- Email: [email protected]
neuroendocrine carcinoma
Lung Cancer 69 (2010) 13–18
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Review
Large cell/neuroendocrine carcinoma Russell Gollard a,∗ , Sejal Jhatakia b , Max Elliott c , Michael Kosty b a
Cancer & Blood Specialists of Nevada, 58 N. Pecos Road, Henderson, NV 89074, United States Scripps Clinic, Division of Hematology and Oncology, 10855 North Torrey Pines, La Jolla, CA 90237, United States c Scripps Clinic, Division of Pathology, 10855 North Torrey Pines, La Jolla, CA 90237, United States b
a r t i c l e
i n f o
Article history: Received 28 August 2009 Received in revised form 4 December 2009 Accepted 20 December 2009 Keywords: Large cell neuroendocrine Large cell Neuroendocrine Lung cancer Uncommon lung cancer
a b s t r a c t Large cell neuroendocrine tumors of the lung represent a recently reclassified subtype of lung cancer with features of both small cell and non-small cell lung cancer. We review diagnostic difficulties, typical presentations, and the natural history of this tumor. We review treatment data, and suggest that as in more common types of lung cancer, multi-modality therapy may be the most promising course of treatment. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Large cell neuroendocrine carcinoma is an uncommon tumor of the lung. It is not rare, however, and constitutes up to 3% of tumors at some institutions [1,2]. There is usually a male predominance and virtually all patients are cigarette smokers [3]. Because of its relatively uncommon incidence, it has not been studied extensively in a prospective, randomized fashion; thus, the clinician is often left in a quandary: should the tumor be treated as a non-small cell cancer or as a small cell cancer? Large cell neuroendocrine tumors can be aggressive and also can be difficult to diagnose [4,5]. 2. Background and pathological characteristics When Charles Moertel wrote about gastric carcinoid tumors in his seminal review “An Odyssey in the Land of Small Tumors,” he was both reviewing the state of the art with respect to treatment and diagnosis in 1988, and was also pointing to Gulliver-like undertaking one embraces in trying to describe and appropriately treat gastrointestinal neuroendocrine tumors, which can arise in any organ system and present as a continuum of biological behavior ranging from indolent to highly aggressive [6,7]. Diagnosing neuroendocrine tumors of the lung share many of the difficulties Charles Moertel wrote of. Neuroendocrine tumors comprise
∗ Corresponding author. Tel.: +1 702 822 2000; fax: +1 702 938 2233. E-mail addresses: [email protected] (R. Gollard), [email protected] (S. Jhatakia), [email protected] (M. Elliott), [email protected] (M. Kosty). 0169-5002/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2009.12.011
approximately 20% of all lung cancers and represent a spectrum of tumors with different biological behaviors arising from neuroendocrine cells in the pulmonary and bronchial epithelium [8]. Laennec first characterized a bronchopulmonary neuroendocrine tumor in 1831 when he described an intrabronchial mass likely representing a bronchial carcinoid [8]. Until recently, pulmonary neuroendocrine tumors were classified into three categories: typical carcinoids, atypical carcinoids and small cell lung cancer [9]. It was not until 1991, when Travis et al. identified a unique entity called large cell neuroendocrine carcinoma with a prognostic spectrum similar to small cell lung cancer, that large cell neuroendocrine cancer was designated as a new distinct form of lung cancer [10]. Neuroendocrine tumors of the lung have been recently divided into 4 categories: typical carcinoid tumor (TC), atypical carcinoid tumor (AC), large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC). The WHO now recognizes large cell neuroendocrine tumors as a distinct subtype from pulmonary large cell tumor, a form of non-small cell lung cancer [2]. The spectrum of neuroendocrine tumors can be distinguished by their clinical characteristics, histology, prognosis and survival (Table 1) [11–14]. Small cell carcinoma (SCLC) and large cell NE carcinoma (LCNEC) are high grade neuroendocrine tumors while typical carcinoids (TC) and atypical carcinoids (AC) are low and intermediate grade [4]. In fact, a mitotic count of 11 or more mitoses per 10 high power fields is the main criterion separating large cell neuroendocrine carcinoma and small cell carcinoma from atypical carcinoids [7]. Large cell neuroendocrine tumors are defined by their neuroendocrine morphology which includes organoid nesting, palisading, trabecular pattern, and rosette like structures (Figs. 1–4). There are
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Table 1 Overview of presentation, prognosis, diagnosis and treatment of neuroendocrine lung tumors. Lung location
Mitotic rate
Cell histology
Growth pattern
IIHC
TC
Young/male or female/non-smoker
Central
2 mitoses per/10 HPF
Organoid, palisading pattern. Necrosis absent.
AC
Young/male or female/non-smoker
Peripheral
2–10 mitoses/10 HPF
Large cells with abundant cytoplasm and no nuclear pleomorphism. No prominent nucleoli. Large cells with abundant cytoplasm and some nuclear pleomorphism. No prominent nucleoli.
LCNEC
Older/male/smoker
Midzone or peripheral
>11 mitoses/10 HPF (mean of 70)
Organoid, palisading pattern. Extensive necrosis present.
SCLC
Older/male/smoker
Central
>11 mitoses/10 HPF (mean of 70)
Large cells with abundant cytoplasm and significant nuclear pleomorphism. Prominent nucleoli. Small cells with scanty cytoplasm and significant nuclear pleomorphism, in a diffused pattern. No prominent nucleoli.
Variable NE marker 5–15% expression. Chromogranin A: 100%. TTF-1 negative. Variable NE marker 25% expression. Chromogranin A: variable. TTF-1 negative. Variable NE marker 40% expression. Chromogranin A: 80% TTF-1 positive. Variable NE marker 90% expression. Chromogranin A: 50–60%. TTF-1 positive.
Organoid, palisading, pattern. Focal necrosis present.
Diffuse sheets of cells. Extensive necrosis present.
Rate of regional metastasis
Therapy
5-Year survival
Surgery for early stage.
100%
Surgery for early stage
70%
No standard. Surgery and 15–25% chemotherapy for early stage and chemotherapy for advanced stage Chemotherapy and <15% radiation for limited stage and chemotherapy for extensive stage.
Fig. 1. Tumor stained for cytokeratin. Normal bronchial epithelium showed positive staining while tumor cells are negative.
Fig. 2. Hematoxylin and eosin stained section of tumor showing moderately large cell with distinct eosinophilic cytoplasm, pleomorphic nuclei and numerous mitotic figures.
often large zones of necrosis. With immunochemical analysis, large cell neuroendocrine cancers express most neuroendocrine markers (chromogranin, neuron specific enolase, synaptophysin, somatostatin) but are negative for the high molecular weight cytokeratins which are typically seen in neuroendocrine tumors such as small cell carcinoma [15]. In one study evaluating 87 patients with large cell neuroendocrine cancers, 91% of the tumors were positive for synaptophysin and NCAM and 82% for chromogranin A. In fact, 100% of the patients expressed one of the neuroendocrine markers reviewed and 68% were positive for all three [3].
Fig. 3. Low magnification of hematoxylin and eosin stain section showing extensive tumor necrosis and focal trabecular growth pattern.
R. Gollard et al. / Lung Cancer 69 (2010) 13–18
NE cancer Clinical characteristics: age/sex/smoking status
R. Gollard et al. / Lung Cancer 69 (2010) 13–18
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Fig. 4. Split field on left showing diffusely strong staining for synaptophysin and on right tumor showing focal staining for chromogranin.
Interestingly, large cell neuroendocrine tumors still maintain many of the cytologic features of non-small cell lung cancers including large cell size, low nuclear to cytoplasmic ratio, fine chromatin and frequent nucleoli. It is these cytologic characteristics that help to distinguish large cell neuroendocrine carcinoma from small cell carcinoma, though the distinction is not always clear [7]. 3. Molecular markers At the cellular level, large cell neuroendocrine carcinomas (LCNEC) have a higher proliferative rate compared to classic large cell carcinomas and other low grade neuroendocrine tumors such as carcinoid and atypical carcinoids [16]. Like small cell lung cancer, they have a high proliferative rate based on Ki-67 staining, abnormal p53 and absent Rb staining. They also express high levels of Bcl-2 which has antiapoptotic activity and p21 which is a marker of angiogenesis [17]. In addition, the frequency of telomerase activity is significantly higher in LCNEC (87%) and SCLC (93%) compared to carcinoid tumors. Telomerases are enzymes that synthesize DNA strands and help to recompense DNA loss with cell division. They correlate with tumors with a high proliferation index [18]. Unlike conventional NSCLC, LCNEC do not show mutational changes of kras-2 and c-raf genes. More recently, researchers have found that receptor tyrosine kinase pathways such as KIT and MET, important in tumor proliferation in small cell lung cancer and other malignancies, may be involved in the pathogenesis of large cell neuroendocrine tumors. Researchers in Italy identified and retrospectively reviewed large cell neuroendocrine tumors that were resected in patients between 1990 and 2004. Among the 83 tumors, 82% expressed PDGFRB, 63% expressed KIT and 47% expressed MET. MET was, however, the only immunohistochemical marker significantly correlated with overall survival and a potential for further targeted therapies [19]. LCNEC tumor cells also expressed thyroid transcription factor 1 [20]. Gene expression profiling can also provide a glimpse into tumor biology and insight into clinical behavior. Jones and his team at the University of Tokyo used gene expression profiling from cDNA microarrays of surgically resected samples and were able to identify distinct groups for carcinoids, large cell carcinoma, adenocarcinoma and normal lung but were unable to distinguish LCNEC from SCLC [9], thus suggesting that LCNEC and SCLC have similar biologic behavior [21].
4. Clinical presentation Most patients with large cell neuroendocrine tumors are male and have a strong smoking history. The median age at presentation is 65 [3]. They more frequently present with peripheral tumors but can be centrally located [7] (Fig. 5). The features of LCNEC on imaging studies, however, are non-specific and indistinguishable from NSCLC. A review of CT imaging in patients with large cell neuroendocrine carcinoma of the lung found that LCNEC generally are peripherally located, expansively growing, and have irregular margins with 10% with calcification [22]. Patients with LCNEC may present with similar symptoms as other patients with lung cancer but consistently lack paraneoplastic syndromes [17]. 5. Diagnosis As stated earlier, large cell neuroendocrine carcinoma can be very difficult to diagnose and probably is under-diagnosed [3]. Although unique cytologic characteristics have been identified,
Fig. 5. Axial CAT scan showing central nature of large cell neuroendocrine tumor (arrow) showing 4 cm tumor tethered to mediastinal structures. With neoadjuvant chemotherapy, tumor became resectable.
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R. Gollard et al. / Lung Cancer 69 (2010) 13–18
immunohistochemical staining concentrating on neuroendocrine features and the evaluation of mitotic rate from histological sections are vital to a correct diagnosis [23–27]. Thus it is very difficult to diagnose patients preoperatively with small biopsy specimens [13]. If a careful pathologic review is not performed, large cell neuroendocrine carcinoma can be mistaken for poorly differentiated NSCLC, atypical carcinoid and even intermediate cell type SCLC [21]. Recent studies have revealed that with IHC evaluation, 13% of poorly differentiated cancer has been reclassified as LCNEC [24]. Further, the size difference between “small” and “large” cells is not absolute and can confuse diagnosis [28]. Sometimes electron microscopy is needed to evaluate ultrastructures [29]. 6. Prognosis It is becoming increasingly evident that large cell neuroendocrine tumors are biologically aggressive cancers that behave similarly to small cell carcinoma [4]. The similarity in biologic behavior between large cell neuroendocrine carcinoma and small cell carcinoma is not only seen at the molecular level but also by the overall poor prognosis of patients. Asamura et al. retrospectively reviewed 318 patients from 10 Japanese institutions with neuroendocrine tumors of the lung. The 5-year survival rate of patients from all stages was as follows: 96.3% for typical carcinoids, 77.8% for atypical carcinoids, 40.3% for large cell neuroendocrine cancers and 35.7% for small cell lung cancers [4]. Stage for stage, there was no difference in prognosis between large cell neuroendocrine and small cell carcinoma and their survival curves overlapped. On multivariate analysis, histologic grade of neuroendocrine tumor was the most significant prognostic factor with a relative risk ratio of 17.40. Other series have reported a similar poor prognosis for large cell neuroendocrine tumors. A Spanish multicenter study by Garcia-Yust et al. found that the 5-year survival rate of TC was 96%, AC 72%, LCNEC 21% and SCLC 14%. Large cell neuroendocrine tumors not only show a poor prognosis in the spectrum of neuroendocrine cancers but also show inferior survival compared to other non-small cell lung cancers [17]. This supports the WHO decision to reclassify large cell neuroendocrine tumors as a distinct subtype of pulmonary large cell tumors [2]. Prior reports have noted that overall survival rate at 5 years after resection of large cell neuroendocrine tumors ranges between 13 and 57% [14]. This is considerably lower than other subtypes of NSCLC. Battafarano et al. analyzed their tumor registry of patients who had undergone surgical resection of lung cancer between July 1988 and December 2002 [29]. Of the 2000 patients who underwent resection, 4% had large cell lung cancer. Overall survival for the entire group was 47.1%. When the analysis was reviewed by histologic subtype, the 5-year survival rates are as follows: 30.2%
for large cell neuroendocrine carcinoma, 30.3% for mixed large cell neuroendocrine carcinoma and 71.3% for patients with large cell carcinoma. The 5-year survival for stage I patients was only 32.5%. Survival was significantly worse for patients with large cell neuroendocrine carcinoma compared to classic large cell cancer. In fact, the presence of large cell neuroendocrine carcinoma in the specimen was significantly associated with decreased survival. Clearly, large cell neuroendocrine carcinomas have a worse prognosis than other non-small lung cancers including large cell carcinoma [30,31]. The presence of neuroendocrine differentiation detected on an ultrastructural or molecular level, is in fact a predictor of an aggressive clinical course [32–34]. Even in patients with stage I lung cancer that is potentially resectable the prognosis is poor. In fact, multiple studies have shown that the survival curves of large cell neuroendocrine cancers mimic those of small cell lung cancer. 7. Treatment The optimal treatment of large cell neuroendocrine carcinoma is not known. Because it is an uncommon malignancy, prospective, randomized trials have not been performed. There are, however, small case series and retrospective reviews which have provided some insight (Table 2). Most patients with early stage LCNEC are surgically treated [8,35,36]. It is becoming increasingly clear, however, that surgery alone is not sufficient to treat LCNEC, even in early stage disease [11,37,38]. Iyoda et al. analyzed clinical factors in 335 cases of pathologic stage Ia NSCLC. They found that large cell neuroendocrine histology has a significant adverse prognostic impact and was predictive of poorer overall survival [39]. Recently, Veronesi et al. retrospectively analyzed 144 surgical cases (50% of the patients were stage I). Induction chemotherapy was given in 21 patients with a response rate of 80% and a postoperative chemotherapy in 24 patients. A trend to better outcome was associated with preoperative or postoperative chemotherapy in stage I disease [40]. Similarly, Saji et al., in a retrospective review found a survival benefit of patients with LCNEC who underwent perioperative chemotherapy compared to surgery alone (p = 0.04). Again, stage I patients showed a favorable prognostic profile with chemotherapy. The most common chemotherapy used was platinum-based combinations of VP-16 and CPT-11 [41]. More information has recently been gathered on the optimum type of adjuvant regimen for LCNEC. Iyoda et al. prospectively analyzed adjuvant chemotherapy for patients with LCNEC. Using SCLC-based regimens, they found prolonged survival with at least 2 cycles of therapy [42,43]. The overall survival rate was 88.9% at 5 years. In a retrospective review by Rossi and his group in Italy, 83 patients with pure pulmonary LCNEC were analyzed for molecular
Table 2 LCNEC prognosis among recent studies. Studies
Publication year
Takei Battafarano
2002 2005
Rossi
Number of patients with LCNEC
5-Year OS
5-Year survival for stage 1
Median f/u
Predictors of survival (multivariate analysis)
87 45
57% 30.3%
67% 32.1%
– 52.8 months
2005
83
27.6%
33%
17 months
Veronesi
2006
144
43%
52%
27 months
Asamura
2006
141
40.3%
57.8%
60 months
Faggiano
2007
41
– LCNEC histology compared to LCC Tumor stage and size (<3 cm vs. ≥3 cm) Stage III, age and type of resection. Histology, age, nodal involvement, incomplete resection. Mitotic count and neuroendocrine marker staining
24%
–
14 months
OS = overall survival; LCNEC = large cell neuroendocrine cancer; LCC = large cell carcinoma; conflict of interest: nothing to disclose.
R. Gollard et al. / Lung Cancer 69 (2010) 13–18
markers, pathologic features and treatment strategies [19]. Among those patients treated, patients treated with a SCLC-based regimen had a significantly better survival compared to standard regiments for NSCLC (median survival, 42 months vs. 11 months; p < 0.0001) [19]. This was especially true in stage I patients. These studies suggest a multi-modality approach to treatment, especially in early stage cancer with polychemotherapy using agents used for small cell lung cancer including platinum and etoposide. There is even less information available in the treatment of unresectable and advanced LCNEC. Part of the problem has been that it has been very difficult to diagnose LCNEC in biopsy specimens in unresectable patients [44]. In a recent study by Igawa et al., 14 patients were analyzed with new criteria for high grade non-small cell neuroendocrine carcinoma (HNSCNEC) small biopsy specimens. These patients were treated with chemotherapy (mostly platinum-based regimens) and compared with patients treated with chemotherapy for extensive stage SCLC. The objective response rate, a 1-year survival rate and median survival time were similar for the two groups: 50% vs. 53% in HNSCNEC vs. SCLC, 34% vs. 48% and 10 months vs. 12.3 months, respectively [44]. Previously, Yamazaki et al. reported on the clinical response of patients with LCNEC to chemotherapy. They found that the response rate of LCNEC to cisplatin-based chemotherapy was comparable to SCLC [45]. Despite the benefits of radiation in limited stage SCLC, the role of radiation in unresectable LCNEC remains undefined [19]. Other avenues of treatment have also been investigated. Filosso et al. evaluated the possibility of using octreotide in patients whose tumor was positive preoperatively with indium 111 scintigraphy [46]. Positive efficacy was noted for postoperative octreotide use alone or in combination with radiotherapy. Further research is needed. There is also ongoing research in the use tyrosine kinase inhibitors and targeted therapy against other neuroendocrine markers such as CD 56 [17]. More randomized prospective trials are needed. 8. Conclusion Large cell neuroendocrine cancer of the lung is a unique malignancy [47]. Histologically, it shares features of both non-small cell carcinoma and small cell carcinoma. Prognostically, it is clearly more aggressive and survival of patients with large cell neuroendocrine cancer echoes that of small cell cancer. The diagnosis of this malignancy is difficult and the best treatment is still unclear. Large phase II and III trials have not been done for this uncommon tumor. Large cooperative groups could possibly accumulate enough patients so that LCNEC could be studied prospectively. At this point, early stage patients are treated with complete resection of the primary tumor. Adjuvant chemotherapy, even in stage I patients, has shown benefit. Neoadjuvant platinum-based regimens may be suitable for marginally resectable tumors. Further studies will be needed to identify novel agents that target specific molecular pathways and can be used in the adjuvant and neoadjuvant setting. Metastases to the brain are purportedly unusual in large cell neuroendocrine tumors, though local spread is not. Early diagnosis followed by surgery and adjuvant platinum-based therapy is best; prophylactic cranial radiation therapy remains undefined. Hopefully, in the coming years we will be able to glean even more information regarding large cell neuroendocrine carcinoma and improve prognosis in this unusual and complex malignancy. Conflict of interest We would like to report that there are no conflicts of interest in our submitted article.
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Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Review
Large cell/neuroendocrine carcinoma Russell Gollard a,∗ , Sejal Jhatakia b , Max Elliott c , Michael Kosty b a
Cancer & Blood Specialists of Nevada, 58 N. Pecos Road, Henderson, NV 89074, United States Scripps Clinic, Division of Hematology and Oncology, 10855 North Torrey Pines, La Jolla, CA 90237, United States c Scripps Clinic, Division of Pathology, 10855 North Torrey Pines, La Jolla, CA 90237, United States b
a r t i c l e
i n f o
Article history: Received 28 August 2009 Received in revised form 4 December 2009 Accepted 20 December 2009 Keywords: Large cell neuroendocrine Large cell Neuroendocrine Lung cancer Uncommon lung cancer
a b s t r a c t Large cell neuroendocrine tumors of the lung represent a recently reclassified subtype of lung cancer with features of both small cell and non-small cell lung cancer. We review diagnostic difficulties, typical presentations, and the natural history of this tumor. We review treatment data, and suggest that as in more common types of lung cancer, multi-modality therapy may be the most promising course of treatment. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Large cell neuroendocrine carcinoma is an uncommon tumor of the lung. It is not rare, however, and constitutes up to 3% of tumors at some institutions [1,2]. There is usually a male predominance and virtually all patients are cigarette smokers [3]. Because of its relatively uncommon incidence, it has not been studied extensively in a prospective, randomized fashion; thus, the clinician is often left in a quandary: should the tumor be treated as a non-small cell cancer or as a small cell cancer? Large cell neuroendocrine tumors can be aggressive and also can be difficult to diagnose [4,5]. 2. Background and pathological characteristics When Charles Moertel wrote about gastric carcinoid tumors in his seminal review “An Odyssey in the Land of Small Tumors,” he was both reviewing the state of the art with respect to treatment and diagnosis in 1988, and was also pointing to Gulliver-like undertaking one embraces in trying to describe and appropriately treat gastrointestinal neuroendocrine tumors, which can arise in any organ system and present as a continuum of biological behavior ranging from indolent to highly aggressive [6,7]. Diagnosing neuroendocrine tumors of the lung share many of the difficulties Charles Moertel wrote of. Neuroendocrine tumors comprise
∗ Corresponding author. Tel.: +1 702 822 2000; fax: +1 702 938 2233. E-mail addresses: [email protected] (R. Gollard), [email protected] (S. Jhatakia), [email protected] (M. Elliott), [email protected] (M. Kosty). 0169-5002/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2009.12.011
approximately 20% of all lung cancers and represent a spectrum of tumors with different biological behaviors arising from neuroendocrine cells in the pulmonary and bronchial epithelium [8]. Laennec first characterized a bronchopulmonary neuroendocrine tumor in 1831 when he described an intrabronchial mass likely representing a bronchial carcinoid [8]. Until recently, pulmonary neuroendocrine tumors were classified into three categories: typical carcinoids, atypical carcinoids and small cell lung cancer [9]. It was not until 1991, when Travis et al. identified a unique entity called large cell neuroendocrine carcinoma with a prognostic spectrum similar to small cell lung cancer, that large cell neuroendocrine cancer was designated as a new distinct form of lung cancer [10]. Neuroendocrine tumors of the lung have been recently divided into 4 categories: typical carcinoid tumor (TC), atypical carcinoid tumor (AC), large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC). The WHO now recognizes large cell neuroendocrine tumors as a distinct subtype from pulmonary large cell tumor, a form of non-small cell lung cancer [2]. The spectrum of neuroendocrine tumors can be distinguished by their clinical characteristics, histology, prognosis and survival (Table 1) [11–14]. Small cell carcinoma (SCLC) and large cell NE carcinoma (LCNEC) are high grade neuroendocrine tumors while typical carcinoids (TC) and atypical carcinoids (AC) are low and intermediate grade [4]. In fact, a mitotic count of 11 or more mitoses per 10 high power fields is the main criterion separating large cell neuroendocrine carcinoma and small cell carcinoma from atypical carcinoids [7]. Large cell neuroendocrine tumors are defined by their neuroendocrine morphology which includes organoid nesting, palisading, trabecular pattern, and rosette like structures (Figs. 1–4). There are
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Table 1 Overview of presentation, prognosis, diagnosis and treatment of neuroendocrine lung tumors. Lung location
Mitotic rate
Cell histology
Growth pattern
IIHC
TC
Young/male or female/non-smoker
Central
2 mitoses per/10 HPF
Organoid, palisading pattern. Necrosis absent.
AC
Young/male or female/non-smoker
Peripheral
2–10 mitoses/10 HPF
Large cells with abundant cytoplasm and no nuclear pleomorphism. No prominent nucleoli. Large cells with abundant cytoplasm and some nuclear pleomorphism. No prominent nucleoli.
LCNEC
Older/male/smoker
Midzone or peripheral
>11 mitoses/10 HPF (mean of 70)
Organoid, palisading pattern. Extensive necrosis present.
SCLC
Older/male/smoker
Central
>11 mitoses/10 HPF (mean of 70)
Large cells with abundant cytoplasm and significant nuclear pleomorphism. Prominent nucleoli. Small cells with scanty cytoplasm and significant nuclear pleomorphism, in a diffused pattern. No prominent nucleoli.
Variable NE marker 5–15% expression. Chromogranin A: 100%. TTF-1 negative. Variable NE marker 25% expression. Chromogranin A: variable. TTF-1 negative. Variable NE marker 40% expression. Chromogranin A: 80% TTF-1 positive. Variable NE marker 90% expression. Chromogranin A: 50–60%. TTF-1 positive.
Organoid, palisading, pattern. Focal necrosis present.
Diffuse sheets of cells. Extensive necrosis present.
Rate of regional metastasis
Therapy
5-Year survival
Surgery for early stage.
100%
Surgery for early stage
70%
No standard. Surgery and 15–25% chemotherapy for early stage and chemotherapy for advanced stage Chemotherapy and <15% radiation for limited stage and chemotherapy for extensive stage.
Fig. 1. Tumor stained for cytokeratin. Normal bronchial epithelium showed positive staining while tumor cells are negative.
Fig. 2. Hematoxylin and eosin stained section of tumor showing moderately large cell with distinct eosinophilic cytoplasm, pleomorphic nuclei and numerous mitotic figures.
often large zones of necrosis. With immunochemical analysis, large cell neuroendocrine cancers express most neuroendocrine markers (chromogranin, neuron specific enolase, synaptophysin, somatostatin) but are negative for the high molecular weight cytokeratins which are typically seen in neuroendocrine tumors such as small cell carcinoma [15]. In one study evaluating 87 patients with large cell neuroendocrine cancers, 91% of the tumors were positive for synaptophysin and NCAM and 82% for chromogranin A. In fact, 100% of the patients expressed one of the neuroendocrine markers reviewed and 68% were positive for all three [3].
Fig. 3. Low magnification of hematoxylin and eosin stain section showing extensive tumor necrosis and focal trabecular growth pattern.
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NE cancer Clinical characteristics: age/sex/smoking status
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Fig. 4. Split field on left showing diffusely strong staining for synaptophysin and on right tumor showing focal staining for chromogranin.
Interestingly, large cell neuroendocrine tumors still maintain many of the cytologic features of non-small cell lung cancers including large cell size, low nuclear to cytoplasmic ratio, fine chromatin and frequent nucleoli. It is these cytologic characteristics that help to distinguish large cell neuroendocrine carcinoma from small cell carcinoma, though the distinction is not always clear [7]. 3. Molecular markers At the cellular level, large cell neuroendocrine carcinomas (LCNEC) have a higher proliferative rate compared to classic large cell carcinomas and other low grade neuroendocrine tumors such as carcinoid and atypical carcinoids [16]. Like small cell lung cancer, they have a high proliferative rate based on Ki-67 staining, abnormal p53 and absent Rb staining. They also express high levels of Bcl-2 which has antiapoptotic activity and p21 which is a marker of angiogenesis [17]. In addition, the frequency of telomerase activity is significantly higher in LCNEC (87%) and SCLC (93%) compared to carcinoid tumors. Telomerases are enzymes that synthesize DNA strands and help to recompense DNA loss with cell division. They correlate with tumors with a high proliferation index [18]. Unlike conventional NSCLC, LCNEC do not show mutational changes of kras-2 and c-raf genes. More recently, researchers have found that receptor tyrosine kinase pathways such as KIT and MET, important in tumor proliferation in small cell lung cancer and other malignancies, may be involved in the pathogenesis of large cell neuroendocrine tumors. Researchers in Italy identified and retrospectively reviewed large cell neuroendocrine tumors that were resected in patients between 1990 and 2004. Among the 83 tumors, 82% expressed PDGFRB, 63% expressed KIT and 47% expressed MET. MET was, however, the only immunohistochemical marker significantly correlated with overall survival and a potential for further targeted therapies [19]. LCNEC tumor cells also expressed thyroid transcription factor 1 [20]. Gene expression profiling can also provide a glimpse into tumor biology and insight into clinical behavior. Jones and his team at the University of Tokyo used gene expression profiling from cDNA microarrays of surgically resected samples and were able to identify distinct groups for carcinoids, large cell carcinoma, adenocarcinoma and normal lung but were unable to distinguish LCNEC from SCLC [9], thus suggesting that LCNEC and SCLC have similar biologic behavior [21].
4. Clinical presentation Most patients with large cell neuroendocrine tumors are male and have a strong smoking history. The median age at presentation is 65 [3]. They more frequently present with peripheral tumors but can be centrally located [7] (Fig. 5). The features of LCNEC on imaging studies, however, are non-specific and indistinguishable from NSCLC. A review of CT imaging in patients with large cell neuroendocrine carcinoma of the lung found that LCNEC generally are peripherally located, expansively growing, and have irregular margins with 10% with calcification [22]. Patients with LCNEC may present with similar symptoms as other patients with lung cancer but consistently lack paraneoplastic syndromes [17]. 5. Diagnosis As stated earlier, large cell neuroendocrine carcinoma can be very difficult to diagnose and probably is under-diagnosed [3]. Although unique cytologic characteristics have been identified,
Fig. 5. Axial CAT scan showing central nature of large cell neuroendocrine tumor (arrow) showing 4 cm tumor tethered to mediastinal structures. With neoadjuvant chemotherapy, tumor became resectable.
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immunohistochemical staining concentrating on neuroendocrine features and the evaluation of mitotic rate from histological sections are vital to a correct diagnosis [23–27]. Thus it is very difficult to diagnose patients preoperatively with small biopsy specimens [13]. If a careful pathologic review is not performed, large cell neuroendocrine carcinoma can be mistaken for poorly differentiated NSCLC, atypical carcinoid and even intermediate cell type SCLC [21]. Recent studies have revealed that with IHC evaluation, 13% of poorly differentiated cancer has been reclassified as LCNEC [24]. Further, the size difference between “small” and “large” cells is not absolute and can confuse diagnosis [28]. Sometimes electron microscopy is needed to evaluate ultrastructures [29]. 6. Prognosis It is becoming increasingly evident that large cell neuroendocrine tumors are biologically aggressive cancers that behave similarly to small cell carcinoma [4]. The similarity in biologic behavior between large cell neuroendocrine carcinoma and small cell carcinoma is not only seen at the molecular level but also by the overall poor prognosis of patients. Asamura et al. retrospectively reviewed 318 patients from 10 Japanese institutions with neuroendocrine tumors of the lung. The 5-year survival rate of patients from all stages was as follows: 96.3% for typical carcinoids, 77.8% for atypical carcinoids, 40.3% for large cell neuroendocrine cancers and 35.7% for small cell lung cancers [4]. Stage for stage, there was no difference in prognosis between large cell neuroendocrine and small cell carcinoma and their survival curves overlapped. On multivariate analysis, histologic grade of neuroendocrine tumor was the most significant prognostic factor with a relative risk ratio of 17.40. Other series have reported a similar poor prognosis for large cell neuroendocrine tumors. A Spanish multicenter study by Garcia-Yust et al. found that the 5-year survival rate of TC was 96%, AC 72%, LCNEC 21% and SCLC 14%. Large cell neuroendocrine tumors not only show a poor prognosis in the spectrum of neuroendocrine cancers but also show inferior survival compared to other non-small cell lung cancers [17]. This supports the WHO decision to reclassify large cell neuroendocrine tumors as a distinct subtype of pulmonary large cell tumors [2]. Prior reports have noted that overall survival rate at 5 years after resection of large cell neuroendocrine tumors ranges between 13 and 57% [14]. This is considerably lower than other subtypes of NSCLC. Battafarano et al. analyzed their tumor registry of patients who had undergone surgical resection of lung cancer between July 1988 and December 2002 [29]. Of the 2000 patients who underwent resection, 4% had large cell lung cancer. Overall survival for the entire group was 47.1%. When the analysis was reviewed by histologic subtype, the 5-year survival rates are as follows: 30.2%
for large cell neuroendocrine carcinoma, 30.3% for mixed large cell neuroendocrine carcinoma and 71.3% for patients with large cell carcinoma. The 5-year survival for stage I patients was only 32.5%. Survival was significantly worse for patients with large cell neuroendocrine carcinoma compared to classic large cell cancer. In fact, the presence of large cell neuroendocrine carcinoma in the specimen was significantly associated with decreased survival. Clearly, large cell neuroendocrine carcinomas have a worse prognosis than other non-small lung cancers including large cell carcinoma [30,31]. The presence of neuroendocrine differentiation detected on an ultrastructural or molecular level, is in fact a predictor of an aggressive clinical course [32–34]. Even in patients with stage I lung cancer that is potentially resectable the prognosis is poor. In fact, multiple studies have shown that the survival curves of large cell neuroendocrine cancers mimic those of small cell lung cancer. 7. Treatment The optimal treatment of large cell neuroendocrine carcinoma is not known. Because it is an uncommon malignancy, prospective, randomized trials have not been performed. There are, however, small case series and retrospective reviews which have provided some insight (Table 2). Most patients with early stage LCNEC are surgically treated [8,35,36]. It is becoming increasingly clear, however, that surgery alone is not sufficient to treat LCNEC, even in early stage disease [11,37,38]. Iyoda et al. analyzed clinical factors in 335 cases of pathologic stage Ia NSCLC. They found that large cell neuroendocrine histology has a significant adverse prognostic impact and was predictive of poorer overall survival [39]. Recently, Veronesi et al. retrospectively analyzed 144 surgical cases (50% of the patients were stage I). Induction chemotherapy was given in 21 patients with a response rate of 80% and a postoperative chemotherapy in 24 patients. A trend to better outcome was associated with preoperative or postoperative chemotherapy in stage I disease [40]. Similarly, Saji et al., in a retrospective review found a survival benefit of patients with LCNEC who underwent perioperative chemotherapy compared to surgery alone (p = 0.04). Again, stage I patients showed a favorable prognostic profile with chemotherapy. The most common chemotherapy used was platinum-based combinations of VP-16 and CPT-11 [41]. More information has recently been gathered on the optimum type of adjuvant regimen for LCNEC. Iyoda et al. prospectively analyzed adjuvant chemotherapy for patients with LCNEC. Using SCLC-based regimens, they found prolonged survival with at least 2 cycles of therapy [42,43]. The overall survival rate was 88.9% at 5 years. In a retrospective review by Rossi and his group in Italy, 83 patients with pure pulmonary LCNEC were analyzed for molecular
Table 2 LCNEC prognosis among recent studies. Studies
Publication year
Takei Battafarano
2002 2005
Rossi
Number of patients with LCNEC
5-Year OS
5-Year survival for stage 1
Median f/u
Predictors of survival (multivariate analysis)
87 45
57% 30.3%
67% 32.1%
– 52.8 months
2005
83
27.6%
33%
17 months
Veronesi
2006
144
43%
52%
27 months
Asamura
2006
141
40.3%
57.8%
60 months
Faggiano
2007
41
– LCNEC histology compared to LCC Tumor stage and size (<3 cm vs. ≥3 cm) Stage III, age and type of resection. Histology, age, nodal involvement, incomplete resection. Mitotic count and neuroendocrine marker staining
24%
–
14 months
OS = overall survival; LCNEC = large cell neuroendocrine cancer; LCC = large cell carcinoma; conflict of interest: nothing to disclose.
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markers, pathologic features and treatment strategies [19]. Among those patients treated, patients treated with a SCLC-based regimen had a significantly better survival compared to standard regiments for NSCLC (median survival, 42 months vs. 11 months; p < 0.0001) [19]. This was especially true in stage I patients. These studies suggest a multi-modality approach to treatment, especially in early stage cancer with polychemotherapy using agents used for small cell lung cancer including platinum and etoposide. There is even less information available in the treatment of unresectable and advanced LCNEC. Part of the problem has been that it has been very difficult to diagnose LCNEC in biopsy specimens in unresectable patients [44]. In a recent study by Igawa et al., 14 patients were analyzed with new criteria for high grade non-small cell neuroendocrine carcinoma (HNSCNEC) small biopsy specimens. These patients were treated with chemotherapy (mostly platinum-based regimens) and compared with patients treated with chemotherapy for extensive stage SCLC. The objective response rate, a 1-year survival rate and median survival time were similar for the two groups: 50% vs. 53% in HNSCNEC vs. SCLC, 34% vs. 48% and 10 months vs. 12.3 months, respectively [44]. Previously, Yamazaki et al. reported on the clinical response of patients with LCNEC to chemotherapy. They found that the response rate of LCNEC to cisplatin-based chemotherapy was comparable to SCLC [45]. Despite the benefits of radiation in limited stage SCLC, the role of radiation in unresectable LCNEC remains undefined [19]. Other avenues of treatment have also been investigated. Filosso et al. evaluated the possibility of using octreotide in patients whose tumor was positive preoperatively with indium 111 scintigraphy [46]. Positive efficacy was noted for postoperative octreotide use alone or in combination with radiotherapy. Further research is needed. There is also ongoing research in the use tyrosine kinase inhibitors and targeted therapy against other neuroendocrine markers such as CD 56 [17]. More randomized prospective trials are needed. 8. Conclusion Large cell neuroendocrine cancer of the lung is a unique malignancy [47]. Histologically, it shares features of both non-small cell carcinoma and small cell carcinoma. Prognostically, it is clearly more aggressive and survival of patients with large cell neuroendocrine cancer echoes that of small cell cancer. The diagnosis of this malignancy is difficult and the best treatment is still unclear. Large phase II and III trials have not been done for this uncommon tumor. Large cooperative groups could possibly accumulate enough patients so that LCNEC could be studied prospectively. At this point, early stage patients are treated with complete resection of the primary tumor. Adjuvant chemotherapy, even in stage I patients, has shown benefit. Neoadjuvant platinum-based regimens may be suitable for marginally resectable tumors. Further studies will be needed to identify novel agents that target specific molecular pathways and can be used in the adjuvant and neoadjuvant setting. Metastases to the brain are purportedly unusual in large cell neuroendocrine tumors, though local spread is not. Early diagnosis followed by surgery and adjuvant platinum-based therapy is best; prophylactic cranial radiation therapy remains undefined. Hopefully, in the coming years we will be able to glean even more information regarding large cell neuroendocrine carcinoma and improve prognosis in this unusual and complex malignancy. Conflict of interest We would like to report that there are no conflicts of interest in our submitted article.
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