 (MEN-1) [12]. The primary treatment modality is surgical resection which offers the best chance for long-term cure [2] with TC patients experiencing an excellent 5-year survival (>87%) [13,14]. Regional lymph node metastases occur in 10–15% of TC patients and distant metastases (most commonly to liver and bone) in an additional 3–5% [15]. ACs are significantly more aggressive than TCs, with higher frequency of nodal and distant metastases in an average of 50 and 20% of the cases, respectively [15,16] together with a reported lower 5year survival of 60% [6]. The majority (95%) of small cell carcinomas of the body originate in the lung as a primary site, whereas extra pulmonary small cell carcinomas arising from other locations (e.g. esophagus, bladder, cervix and prostate) are extremely rare [17]. It is invariably associated with positive smoking history to the extent that the diagnosis in a nonsmoker is considered exceptional and should be carefully re-evaluated [2]. Most of the patients present with hilar nodal metastases and almost two-thirds with distant metastases (typical sites are brain, liver, adrenal, bone, and bone marrow) [18]. SCLC presenting as a solitary mass without evidence of metastasis is a rare occurrence in <5% of the patients [19]. Ectopic hormone production and paraneoplastic syndromes are frequent clinical findings in SCLC, including the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and Cushing syndrome due to ectopic ACTH secretion [2]. It is a rapidly fatal disease with dismal median survival- still measured in months- and long-term survival is highly unlikely (5-year survival is <5%) [20]. SCLC is generally considered a nonsurgical disease, but is extremely sensitive to chemotherapy (cisplatin plus etoposide is a standard regimen) and radiation therapy. Evidence is emerging that surgical resection may indeed extend the survival of a rare group of patients (<5%) in whom the disease presents as a solitary mass without extra-thoracic spread [21,22]. A unique clinical feature of SCLC is its tendency for brain metastases, which develop in about 50–80% of patients; that is why prophylactic cranial irradiation (PCI) is indicated for this disease, but not for other lung NETs or NSCLC [22]. LCNEC, being a high grade tumor, is also considered a highly aggressive disease with a reported wide range of survival (15–57%) with a weighted mean of 34%
[23]. In some reports, the prognosis of LCNEC is as poor as that of SCLC [24]. The objective of the current study is to evaluate the clinicopathologic characteristics and prognostic factors affecting survival in patients with different lung NETs who presented to NCI-E during a five-year period.
Patients and methods This is a retrospective cohort study for evaluating patients with the diagnosis of lung NETs, who presented to NCI-E during a 5-year period between January 2010 and December 2014. The inclusion criteria were adult patients of both genders aged 18 years with definite pathological diagnosis of a primary lung NET by morphological criteria and positivity of at least one of the neuroendocrine (NE) markers [synaptophysin, chromogranin A (CgA), neuron specific enolase (NSE) and CD56] by immunohistochemistry (IHC); all disease stages were included. Tumors which showed negative reactions to all previously mentioned NE markers were excluded from this study. By searching the NCI-E database for this diagnosis, thirty five cases were found fulfilling the inclusion criteria during the specified period. Archived files of these cases were retrieved from the medical records and all available data extracted, including patient demographics (age, gender, residence, smoking history, co-morbidities and family history of cancer), clinical profile including date of diagnosis, presenting symptoms, ECOG performance status (PS), tumor location in the lung, TNM stage (according to the 8th edition of the AJCC cancer staging system [25]), metastases and their site if present initially, date of relapse after curative surgery and its site (either loco-regional or distant), disease progression in initially advanced or metastatic cases and its date, as well as status at last follow up (alive or dead) and its date. The methods of diagnosis included different imaging modalities, bronchoscopy, surgical biopsy and fine needle aspiration cytology (FNAC). Management included surgery (date and type), neoadjuvant, adjuvant or palliative chemotherapy and radiotherapy. Each line of chemotherapy was assessed regarding date of start, number of cycles, and response.
Pathology review All the archived hematoxylin & edosin (H & E) slides and paraffin blocks of the 35 cases were retrieved from the pathology department and revised by the pathologist in charge of this study. Typing of the tumors was done according to the WHO classification [4]. SCLC was diagnosed on appreciation of small blue cells arranged in sheets (less than the diameter of 3 times that of a resting lymphocyte) with undefined cell borders, scanty cytoplasm, high nuclear cytoplasmic ratio, granular chromatin and no or inconspicuous nucleoli with commonly extensive necrosis with a high mitotic rate (average 80/2 mm2). LCNEC shows histological neuroendocrine features, the cells are generally large, with moderate to abundant cytoplasm. The nucleoli are frequent, prominent and their presence facilitates distinction from SCLC. Mitotic counts are typically > 10 (average 75/2 mm2). Carcinoid tumours are characterized by growth patterns (organoid, trabecular, insular, palisading, ribbon, rosette-like arrangements) that suggest neuroendocrine differentiation with uniform cytologic features and moderate eosinophilic, finely granular cytoplasm, and nuclei with a finely granular chromatin pattern. TC are larger than 0.5 cm displaying < 2 mitoses/2 mm2 with absence of necrosis. None of the cases had the pathology of AC. Positivity of at least one of the NE markers (NSE, Cg A, synaptophysin, CD56) was revised and documented for each case.
Please cite this article as: M. Saber, Y. Ismail, N. Alieldin et al., Neuroendocrine tumors of the lung: A five-year retrospective experience of Egyptian NCI (2010–2014), Journal of the Egyptian National Cancer Institute, https://doi.org/10.1016/j.jnci.2018.10.005
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Statistical methods All analyses were done using SPSSÒ (Statistical Package for Social Sciences) software, version 12.0.1, Chicago, USA. Quantitative data were presented as mean, standard deviation, median and range as appropriate. Qualitative data were presented as frequency and percentage. Survival analysis was done using KaplanMeier method; comparison between two survival curves was done using log rank test. All tests were two-tailed. A p-value 0.05 was considered significant. Overall survival (OS) was measured from the date of diagnosis to date of death or date of last follow up. Event-free survival (EFS) was measured from the date of first treatment to the date of relapse, progression, death or last follow up. Ethical issues Being a retrospective study, there were no additional risks to the patients. Data collection and presentation were anonymous and both privacy and confidentiality were protected to the maximum possible standards. The study was initiated after getting the approval of the Institutional Review Board (IRB) of NCI-E. Results A total of 35 cases of lung NETs who presented between January 2010 and December 2014 were retrieved from the database of NCIE. The mean age of the patients was 52 ± 11.2 years (median 54, range: 24–76). There was male predominance with male to female ratio 7.75:1. More than three quarters of the patients (83%) gave history of smoking. Nearly half of the cases (48.6%) had ECOG PS I on initial presentation, PS II and III were reported in 37.1 and 14.3%, respectively. Shortness of breath was the most common presenting complaint reported by more than half of the patients (54.3%), followed by chest pain and cough in 34 and 28.6%, respectively. The right lung was the dominant primary tumor location in 77% of the cases and the mean tumor size was 7.2 ± 2.7 cm (median 7.5, range 2–16 cm). SCLC was the prevalent histology depicted in almost two thirds of the cases (68.6%), followed by LCNEC and TC tumors in 20 and 11.4%, respectively. Stage IV at initial presentation was found in 21 cases out of 24 patients with SCLC (87.5%) and in 3 cases out of the 7 with LCNEC (43%). The liver was the most common metastatic site in 45.8% of cases, followed by pleural effusion and brain metastasis in 33.3 and 20.8%, respectively (Table 1). All cases tested positive to at least one of the NE markers with synaptophysin positivity encountered in the majority of cases (62.8%) (Figs. 1a, 1b, 2a, 2b, 3a, 3b). With respect to the treatment employed, none of the 24 cases of SCLC underwent surgery, as all the patients presented with inoperable or stage IV disease. Three patients (12.5%) presented with limited stage disease and received concomitant chemoradiation (CCRT) with a platinum/etoposide regimen followed by prophylactic cranial irradiation (PCI) in two of them who showed good partial response. Palliative chemotherapy was administered in 20 (83.3%) of the metastatic patients (platinum-based), the remaining patient did not receive chemotherapy due to poor PS and received only palliative radiotherapy. As for the seven patients with LCNEC, four of them (57%) underwent curative surgery with chemotherapy employed preoperatively in two cases and postoperatively in the other two. The remaining three patients who presented with stage IV received palliative chemotherapy, also platinum-based. On the contrary, curative surgery was carried out in all 4 (100%) TC patients; none of them received chemotherapy (Table 2). Regarding survival analysis, the median follow up period was 12.3 months (range 1.3–65). At the end of this period, 27 patients (24 SCLC and 3 LCNEC) were dead. For the entire cohort, the med-
Table 1 Demographics and clinicopathological profile of 35 lung NETs cases. Item
Number (n = 35)
Percent (%)
Age (years) Mean ± SD (52 ± 11.2)
Median (54)
Range (24–76)
Gender Male Female
31 4
88.6 11.4
Method of diagnosis Computed tomography Others
30 5
85.7 14.3
History of smoking Positive Negative
29 6
83.0 17.0
Presenting complaint* Dyspnea Chest pain Cough Hemoptysis Swelling Change of voice Mediatinal syndrome
19 12 10 5 2 1 1
54.3 34.3 28.6 14.3 5.7 2.9 2.9
ECOG PS at initial presentation I II III
17 13 5
48.6 37.1 14.3
Laterality Right lung Left lung
27 8
77.1 22.9
Anatomical site of primary tumor Upper lobe Middle lobe Lower lobe Hilar Others Tumor size (Mean ± SD 7.2 ± 2.7)
16 1 4 11 3 (Median 7.5)
45.7 2.9 11.4 31.4 8.6 (range 2–16.5)
Pathology SCLC LCNEC TC Grade High Low
24 7 4
68.6 20 11.4
31 4
88.6 11.4
TNM Stage at presentation I II III IV
2 4 5 24
5.7 11.4 14.3 68.6
Stage IV at presentation per pathology (n = 24) SCLC 21 LCNEC 3 TC 0
87.5 12.5 0
Positive neuroendocrine markers** Synaptophysin NSE CgA CD56
22 7 13 10
62.8 20 37 28.5
LN involvement on imaging Positive Negative
29 6
82.9 17.1
Site of metastasis*** (n = 24) Liver Pleural effusion Brain Bone Adrenal
11 8 5 4 2
45.8 33.3 20.8 16.7 8.3
CgA: chromogranin A ECOG: Eastern Cooperative Oncology Group LCNEC: large cell neuroendocrine carcinoma LN: lymph node NSE: neuron specific enolase PS: performance status SCLC: small cell lung cancer SD: standard deviation TC: typical carcinoid TNM: tumor, node, metastasis. * Fifteen patients reported more than one complaint. ** Ninteen patients showed positivity to > one marker. *** Seven patients had > one site of metastasis.
Please cite this article as: M. Saber, Y. Ismail, N. Alieldin et al., Neuroendocrine tumors of the lung: A five-year retrospective experience of Egyptian NCI (2010–2014), Journal of the Egyptian National Cancer Institute, https://doi.org/10.1016/j.jnci.2018.10.005
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Fig. 3a. LCNEC [H&Ex400]. Fig. 1a. TC (low grade) [H&Ex200].
Fig. 3b. LCNEC with strong synaptophysin positivity [IHCx400]. Fig. 1b. TC with strong synaptophysin positivity [IHCx200].
Fig. 2a. SCLC [H&Ex200].
and p = 0.001, respectively, Figs. 5a and 5b). The median EFS and OS for SCLC cases were 5.4 and 7.7 months, respectively, whereas the cumulative OS at 1 and 3 years were 45 and 0%, respectively. On the other hand, the cumulative OS at 3 years for LCNEC and TC were 57 and 100%, respectively. Analysis of survival according to the patients’ initial ECOG PS revealed that patients who presented with PS I demonstrated significantly higher EFS (p = 0.0021) and OS (p = 0.002) in comparison to patients with PS II and III (Figs. 6a and 6b). With respect to gender, there was no significant impact on EFS, but females-despite their small number- showed significantly higher OS than males (P = 0.035) (Figs. 7a and 7b). Comparison of survival according to the stage of the disease showed a significant EFS and OS survival difference in favor of locoregional disease versus metastatic disease (P = 0.0001 and P = 0.00001, respectively) (Figs. 8a and 8b). Age showed no significant impact on EFS or OS (Table 3).
Discussion
Fig. 2b. SCLC with strong CD56 positivity [IHCx200].
ian EFS and OS were 8.0 and 13.7 months, respectively, whereas the cumulative EFS and OS at 3 years were 17.8 and 20%, respectively (Figs. 4a and 4b). Analysis of survival in relation to different prognostic factors (Table 3) revealed that the histological subtype had significant impact on survival as SCLC patients showed significantly worse EFS and OS than LCNEC and TC patients (p = 0.009
The results of this retrospective analysis of 35 patients with lung NETs showed male predominance (88.6%) with M: F ratio of 7.75:1. A similar gender distribution with male predominance was reported by other authors, Mokhtar et al. (83.8% males) [3] and Asamura et al. (79.3% males) [26]. Although there were only 4 cases of TC with M: F ratio 1:1, other studies that included larger numbers of patients reported female predominance in this histological subtype as García-Yuste et al. [27], Simbolo et al. [28] and Chong et al. [29]. The mean age of the patients was 52 years which is almost 10 years younger than that reported in the studies of Mokhtar et al. (mean 62.3 years) [3] and Simbolo et al. (mean 61.6 years) [28]. This finding might be due to the relatively small number of the cases in the current study in comparison to other studies. The prevalent histology in the current study was SCLC (68.6%), followed by LCNEC (20%) then TC (11.4%). This predominance of SCLC between lung NETs goes with the worldwide incidence being
Please cite this article as: M. Saber, Y. Ismail, N. Alieldin et al., Neuroendocrine tumors of the lung: A five-year retrospective experience of Egyptian NCI (2010–2014), Journal of the Egyptian National Cancer Institute, https://doi.org/10.1016/j.jnci.2018.10.005
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M. Saber et al. / Journal of the Egyptian National Cancer Institute xxx (xxxx) xxx Table 2 Treatments employed according to histology for 35 lung NET cases. SCLC (n = 24)
LCNEC (n = 7)
Number of patients NACT Curative Surgery
Treatment given
0 0
*
CCRT PCI** ACT
3 2 0
ART PCT***
0 20
PRT
8
PE + RT
PE CE TC Vinorelbine Gemcitabine Irinotecan
TC (n = 4)
Number of patients
Treatment given
Number of patients
2 4
GCis Lobectomy
0 0 1 1 1 3
CE VC
0 2 2 0 0 0
Treatment given Lobectomy Pneumonectomy
0 0
TC GC VC CE
0
0
1.0
1
0.8
0.8
Cummulative Survival
Cummulative Survival
ACT: adjuvant-chemotherapy ART: adjuvant radiotherapy CCRT: concomitant chemo-radiation CE:carboplatin/etoposide GC: gemcitabine/carboplatin GCis: gemcitabine/cisplatin NACT: neoadjuvant chemotherapy. PCI: prophylactic cranial irradiation PCT:palliative chemotherapy PE:plationl/etoposide PRT: palliative radiotherapy RT: radiotherapy TC: taxol/carboplatin VC: vinorelbine/carboplatin. * For three patients with limited stage disease. ** For two patients with limited stage disease who showed good partial response after CCRT. *** Nine patients received more than one line of chemotherapy.
0.6
0.4
0.2
0.6
0.4
0.2
0.0 0
0
12
24
36
48
60
72
EFS (months) Fig. 4a. EFS of 35 Lung NETs cases.
the most common subtype reported [2]. Mokhtar et al. also previously reported that SCLC was the predominant histological subtype of lung NETs among NCI-E patients (92.8%) during a 10-year period (2000–2009) [3],whereas LCNEC was the dominant histological subtype in the studies of Iyoda et al. [23] and Asamura et al. [26]. TC was the most common subtype in the studies of GarcíaYuste et al. [27] and Simbolo et al. [28]. None of the current cases presented with the pathology of atypical carcinoid (AC). Rekhtman [2] reported the strong association of SCLC with smoking to the extent that the diagnosis in a patient with negative smoking history is considered exceptional and should be carefully reevaluated. This statement was typically confirmed in the current study where positive smoking history was documented in 29 (83%) cases, with SCLC patients representing the major fraction (24 cases) of this population.
0
12
24
36
48
60
72
OS (months) Fig. 4b. OS of 35 Lung NETs cases.
Concerning the management employed, radical curative surgery was offered to approximately one fifth (23%) of the cases only (4 TC and 4 LCNEC), which is relatively low compared to other reports [23,26,27] where all the patients included in these studies were treated surgically. This finding could be explained by the predominance of SCLC cases (68.5%) in the current study with the majority of these patients being inoperable and advanced at time of presentation (87.5% stage IV). A similar finding was reported in the work of Elliott et al. [18] who documented that most patients with SCLC had hilar nodal metastases at the time of initial presentation and distant metastases in two-thirds of them. SCLC are exquisitely sensitive to chemotherapy (cisplatin plus etoposide is a standard regimen) and radiation therapy [22]. In the current study, the commonest chemotherapy regimen used, whether with concomitant radiation or in a palliative setting, was cisplatin/eto-
Please cite this article as: M. Saber, Y. Ismail, N. Alieldin et al., Neuroendocrine tumors of the lung: A five-year retrospective experience of Egyptian NCI (2010–2014), Journal of the Egyptian National Cancer Institute, https://doi.org/10.1016/j.jnci.2018.10.005
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M. Saber et al. / Journal of the Egyptian National Cancer Institute xxx (xxxx) xxx
Table 3 Analysis of the prognostic factors affecting survival in the 35 lung NET cases. Number (n)
Event free survival
1 year
3 years
All cases
35
28
23.7
Histopathology SCLC LCNEC Typical Carcinoid
24 7 4
24 3 1
Performance status I 17 II&III 18 Gender Males Females
Number of events
Over all survival
Survival probability (%) at
Median EFS (months)
P value
Number of events
1 year
3 years
17.8
8
NA
27
53.4
8.3 57 67
0 57 67
5.4 Not reached Not reached
0.0092
24 3 0
10 18
44 6
38 0
11 1.8
0.0021
31 4
26 2
20 50
13.4 50
6.2 8
Stage Locoregional Metastatic
11 24
4 24
71 4
61 0
Age 50 <50
23 12
18 10
18.4 33.3
18.4 16.7
P value
20
13.7
NA
45 57 100
0 57 100
7.7 Not reached Not reached
0.0012
9 18
76 33.3
44 6
18.6 5.8
0.002
0.1812
26 1
47.2 NA
12.7 75
11.2 Not reached
0.0349
Not reached 2
0.0001
3 24
91 37.5
71 4
Not reached 7.1
0.00001
5.4 8.3
0.6145
18 9
46 66.7
18.4 22
11.2 14.7
0.4951
TC
0.4
P=0.0092
0.2
LCNECcensored TC-censored
0.8
Cummulative Survival
0.6
Pathology LCNEC SCLC
1.0
LCNEC SCLC TC LCNECcensored TC-censored
0.8
Cummulative Survival
Median OS (months)
Pathology
1.0
Survival probability (%) at
0.6
P=0.0012 0.4
0.2
0.0
0.0 0
12
24
36
48
60
0
72
12
36
48
60
72
Fig. 5b. OS of Lung NETs patients according to different histologies.
Fig. 5a. EFS of Lung NETs patients according to different histologies.
PS 1 2&3 1-censored
1.0
0.8
Cummulative Survival
poside similar to the studies of Chong et al. [29] and Veronesi et al. [30]. In terms of prognosis, the pathological subtype of the lung NETs demonstrated a powerful and significant impact on survival in the current study cohort. Merrill et al. [20] previously reported that the typical survival for SCLC patients was measured in months, and long-term survival was highly unusual (5-year survival is <5%). This conclusion was typically depicted in the current study as SCLC cases showed significantly the worst and poorest survival in comparison to TC and LCNEC (p = 0.001), with a median survival of 7.7 months and a 3-year survival of 0%. However, other studies that reported survival rates at 5 years showed higher figures; Travis et al. (9%) [13], García-Yuste et al. (14%) [27], Iyoda et al. (16.4%) [23] and Asamura et al. (35.7%) [26], This discrepancy in reported survival might be due to the fact that none of the SCLC cases of the current study were operable while most of the patients included in the other studies underwent surgery with curative intent. On the other end of the spectrum, TC patients showed the
24
OS (months)
EFS (months)
0.6 P=0.0021 0.4
0.2
0.0 0
12
24
36
48
60
72
EFS (months)
Fig. 6a. EFS according the patients’ initial PS.
Please cite this article as: M. Saber, Y. Ismail, N. Alieldin et al., Neuroendocrine tumors of the lung: A five-year retrospective experience of Egyptian NCI (2010–2014), Journal of the Egyptian National Cancer Institute, https://doi.org/10.1016/j.jnci.2018.10.005
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M. Saber et al. / Journal of the Egyptian National Cancer Institute xxx (xxxx) xxx
PS 1 2&3 1-censored
1.0
0.8
Cummulative Survival
Cummulative Survival
0.8
0.6
P=0.002 0.4
0.2
0.6 P=0.0001 0.4
0.2
0.0
0.0
0
12
24
36
48
60
72
0
OS (months)
12
24
36
48
60
72
EFS (months)
Fig. 6b. OS according the patients’ initial PS.
Fig. 8a. EFS difference of lung NETs cases according to stage at presentation.
gendre F M F-censored M-censored
1.0
0.6
0.4 P=0.1812
Stage 1,2,3 4 1,2,3-censored
1.0
0.8
Cummulative Survival
0.8
Cummulative Survival
Stage 1,2,3 4 1,2,3-censored
1.0
0.6 P=0.00001 0.4
0.2
0.2
0.0
0.0 0
0
12
24
36
48
60
12
24
36
48
60
72
OS (months)
72
EFS (months)
Fig. 8b. OS difference of lung NETs cases according to stage at presentation. Fig. 7a. EFS difference of lung NETs cases according to gender.
gendre F M F-censored M-censored
1.0
Cummulative Survival
0.8
0.6 P=0.0349 0.4
0.2
0.0 0
12
24
36
48
60
72
OS (months)
Fig. 7b. OS difference of lung NETs cases according to gender.
highest cumulative 3-year OS (100%); this excellent survival rate is exactly similar to what was reported by Iyoda et al. [23], whereas it was 96% in both Asamura et al. [26] and García-Yuste et al. [27]. It was lower, but still excellent (87%), in the study of Travis et al. [13]. This astonishing survival for the TC patients may be explained by the fact that all patients underwent curative surgery and the native indolent behavior of this low grade tumor.
Concerning the LCNEC patients, the 3-year OS rate was 57%. Takei et al. [9] reported exactly the same rate but at 5 years; however, other studies reported lower 5-year survival rates for this pathological entity like García-Yuste et al. (21%) [27] Travis et al. (27%) [13], Iyoda et al. (32%) [23], Asamura et al. (40%) [26] and Veronesi et al. (43%) [30]. In an attempt to explore the reasons for these reported low survival rates for this lung NET subtype, Asamura et al. [26] directly compared the 5-year OS of LCNEC vs. SCLC patients. They did not find a significant difference (p = 0.9) and concluded that LCNEC showed almost the same prognosis as SCLC. The latter finding was similarly reported by others; Travis et al. [13], Iyoda et al. [23] and García-Yuste et al. [27]. Also, the results of the study of Takei et al. showed that the prognosis of LCNEC was poor, even for early stage disease as the survival of stage I was poorer than the same stage of other NSCLCs; they concluded that because of its aggressive clinical behavior and poor prognosis, LCNEC should be recognized as one of the poorest prognostic subgroups among primary lung cancers [9]. In the current study, LCNEC patients showed a significantly higher OS than SCLC (p = 0.01); this contradictory finding to the aforementioned studies could be explained by two reasons; firstly because almost all SCLC cases had stage IV at presentation whereas 57% of the LCNEC cases underwent curative surgery and, secondly, due to the small number of LCNEC cases included in the current study in comparison to SCLC (7 vs. 24, respectively). Another prognostic factor that displayed significant correlation with survival in this study was the patients’ ECOG PS at time of
Please cite this article as: M. Saber, Y. Ismail, N. Alieldin et al., Neuroendocrine tumors of the lung: A five-year retrospective experience of Egyptian NCI (2010–2014), Journal of the Egyptian National Cancer Institute, https://doi.org/10.1016/j.jnci.2018.10.005
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M. Saber et al. / Journal of the Egyptian National Cancer Institute xxx (xxxx) xxx
presentation. Patients who presented with PS I had significantly higher EFS and OS (p = 0.002 for both) than those with PS II and III. Similar to this finding, Kawahara et al. reported the impact of initial PS on survival in a study that included only SCLC patients; they found significantly higher OS (p = 0.0001) in patients who presented with PS 0/I than PS II/III [31]. Paesmans et al. also demonstrated the effect of PS as a prognostic factor in SCLC, but they used the Karnofsky score instead of ECOG; they found that patients with Karnofsky score 80 had significantly better survival (p = 0.001) compared to those with 70 [32]. The authors could not depict from the literature other studies that evaluated PS as a prognostic factor in relation to different subtypes of lung NETs. The authors admit to the limitations of the current study, firstly being a retrospective one, secondly the relatively small number of the whole cohort and within the subgroups, and thirdly the absence of one of the basic four subtypes of lung NETs (atypical carcinoid) for analysis. The study describes one of the less common entities in cancer, so retrospectivity is mostly the appropriate method of research in the literature, and being limited to a specified period (2010–14), the limitations of the sample size and missing one subtype were absolutely unavoidable events. Conclusions This retrospective analysis showed that in NCI-E, the commonest histological subtype of lung NETs is SCLC which corresponds to the worldwide incidence and almost all the cases of this pathology presented with advanced or metastatic stage that predicted dismal survival. The pathological subtype of lung NET, stage and initial PS are prognostic factors significantly affecting survival. This conclusion needs to be confirmed by larger studies. References [1] Pearse AG. The cytochemistry and ultrastructure of polypeptide hormone producing cells of the APUD series and the embryologic, physiologic and pathologic implications of the concept. J Histochem Cytochem 1969;17 (5):303–13. [2] Rekhtman N. Neuroendocrine tumors of the lung: an update. Arch Pathol Lab Med 2010;134(11):1628–38. [3] Mokhtar N, Salama A, Badawy O. Neuroendocrine tumors. In: Mokhtar N, Asmaa S, Badawy O, Khorshed E, Mohamed G, Ibrahim M, editors. Cancer pathology registry 2000–2011. Cairo, Egypt: Cairo Press; 2016. p. 220–5. [4] Travis WD, Brambilla E, Burke AP, Marx A, Nicolson AG, editors. World Health Organization Classification of Tumours. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: IARC Press; 2015. [5] Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB, et al. The 2015 world health organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol 2015;10:1243–60. [6] Beasley MB, Thunnissen FB, Brambilla E, Hasleton P, Steele R, Hammar SP, et al. Pulmonary atypical carcinoid: predictors of survival in 106 cases. Hum Pathol 2000;31(10):1255–65. [7] Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC, editors. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: IARC Press; 2004. [8] Travis WD. Neuroendocrine lung tumors. Pathol Case Rev 2006;11(6):235–42. [9] Takei H, Asamura H, Maeshima A, Suzuki K, Kondo H, Niki T, et al. Large cell neuroendocrine carcinoma of the lung: a clinicopathologic study of eightyseven cases. J Thorac Cardiovasc Surg 2002;124:285–92.
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Please cite this article as: M. Saber, Y. Ismail, N. Alieldin et al., Neuroendocrine tumors of the lung: A five-year retrospective experience of Egyptian NCI (2010–2014), Journal of the Egyptian National Cancer Institute, https://doi.org/10.1016/j.jnci.2018.10.005