Ann Thorac Surg 2007;84:702-707
© 2007 The Society of Thoracic Surgeons
Reviews
Pulmonary Large Cell Neuroendocrine Carcinoma: Its Place in the Spectrum of Pulmonary Carcinoma*
Akira Iyoda, MD, PhD*,
Kenzo Hiroshima, MD, PhD,
Yukio Nakatani, MD, PhD,
Takehiko Fujisawa, MD, PhD
Departments of Thoracic Surgery and Diagnostic Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan
* Address correspondence to Dr Iyoda, Department of Thoracic Surgery, Chiba University, Graduate School of Medicine, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8670, Japan (Email: aiyoda{at}faculty.chiba-u.jp).
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Abstract
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In 1999, the World Health Organization categorized large cell neuroendocrine carcinoma (LCNEC) as a variant of large cell carcinoma. The World Health Organization categorization not only classified histologic types of large cell carcinomas of the lung in detail, but also revealed that histologic subtypes of lung carcinomas were closely related to the prognosis of patients with those carcinomas. Large cell neuroendocrine carcinomas are common tumors that are now more frequently diagnosed by pathologists as recognition of LCNEC improves. Since the first report of LCNEC in 1991, many authors have reported that LCNECs are aggressive tumors and that patients with LCNECs have a very poor prognosis. Although LCNEC is categorized as a variant of large cell carcinoma, the biological behaviors of LCNEC tumors resemble those of small cell lung carcinomas, and LCNEC reveals the feature of a high-grade neuroendocrine tumor. Because patients with LCNEC have a poor prognosis, surgery alone is not sufficient. Multimodality therapies (including adjuvant chemotherapy) appear to be promising for the improvement of the prognosis in patients with LCNEC, even if the pathologic stage is IA, and should be evaluated further in larger multi-institutional trials.
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Introduction
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The World Health Organization (WHO) [1] reclassified the histologic classification of lung carcinomas in 1999, and categorized large cell neuroendocrine carcinoma (LCNEC) as a variant of large cell carcinoma. The clinical and biological features of LCNEC resemble those of small cell lung carcinoma (SCLC); however, LCNEC is classified as a non-SCLC. Therefore, there is no consensus on the treatment strategy for LCNEC. The percentage of LCNEC found in lung carcinomas is low; however, the number of reports of LCNEC increased and the clinicopathologic features of LCNEC became clearer as more pathologists recognized the hallmarks of LCNEC. Here we review reports of LCNEC, and examine its characteristics and the strategy of treatments for it.
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The History of LCNEC
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In 1980, pulmonary neuroendocrine tumors were categorized as typical carcinoids, atypical carcinoids, and SCLC [2]. However some authors indicated that a fourth category may exist between atypical carcinoids and SCLC in prognosis [3, 4]. In 1991, Travis and colleagues [5] proposed a new category for LCNEC, and reported that the prognosis of LCNEC fell between atypical carcinoids and SCLC [5]. In 1998, Travis and colleagues [6] reported further LCNEC cases. In 1999, the WHO [1] categorized LCNEC as a variant of large cell carcinoma.
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WHO Classification
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In the WHO classification, LCNEC was categorized as a variant of large cell carcinoma. If the LCNEC was combined with adenocarcinomas, squamous cell carcinomas, or giant cell carcinomas, it was categorized as combined LCNEC. If LCNEC was combined with SCLC, it was classified as combined SCLC.
Large cell neuroendocrine carcinoma has histologic features of both neuroendocrine morphology and neuroendocrine differentiation, frequent mitosis, and the cellular features of non-SCLC. The morphologic features of LCNEC showed (1) organoid, palisading rosettes; (2) high mitotic rates of 11 or more (when 10 high-power fields of 2 mm2 were analyzed); (3) abundant necrosis; (4) large cell size (nuclear size is comparable with [or more than] three lymphocytes); (5) comparatively low Nuclear/Cytoplasm ratios; and (6) clear nucleoli. The cytologic features are identical to those of nonsmall cell carcinomas. Neuroendocrine differentiation refers to tumor cells that are positive for neuroendocrine markers or tumor cells with neuroendocrine granules that are detected by electron microscope. The WHO suggested that chromogranins and synaptophysin are reliable neuroendocrine markers, and that the neural cell adhesion molecule is helpful. In contrast, neuron specific enolase, which has been used previously as a neuroendocrine marker, was not specific for neuroendocrine tumors and was not recommended.
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Clinical Features
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It is difficult to diagnose LCNEC from only preoperative biopsy specimens, although the cytologic characteristics of LCNEC have been studied [7, 8]. To date, most LCNECs have been diagnosed in surgical specimens postoperatively. Therefore, most reports of LCNEC are cases which were diagnosed retrospectively, because most patients with LCNEC had been initially classified as atypical carcinoids, poorly differentiated carcinomas, or SCLCs with an intermediate cell type [9]; the proportion of LCNEC is 2% to 3% (2.4% [10]), 2.87% [11], and 3.1% [12]) of patients with lung cancer, respectively. Patients with LCNEC are predominantly male (84.0% [10], 89.4% [13], 81.3% [14]), are older [10] and are heavy smokers [10].
The population of smokers in LCNEC cases was reported as 98.6% [13] or 94% [14]. With respect to tumor markers, carcinoembryonic antigen was elevated in 37.8% [10] or 48.5% [13], neuron-specific enolase in 34.5% [10] or 12.4% [13], pro-gastrin-releasing peptide in 25.8% [13], and carcinoembryonic antigen was elevated in many LCNEC cases.
In surgical specimens, LCNEC has high mitotic rates (mean, 60/2 mm2), frequent lymph node metastases, and advanced pathologic stages [10]. Takei and colleagues [12] reported positive immunohistochemical staining in 82% of 87 cases with chromogranins, 91% of 85 cases using synaptophysin, and 91% of 86 cases with neural cell adhesion molecule. There was no one marker expressed in all LCNEC cases, and 68% of LCNECs expressed all three markers. However 13 cases (14.9%) expressed only one marker in 87 LCNEC cases. Oshiro and colleagues [15] studied computed tomographic findings of LCNEC patients and reported that LCNEC usually appeared as a well-defined and lobulated tumor with no air bronchogram or calcification.
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Biological Features
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When we plan the strategy for treatment it is very important to understand the biological features of LCNEC. To date, LCNEC was classified as a variant of large cell carcinomas in non-SCLC. Cytomorphologically, LCNEC shows characteristic arrangements such as palisading or rosettes with necrosis. In contrast, classic large cell carcinomas show bizarre cells with inflammatory cell infiltration. The analysis of morphometry showed significantly different tumor cell sizes between LCNEC and classic large cell carcinomas [8]. Iyoda and colleagues [16] studied the expression of P53 protein, Bcl-2 protein, and Ki-67 labeling index in LCNEC and classic large cell carcinomas. The results showed that LCNEC had significantly higher expression rates of Bcl-2 and Ki-67 labeling index, yet there was no difference in the expression of P53 protein between LCNEC and classic large cell carcinoma. These results revealed that the biological behavior of LCNEC was different from that of classic large cell carcinoma. Basaloid carcinoma was also classified as a variant of large cell carcinomas in 1999, and basaloid carcinoma and LCNEC may overlap in their morphology. Sturm and colleagues [17] studied two markers (ie, 34betaE12 and thyroid transcription factor-1) in basaloid carcinoma and LCNEC, and they reported that the specificity of thyroid transcription factor-1 for LCNEC was 100%, whereas the specificity of 34betaE12 for basaloid carcinoma was 98.3%. Thus these markers are useful to distinguish LCNEC from basaloid carcinoma.
There are many reports that refer to the relationship between LCNEC and classic neuroendocrine tumors, such as carcinoid or SCLC. Iyoda and colleagues [18] categorized patients with neuroendocrine morphology or neuroendocrine differentiation in large cell carcinomas as large cell carcinoma with neuroendocrine features (LCNFs), and compared LCNFs with other neuroendocrine tumors such as typical carcinoids, atypical carcinoids, or SCLCs. These results showed that patients with typical carcinoids or atypical carcinoids are relatively young, both male and female, and include nonsmokers. In contrast, patients with LCNFs or SCLC are older, predominantly male, and are heavy smokers. Histopathologically, tumors with LCNFs or SCLC had frequent lymph node metastases, large tumor size, and multiple mitoses, and patients with LCNFs or SCLC had significantly poorer prognosis than those with typical or atypical carcinoids.
Onuki and colleagues [19] reported that the frequencies of loss of heterozygosity and gene mutation are different among pulmonary neuroendocrine tumors. Rusch and colleagues [20] reported that the expression of Ki-67, P53, or Rb was useful in distinguishing LCNEC from carcinoids. The expression of Bcl-2 protein was frequently observed in LCNEC and SCLC tumors, but not in typical carcinoids [21]. Przygodzki and colleagues [22] reported that the biological behavior and immunohistochemical staining results of LCNEC were similar to those of SCLC. Arbiser and colleagues [23] also reported that LCNEC tumors had higher proliferation rates than carcinoid tumors. Gugger and colleagues [24] studied fluorescence in situ hybridization and immunohistochemistry in typical carcinoids, atypical carcinoids, LCNEC, and SCLC, and reported that the expression of p53 and Rb in LCNEC and SCLC was different from that observed in typical carcinoids and atypical carcinoids. Jones and colleagues [25] reported that a microarray analysis could not differentiate LCNEC from SCLC, but could differentiate patients who had high-grade neuroendocrine tumors with better prognosis from those with poor prognosis. Hiroshima and colleagues [26] examined loss of heterozygosity using micro-satellite markers and methylation of the p16 gene in LCNEC, SCLC, and classic large cell carcinomas, and reported that loss of heterozygosity patterns of LCNEC resembled those of SCLC, although LCNEC also resembled classic large cell carcinomas with regard to p16 methylation. Therefore, LCNEC is classified as a variant of large cell carcinomas, and LCNEC tumors have pathologic and biological features of nonsmall cell carcinomas; however, the clinicopathologic and biological features of LCNEC are similar to those of SCLC. Shin and colleagues [27] reported frequent loss of heterozygosity on chromosome 5q by micro-satellite analyses of LCNEC, and they suggested the presence of tumor suppressor genes on chromosome 5q in LCNEC. Zaffaroni and colleagues [28] reported that LCNEC tumors showed frequent telomerase activity comparable with SCLC.
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Treatment and Prognosis
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Because it is difficult to diagnose patients with LCNEC preoperatively, and most cases are diagnosed in surgically resected specimens, reports on LCNEC were mainly limited to surgical cases. Patients with LCNEC have poor prognosis, and Iyoda and colleagues [10] revealed a 5-year survival rate of 35.3% and a 5-year disease-free survival rate of 27.4%. Although there is a report that referred to the prognosis of patients with LCNEC as the same as with large cell carcinomas [29], most reports revealed that patients with LCNEC had poor prognosis with 5-year survival rates of 15% to 57% [10–14, 30–33].
Even if patients are at pathologic stage I, patients with LCNEC have poor prognosis with 5-year survival rates of 27% to 67% (Table 1). The rarity of this type of tumor dictates that the optimal treatment remains to be determined [34]. Mazieres and colleagues [35] reported that 13 of 18 LCNEC patients without postoperative adjuvant chemotherapy had relapse with distant metastases. They concluded that applying LCNEC to non-SCLC led to poor prognosis, and patients with LCNEC should have efficient chemotherapy.
Therefore, surgery alone is not sufficient to treat LCNEC [36], and patients with LCNEC need adjuvant therapy after surgery [37]. Adjuvant chemotherapy is effective for patients with nonsmall cell carcinomas [38–40], and patients with pathologic stage IB or more should have adjuvant chemotherapy. Therefore, LCNEC patients in advanced stages must have adjuvant chemotherapy after surgery. However the effectiveness of adjuvant chemotherapy for LCNEC patients with pathologic stage IA is controversial. Iyoda and colleagues [41] compared the prognosis of LCNEC patients with pathologic stage IA to those with adenocarcinomas or squamous cell carcinomas in pathologic stage IA, and it was revealed that the 5-year survival rate of LCNEC patients with pathologic stage IA was 54.5%, but was 89.3% in patients with adenocarcinomas or squamous cell carcinomas. Multivariate analysis also revealed that LCNEC was a significant negative prognostic factor. Therefore, the authors concluded that patients with LCNEC should have adjuvant therapy, even if the tumors are stage IA.
There are few reports on adjuvant therapy for patients with LCNEC. In 1997, Dresler and colleagues [42] reported that adjuvant chemotherapy, radiation therapy, or both were not effective for patients with LCNEC. However the study was published before the WHO classification was presented in 1999, the criteria for LCNEC histology did not match the WHO classification, and the study included many carcinoid patients among LCNEC patients. Therefore this study could not accurately evaluate the effectiveness of therapy for patients with LCNEC. In 2001, Iyoda and colleagues [43] revealed that adjuvant chemotherapy was effective for patients with LCNEC. Subsequently, some reports found that LCNEC tumors had good responses to chemotherapy [44]. Veronesi and colleagues [14] reported that 12 of 15 LCNEC cases with induction chemotherapy were responsive (partial response in 11 patients, complete response in 1 patient). It was not concluded what chemotherapeutic regimens were effective. Iyoda and colleagues [45] performed a prospective study of adjuvant chemotherapy for patients with LCNEC followed since 2000, and selected cisplatin+VP-16 as chemotherapeutic regimens similar to those for SCLC, because the clinicopathologic and biological features of LCNEC are very similar to those of SCLC. The results showed that patients with adjuvant chemotherapy based on cisplatin+VP-16 after complete surgical resection had good prognosis. In 2005, Rossi and colleagues [31] reported that adjuvant chemotherapy based on cisplatin+VP-16 was effective for patients with LCNEC in a retrospective study. Most reports concluded that patients with LCNEC needed to undergo adjuvant chemotherapies, and large-scale clinical trials should be planned in the near future to select more effective chemotherapeutic regimens and duration of treatment.
The effectiveness of prophylactic cranial irradiation for patients with LCNEC is unclear. Although there are trials for advanced non-SCLC, up to now the prophylactic cranial irradiation is not a standard option [46]. However, this method improved both overall survival and disease-free survival among patients with SCLC [47], and it may be promising for patients with LCNEC.
Some authors [48, 49] reported that patients with LCNEC that express the c-kit protein, which is the tyrosine-kinase receptor, had poor prognosis, and that the c-kit might be a target molecule for therapy. In contrast, Pelosi and colleagues [50] reported that although CD117, which is encoded by c-Kit, was immunohistochemically documented in 77% of LCNEC tumors, there was no association between CD117 immunoreactivity and survival in patients with LCNEC. Novel target therapy for patients with LCNEC is controversial [51]. Filosso and colleagues [52] concluded that octreotide (ie, used for the treatment of carcinoid syndrome) was effective for patients with LCNEC. These therapies are promising and further examination is expected.
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Differentiation From SCLC
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It is sometimes difficult to differentiate LCNEC from SCLC, especially intermediate cell types of SCLC in the second revision of the WHO classification, and even in surgically resected specimens.
Travis and colleagues [53] reported on the reproducibility of pulmonary neuroendocrine tumors evaluated by five pathologists. They found that 4 of 10 LCNEC cases were agreed on by all five pathologists, and 5 of 10 LCNEC cases were done by four pathologists. They concluded that the most common disagreements fell between LCNEC and SCLC. Some authors [6, 13, 18] reported that there was no difference in the prognosis between LCNEC and SCLC, and the clinical behavior and morphology of LCNEC were similar to that of SCLC. However, Nitadori and colleagues [54] indicated that the expression of CK7, CK18, E-cadherin, and ß-catenin is more characteristic of LCNEC than of SCLC, and suggested that LCNEC and SCLC are separate entities morphologically and immunophenotypically. Ullmann and colleagues [55] examined comparative genomic hybridization for LCNEC and SCLC, and reported that there were differences in the expression at 3q, 6p, 10q, 16q, and 17p. Peng and colleagues [56] studied array-based comparative genomic hybridization for LCNEC and SCLC, and reported differences in expression at 2q, 3p, 4q, and 6p, although there were common sites of deletions or amplifications. Although the clinicopathologic features of LCNEC were similar to those of SCLC, some biological behaviors of LCNEC were different from those of SCLC. Therefore, it is necessary to examine the differences in biological features to differentiate LCNEC from SCLC [57]. It will become clear whether the strategy for the treatment of SCLC should be applied to that of LCNEC when the study of the sensitivity of LCNEC to chemotherapy or radiation therapy progresses.
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Phenotypes of LCNEC
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Although the phenotypes of LCNEC are referred to only in the introduction section of the WHO classification from 1999, there are large cell carcinoma with neuroendocrine morphology (LCCNM) and large cell carcinoma with neuroendocrine differentiation (LCCND). Large cell carcinoma with neuroendocrine morphology means large cell carcinoma without neuroendocrine differentiation but with neuroendocrine morphology. Large cell carcinoma with neuroendocrine differentiation is large cell carcinoma that expresses neuroendocrine markers or with neuroendocrine granules detected by electron microscopy, although these tumors did not have neuroendocrine morphology. However, it did not become clear how to treat patients with LCCNM or LCCND. Hiroshima and colleagues [58] reported that adenocarcinomas with neuroendocrine differentiation had significantly poorer prognoses than those without neuroendocrine differentiation. Pelosi anc colleagues [59] also reported that stage I adenocarcinoma with neuroendocrine differentiation were clinically aggressive tumors. However, Howe and colleagues [60] reported that the presence of immunohistochemically detected neuroendocrine differentiation in non-SCLC was not of prognostic significance. Iyoda and colleagues [10] studied the clinicopathologic features of LCCNM and LCCND, and reported that those of LCCNM and LCCND were similar to that of LCNEC and that the prognoses of LCCNM and LCCND were poorer than that of classic large cell carcinomas. They concluded that patients with LCCNM or LCCND should be treated the same as LCNEC patients.
Interestingly, the morphologic features of LCCNM are the same as those of LCNEC [61]. However, Peng and colleagues [62] showed immunohistochemical analyses that revealed that LCNEC was similar to SCLC and different from LCCNM, although loss of heterozygosity analyses showed the LCNEC similarity to both SCLC and LCCNM. These results suggested that the biological features of LCCNM might not be identical to those of LCNEC. However, this is controversial, as the difference between LCCNM and LCNEC is only in the expression of neuroendocrine markers. SCLC, which is a representative pulmonary neuroendocrine tumor, is not necessary to express neuroendocrine markers such as chromogranins, synaptophysin, or neural cell adhesion molecule. In addition, the sensitivity of expression in LCNEC is not 100% with chromogranins, synaptophysin, or neural cell adhesion molecule. Therefore, if more sensitive and more specifically new neuroendocrine markers are developed, a part of LCCNM may be reclassified as LCNEC. For that reason, patients with LCCNM might be treated in the same way as patients with LCNEC.
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In the Future
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The study of LCNEC has just begun. Molecular analyses using microarray or comparative genomic hybridization methods must progress. These studies may produce specific genes or markers for LCNEC tumors. These advancements may solve the preoperative diagnostic rate, improve reproducibility, and lead to more responsive chemotherapy drugs or gene therapies. These methodologies resemble the possibility of induction therapy. Moreover, the analyses of clinicopathologic and biological features in LCCNM and LCCND, and more sensitive and more specific new markers for pulmonary neuroendocrine tumors, may be associated with new tumor categories. These works are important but difficult to resolve. However we should strive to improve the prognosis of patients with LCNEC.
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Acknowledgments
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This work was supported in part by a Grant-in-Aid for Scientific Research (C) 17591458 of the Japanese Ministry of Education, Culture, Sports, Science, and Technology.
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Footnotes
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* A part of this report was presented by Iyoda A et al. Pulmonary large cell neuroendocrine carcinoma. JJLC 2006;46:315–20 [in Japanese with English abstract]. 
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Abstract
Introduction
